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+{"text": "Recent advances in the field of molecular pathology and the publication of the revised fourth edition of the WHO Classification of central nervous system (CNS) tumors have significantly reshaped the approach to both diagnosis and therapy of brain tumors . Due to This Research Topic entitled \u201cMolecular Advances in Diagnosis and Treatment of CNS Tumors\u201d includes 22 original research articles and 3 review articles that cover several important themes:Glioblastoma (GBM) is the most common and devastating primary brain tumor in adults. It is therefore essential to identify novel and effective biomarkers or risk signatures for GBM patients. Wang et al. examined differentially expressed genes between GBM and low-grade glioma (LGG) and selected five genes  to construct a risk signature to independently predict the outcome of GBM patients, as well as stratified by radio-chemotherapy, isocitrate dehydrogenase 1 (IDH1) and O6-methylguanine-DNA methyltransferase (MGMT) promoter status. Zhang et al. evaluated the expression level of integrin beta 5 (ITGB5) and the relationship of its elevated expression with glioma progression and poor survival in GBM patients. It appears ITGB5 plays important regulatory roles in angiogenesis and the immune response, and is required for invasion and migration of neoplastic cells and endothelial proliferation in GBM. Zusman et al. discussed how harvesting GBM tissue using traditional surgical approach and the automated resection NICO Myriad\u2122 system may impact the translational research value of the sample. Their study further supports the need to harvest and analyze multiple specimens for each tumor, in order to capture the genomic diversity and maximize the benefits of molecularly-based therapeutics. Zhang et al. demonstrated that Forkhead Box P2 (FOXP2) was the target protein of miR-9-5p. In addition, high expression of miR-9-5p and low expression of FOXP2 were related to better outcome in GBM patients, whereas down regulated FOXP2 expression was capable of inhibiting glioma proliferation through cell cycle arrest. Liu et al. determined the candidate genes that may function as biomarkers to further distinguish patients with IDH-wildtype GBM. The investigators developed a seven-gene-based signature, which allocated each patient to a risk group (low or high). Subsequent bioinformatics analysis predicted that the seven-gene signature was involved in the immune response, inflammatory response, cell adhesion, and apoptotic process. Marchi et al. attempted to correlate the biomolecular aspects of MGMT methylation status in relation to the maximal surgical extent of resection. Interestingly, a positive prognostic value exists only in case of the presence of residual tumor tissue. Dent et al. explored whether a multiple sclerosis drug, Fingolimod would synergize with dimethyl fumarate and its plasma breakdown product MMF to kill GBM neoplastic cells. Indeed, the data demonstrated that the above combination produced reactive oxygen species and killed tumor cells more effectively via death receptor signaling and autophagy induction. Hu et al. conducted a systematic analysis of survival-associated alternative splicing event. The nomogram with age, pharmaceutical and radiation therapy, alternate donor site, and exon skip signatures provided excellent prognostic predictive value.Treatment effectiveness and overall prognosis for glioma patients depend heavily on the genetic and epigenetic factors in each individual tumor. Gates et al. discovered that primary brain tumors are genetically heterogeneous, and the physical distance within a given glioma positively correlates to genomic distance in number of genes, copy number variations, and methylation profiles. They further derived quantitative linear relationships between physical and genomic distances. Su et al. showed that \u03b3Klotho  is highly expressed in gliomas epigenetically and its expression is significantly associated with high tumor aggressiveness and poor outcomes for glioma patients. Mechanistically, LCTL might play an important immunosuppressive role via FGF signaling in glioma. Yang et al. performed weighted gene co-expression network analysis in a large public database of glioma samples. The derived brown co-expression module and the biomarker TNFRSF1A were strongly related to glioma grading. Furthermore upregulated TNFRSF1A was tightly associated with clinical features. Zhang et al. systematically analyzed the relationship between methyltransferase-related gene expression profiles and clinical outcomes in glioma patients and identified a novel methyltransferase-related risk signature for predicting the prognosis of gliomas.Recently non-coding types of RNA have been shown to play a vital role in glioma tumorigenesis. Jin et al. characterized a novel non-coding RNA, lipocalin-2-derived circular RNA, in glioma tumorigenesis. The investigators demonstrated that it facilitated glioma progression by sponging miR-661 to increase RAB3D expression. Similarly, Zheng et al. characterized non-coding competitive RNA networks as alternative therapeutic targets in the treatment of GBM. Sun et al. explored the expression profiles and potential relationship between long non-coding RNAs (lncRNAs) and mRNAs in glioma patients. Both lncRNAs and mRNAs exhibited dynamic differential expression profiles, consistent with their roles in critical biological processes and pathways associated with tumor pathogenesis.Several manuscripts cover some of the most fascinating developments in the field. Zhang et al. conducted a meta-analysis to evaluate the prognostic role of connexin protein Cx43 in glioma. The results showed that Cx43 expression was a clearly negative factor with tumor grades and beneficial for survival time, offering evidence that Cx43 is generally a tumor suppressor. Deng et al. explored the influence of IDH1 mutation on the immune microenvironment and developed an IDH1-associated immune prognostic signature to help classify LGG patients into subgroups with distinct outcomes and immunophenotypes. Liu et al. discussed the correlations of soluble PD-L1 (sPD-L1) with clinical features in brain tumors and assessed its diagnostic value in gliomas. Both serum and CSF sPD-L1 showed significant value, but serum sPD-L1 rather than blood-based inflammatory markers had the best diagnostic performance in the diagnosis and stratification of glioma. In addition, a descending trend in the level of serum sPD-L1 was observed in postoperative patients. Hung et al. studied the important question of glioma stem-like cells contributing to drug resistance and tumor recurrence. Their study suggests that a sonic hedgehog (Shh) inhibitor could induce autophagy of CD133+ GSCs through mTOR independent pathway. Therefore, targeting the Shh signal pathway may overcome chemoresistance and provide a therapeutic strategy for patients with malignant gliomas.Informative Review Articles:Tang et al. reviewed the advantages and possible limitations of mRNA-based gene therapy including the in vitro synthesis of mRNA, the feasible methods for synthetic mRNA delivery and clinical therapeutic prospects of mRNA-based gene therapy for glioblastoma. Yu et al. reviewed the regulation of MGMT expression and its role in chemotherapy, especially in glioma. Targeting MGMT seems to be a promising approach to overcome chemoresistance. Hu et al. reviewed the relationship between ferroptosis, a new type of cell death, and temozolomide (TMZ) resistance. Importantly, targeted ferroptosis can be used to reverse TMZ resistance.In summary, management of CNS tumor patients has undergone a molecular revolution driven by the development of high throughput molecular techniques. Molecular testing has become an essential part for the optimal CNS tumor patient workup. At the current stage, a combination of FISH, copy number array, NGS panel and genome-wide methylation profiling can be used to detect molecular alterations in order to provide the best possible patient care. It is true that our ability of amassing molecular data currently surpasses our ability to utilize this information for treatment; however, it is clear that informative molecular biomarkers will guide future clinical trials and lead to the development of new therapeutic strategies.Z-HZ, M-TL, and LC are the coeditors for this Research Topic. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recently, Johansson and colleagues published an article about the mechanisms causing female reproductive disorders with a special focus on the ovaries (Johansson et al. In recent years, stem cell-based tests have been established where precursor cells are exposed to test compounds during the differentiation period (Krug et al."}
+{"text": "In 2015, the World Health Organization (WHO) published the guideline \u201cSugars intake for adults and children\u201d [The paper presented by Anderson et al.  studied While still more research is needed on the association of both pure fruit juice and ASB consumption with all-cause mortality risk, Anderson et al. provide an important contribution to the current scientific evidence in this field by finding different associations for all-cause mortality between consumption of SSBs and consumption of pure fruit juice. Since the association between SSB consumption and all-cause mortality is well established , 5, 6, i"}
+{"text": "Short (<200 nt) and long (>200 nt) non-coding (nc) RNAs account for majority of mammalian transcriptional output and encompass RNA species critical for various aspects of development and disease Ambros, . We haveDeeper insight into these enigmatic RNA species clearly requires efforts from both wet-lab and computational avenues of research . One of them, miR-30c, directly repressed cyclin-dependent kinase 12 (CDK12) through a complementary site in the 3\u2032 UTR . Several DNA damage response (DDR) genes were significantly downregulated after introducing miR-30c or repressing CDK12, suggesting that miR-30c regulates embryo development through the DDR pathway .Zhao et al. examined deregulated miRNAs, lncRNAs and circRNAs in the hair follicle cycle of Angora Rabbit (Oryctolagus cuniculus) and provides comprehensive repository of ncRNAs potentially relevant to this process.Mature hair follicles in mammals undergo periodic self-renewal processes called hair follicle cycles. Understanding the molecular regulatory mechanisms of the renewal cycle is important in medicine and developmental biology. Wang et al. profiled lncRNAs in the CD4+ T cells in the mouse model of acute asthma. They found 36 up- and 98 down-regulated lncRNAs in the disease compared with the control samples . The potential functions of deregulated lncRNA were analyzed by performing miRNA binding analysis .Xun et al. proposed an efficient experimental method to find miRNA binding sequences in genomic DNA in vivo, thus potentially identifying miRNA binding sites in the regulatory regions of genes.It has been well-established that miRNAs work by guiding RNA-induced silencing complex (RISC) to their target RNA binding sites in cytoplasm Bartel, . HoweverOu-Yang et al. proposed a novel method called two-side sparse self-representation (TSSR) for predicting lncRNA-disease associations. TSSR significantly outperformed other tested methods and identified some candidate lncRNA-disease associations .Zhang et al. proposed a method called CRlncRC2 for predicting associations between lncRNAs and cancers. More than four hundred cancer-related lncRNA candidates were identified, which were evaluated by examining the Lnc2Cancer database, reviewing literature, and performing statistical analysis of multiple relevant data sources containing information on mutations and differential gene expression in cancers . These results demonstrated that CRlncRC2 is an effective and accurate method for identification of cancer-related lncRNAs .Shen et al. proposed a new method for identifying lncRNA-protein interactions by employing Kernel Ridge Regression, based on Fast Kernel Learning (LPI-FKLKRR). LPI-FKLKRR demonstrated a superior performance compared with a series of other methods as judged by area under precision recall curve.LncRNAs are assumed to realize their functions by interacting with other molecules, such as proteins, chromatin and other RNA species. Huang et al. introduced a computational method to predict interactions between lncRNAs and miRNAs leveraging the information of expression profile data for these transcripts and the graph convolution technique. The proposed model is based on the assumption that the interaction between an lncRNA and a miRNA could be deciphered from their co-expression pattern. Compared with the conventional miRNA-target prediction algorithms based on sequence matching, their work presents a new approach to predict lncRNA:miRNA interactions.Fukunaga et al. introduced a web server, called LncRRIsearch, for predicting lncRNA:lncRNA and lncRNA:mRNA interactions in human and mouse. The tissue-specific expression and cellular localization data of lncRNAs are integrated in this web server to explore tissue-specific or subcellular-localized lncRNA interactions .Li and Liu summarizing recent evidences suggesting that coding and non-coding properties are inherent to both coding and non-coding transcripts. In other words, some lncRNAs and circRNAs could be used to produce short peptides, i.e., have coding capabilities. On the other hand, 3\u2032 and 5\u2032 UTRs of coding genes have non-coding functions such as recruiting RNA-binding proteins (Li and Liu).Smith et al. reviewed the miRNAs and lncRNAs that play key roles in the initiation and progression of pediatric solid tumors. Pediatric tumors, due to lower mutation load compared with adult ones, are assumed to arise from mis-regulation of networks normally functioning during development at transcriptional level . The authors summarized accumulating evidence of involvement of miRNAs and lncRNAs in the regulatory networks functioning during oncogenesis.Watson et al. explored small RNAs in neurodegenerative diseases. This comprehensive review discusses roles of various small RNAs in multiple neurodegenerative diseases, including Alzheimer's, Parkinson's, multiple sclerosis, Amyotrophoic lateral sclerosis, and Huntington's disease.Ram\u00f3n y Cajal et al. proposed that the interactions between miRNAs and lncRNAs might contribute to the cell-type specific outcomes and to the determination of cell fate. In one model, miRNAs could be competitively sequestered by tissue-specific lncRNAs. In another context, miRNAs released to extracellular space as ligands could interact with lncRNAs in different organs as receptors to either sequester the miRNAs or induce degradation of the miRNAs or the lncRNAs.Recent evidences show that ncRNAs, both miRNAs and lncRNAs, could serve as communication factors between cells (Bayraktar et al., Non-coding RNAs have been associated with various biological processes and human diseases. These phenomena were further expanded and reviewed by several studies in this Research Topic. A number of wet lab and computational methods as well as database resources reported in the Topic should help to refine the connections between ncRNAs and diseases and identify the mechanisms of actions of the former, thus further contributing to the advancement of the ncRNA field.YZ and PK conceived of the work and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control (18 studies) and pollination services (17 studies) in adjacent crops in North America, Europe and New Zealand. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimise floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future. Our quantitative synthesis of the impacts of floral plantings on pest control, crop pollination and yield reveals that flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average, while effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of this variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively, with important implications for the the design and implementation of these measures to effectively promote ecological intensification of agriculture in the future The \u2018exporter\u2019 hypothesis  the extent to which flower strips and hedgerows enhance pollination and pest control services in adjacent crops; (2) how service provisioning changes with distance from floral plantings; (3) the role of plant diversity and time since establishment of floral plantings in promoting pollination and pest control services; (4) whether simplification of the surrounding landscape modifies the responses; and (5) whether floral plantings enhance crop yield in adjacent fields.Our synthesis reveals general positive effects of flower strips but not hedgerows on pest control services in adjacent crop fields. Effects on crop pollination, however, depended on flowering plant diversity and age since establishment, with more species\u2010rich and older plantings being more effective. However, no consistent impacts of flower strips on crop yield could be detected, highlighting the need for further optimisations of plantings as measures for ecological intensification.To identify data sets suitable to address our research questions, we performed a search in the ISI Web of Science and SCOPUS (records published until 31.12.2017 were considered). To minimise potential publication bias  because (1) average z\u2010scores follow a normal distribution, and (2) the variability present in the raw data is not constrained as in other indices that are bound between 0 and 1  therefore focus on flower strip effects on pollination and pest control services. Information on plant species richness was available in 12 out of 18 pest control studies and 10 out of 17 pollination studies. Whenever available, the species richness of flowering plants was used. Otherwise, for some flower strip studies, the number of sown, potentially flowering plant species (excluding grasses) was used. Time since establishment of flower strips, that is the time span between seeding or planting and data sampling, was available for all studies ranging from 3 to 122\u00a0months.et al., et al., The proportional cover of arable crops was available and analysed as a proxy for landscape simplification . Only 10 studies measured services in several years since establishment  linear mixed\u2010effect models with planting (field with or without planting) were separately fitted for flower strips and hedgerows for the response variables pollination service and pest control service. To test how the effects on service provisioning change with distance  from plantings (question 2) and with landscape simplification (question 4) these explanatory variables and their interactions with the fixed effects described earlier were included in the models. Exploratory analyses showed that neither distance nor landscape simplification effects differed between flower strips and hedgerows; that is no significant interactive effects of planting type with any of the tested fixed effects. We therefore pooled flower strip and hedgerow data in the final models, excluding planting type and its two or three\u2010way interactions as fixed effects. In addition to linear relationships we tested for an exponential decline of measured response variables from the border of the field by fitting log10(distance) in the linear mixed\u2010effect models described earlier. In this case, field nested within study was included as a random effect. To test the intermediate landscape complexity hypothesis, we tested for linear as well as hump\u2010shaped relationships between landscape context, and its interaction with local floral plantings by fitting landscape variables as a quadratic fixed predictor in the models described earlier . To present the ranges covered by the agricultural landscape gradients, we did not standardise measures of landscape simplification within studies  recommended for testing significant effects of , et al. . All staThe provisioning of pest control services in crop fields adjacent to flower strips was enhanced by 16% on average compared to fields without flower strips. On average, pest control services were also increased in crops adjacent to hedgerows, but effects were more variable and overall not statistically significant Fig.\u00a0; Table\u00a01Crop pollination effects were more variable across studies and overall not significantly different between crops with or without adjacent floral planting across all studies and within\u2010field distances Fig\u00a0; Table\u00a01Crop pollination services, but not pest control services, tended to increase with flowering plant species richness of the adjacent flower strip . These results indicate that floral plantings have great potential to benefit ecosystem service provision, but to do so will need to be carefully tailored for functioning at specific spatial scales. Flower diversity and strip age are important drivers through which this can be achieved and they should be considered integrally before floral plantings can make a significant contribution to the ecological intensification of agricultural production.sensu Morandin and Kremen, et al., et al., We found positive effects of flower strips on ecosystem service provisioning in support of the \u2018exporter\u2019 hypothesis . We fou, et al, .et al., et al., et al., et al., et al., et al., et al., et al., Consistent with previous studies (e.g. Dainese et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Crop yield is affected by a complex interplay of a multitude of agricultural management practices such as fertilisation, level of pesticide use, pest pressures, soil cultivation and other factors such as local soil and climatic conditions (e.g. Bartomeus Our synthesis demonstrates enhanced natural pest control services to crops adjacent flower strips plantings, across a broad suite of regions, cropping systems and types of flower strips studied. However, it also reveals inconsistent and highly variable effects of flower strips and hedgerows on crop pollination services and yield. This highlights a strong need to identify the key factors driving this variability and the effectiveness of different types of floral plantings in contributing to ecosystem service delivery. Informed by such improved understanding, the design, implementation and management of floral plantings can increase their effectiveness as measures for ecological intensification. This synthesis identifies several promising pathways towards more effective floral plantings for the provision of ecosystem services and ecological intensification: the modelled exponential distance\u2010decay function of pollination service provisioning by floral plantings into crop field helps to predict service provision in crop fields; together with the lack of a strong planting area effect, our findings suggest that a dense spatial network of relatively small plantings will be more effective than a few large ones to optimise pollination service provisioning. Moreover, it identifies important drivers of the effectiveness of floral plantings for delivery of crop pollination services: flowering plant diversity and age. Based on these findings we strongly encourage the establishment, adequate management and restoration of existing perennial floral plantings that ensure the availability of high floral diversity across several years as promising pathways towards optimised measures for ecological intensification.MA and LS designed the study. MA, DK, MT, BRB, RB, AJC, MD, FD, MHE, DG, ADG, DG, HG, HH, FH, RI, KJ, PJ, MJ, EK, CK, DAL, GML, LM, MMK, LM, SCP, SGP, MR, HS, AS, CT, TT, EV, EV, IMGV, AW, DBW, FW, KW, NMW, MW, SW and LS contributed data. MA compiled the dataset. LS and MA analysed the data. MA, LS, DK, MG, SGP and MR interpreted results. MA wrote the paper and all authors contributed to revisionFig S1Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file.Table S4Click here for additional data file.Table S5Click here for additional data file."}
+{"text": "Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-\u03b2) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor \u03b1-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer. Almost eighty percent of advanced cancer patients are affected by involuntary wasting, which is inversely related to handgrip strength, high toxicities of anti-cancer drugs, quality of life, and survival.18Since cachexia preferentially causes loss of LBM more than FM, there is a need for a biomarker for the early diagnosis of cachexia, especially the atrophy in skeletal muscle.et al. demonstrated reversal of cancer cachexia by injecting anti-bodies against Act A and Mstn in mice model leading to prolong survival.et al., demonstrated that GDF15 inhibitors reversed the loss of LBM and FM in mice.In recent years, several markers have been reported to be involved in skeletal muscle atrophy in cancer cachexia.et al. found that cancer-related weight loss was linked to changes in the diet and inflammatory cytokines.Table .In 2005, Fouladiun  et al.'s recommendation in 2000, the protein was coined growth differentiation factor 15 (GDF15).49Almost two decades ago GDF15 was identified as a member of the TGF-\u03b2 superfamily.et al. injected GDF15 subcutaneously into mice which caused a rapid decrease in food intake and hence, a decline in weight.et al. in 2012 further demonstrated that the overexpression of GDF15 in tumors led to the inhibition of food intake in an animal model which subsequently causes loss of both LBM and FM.58Several studies demonstrated the overexpression of GDF15 in many advanced cancers such as prostate, urothelial, breast, gastric, colorectal, and esophagus.in-vivo and in-vitro studies which were responsible for its anti-tumorigenic effect.et al. demonstrated a strong association of elevated plasma GDF15 levels with metastasis in prostate cancer.46GDF15 may have a context-dependent role in cancers: an antitumorigenic role of GDF15 was observed in early cancer while an association of GDF15 with the induction of tumor growth was observed in advanced cancer depending on a tumor type and its micro-environment.In one animal study, GDF15 was identified as the only biomarker for the loss of skeletal muscle and weight in cancer.65et al. showed an absence of a postprandial increase in GDF15 serum levels in healthy participants suggesting that it is unlikely that this hormone acts as a 'satiety factor'.et al., in 2017 showed that GDF15 serum levels induced a minimal change in response to caloric surpluses or deficits in both mice and humans, differentiating its action from intestinally derived satiety hormones and leptin. Furthermore, the same group showed that GDF15 expression was regulated by the tissue stress response in mice, and its administration triggered conditioned taste aversion suggesting that GDF15 induces an aversive response to nutritional stress.et al. in 2019, also demonstrated that GDF15 administration triggered conditioned taste aversion via GFRAL, while Borner et al. showed that GDF15 Induces anorexia through nausea and emesis in the mouse model. Globally, these findings indicate that GDF15 does not act as an 'anti-hunger' hormone or has any 'satiety effect' but induces an aversive response to nutritional stress. In 2017, the GDF15 receptor was identified as the glial cell-derived neurotrophic factor (GDNF) family receptor alpha-like (GFRAL) expressed in the brainstem.et al. identified novel characteristics of GDF15 in disease tolerance in the context of infection. This group showed in a mouse model that GDF15 is induced in inflammatory diseases through the central induction of metabolic adaptation and contribute to a protective effect in organ damage. This inflammation-induced tolerance effect is achieved by metabolic reprogramming and the production of triglycerides via hepatic sympathetic outflow, hence preventing cardiac damage after an LPS endotoxemic challenge.73It was established in the 1980s that the \u03b2 adrenergic stimulation causes increase lipolysis and inhibit the activity of the lipoprotein lipase resulting in increased plasma triglycerides.In August 2020, Suriben et al. were the first to link the GDF15/GRFAL sympathetic pathway with the hepatic lipid oxidation in a cancer cachexia mouse model.Despite the breakthrough in inhibiting the GDF15/GFRAL pathway for the treatment of cachexia in the mouse model, several issues concerning interplay between host and tumor must be addressed for cachectic cancer patients.65For most patients with metastatic cancers, the cause of death is due to cachexia more than the direct effect of tumor bulk and organ failure. Based on the absence of any therapy for improving cachexia and on similar mechanistic evidence in the animal model and human, clinical trials testing anti-GDF15/GFRAL treatments appear promising, specifically in patients with elevated circulating GDF15 levels.Beyond its cachectic effect, GDF15 has been also implicated in tumor cell apoptosis and the development of metastasis. In addition, GDF15 can also modulate the tumor microenvironment, innate immune surveillance, and response to immunetherapy.47Globally, considering both host and cancer factors, only the completion of clinical trials using an inhibitor of the GDF15/GFRAL pathway will provide clinical evidence on the merit of reversing this \u201cmetabolic signature\u201d to improve the lives of those living with advanced cancer.81GDF15 plasma level correlates with tumor progression and has been considered as a tumor biomarker."}
+{"text": "TheFinally, safety is not guaranteed for nutrients, given the known issues with intakes above tolerable upper intake levels (UL). Adverse events were inadequately assessed in the context of purported benefits. Calder et al.\u2019s recommended intakes do not adequately define amounts  or intended population given differences in UL by age/sex . The systematic review of omega-3 fatty acids and antioxidants that they cited could not rule out adverse events .Though recommendations by Calder et al. are made in the context of the COVID-19 pandemic, we note that this review offers no direct evidence to support the claim for dietary supplements for prevention or treatment of COVID-19, per se ["}
+{"text": "Despite efficient virological suppression on antiretroviral therapy (ART), people living with HIV (PLWH), experience an increased burden of premature co-morbidities, such as cancer and end-organ disease. With remaining challenges in terms of access to therapy, adherence and potential long-term drug toxicity, improving their long-term healthcare outcome, including new strategies for HIV clearance, remains a global priority. There is, therefore, an ongoing need to better characterize and harness the immune response in order to develop new strategies and supplement current therapeutic approaches for a \u201cfunctional\u201d cure. Current efforts toward HIV eradication to enhance immune recognition and elimination of persistently infected cells have highlighted the need for an optimized \u201ckill\u201d approach. Natural killer (NK) cells play an important role in antiviral defense and by virtue of their innate and adaptive features hold great promise as a focus of \u201ckill\u201d efforts. Galvanized by advances in the cancer field, NK cell exploitation, represents a transformative approach to augment HIV therapeutic modalities, circumventing many of the limitations inherent to T cell approaches. In this review we will discuss recent advances in our understanding of the development of NK cell adaptive/memory responses in HIV infection and highlight new and exciting opportunities to exploit the beneficial attributes of NK cells for HIV immunotherapy. NK cells are multipotent innate effector cells that play pivotal roles in antiviral and tumor immunity  that target the interaction between MHC class I and NK cell inhibitory receptors represents one strategy that is currently used to enhance NK cell anti-tumor activity  .Following the rise of single cell cloning techniques, next-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) with greater potency/breadth and the ability to suppress viral replication and potential for Fc-mediated clearance of virus-infected cells have now entered the clinical arena  could differentiate into effector NK cells mediating an innate antiviral response and protection against HIV -engineered NK cells offer great promise as a new immunotherapeutic tool in the HIV field. The recent success of CAR NK cells derived from cord blood transduced with a retroviral vector, expressing the genes encoding anti-CD19, IL-15, and a safety switch (inducible caspase 9), in patients with refractory or relapsed CD19 positive cancers, represents a remarkable achievement in the field   (Wang et al., In addition to the influence of CMV co-infection, a recent study demonstrated that the pro-inflammatory milieu in HIV infected patients drives the expansion of a defined NK subset with memory-like properties, characterized by CD94loCD69+T-betloEomeshi signature (Stegmann et al., Antigen-specific NK cells have been reported in rhesus macaques infected with SIV/SHIV (Reeves et al., in vivo persistence they are endowed with enhanced capacity for ADCC (Schlums et al., Adaptive NK cells make a significant proportion of the peripheral NK cell pool in HIV infection (Zhou et al., A concern with utilizing bulk NK cells for immunotherapy is their potential for unwanted immunoregulatory functions, such as regulation of T cell responses (Peppa et al., in vitro expansion capability with predictable selectivity as an alternative or combination strategy for a functional cure. Utilizing HLA-E expressing transfectants has been a successful strategy for obtaining robust proliferation of functional adaptive NK cells, with profound skewing toward a single self KIR, and enhanced NKG2C effector potential against allogeneic acute lymphoblastic leukemia primary blasts (Liu et al., Importantly adaptive NK cells have Indeed, adoptive transfer of cytokine-induced adaptive NK cells are being tested in phase I clinical trials in AML patients (Romee et al., ex vivo expansion for clinical application represents an exciting new avenue for the development of novel therapeutic interventions in the field of HIV infection. These approaches can be combined with therapeutic antibodies improving their efficacy. In addition, the generation of memory NK cell represents a novel goal of new vaccination approaches incorporating targeted adjuvants or through enhancing presentation via HLA-E. Future innovative strategies for cure include manipulation of the metabolic machinery of immune cells and attempts to intrinsically rewire NK cells to improve their immunotherapeutic potential.The study of adaptive NK cell subpopulations and Despite the considerable amount of progress, additional work is required to fully unravel the unique properties of specialized and memory NK cells subsets, especially within key effector sites, along with their potential for functional exhaustion. This knowledge would be critical in order to leverage their distinct features and maximize their therapeutic use in chronic viral infections while offsetting any detrimental effects to adaptive immunity and the host.AA, AO, and EM contributed to writing specific sections. DP edited the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This special issue is dedicated to entropy-based fatigue, fracture, failure prediction and structural health monitoring. The unification of laws of thermodynamics and Newtonian mechanics has been a pursuit of many scientists since the mid-19th century. Distinguished scientists from around the world who contributed to this special issue all show that unification of Newtonian mechanics with thermodynamics using entropy as a link eliminates the need for phenomenological continuum mechanics, where the second law of thermodynamics is usually imposed only as an external constraint, but is not satisfied at the material level, because derivative of displacement with respect to entropy is assumed to be zero. For example, the theory of elasticity assumes that there is no entropy generation at the material level. As a result, everything is reversible, which violates the second law of thermodynamics.Group from Indian Institute of Technology Madras and University at Buffalo used unified mechanics theory for low cycle fatigue life prediction of Ti-6Al-4V alloys. Bin Jamal et al.  show thaScientists from Belarus State University contributed a noteworthy paper with their recent advances on mechanothermodynamics, which is essentially a theory almost identical to the unified mechanics theory. They both use entropy generation rate for degradation and unification of Newtonian mechanics and thermodynamics laws. Sosnovskiy and Sherbakov  formulatA Purdue University group contributed their outstanding work on using maximum entropy models for fatigue damage in metals with application to low-cycle fatigue of aluminum 2024-T351. Young and Subbarayan [University of Maryland, College Park scientists contributed an excellent study on measures of entropy to characterize fatigue damage in metallic materials. Yun and Modarres  show thaUniversity of Texas at Austin researchers contributed an excellent paper on degradation-entropy generation methodology for system and process characterization and failure analysis. Osara and Bryant  formulatScientists from Northwestern Polytechnical University and Xi\u2019an University of Architecture and Technology contributed an exceptional study titled an entropy-based failure prediction model for the creep and fatigue of metallic materials. Wang and Yao  state th\u22127 m/cycle. In conclusion, they prove that entropy generation can accurately predict the fatigue crack growth rate of dual-phase steels under spectrum loading.Universiti Kebangsaan Malaysia group, contributed a great study on prediction of fatigue crack growth rate based on entropy generation. Idris et al.  present Researchers from Beihang University and Beijing Aeronautical Science & Technology Research Institute contributed a very interesting study on using copula entropy for quantifying dependence among multiple degradation processes. Sun et al.  studied Scientists from Beihang University and North China University of Water Resources and Electric Power contributed an indirectly related paper on intelligent analysis algorithm for satellite health under time-varying and extremely high thermal loads. Li et al.  present 2FeCoMo0.5V0.2 medium entropy alloy by rotationally accelerated shot peening. Liang et al. [2FeCoMo0.5V0.2 medium-entropy alloy by rotationally accelerated shot peening (RASP). Transmission electron microscopy analysis revealed that deformation twinning and dislocation activities are responsible for the effective grain refinement of the high-entropy alloy. In order to reveal the effectiveness of surface nano-crystallization on the Ni2FeCoMo0.5V0.2 medium-entropy alloy, a common model material, Ni, is used as a reference.Nanjing University of Science and Technology and City University of Hong Kong teams participated with their paper titled effective surface nano-crystallization of Nig et al.  reported"}
+{"text": "Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.We analysed summary statistics from genome-wide association studies (GWAS) of depression  and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification. Major depressive disorder (MDD) is a leading cause of morbidity worldwide, currently affecting approximately 4% of the world's population , is a robustly and consistently replicated dimension of personality that is relatively stable over time Eysenck, . Neu feaet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Twin, family and genomic studies have shown that population variation in Neu and liability to depression are conferred by both genetic and environmental risk factors . We compared the depression summary statistics with summary statistics for Neu .We used depression summary statistics from the Psychiatric Genomics Consortium (PGC) ; for Neu we used summary statistics from the UK Biobank sample . We used the munge_sumstats.py tool . Using these filtered summary statistics, the gwas-pw program  and within 3\u00a0Mb, then used MAGMA  genes and conducted GWAS catalogue lookups using FUMA . We defined segments that were associated with neither trait as those that had a total posterior probability of association <0.2 and that did not contain any genome-wide hits for either trait. To examine the depression-only signal, we excluded segments associated with Neu or with both traits from the depression summary statistics, clumped single-nucleotide polymorphisms (SNPs) that were in linkage disequilibrium (LD)  with either MDD or Neu. These included psychiatric disorders, personality traits, cardiovascular and inflammatory diseases, anthropometric and life-history traits, education and lifestyle factors. We supplemented this list of traits with BMI since obesity has been identified as a potential stratifying factor for depression  but not with Neu after adjusting for depression (Neu\u00b7adjMD). Finally, we identified traits with the opposite patterns of having genetic correlations that were specific to Neu or to Neu after adjusting for depression. We tested whether unadjusted and adjusted correlations were different from zero and whether adjusted correlations were smaller than their unadjusted counterparts and corrected for multiple testing using False Discovery Rate  explained by the genetic architecture shared between depression and Neu (\u2018neurotic depression\u2019) or (2) specific to depression and independent of Neu (\u2018non-neurotic depression\u2019) (and vice versa for \u2018depressive neuroticism\u2019 and \u2018non-depressive neuroticism\u2019). We estimated the genetic covariance among MD, Neu and each trait using GenomicSEM  (We used pairwise GWAS (Pickrell ability) , Table 1et al., p\u00a0<\u00a02.77\u00a0\u00d7\u00a010\u22126) with the partitioned genomic segments. There were 30 genes significantly associated with depression only (online Supplementary Table S3), 203 genes associated with Neu only (online Supplementary Table S4) and 104 genes associated with both depression and Neu (online Supplementary Table S5). We used FUMA  and to coronary heart disease (p\u00a0=\u00a03.2\u00a0\u00d7\u00a010\u22123). Neu-only gene sets were related to traits such as intracranial volume, Parkinson's disease and high-density lipoprotein cholesterol. The gene sets shared by depression and Neu were related to cross-disorder psychiatric traits, coffee consumption and epilepsy, among other traits (online Supplementary S6).We used MAGMA  and with Neu where overlap with depression has been removed (Neu\u00b7adjMD) , schizophrenia, bipolar disorder, coronary artery disease and age of first birth. There were three additional traits  that showed a similar pattern of full and partial correlations with MD, but where the effect sizes overlapped with those for Neu, and thus their status of having a specific relationship was less well supported. Finally, there were three traits  that showed specific relationships with Neu after removing shared overlap with MD.RFWD2 (ring finger and WD repeat domain 2), a gene that can promote tumour growth  which is involved in the Krebs cycle; rs4143229 is in an intron of the ecto-NOX disulphide-thiol exchanger 1 gene (ENOX1) which is expressed in the nervous systems and has been implicated in autoimmune disorders  and immune  systems  gene, which has been implicated in childhood asthma  gene. A second association signal (rs12129573) was in the intron of an uncharacterised non-protein coding RNA (LOC105378800). In a further region, a signal was found (97.8\u2013100.6\u00a0Mb on chromosome 6) that showed a clear separation between the association signals for each trait . The SNP associated with depression (rs12202410) was near the F-box and leucine-rich repeat protein 4 (FBXL4) gene which is related to energy homoeostasis  contained two association signals for depression. The first signal (rs1460942) was shared with Neu and was close to the neuronal growth regulator 1 (et al., Using a GWAS catalogue lookup with FUMA (Watanabe et al., et al., et al., et al., Differential association of MD with other traits, once shared overlap with Neu was accounted for, was also shown in our analysis of LD score genetic correlations. We found that, unlike Neu, MD was genetically correlated with BMI, triglyceride levels and coronary artery disease, suggesting the atypical depressive subtype related to cardio-metabolic traits (Lasserre et al., et al., et al., et al., et al., et al., et al., et al., One limitation of our study is that by using summary statistics from GWAS, we were only able to assess the overlap in genetic architecture between depression and Neu that arises from common variants. Even biobank-sized samples of millions of participants can be underpowered for detecting associations with rare variants unless such variants have very large effect sizes (Visscher et al., et al., et al., et al., et al., et al., just noisy measures of the same underlying liability. If these differences represent distinct genetic subtypes of depression, then most cases of depression will stem from this Neu\u2013depression nexus, while a smaller proportion may have aetiologies that are distinct from Neu. Some of these associations, such as between depression, chronotype and metabolic phenotypes, are suggestive of endogenous depression's features but do not point to all the characteristics of this previously described subtype. Confirming known depression subtypes and identifying new subtypes will be useful for phenotypic and clinical stratification. The unique associations of triglyceride levels and BMI with depression, but not at all with Neu, confirms that depression with comorbid obesity and other metabolic factors should be studied as a subtype when exploring aetiology and testing treatment efficacy. The partial genetic correlations that ADHD, schizophrenia and bipolar disorder have with depression after adjusting for Neu imply that polygenic risk scores for these other disorders may be useful to screen or stratify participants even if they do not manifest these other disorders.Neu is a major risk factor for depression (Bagby et al., et al., et al., et al., et al., Neither depression (Kendler"}
+{"text": "Due to their enormous surface area compared to other cell types, neurons face unique challenges in properly handling supply and retrieval of the plasma membrane (PM)\u2014a process termed PM turnover\u2014in their distal areas. Because of the length and extensiveness of dendritic branches in neurons, the transport of materials needed for PM turnover from soma to distal dendrites will be inefficient and quite burdensome for somatic organelles. To meet local demands, PM turnover in dendrites most likely requires local cellular machinery, such as dendritic endocytic and secretory systems, dysregulation of which may result in dendritic pathology observed in various neurodegenerative diseases (NDs). Supporting this notion, a growing body of literature provides evidence to suggest the pathogenic contribution of dysregulated PM turnover to dendritic pathology in certain NDs. In this article, we present our perspective view that impaired dendritic endocytic and secretory systems may contribute to dendritic pathology by encumbering PM turnover in NDs. Dendrites are neuronal compartments essential for receiving electrochemical signals from presynaptic neurons through formed synapses. Accurate neuronal wiring relies critically on the proper establishment of the dendritic field that is achieved by both structural build-ups of dendritic arbors and functional maturation of synapses . This process of PM turnover is mediated primarily by endocytic and secretory pathways. However, due to its highly elaborate dendrites, a typical neuron has a 10,000 times larger surface area than does a typical epithelial cell , such as Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), polyglutamine (polyQ) diseases, and amyotrophic lateral sclerosis  expand or reduce its size; (2) alter its shape; and (3) insert or remove from its PM the membranous lipids and proteins needed to convey both intra- and extra-cellular signals.N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes required for the membrane fusion do not form  neurons, defects in exocytosis-mediated dendritic growth were mitigated by blocking clathrin-mediated endocytosis (CME) using a temperature-sensitive dominant-negative allele of shibire , has a specialized membrane-stacked morphology similar to that of Golgi Gray, ,b. BasedDrosophila , which was first defined in cultured hippocampal neurons  GTPase proteins are among the most compelling candidate molecular machinery that may play crucial roles in (dendritic) PM turnover. Rabs, which were first found in rat brains , Rab GTPase-activating proteins (Rab GAPs), and Rab-GDP dissociation inhibitors (Rab GDIs) control the guanine nucleotide status of Rab  complexes initiate vesicle budding from PM at clathrin-coated pits  pathway, through which membrane vesicles are transported directly from EEs to PM; and the slow recycling (10\u201320 min) pathway, through which membrane vesicles are transported to PM Rab35 , where membrane fission actively occurs  neurons that mutation of a dynein subunit gene, dlic, led to proximally \u201cbushy\u201d dendrites and that dlic and Rab5 double mutation resulted in greatly simplified dendritic morphology. Interestingly, this double mutant phenotype was similar to those seen in neurons with Rab5 mutation only. These data indicate that Rab5, in a co-operation with dlic, plays a regulatory role in dendrite morphogenesis. Another study on the genetic interaction between Protein Kinase A (PKA) and Rab5 in C4 da neurons showed that PKA could also contribute to the dendritic arbor development by altering Rab5-endosomal transport in dendrites , in primary cortical neurons increased dendritic branches and decreased endolysosomal trafficking in dendrites  seems to be involved. In this section, we will briefly outline the generalized characteristics of the early secretory pathway by describing some of its key regulators and make extensions to the dendritic secretory pathway and NDs where appropriate.Drosophila and yeast are mediated by coat protein complex II (COPII) vesicles (Brandizzi and Barlowe, cis-Golgi (Suda et al., cis-Golgi (Sztul and Lupashin, The secretory pathway comprises the transport of secretory and membranous materials from ER to Golgi and ultimately to PM. ER-to-ERGIC and ERGIC-to-Golgi in mammals and ER-to-Golgi transport in other less-developed species such as via Dsl1 tethering complex in yeast (Andag and Schmitt, The transport process between the ER and Golgi is not unidirectional. The best characterized retrograde transport process from Golgi to ER is the COPI pathway Spang, . COPI coAlthough the origins of dendritic secretory units are mostly unknown, we suspect that they are not entirely discrete from the canonical secretory units in the soma. Indeed, a study reported that GOPs may originate from somatic Golgi in rat hippocampal neurons (Quassollo et al., Drosophila has also provided a link between the dendritic secretory pathway and dendritic pathology. Chung et al. (CrebA mRNA level. Because CrebA is the master regulator of the secretory pathway (Abrams and Andrew, Sec31 (Chung et al., Sar1 in Drosophila da neurons (Ye et al., A recent study on polyQ toxicity in g et al.  showed tLrrk2, Sec16A detached from the dendritic ERES, which led to the impairment of ER-to-Golgi transport and NMDA receptor trafficking in mouse primary hippocampal neurons (Cho et al., Drosophila ortholog of LRRK2, co-localized with somatic Golgi and GOPs in Drosophila da neurons, and that overexpression of a PD-linked mutant form of LRRK2, LRRK2 G2019S, suppressed anterograde movements of GOPs marked by ManII-eGFP. This GOP transport defect may underlie the dendrite degeneration observed in LRRK2 G2019S-expressing Drosophila da neurons (Lin et al., Glutamatergic excitotoxicity involving the NMDA receptor is often observed in animal models of NDs (Lewerenz and Maher, Neuronal dendrites seem to be highly vulnerable to neurotoxic insults, including those that arise in NDs (Luebke et al., Sec31 and nuclear polyQ expression lead to the loss of GOPs, but not somatic Golgi (Chung et al., Sec31, Rab1, and Sar1, all lead to impaired arborization of dendrites, but normal morphology of axons in Drosophila da neurons (Ye et al., Drosophila model for progressive myoclonus epilepsy (Praschberger et al., Drosophila motoneurons (Ryglewski et al., Although the dendritic and the canonical pathways occur in distinct areas of the neuron, they share many of the regulatory molecules. Also, pieces of evidence show that at least parts of the dendritic secretory system, such as GOPs, may be derived from the canonical somatic secretory system (Quassollo et al., In this review article, we presented our perspective view that impaired PM turnover involving dysregulation of the dendritic endocytic and secretory pathways may contribute to dendritic pathology in NDs. Although there is a growing body of evidence for the potential link between impaired PM turnover and dendritic pathology in NDs, our understanding of the exact pathogenic mechanisms remains largely elusive. We propose that dendritic pathology in NDs may involve dysregulation of the regulatory machinery, such as Rab GTPases and COPI/COPII, for the dendritic endocytic and secretory pathways described above. Dysregulation of the dendritic pathways appears to complement cytoskeleton impairment as underlying pathogenic mechanisms for dendritic pathology. Because dendritic defects are often early features of ND, future studies to elucidate the pathogenic mechanisms by which impaired PM turnover contributes to dendritic pathology in NDs will deepen our understanding of the early pathogenesis of NDs.JP, CC, SP and SL conceptualized the theme of the review and wrote the manuscript together. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Alzheimer\u2019s disease (AD) is a neurodegenerative disorder characterized by amyloid-\u03b2 (A\u03b2) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. In response to A\u03b2 and tau aggregates, microglia, the primary innate immune cells of the central nervous system (CNS), facilitate A\u03b2 and tau clearance and contribute to neuroinflammation that damages neurons. Microglia also perform a wide range of other functions, e.g., synaptic pruning, within the CNS that require a large amount of energy. Glucose appears to be the primary energy source, but microglia can utilize several other substrates for energy production including other sugars and ketone bodies. Recent studies have demonstrated that changes in the metabolic profiles of immune cells, including macrophages, are important in controlling their activation and effector functions. Additional studies have focused on the role of metabolism in neuron and astrocyte function while until recently microglia metabolism has been considerably less well understood. Considering many neurological disorders, such as neurodegeneration associated with AD, are associated with chronic inflammation and alterations in brain energy metabolism, it is hypothesized that microglial metabolism plays a significant role in the inflammatory responses of microglia during neurodegeneration. Here, we review the role of microglial immunometabolism in AD. Alzheimer\u2019s disease (AD) is an age-related neurodegenerative disorder associated with memory loss and impaired cognitive abilities. AD is a major cause of disability and dependency in the United States and worldwide, causing a significant impact on not only the individual patient, but also their family, community, and the healthcare system , account for 10\u201315% of the adult glial cell population in the brain  inflammasome is activated by glycolytic enzymes  activity compared to wild-type cells; decreases in mTOR signaling were associated with increased autophagy. Additionally, the metabolic deficiency, and lack of microglial responsiveness, was restored in Trem2\u2212/\u2212 5XFAD mice by increasing microglial energy capacity with cyclocreatine  and glucose metabolism in neurodegeneration has been identified , and acetoacetate Laffel, . Levels To date AD drug discovery research has focused on tauopathy or A\u03b2 reduction. As discussed above, glycolysis is a major factor in maintaining activated microglia, while non-activated microglia rely more on oxidative metabolism (Bernhart et al., Microglia shift to an anti-inflammatory phenotype in response to BHB (Huang et al., APOE4 allele do not see the improvement in cognitive function as subjects administered CT who are not carriers of the APOE4 allele (Reger et al., Medium-chain triglyceride diets have been developed to provide a more palatable alternative to the ketogenic diet (Huttenlocher et al., TREM2 deficiency results in decreased neuroinflammation and protects against neurodegeneration (Leyns et al., TREM2 increases tau pathology (Bemiller et al., Another approach to AD treatment is to target microglial genes important in microglial metabolism. As previously discussed, TREM2 is vital to microglial metabolic fitness (Ulland et al., The emerging field of immunometabolism has provided significant progress in our understanding of how cellular and systemic metabolism affects immune responses. More importantly, these data suggest that targeting immune cell metabolism may be a valuable strategy for the development of advanced therapeutics to treat human disease (Bettencourt and Powell, DS drafted the manuscript. TU reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Minimal hepatic encephalopathy (MHE), which shows mild cognitive impairment, is a subtle complication of cirrhosis that has been shown to affect daily functioning and quality of life. However, until 2014, relevant guidelines do not give much attention to the diagnosis and treatment of MHE, resulting in patients being ignored and denied the benefits of treatment. In this review, we summarize recent cognition-based research about (1) alteration of nerve cells, including astrocytes, microglial cells and neurons, in mild cognitive impairment in MHE; (2) comparison of methods in detecting cognitive impairment in MHE; and (3) comparison of methods for therapy of cognitive impairment in MHE. We hope to provide information about diagnosis and treatment of cognitive impairment in patients with MHE. Minimal hepatic encephalopathy (MHE), which affects 30\u201355% of cirrhosis patients, is a subtle complication of cirrhosis that may have a detrimental effect on daily functioning. In the MHE phase, patients show mild cognitive impairment, which lead to deficits of attention, and psychomotor slowing  diagnostic criteria have not been standardized; (2) there is no overt clinical manifestation in patients with MHE; and (3) hyperammonemia is present with inflammation and certain levels of ammonemia  the relationship between cognitive impairment and nerve cell injury; (2) comparison of diagnostic methods for MHE; and (3) comparison of therapeutic methods for MHE.During MHE, the main contributor to cognitive impairment is hyperammonemia. In patients with liver disease, ammonia accumulates in blood due to deficient activity of hepatic urea cycle enzymes. In the brain, nerve cells take up ammonia and cause cognitive impairment. For example, astrocytes take up ammonia and glutamine synthetase detoxifies ammonia into glutamine. The rapid accumulation of glutamine creates an osmotic gradient that results in astrocyte swelling  secretion, play important roles in nerve cell impairment. For example, hyperammonemia significantly reduces long-term potentiation and alters mRNA for DA receptors, which cause deficits in disturbed synaptic plasticity and novelty acquisition in hippocampal and corticostriatal pathways involved in goal-directed and learning behavior -\u03b1. Astrocytic TNF-\u03b1, which triggers neurodegenerative progression consequently or indirectly, resulting in cognitive impairment. Ding et al. found that low-dose DA (10\u00a0\u03bcM) produced TNF-\u03b1 in primary astrocytes, and co-culture of these astrocytes and neurons exhibited neuronal apoptosis compared with control group , which often occurs in cirrhosis patients, contributes to the MHE pathogenesis. Ding et al. found that the final production of neurotrophic factors, including PI3K/AKT signaling pathway to the phosphorylation of N-Methyl-d-Aspartate receptors and downstream activation of the CaMKIV/CREB pathway, was impaired in MHE rats -1\u03b2, Toll-like-receptor (TLR)-4 agonist lipopolysaccharide, and TNF-\u03b1. These pro-inflammatory microglia are characterized by immune-potentiating abilities, antigen-presenting and microbicidal -E2 and IL-6. And hyperammonemia also caused reduced Anti-inflammatory IL-10 and microglia activation in hippocampus. Increased TNF-\u03b1 and IL-1\u03b2 levels and phosphorylation (activity) of p38 cause GABAergic and glutamatergic neurotransmission. For example, membrane expression of GluR2 of AMPA receptor and subunits \u03b11 of etc. GABAA receptor is increased, while expression of subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors is reduced. These altered membrane expression receptors are associated with hyperammonemia-induced microglial activation. And are responsible for impairment of spatial learning and altered neurotransmission in the radial maze. In turn, these inflammatory injuries contribute to microglial differentiation from anti-inflammatory M2 to pro-inflammatory M1 phenotype  is involved in the perturbation of neural synaptogenesis. Cholinesterase (CHO) overload in combination with DA burden elicits memory loss and cognitive decline via the peroxisome proliferator-activated receptor (PPAR) \u03b3/extracellular signal-regulated kinase (ERK)/CREB pathway in MHE. In turn, DA triggers CHO biosynthesis via activation of the C-Jun N-terminal kinase 3/sterol regulatory element-binding protein 2 signaling pathway in primary cultured astrocytes. Zhuge et al. found that CHO secreted from astrocytes stimulated secretion of DA from primary cultured neurons. PPAR\u03b3/pERK/pCREB expression was decreased by DA-induced synergistic leads to synergistic synaptic impairment in   represents the ability to suppress irrelevant motor or cognitive processes, and is useful for diagnosis of MHE (Di Lemma and Field The novel electronic number connection test (eNCT) has test\u2013retest reliability to detect cognitive function and monitor cognitive impairment in patients with cirrhosis. Wuensch et al. found that the eNCT performance was negatively correlated with PHES performance in patients with cirrhosis. Control participants showed significantly faster eNCT completion times compared with cirrhosis patients  in the transition from an unimpaired mental state to HE  applies electromagnetic waves emitted by a graded magnetic field to acquire the internal structure of the objects (Lockwood et al. Different kinds of MRI play an important role in the detection of MHE. Kooka et al. demonstrated magnetic resonance spectroscopy, which shows that reduced magnetization transfer ratio in the whole brain field and an increase in glutamate/glutamine or taurine in chronic HE patients contribute to early and objective diagnosis of MHE. The levels of brain glutamine were significantly lower and the levels of brain myo-inositol were significantly higher in the control group compared with the MHE group (Kale et al. In addition to hyperammonemia, inflammation also modulates neuropsychological function in patients with MHE. For example, Circulating IL-6 is negatively associated with memory function in low-dose endotoxemia (Krabbe et al. Paper-and-pencil test used in PHES is the gold standard for diagnosis of MHE. But the process of diagnosis of PHES is inconvenient and affected by many factors. The diagnostic methods take time, and are affected by demographic factors, and lack ecological validity and language functions, such as verbal memory. PHES focuses on only two cognitive domains but it is not sensitive enough to detect early neurological alterations. Patients classified as without MHE by PHES have a high risk of suffering overt HE. Around 40% of patients without MHE according to PHES fail two other psychometric tests Bajaj . Other kCFF is a noninvasive, rapid, simple test for diagnosis of MHE. Compared with PHES, CFF has a positive predictive value of 93.2\u2009\u00b1\u20097.44%, specificity of 92.7\u2009\u00b1\u20097.96%, negative predictive value of 90.4\u2009\u00b1\u20098.91% and sensitivity of 91.1\u2009\u00b1\u20098.32%. CFF is excellent for diagnosis of MHE, with an area under the curve of 0.937 (Metwally et al. Neuroimaging studies can detect diffuse abnormal metabolic activity of nerve cells, which is a typical feature of patients with MHE. MRI can provide objective and reliable imaging biomarkers that are necessary to help diagnose or identify MHE (Zhang et al. In addition to hyperammonemia, there is a parallel relationship between inflammatory cytokines and MHE, or a significant correlation between proinflammatory cytokines with MD values on diffusion tensor imaging (Srivastava et al. Recent guidelines suggest that either alternative techniques, such as computerized tests, neurophysiological testing or EEG should be used alongside PHES for multicenter studies (Morgan et al. As mentioned above, nerve cell injury plays an important role in MHE progression, so protection of nerve cells is one way to prevent and treat MHE. Good nutritional status is an important way to relieve nerve cell damage. Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE. Venous ammonia is significantly higher in patients with sarcopenia and myosteatosis and inversely correlated with both parameters (Nardelli et al. Reducing neuroinflammation is also an important way to relieve nerve cell damage. Malaguarnera et al. demonstrated that bicuculline decreases anxiety and improves working memory and spatial learning in hyperammonemic rats. Bicuculline can reduce activation of GABAA receptors, which contributes to neuroinflammation. Meanwhile, bicuculline reduces astrocyte activation and not microglial activation. Bicuculline reverses the changes in membrane expression of AMPA and NMDA receptor subunits (Malaguarnera et al. Disorder of intestinal flora and bacterial translocation, which increase production and absorption of intestinal toxins, are closely related to HE. There are different degrees of intestinal flora disorder in patients with chronic liver disease. Beneficial bacteria such as bifidobacteria are decreased while urease-producing bacteria are the source of gut-derived toxins. Production and absorption of intestinal toxins significantly increase, but the liver cannot metabolize these toxins completely, which leads to toxin retention (McPhail et al. Enterococcus and Enterobacteriaceae were significantly decreased while the predominant bacteria were significantly enriched (Xia et al. MHE is also associated with individual microbiota signatures. For example, the relative abundance of Lactobacillaceae is higher in MHE, whereas abundance of autochthonous Lachnospiraceae is higher in those without MHE (Bajaj et al. Probiotics are well-tolerated, natural and safe and appropriate for long-term treatment of MHE (Jiang et al. Rifaximin is a non-absorbed, gut-selective antibiotic with a low resistance profile that is commonly used to treat HE. It achieves high concentrations in the human intestine, where it is active against many enteropathogens (Goel et al. Rifaximin has always been a second-line drug in the treatment of HE, but there are no unified conclusions for treatment of MHE. Bajaj et al. demonstrated that over the 8-week period, MHE patients treated with rifaximin showed significant improvements in avoiding total driving errors, speeding, and illegal turns. Rifaximin also made improvements in the psychosocial dimension of the sickness impact profile and the anti-inflammatory cytokine IL-10 levels (Bajaj et al. LOLA may be administered orally or parenterally. The benefits of LOLA for the treatment of HE have been known for 50\u00a0years (Buyeverov et al. Lactulose is a disaccharide composed of galactose and fructose. As early as 1957, the prebiotic properties of lactulose were reported in both adults and infants. Due to promising outcomes, low price and high availability, Lactulose does not undergo cleavage by human gastrointestinal enzymes (Ruszkowski and Witkowski Psychometric tests improved in 75% of MHE patients after treatment with lactulose (El-Karaksy et al. Probiotics, rifaximin, LOLA and lactulose can improve MHE, but they also have some weaknesses Table . ProbiotStreptococcus abundance in the gut (Zuo et al. In recent years, many scientists have compared the efficacy of these drugs in preventing and treating MHE, and there was no difference between probiotics and lactulose (Jiang et al. Given the adverse effects of lactulose, cost of rifaximin and the safety of probiotics, LOLA appears to have beneficial effects in MHE, although its role in therapy is not clearly defined Table .MHE has serious consequences for quality of life, increasing the number of accidents, falls, hospitalizations and associated costs (Llansola et al. Timely and accurate discovery of cognitive impairment is the key to diagnosis of MHE. Psychometric tests, CFF, EEG and MRI are useful to evaluate cognitive function in an intuitive or abstract way. Psychometric tests are irreplaceable now. Compared with other psychometric tests, ANT is little influenced by age and education level. MRI, which can more accurately reflect changes in cognitive function, may be the best option in the future, if the problem of lack of detection accuracy of the measured signal can be resolved. CFF and EEG should be used alongside PHES Table .Timely correction of cognitive impairment is the key to treatment of MHE. One method is to prevent nerve cell injury, through improving the nutritional status of nerve cells, and blocking their injury by inflammatory mediators. Another method is to improve intestinal flora and reduce serum ammonia level. Among the drugs to improve intestinal flora, LOLA has few adverse effects and low cost, which may become the ideal choice in the future Table ."}
+{"text": "Forster et al.  performeThe median-joining network approach employed in Forster et al.  is a metAs an evolutionary biologist working in a developing country, I have experienced firsthand how sensational findings can influence decision-making processes by diverting time and resources to control virus strains deemed to be \u201cmore aggressive.\u201d In the fog of war, scarce resources are allocated in haste, and the developing world does not have well-informed science advisers sitting in every key meeting to help provide balanced scientific viewpoints. The scientific community, as a whole, needs to be extra cautious in interpreting new findings related to coronavirus disease 2019 (COVID-19), and any potential misinformation must be promptly addressed. Scientific discourse is the basic foundation of science, and high-profile publications, especially controversial ones, require constructive dialogues for advancement of science and betterment of society, particularly during an ongoing war against a global pandemic."}
+{"text": "Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug\u2013induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans. IP3Rs in the ER are involved in Ca2+ release into the cytosol and are coupled with mitochondrial VDAC in MAMs  to transiently elevate intracellular Ca2+ levels, they observed increased mitochondrial Ca2+ uptake that corresponded with an increase in mitochondrial transmembrane potential (\u0394\u03a8m), suggesting that even transient increases in mitochondrial Ca2+ can affect mitochondrial activity in hair cells. Cumulatively, these results show that under non-pathological conditions mitochondria take up Ca2+ released from the ER and that changes in mitochondrial Ca2+ can alter mitochondrial activity.In conjunction with the mitochondrion, the endoplasmic reticulum (ER) is also a critical regulator of Cah Vance, . In zebrg et al.  combined2+ indicators described earlier, Pickett et al.  collapses, followed by a spike in cytosolic Ca2+  wild-type strain of zebrafish were less vulnerable to gentamicin-induced hair-cell loss than the ABOne consequence of oxidative phosphorylation is the generation of ROS. Mitochondrial ROS are generally produced in the form of superoxide or hydrogen peroxide due to oxidation of metabolic intermediates in the electron transport chain complexes I and III Brand, . Hydroxym and mitochondrial oxidation, as reflected by the indicator mitoSOX (2+ uptake; blocking entry of Ca2+ into the mitochondria with Ru360 reduced ROS levels and mitochondrial oxidation after neomycin exposure. Cumulatively, these data suggest that mitochondrial Ca2+ uptake is an event upstream of neomycin ototoxicity, with ROS playing an additional role.Mitochondrial ROS production may play a role in aminoglycoside ototoxicity. It has been shown that aminoglycosides bind to iron salts and stimulate the production of free radicals by Fenton chemistry (Priuska and Schacht,  mitoSOX . These oin vitro, also protected against neomycin-induced hair-cell loss (Hirose et al., 2DCFDA labeling (Exogenous antioxidants have shown promising otoprotective effects in zebrafish lateral line and mammalian cochlear explants (Ton and Parng, labeling .d-methionine prevented this sonic-induced hair-cell loss, suggesting a role for oxidative stress in this model. Because zebrafish can be exposed to drugs by bath application, they are an optimal system in which to screen for protective or harmful drugs. By screening a redox library for compounds that protected against damage, glutathione, baicalein, d-\u03b1-tocopherylquinone, and ferulic acid ethylester were identified as protective agents (Uribe et al., In mammals, it has been shown that ROS are generated in the cochlea after noise exposure, and that antioxidants administered before or after exposure can potentially ameliorate noise-induced damage (Yamane et al., It has been suggested, specifically in the context of aminoglycoside ototoxicity, that hair cells \u201cfind a way to die\u201d such that inhibition of one death pathway will lead to the activation of other death pathways, and that it may be necessary to target multiple pathways to fully protect hair cells from ototoxins, such as by using drug cocktails or by using drugs that have multiple modes of action (Vandenabeele et al., Cisplatin is an anti-cancer chemotherapeutic drug that is commonly used to treat a number of different cancers. Notably, cisplatin treatment causes hearing loss in up to 80% of patients (Frisina et al., Similar to work with aminoglycosides, protection against cisplatin ototoxicity using antioxidants and ROS scavengers has been an intriguing topic of recent study. Epicatechin, a ROS scavenger derived from tea leaves, has been shown to protect zebrafish from cisplatin-induced lateral-line hair-cell loss (Kim C. H et al., While acquired hearing loss can be caused by exposure to noise or ototoxic drugs, some hearing loss is inherited (Lenz and Avraham, Zebrafish have been a popular model for genetic studies due to their high fecundity and ease of genetic manipulation. Forward genetic screens in zebrafish have proven useful for identifying genes required for hearing and balance as well as in pathways involved in aminoglycoside-induced death (Nicolson et al., pappaa, which encodes pregnancy-associated plasma protein-aa (Wolman et al., pappaap170 mutant zebrafish were more susceptible to neomycin-induced hair-cell death and had elevated ROS levels in their hair cells. In addition, pappaap170 mutant hair cells had increased mitochondrial Ca2+, hyperpolarized \u0394\u03a8m, and reduced expression of the mitochondrial antioxidant genes gpx, sod1, and sod2, all of which could contribute to increased ROS levels. Treatment with the ROS scavenger mitoTEMPO rescued pappaap170 mutant susceptibility to neomycin-induced hair-cell death, suggesting that elevated ROS underlies the enhanced hair-cell death in pappaap170 mutants. The study supports the utility of zebrafish forward genetic screens in identifying novel genes involved in mitochondrial function and hair-cell vulnerability.Forward genetic screens have been particularly useful for identifying novel gene function in the zebrafish lateral line. One such gene identified using forward genetics is mtu1 to study its function in hair cells (Zhang et al., mtu1-deficient zebrafish had deficient thiolation of mitochondrial tRNA, as well as decreased levels of mitochondrial tRNA and mitochondrial proteins (Zhang et al., mtu1\u2212/\u2212 zebrafish also had deficient oxidative phosphorylation and reduced ATP. In the lateral line, mtu1\u2212/\u2212 zebrafish had fewer hair cells per neuromast. These results support a role for mitochondrial tRNA modification in deafness and demonstrate the value in using reverse genetics to study gene function in hair cells.Another study used CRISPR/Cas9 technology to delete the gene in vivo. Studies utilizing this system have shed light on the roles of mitochondria in calcium homeostasis and synapse regulation as well as supported roles of mitochondria in cell death pathways, particularly in response to ototoxic drugs like aminoglycosides. The strides made from zebrafish studies contribute to the understanding of hearing loss in humans and will lead to development of preventative or protective therapies in the future.The zebrafish lateral line is a valuable model system in which to study hair-cell mitochondria and offers unique tools such as the ability to visualize mitochondrial dynamics MH and LS wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The importance of training in regulating body mass and performance is well known. Physical training induces metabolic changes in the organism, leading to the activation of adaptive mechanisms aimed at establishing a new dynamic equilibrium. However, exercise can have both positive and negative effects on inflammatory and redox statuses. In recent years, attention has focused on the regulation of energy homeostasis and most studies have reported the involvement of peripheral signals in influencing energy and even inflammatory homeostasis due to overtraining syndrome. Among these, leptin, adiponectin, ghrelin, interleukin-6 (IL6), interleukin-1\u03b2 (IL1\u03b2) and tumour necrosis factor a (TNFa) were reported to influence energy and even inflammatory homeostasis. However, most studies were performed on sedentary individuals undergoing an aerobic training program. Therefore, the purpose of this review was to focus on high-performance exercise studies performed in athletes to correlate peripheral mediators and key inflammation markers with physiological and pathological conditions in different sports such as basketball, soccer, swimming and cycling. In elite athletes, there is large disparity among the training protocols; the effects on oxidative stress (OS) and inflammatory cytokines are still not well known. Is important to highlight that excessive training loads are able to trigger the syndrome known as overtraining syndrome (OTS), a phenomenon in which there is an increase in pro-inflammatory markers and consequently a decrease in sport performance . TherefoPeripheral mediators could be used to monitor both long- and short-term effects in elite athletes during training exercise. Leptin, adiponectin and ghrelin exert important effects on the hormonal regulation in response to acute exercise and chronic training and are related to each other. It is interesting to evaluate the effects of specific training on these molecules and on metabolic state in athletes since cytokine responses are linked to changes in physical performance. J\u00fcrim\u00e4ea et al.  found thProfessional cyclists are a class of highly trained athletes subjected to different schedules of training and often to ultra-endurance training. Serrano et al.  reportedNieman et al.  reportedThey suggest a possible link between the increase in adiponectin and the training improvement due to the endurance or resistance training in cyclists. C\u00f3rdova Mart\u00ednez et al.  determinIn young well-trained female basketball players, Plinta et al.  found, aThe study of Souglis et al.  reportedUnal et al.  carried Mart\u00edn-S\u00e1nchez et al. , using aIn conclusion, in elite soccer players, more than in other athletes, an intensive and inadequate training program modifies the inflammatory status, and this may be associated with a reduction in performance.Karamouzis et al.  reportedAerobic and anaerobic exercises result in alterations of redox homeostasis in untrained, trained and well-trained athletes. Following intensive physical activity in elite athletes, the source of systemic oxidative stress (OS) is not fully understood but it is proposed that skeletal muscle is the main contributor to the exercise-induced ROS . In this2O2, glutathione disulfide (GSSG) level and catalase (CAT) activity in well-trained female athletes who practice anaerobic/aerobic sports. They conclude that these results could be related to the adaptation mechanisms of antioxidative defense that depends on the type of sport. The results of a study by Souglis et al. [The influence of seasons on training has been analyzed by Balog et al.  measurins et al.  showed ts et al. , we suggs et al.  reportedAltitude exposure can increase markers of OS after acute exercise and this is observed in endurance-trained cyclists. McGinnis et al.  simulateDifferent studies demonstrated damage associated with OS in DNA following exhaustive/high-intensity endurance exercise, eccentric exercise and unaccustomed exercise. However, this effect is recovered after adequate rest. DNA damage is measured with an increase in 8-hydroxy-2\u2032-deoxyguanosine (8-OHdG) plasma levels because the activity of several DNA-repairing enzymes (among them: human 8-oxoguanine DNA glycosylase1 and oxidized purine-nucleoside triphosphate) is increased to protect against exercise-induced DNA damage. Yasuda et al.  determinIn a short report, Lekhi et al.  analyzedIn a recent study, Maleki et al.  reportedDuring the season, elite basketball players train twice a day and play one or two games per week. Even though both aerobic and anaerobic systems are activated, several studies have demonstrated that anaerobic metabolism is the primary energy pathway activated in basketball players because basketball requires movements with variable velocity, continuous accelerations, decelerations, stopping and sudden changes of direction. These authors reported that elite basketball players show good anaerobic power  and modeThe overall duration of a typical basketball match is 40\u201348 min, in which an athlete carries out a combination of high-intensity actions  interspersed with low-intensity activities  and active or passive recovery . In one 2\u2013 and H2O2 remained unchanged. On the other hand, SOD and CAT activity increased, while GSH decreased. Le Moal et al. [The physical demands activity required for soccer players includes: sprints, change of direction and high-intensity running involving both aerobic and anaerobic energy pathways leading to alterations of biological processes such as inflammation, muscle damage and OS. Jakovljevi\u0107 et al.  investigl et al.  followedIn summary, oxidative stress is markedly upregulated after a soccer game and it is correlated with cumulated training loads during the football season.Competitive swimming combines factors such as the simultaneous contribution of arms and legs to propulsion, water immersion and prone position and allows muscles to work in harmony and in accordance with each other, since gravity drops down to almost zero in water. Unlike other popular sports, the OS that occurs in swimming is largely affected by the type of competitions, and swimmers require a sophisticated training for both aerobic (endurance exercises) and anaerobic (short high-effort exercises below 200 m) exercise to increase performance. Several studies indicate that swimming is involved in OS homeostasis changing but the duration and intensity of the stress are strictly correlated with the effort . The stuThe purpose of this review was to focus on high-performance exercise studies performed in athletes to correlate peripheral mediators and key inflammation markers with physiological and pathological conditions in different sports such as basketball, soccer, swimming and cycling. The main source of discrepancies among reviewed studies indeed mainly concerns differences in the type, duration and intensity of training . In well"}
+{"text": "Many nematodes show context-dependent, experience-dependent and/or life-stage-dependent behavioural responses to CO2, suggesting that CO2 plays crucial roles throughout the nematode life cycle in multiple ethological contexts. Nematodes also show a wide range of physiological responses to CO2. Here, we review the diverse responses of parasitic and free-living nematodes to CO2. We also discuss the molecular, cellular and neural circuit mechanisms that mediate CO2 detection in nematodes, and that drive context-dependent and experience-dependent responses of nematodes to CO2.Carbon dioxide (CO The initial repulsion from CO2 experienced by Heligmosomoides polygyrus iL3s on feces may enable them to disperse off of feces and into the environment to host seek. Following a prolonged period without feces, CO2 attraction may drive them towards new hosts or fresh host feces to increase their chances of host entry through ingestion  in passively ingested ruminant parasites such as Haemonchus contortus  are parasites that infect and kill insects , suggesting that jumping is highly sensitive to environmental CO2  in Steinernema scapterisci is in fact regulated by ambient CO2 levels.Like some mammalian-parasitic nematodes, some EPNs exhibit plasticity in their olfactory responses to COof weeks   are a major cause of agricultural crop damage throughout the world. It has been estimated that PPNs are responsible for approximately 100 billion dollars of crop loss per year worldwide  are repelled by CO2. CO2 repulsion by JIVs plays an important role in dispersal from its insect vector, the pine sawyer beetle, into the pine tree  levels, as well as immediate O2 context. For example, animals exposed to elevated CO2 levels (2.5% CO2) become robustly attracted to CO2 over the course of hours in a reversible manner  inhibits egg-laying behaviour, at least transiently  mutations in npr-1 and animals carrying the natural variant of npr-1 avoid CO2 under low O2 conditions but do not respond to CO2 at normal atmospheric O2 levels (21% O2)  mutation or a natural variant of npr-1, the URX neurons are tonically active under high O2 conditions and inhibit CO2 avoidance at high O2. The RIA interneurons appear to act downstream of URX to partially mediate its effects on the CO2 circuit (Kodama-Namba et al., glb-5 also acts via the URX neurons to modulate CO2 responsiveness as a function of ambient O2 levels (McGrath et al., et al., The extent to which CO2 responsiveness in C. elegans have been elucidated in some detail. The shift in CO2 response from repulsion to attraction when animals are moved from low CO2 to high CO2 cultivation conditions results from the differential activity of a single set of interneurons downstream of the BAG sensory neurons (Guillermin et al., 2, CO2 exposure inhibits the AIY interneurons and activates the RIA and RIG interneurons. In contrast, in animals that have been cultivated at high CO2, CO2 exposure activates AIY and inhibits RIA. Moreover, RIG is silenced such that it no longer responds to CO2 (2 response is not determined by whether an \u2018attractive\u2019 or \u2018repulsive\u2019 pathway is activated; rather, it is determined by experience-dependent modulation of interneuron activity in a single pathway (Guillermin et al., 2 responsiveness in animals cultured under high vs low CO2 conditions (et al., The mechanisms underlying experience-dependent modulation of COs to CO2 . Thus, Cnditions  (Guiller et al., .2 repulsion to CO2 attraction that occurs during starvation also arises due to the differential activities of the AIY and RIG interneurons (Rengarajan et al., 2 evokes activating and inhibiting responses with approximately equal frequency (2 is attractive or repulsive is regulated by biogenic amine signalling. Dopamine promotes CO2 avoidance in well-fed animals by promoting activation of RIG and inhibition of AIY, while octopamine promotes CO2 attraction in starved animals by promoting activation of AIY (et al., 2 circuit is modulated during starvation by opposing biogenic amine signals. Neuropeptide signalling also regulates CO2 responsiveness during starvation (et al., 2 attraction in dauer larvae is less well understood but is regulated at least in part by neuropeptide signalling (Lee et al., The shift from COrequency . At the n of AIY  (Rengara et al., . Thus, tarvation  (Rengara et al., . Finally2 on other behaviours in C. elegans have also been elucidated. For instance, CO2-evoked activity in the AWC sensory neurons triggers a cGMP signalling pathway that ultimately inhibits the activity of the HSN neurons, resulting in the inhibition of egg-laying behaviour (Fenk and de Bono, C. elegans, resulting in increased longevity in BAG-ablated animals (Liu and Cai, jnk-1 and kgb-2 suppress CO2-induced fertility defects, indicating that JNK signalling may be involved in regulating fertility in response to CO2 (Vadasz et al., Some of the molecular and cellular mechanisms that mediate the effects of CO2 responsiveness in C. elegans have been elucidated in appreciable detail, several questions remain unexplored. For example, more information is needed to fully understand how the differential flow of information from BAG neurons to downstream interneurons generates experience-dependent plasticity of CO2-evoked behaviour. One intriguing possibility is that the BAG neurons express or release different neurotransmitters or neuropeptides in response to CO2 under varying conditions. Consistent with this possibility, the BAG neurons modulate the expression of FLP-19 neuropeptides as a function of their CO2-evoked activity (Rojo Romanos et al., 2-sensing neurons have not been identified. Finally, the CO2 microcircuit that drives CO2 attraction in dauers remains poorly understood, although it appears to involve dauer-specific, gap-junction-mediated signalling between the BAG neurons and the downstream AIB interneurons (Bhattacharya et al., 2 attraction in dauers. A better understanding of the neural circuits and signalling pathways that regulate CO2 responsiveness as a function of experience, context and life stage will provide important insights into how a single sensory cue can give rise to diverse behavioural responses in an ethologically-appropriate manner.Although the mechanisms underlying COet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., 2 responsiveness in C. elegans as a starting point for launching investigations into the mechanisms of CO2 responsiveness in parasitic nematodes. In the case of both the necromenic nematode Pristionchus pacificus and the EPNs Heterorhabditis bacteriophora and Steinernema carpocapsae, BAG neurons were identified on the basis of conserved neuroanatomical position and shown to be required for behavioural responses to CO2 by laser ablation analyses (Hallem and Sternberg, et al., Pristionchus pacificus adults do not show acute CO2 avoidance, and BAG-ablated Heterorhabditis bacteriophora and Steinernema carpocapsae IJs do not show CO2 attraction (Hallem et al., 2-evoked jumping behaviour in Steinernema carpocapsae requires the BAG neurons (Hallem et al., 2 response are at least partly conserved across nematode species. However, the interneurons that operate downstream of BAG neurons to mediate CO2 responsiveness in other nematode species have not yet been identified. Moreover, nothing is currently known about the neural circuits and molecular signals that promote CO2 responsiveness in mammalian-parasitic nematodes. In future studies, it will also be interesting to determine whether similar or distinct mechanisms operate in C. elegans and parasitic nematodes to modulate CO2 responses depending on context, previous experience or life stage.The anatomy and function of nematode sensory neurons are generally conserved across species (Ashton 2 responsiveness in mammalian-parasitic nematodes. The identification of the neural mechanisms that drive or regulate the CO2 responses of mammalian-parasitic nematodes both inside and outside the host could lead to the identification of new drug targets or new strategies for nematode control. Until recently, investigations into the mechanisms underlying sensory behaviours in parasitic nematodes were limited to laser ablation analysis due to the dearth of resources and tools required for the genetic manipulation of these parasites. Laser ablation analysis has been used to establish the function of a number of different sensory neurons in mammalian-parasitic nematodes, including Strongyloides stercoralis, hookworms and Haemonchus contortus (Ashton et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., A major focus going forward will be on elucidating the cellular and molecular mechanisms underlying COStrongyloides stercoralis and Strongyloides ratti. Strongyloides stercoralis and Strongyloides ratti are more readily amenable to genetic manipulation than other parasitic nematodes because they can undergo one free-living generation (Viney, C. elegans (Evans, Strongyloides stercoralis is a human parasite that infects approximately 370 million people worldwide (Page et al., Strongyloides stercoralis is of interest as a model for other human-parasitic nematodes such as hookworms that cannot be genetically manipulated.The most genetically tractable parasitic nematodes are n Viney, . Foreigns Evans, . Most ot1 progeny of the microinjected adults (Lok and Massey, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Strongyloides has been aided by the identification of several promoters that drive expression in single cells or subsets of cells (Junio et al., et al., et al., C. elegans are stably expressed across generations, extrachromosomal arrays in Strongyloides are silenced after the F1 generation by as-yet-unknown mechanisms (Junio et al., et al., Strongyloides by methods that promote genomic integration of transgenes, such as transposon-mediated random integration (Shao et al., et al., Transgenic nematodes can be generated by introducing plasmid DNA containing exogenous genes; these genes are then expressed as extrachromosomal arrays in the FStrongyloides stercoralis and Strongyloides ratti. The recent development of an approach for CRISPR/Cas9-mediated targeted gene disruption in these species provided the first insights into the genetic mechanisms that drive sensory behaviours (et al., et al., et al., Strongyloides stercoralis infective larvae (Bryant et al., Strongyloides ratti. RNAi approaches using both dsRNA and siRNA have been used to study the effects of transcriptional knockdown of genes in several parasitic nematode species, although with varying efficacy (Geldhof et al., et al., et al., et al., et al., et al., Strongyloides ratti, a recent study demonstrated the first successful knockdown of multiple mRNAs using an siRNA approach (Dulovic and Streit, Strongyloides ratti iL3s, although mapping the locations of these mutations has not been possible yet (Viney et al., et al., Methods for disrupting gene function are also now available for haviours  (Gang etStrongyloides stercoralis to CO2. For example, it will be interesting to determine whether the BAG neurons, which sense CO2 and promote behavioural responses to CO2 in C. elegans, play a similar role in Strongyloides stercoralis. It will also be important to elucidate the neural circuitry that operates downstream of the CO2-sensing neurons to mediate or modulate CO2-evoked behaviours in Strongyloides stercoralis. An intriguing possibility is that while sensory neuron function may be generally conserved across species, interneuron function may be less well conserved and may instead reflect species-specific behavioural and physiological responses to CO2. In addition, through the systematic screening of candidate genes known to be involved in CO2 responsiveness in C. elegans, it might be possible to uncover molecular signals that regulate parasite\u2013host interactions or that are required for successful parasitism. In the long run, a better understanding of the molecular and cellular bases of CO2-evoked behaviours in parasitic nematodes may lead to new avenues for nematode control. It may also shed light on some of the unique sensory mechanisms that operate in parasitic nematodes to shape parasite-specific behavioural responses.Using a combination of the above approaches, it should be possible to identify the neural mechanisms and molecular pathways that are involved in driving behavioural and physiological responses of"}
+{"text": "We read with great interest the recent article by Shimazui et al. who concluded that in septic patients, mortality in non-elderly patients was increased with hypothermia and decreased with fever, while mortality in elderly patients was not associated with body temperature (BT) . We woul We read with great interest the letter by Honore et al., concerning the potential confounding effect of continuous replacement therapy (CRRT) on body temperature (BT) measurement. The generally higher risk of developing acute kidney injury (AKI) in elderly patients might also influence the results.2 ). However, non-elderly patients were more frequently initiated on CRRT within first 24\u2009h compared to elderly patients ; non-elderly patients had higher chance of temperature alteration by CRRT. In addition, adding \u201cCRRT\u201d as covariates including previously reported analysis in the Cox regression for the hazard of death over 90\u2009days by the BT adjusted with potential imbalances of age (per year), sex, chronic steroid use, and APACHE II score yielded results similar to the primary findings .As Honore et al. have pointed out, the morbidity of AKI on admission was significantly higher in elderly patients compared to non-elderly patients (elderly 82.5%, non-elderly 73.8%, According to these results, we conclude that the BT, especially hypothermia, may be associated with mortality in non-elderly septic patients including those treated with CRRT, while the association between BT and mortality remains inconsistent in elderly septic patients even after adjusting the CRRT effects."}
+{"text": "This editorial summarizes eight research articles included in this supplement issue for the 2020 International Conference on Intelligent Biology and Medicine (ICIBM 2020) conference, that was held on August 9-10, 2020 ,with a topic on data-driven analytics in biomedical genomics. These articles cover a wide range of topics in medical genomics that focus on integrative analysis of genomics data together with other types of data toward understanding complex human diseases,including cancer. With the growing importance of data analytics in biomedical science, we expect this collection of research articles provides scientific discussions in this direction. The 2020 International Conference on Intelligent Biology and Medicine (ICIBM 2020), the official conference of the International Association for Intelligent Biology and Medicine (IAIBM), was held virtually from August 9th to 10th, 2020 due to the COVID-19 pandemic. Established in 2012, the ICIBM conference has grown as a venue to cultivate interdisciplinary research and education at the intersection of bioinformatics, intelligent computing, systems biology, and medical informatics. The first virtual conference of ICIBM (ICIBM 2020) had approximately 300 attendees, with 41 oral presentations scheduled in four live sessions selected from 75 original submissions. With rigorous review for ICIBM 2020 followed by second-round reviews for journal submissions, eight high-quality manuscripts were selected to be published in the ICIBM 2020 BMC Medical Genomics special issue.This supplementary issue includes eight manuscripts that cover a variety of topics in medical genomics, with a focus on data-driven analytics in biomedical genomics research. Here we summarize the contribution of each of these eight manuscripts.In the manuscript titled \u201cA pan-kidney cancer study identifies subtype specific perturbations on pathways with potential drivers in renal cell carcinoma\u201d, Zhan et al.  introducIn the study of \u201cPinpointing miRNA and genes enrichment over trait-relevant tissue network in Genome-wide Association Studies\u201d, Li et al.  combinedIn the manuscript titled \u201cCharacterization of genome-wide association study data reveals spatiotemporal heterogeneity of mental disorders\u201d, Dai et al.  presenteIn \u201cNetwork-based Drug Sensitivity Prediction\u201d, Ahmed et al.  exploredIn the study of \u201cDifferential alternative splicing (AS) between hepatocellular carcinoma with normal and elevated serum alpha-fetoprotein\u201d, Jin et al.  reportedIn the manuscript titled \u201cIntegrative analysis of histopathological images and chromatin accessibility data for estrogen receptor-positive breast cancer\u201d, Xu et al.  providedIn the manuscript titled \u201cThe circular RNA expression profile in ovarian serous cystadenocarcinoma reveals a complex circRNA-miRNA regulatory network\u201d, Zhuang et al.  studied In the manuscript titled \u201cConditional transcriptional relationships may serve as cancer prognostic markers\u201d, Yu et al.  incorporThis supplementary issue includes a collection of eight manuscripts that are focused on various perspectives of integrating data across multiple data types , to understand the etiology, prognostics and progression of diseases. With the emerging big data with regards to its volume, velocity, and variety in biomedical science, we anticipate integrative analytics will significantly propel future biomedical advances in realizing the full potentials of big data in biomedicine."}
+{"text": "Recently, a growing attention has been observed toward potential advantages of stem cell (SC)-based therapies in regenerative treatments. Mesenchymal stem/stromal cells (MSCs) are now considered excellent candidates for tissue replacement therapies and tissue engineering. Autologous MSCs importantly contribute to the state-of-the-art clinical strategies for SC-based alveolar bone regeneration. The donor cells and immune cells play a prominent role in determining the clinical success of MSCs therapy. In line with the promising future that stem cell therapy has shown for tissue engineering applications, dental stem cells have also attracted the attention of the relevant researchers in recent years. The current literature review aims to survey the variety and extension of SC-application in tissue-regenerative dentistry. In this regard, the relevant English written literature was searched using keywords: \u201ctissue engineering\u201d, \u201cstem cells\u201d, \u201cdental stem cells\u201d, and \u201cdentistry strategies\u201d. According to the available database, SCs application has become increasingly widespread because of its accessibility, plasticity, and high proliferative ability. Among the growing recognized niches and tissues containing higher SCs, dental tissues are evidenced to be rich sources of MSCs. According to the literature, dental SCs are mostly present in the dental pulp, periodontal ligament, and dental follicle tissues. In this regard, the present review has described the recent findings on the potential of dental stem cells to be used in tissue regeneration. Losingal., 2010). One ofal., 2010; Abou Neal., 2010). It canal., 2010). SC-basal., 2010). In thial., 2010). AccordThe SC types ever investigated for application in regenerative medicine can be divided into two categories: embryonic stem cells (ESCs) and adult stem cells (ASCs). ESCs are pluripotent stem cells originating from the inner cell mass of the blastocyst-stage embryos  they are much higher scalable in the undifferentiated state compared to other SC types  is a more general terminology for pluripotent human embryonic stem (hES) cells with stem cell-like developmental quality dda, 2009). The hEdda, 2009), 3) thedda, 2009). Findindda, 2009; Sternbedda, 2009). The cldda, 2009). While dda, 2009). Previodda, 2009). Using dda, 2009).Dental pulp pluripotent stem cells (DPPSCs or DPSCs) originate from the cranial neural crest in the embryonic stage . The isin-vitro or in-vivo, SHED populations can successfully differentiate into various specialized cell populations such as odontoblasts, osteoblasts, chondrocytes, adipocytes, and neural cells   or the primary teeth are among the most studied SC types and the most valuable source of stem cells in tissue engineering studies and cell-based regenerative medicine therapies . The real., 2016). In 200al., 2016). This ral., 2016). The SHal., 2016). Fortunal., 2016). In 200al., 2011). The odal., 2011). More ral., 2016). In thial., 2016; Rosa etal., 2016). The scal., 2016). Tetracal., 2016). in-vitro , drug developments, and inventing novel therapies  have already shown great promises in animal model trials for regenerative treatment of Parkinson's disease and sickle cell anemia . Human al., 2010), and soal., 2012). The iPal., 2012). The hial., 2012). Despital., 2012). Anotheal., 2012). TherefThe stem cells from the apical papilla (SCAPs) belong to a unique SC line locating at the apical tissues of the growing tooth roots when at least two-thirds of the root have formed  were first obtained from the bone marrow of the iliac crest . HoweveEmersion and recovery of dental diseases such as deterioration, is substantially under the effect of the teeth microenvironment, so that any pathologic alteration that can affect the endogenous MSCs' functions and their regeneration capacity may lead to substantial bone loss. Similarly, transplanted exogenous MSCs are highly influenced by the microenvironment of both donor and recipient niches that creates a major challenge to using MSCs for therapeutic regeneration purposes in diseased microenvironments .Adipose tissue-derived stem cells (ASCs) are considered an abundant MSC source that can be obtained through lipectomy or lipoaspiration from different adipose tissues such as the chin, hips, upper arms, and abdomen . The ASEpithelial stem cells and MSC-like cells are reported to locate within particular niches in dental pulp, dental follicle, and periodontal tissues (ligament stem cells) . Dentalal., 2007). Furtheal., 2007). The \u201ctal., 2018). The dental follicle stem cells (DFSCs) are located within the dental follicle or bilayered Hertwig's epithelial root sheath (HERS); they originate from the ectomesenchymal progenitor cell population and differentiate into cementoblasts or osteoblasts (cementogenesis) during tooth root formation . DFSCs in-vitro and in-vivo studies  are a few mesenchymal progenitor cells within the PDL that remain proliferative, and their differentiation potential provides great promises for SC-based regenerative therapies in dentistry . Yet, tal., 2015). PDLSCsal., 2016). PDLSCsal., 2016; Bright al., 2016). In perGingival mesenchymal stem cells (GMSCs) originate from gingival connective tissue, mostly referred to as lamina propria . The giSalivary gland-derived stem cells (SGSCs) were firstly isolated from a rat submandibular gland . Similain-vitro and in-vivo researches imply the mediation of cell chemo-attraction, differentiation, and proliferation in the GFs capability of increasing tissue regeneration capacity  are natural biological molecules with growth-promoting activities that usually have been initially identified for their functions as mediators and regulators in cellular events . Based al., 2011). Despital., 2011; \u00d6zdemiral., 2011). Next tal., 2011). Anotheal., 2011). EMD isal., 2011). Considal., 2011). Severaal., 2011). BMP-2,al., 2011). Therefin-vivo and the ex-vivo methods. During the in-vivo strategy, natural healing potential of pulp tissue is elevated by injecting BMP proteins or BMP genes, while in the ex-vivo strategy, DPSCs are isolated and differentiated in the laboratory using BMP proteins or BMP genes. The induced SCs are then transplanted into the tooth  are multi-functional growth factors from the transforming growth factor-beta (TGF\u03b2) superfamily . The gral., 2011).In-vivo study of VEGF in immuno-deficient mice has shown its potential for angiogenesis induction and enhances the survival of subcutaneously transplanted dental pulp cells . The moal., 2008).In-situ hybridization technique has shown that four highly homologous genes encode FGFR family isoforms, which differentially express in dental epithelium and mesenchyme  family consists of 18 receptor-binding members that regulate cellular activities  such asal., 2013, 2017). ). ex-vivIn these SC-based therapeutic strategies that use DPSCs for regenerating dentin-pulp complex, GF concentrations in the dentin matrix should be precisely considered, because they are directly in contact with the pulp and consequently, have a significant effect on DPSCs proliferation as the first stage of pulp repair . The de\u03b2-tricalcium phosphate/type I collagen, gelatin sponge, HA disks, etc.) and successfully achieve regenerated periodontium tissues   that pivotally contribute to embedding the tooth in the jaw, maintaining the tooth homeostasis, repairing, feeding, and also harboring progenitor cell populations called PDLSCs . PDLSCsal., 2011; Han et al., 2011; Ninomiyal., 2011). These al., 2011; Tsumanual., 2011). The tral., 2011; Han et al., 2011); howeveal., 2011; Ninomiyal., 2011). As an al., 2011). In anoal., 2011).2+, and actuate the protein kinase C (PKC) cascade. These mechanisms lead to the migration and preferential adhesion of progenitor cells. The cementum-specific proteins (CEMPs) associated with these activities contain cementum-derived growth factor (CDGF), cementum attachment protein (CAP), and cementum protein-1 (CEMP1). The CEMPs' activity induces the differentiation of periodontal ligament stem cells (PDLSCs), dental follicle stem cells (DFSCs), and, adipose-derived stem cells (ADSCs) into cementoblasts and osteoblasts resulting in periodontium regeneration, PDL fibers formation, periodontal angiogenesis, and creation of a cementum-like mineralized extracellular matrix (ECM)  cells are considered to be cementogenetic and able to produce a thin layer of acellular cementum around the root neck. HERS also can cover the lower part of the root by thicker cellular cementum. A challenge in periodontal regeneration researches using cellular intrinsic fiber cementum (CIFC) is achieving an adequate attachment function. The low-quality attachment of the newly-formed cementum in CIFC is due to lack of acellular extrinsic fiber cementum (AEFC), low density of the inserting fibers, and weak interfacial tissue bonding . In damal., 2019). in-vitro floating sphere assays, and two-dimensional (2D) or 3D cultures of salivary gland cells . The pral., 2017). The SGal., 2017). The ocal., 2017; Paz et al., 2017). Entire-tooth loss can lead to several physical and mental sufferings which may extensively compromise the life quality and self-esteem of the patient. Even, in some wildlife species, losing the complete dentition can end their life. The regeneration of the entire tooth has come to the focus of many pieces of research after successful results of regenerating tooth elements. As a major organ, a tooth is constructed from multiple hard and soft tissues. Enamel, dentin, and cementum are the hard tissues that surround the dental pulp as the only vascularized tissue in teeth . A releal., 2008). Beforeal., 2008). In somal., 2008; Botelhoal., 2008). In a cal., 2008). In anoal., 2008). Also, al., 2008; Kim et al., 2008). Then, al., 2008). Considex-vivo cell manipulation makes cell homing more easily adjustable and more potential to be commercialized for clinical processes. Therefore, this under-recognized strategy can be offered as an alternative to cell-delivery-based tooth regeneration . Cell hal. (201060]) use) useex-val. (2010[60]). Inal. (2010). de novo regeneration of the whole tooth structures . Howeveani, 2014). De noval., 2011). Howeveal., 2011). In craal., 2011). Regardal., 2011). In thial., 2011). Anotheal., 2011). Despital., 2011), and thal., 2011). \u03b3 secretion, and promote cytotoxic effects on the virus-infected cells . MSCs cal., 2016). Their al., 2016). MSCs cal., 2016). MSCs cal., 2016). MSCs cal., 2016). MSCs aal., 2016). Regenerative dentistry is increasingly recognized as a state-of-the-art field of medicine among dental clinicians during dental treatments as a procedure of acquiring stem cells  and storing them for potential future autologous treatments. Adult stem cells have been successfully acquired from sources such as oral and maxillofacial regions. For achieving the ultimate purpose, which is craniofacial regeneration, there has remained a long way to be paved for identifying the effective factors in immunomodulatory functions of adult MSCs, BMSCs, and pluripotent stem cells. Such information is required for a more effective outcome of SC-based bone and periodontal tissue restoration, especially for transplanting at the inflamed sites. Knowing the immunomodulatory properties of adult stem cells used in dental and periodontal regeneration is vital for reaching optimal tissue regeneration and controlling the local immune responses during transplantation. Among different strategies in the regenerative dentistry field, tissue engineering and chair-side cellular grafting approaches are more promising because of their more predictable regenerative results. The randomized controlled type of clinical trials with long follow-ups is the most required type of scientific evidence for a comprehensive establishing of reconstructive dental therapeutics. Another necessary field to be elaborated is understanding the biological processes underlying both graft donor and recipient during bone regeneration. Despite all unrecognized aspects of stem cell-based bone and periodontal tissue reconstruction, prosthodontists are increasingly being attracted to stem cell biology because of its successful results as well as the unresolved inefficiencies of implant dentistry. The mechanisms that control the fates and functions of the transplanted stem cells need to be studied. Despite multiple SC-based studies on the dental pulp and periodontal regeneration in animal models, serious considerations, and clinical trials with long-term follow-up are necessary to speed up the translation of basic and preclinical SC-based studies to the dental clinics in terms of regulation, immunity, technology, ethics, and any other possible clinical restriction. These fundamental concerns need to be sorted out to make regenerative treatments practically applicable and beneficial for patients with pathological or injured dental pulp and/or periodontal tissues. Autologous stem cells are already started to be used in some clinical trials for regenerating pulp and periodontal tissues; however, their approval as well as outcomes have not yet been broadcasted and transmitted to the guidelines or indications. Stem cell-based regenerative approaches can help many people around the world who suffer from dentistry complications that strongly warrant further studies. Fortunately, the technologies of modern imaging systems, nanotechnology, and mathematical modeling are increasingly developing and coming to help stem cell-based regenerative studies achieve more reliable and qualitative outcomes in a much shorter time. Mohsen Yazdanian and Hamid Tebyanian  equally contributed as corresponding authors.The authors declare that this work was done by the persons named in this article. Armin Soudi, Mohsen Yazdanian, Reza Ranjbar, Hamid Tebyanian, and Alireza Yazdanian were involved in study design and data collections. Armin Soudi, Mohsen Yazdanian, Reza Ranjbar, Hamid Tebyanian, Elahe Tahmasebi, Ali Keshvad, and Alexander Seifalian were involved in critically reviewing the data and writing the review article.The authors would like to acknowledge the useful comments were given by colleagues at the Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.There was no financial support.This article is a review and does not contain any experiment on humans or animals performed by any of the authors.The authors declare that they have no competing interests."}
+{"text": "Several studies suggested that depression might worsen the clinical outcome of diabetes mellitus; however, such association was confounded by duration of illness and baseline complications. This study aimed to assess whether depression increases the risk of diabetes complications and mortality among incident patients with diabetes.This was a population-based matched cohort study using Taiwan's National Health Insurance Research Database. A total of 38 537 incident patients with diabetes who had depressive disorders and 154 148 incident diabetes patients without depression who were matched by age, sex and cohort entry year were randomly selected. The study endpoint was the development of macrovascular and microvascular complications, all-cause mortality and cause-specific mortality.Among participants, the mean (\u00b1SD) age was 52.61 (\u00b112.45) years, and 39.63% were male. The average duration of follow-up for mortality was 5.5 years, ranging from 0 to 14 years. The adjusted hazard ratios were 1.35  for macrovascular complications and 1.08  for all-cause mortality. However, there was no association of depression with microvascular complications, mortality due to cardiovascular diseases or mortality due to diabetes mellitus. The effect of depression on diabetes complications and mortality was more prominent among young adults than among middle-aged and older adults.Depression was associated with macrovascular complications and all-cause mortality in our patient cohort. However, the magnitude of association was less than that in previous studies. Further research should focus on the benefits and risks of treatment for depression on diabetes outcome. Patients with type 1 diabetes mellitus were identified if their ICD-9 diagnostic code was 250.x1 or 250.x3 and they never used oral antidiabetic drug; the patients who remained were categorised into type 2 diabetes mellitus. The first date of antidiabetic prescription was defined as the cohort entry date. Given that some patients delayed treatment and had complications when diabetes was diagnosed, we excluded those with macro- or microvascular complications before or on the cohort entry date (n\u00a0=\u00a0758\u00a0041). We did not include patients with a diagnosis of schizophrenia or bipolar disorders (n\u00a0=\u00a05664). In addition, those with information errors regarding sex, age or mortality date were also excluded (n\u00a0=\u00a013\u00a0259). The study population included 1\u00a0087\u00a0125 incident patients with diabetes.Using the NHIRD, we identified incident patients with diabetes aged 20 years or more who were firstly prescribed antidiabetic agents and had at least a diagnosis of diabetes mellitus  code: 250.x) between 2001 and 2014 ; major depressive disorder, single episode (ICD-9 code: 296.2x); dysthymic disorder (ICD-9 code: 300.4) or depressive disorder not otherwise specified (ICD-9 code: 311). If a patient has two or more different diagnostic codes of depression, the types of depression were categorised based on the above-mentioned hierarchy. Finally, we identified a total of 38\u00a0537 patients with diabetes who had depressive disorders.We identified 154\u00a0148 eligible comparison participants with diabetes mellitus, who had no preexisting complications and no diagnosis of severe mental illnesses. For each patient with diabetes who had a depressive disorder, we randomly selected four comparison participants matched by age (year of birth), sex and the cohort entry year. The comparison participants were censored if they were diagnosed with a depressive disorder after the cohort entry date. The details of the selection procedure are shown in et al., et al., The study outcomes included macro- and microvascular diabetes complications, which were identified based on ICD-9-CM diagnostic and procedural codes and the NHI procedural codes from outpatient and inpatient claims records. Macrovascular complications included hospitalisation for acute coronary syndrome (ICD-9-CM: 410.x-411.x) and stroke (ICD-9-CM: 430.x-438.x). Validation of the inpatient diagnosis of the acute coronary syndrome and stroke has been well documented : I00\u2013I99) or diabetes . To test the sensitivity of our methods, we included unnatural death  and suicide .Patients' demographic variables included age, sex and the year of cohort entry. The duration between the first diagnosis of diabetes and the initiation of pharmacotherapy was also measured and categorised into <1 and \u2a7e1 year. Potential confounders, which were associated with both diabetes complications and depressive disorders, were assessed in the year preceding the cohort entry date, which included comorbid conditions of hypertension (ICD-9 code: 401.x-405.x), dyslipidemia (ICD-9 code: 272.x), chronic pulmonary disease , chronic liver disease  and alcohol- and substance-related disorders . In addition, medication use that reflected underlying medical conditions was assessed, including angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) (ATC code: C09), beta blockers (ATC code: C07), calcium channel blockers (ATC code: C08), lipid-lowering agents (ATC code: C10) and nonsteroidal anti-inflammatory drugs (ATC code: M10).We calculated the incidence of macro- and microvascular diabetes complications and mortality rates based on the event number divided by follow-up person-years. Multivariate Cox proportional hazards models were used with adjustment for the abovementioned confounders, to estimate the hazard ratios (HRs) of depressive disorders for the study outcomes. Subgroup analyses were conducted to evaluate whether the risks of depression for diabetes complications and mortality were modified by types of depression, age, sex and duration between diabetes diagnosis and initiation of pharmacotherapy.post-hoc analyses to evaluate whether there were differences in the quality of diabetes care during the follow-up period between patients who had diabetes, with and without depressive disorder. Indicators of care quality included medication adherence for antidiabetic drugs, frequency of receiving blood sugar testing (HbA1c or fasting blood sugar), lipid profiles, serum creatinine, retina examinations and electrocardiograms during the follow-up period. Antidiabetic drug adherence was measured using the medication possession ratio (MPR), which was defined as the total days of prescribed antidiabetic medication supply divided by the follow-up period. Antidiabetic drug adherence was categorised as poor, irregular and good, based on the MPR .The quality of diabetes care might be a mediator in the association of depression with diabetes complications and mortality; therefore, we did not include these variables in our model. We used p values <0.05.All statistical analyses were conducted using SAS version 9.4 . The statistical significance of relationships was assessed using 95% confidence intervals (CI) or There were 38\u00a0537 patients with diabetes who had depressive disorders and 154\u00a0148 patients with diabetes with no depressive disorders, as comparison participants. The average follow-up period was 5.5 years (ranging from 0 to 14 years). The mean (\u00b1SD) age of participants was 52.61 (\u00b112.45) years, and 39.63% were male. Most of the patients have type 2 diabetes mellitus 99.4%. Among patients with depressive disorders, 26.21% had major depressive disorder, recurrent episode, 15.96% had major depressive disorder, single episode; 48.11% had dysthymia and 9.72% had depressive disorder, not otherwhere classified. Patients with diabetes who had depressive disorders had a higher proportion of comorbid conditions and medication use, except for ACEI/ARB use. The percentage of duration between diabetes diagnosis and initiation of pharmacotherapy \u2a7e1 year was 17% for patients with diabetes and depression and 24% for comparison subjects see .Table 1v. 2.29 per 1000 person-years), unnatural mortality (2.46 v. 0.77 per 1000 person-years), suicide (1.41 v. 0.27 per 1000 persona-years) and all-cause mortality (21.91 v. 15.96 per 1000 person-years) between patients who had diabetes, with and without depressive disorders. However, there was no difference with respect to microvascular complications and mortality due to diabetes mellitus  for comparison participants. The same was true for the crude incidence of mortality due to cardiovascular diseases , unnatural mortality , suicide  and all-cause mortality  than comparison participants. However, there was no statistically significant difference in microvascular complications and death owing to cardiovascular diseases. We found that depression was associated with a reduced risk of death owing to diabetes .Table 3In subgroup analyses, we found that the magnitude of associations with developing macrovascular complications, unnatural death, suicide and all-cause mortality was higher among those with major depression with recurrent episode than those with dysthymia or depressive disorder, not otherwise specified (the 95% CIs were not overlapping). In terms of the modifying effect of sex, we found that the associations between depression and developing macrovascular complications and unnatural mortality were stronger among women than among men. Otherwise, sex did not have a modifying effect on the incidence of microvascular complications and all-cause and other cause-specific mortality. In terms of age, there were effect modifications on diabetes complications and mortality. HRs in young adults (aged 20\u201344 years) with depressive disorders for all diabetes complications, all-cause mortality and all cause-specific mortality were higher than those among middle-aged (aged 45\u201364 years) and older (aged 65 years or more) adults. Furthermore, we found that duration between diabetes diagnosis and initiation of pharmacotherapy had a significant modifying effect on the associations with microvascular complications, diabetes-related death and all cause-mortality; the associations were stronger among patients with duration \u2a7e1 year than those with duration >1 year.Assessment of the quality of diabetes care showed that patients with diabetes who had depressive disorders had slightly higher proportions of good antidiabetic compliance and higher rates of undergoing screening tests; however, the difference was quite small .Table 4In this study, we found that depression was associated with an increased risk of macrovascular complications, unnatural mortality, suicide and all-cause mortality among patients with incident diabetes mellitus. In contrast, there was no association between microvascular complications and mortality owing to diabetes mellitus and cardiovascular diseases. We found that age had a multiplicative effect modification on such associations. The magnitude of association was higher among young adults than middle-aged and older adults. Regarding the quality of care, we found that patients with diabetes who had depressive disorders had slightly better antidiabetic medication compliance and a slightly higher proportion of undergoing screening tests.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The findings of a positive association between depression and macrovascular complications were consistent with those of several previous studies (Black et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., We also found that depression was related to an increased all-cause mortality rate; however, the magnitude was smaller than that found in previous studies (Black et al., et al., et al., et al., et al., et al., et al., et al., We found there was no association between depression and microvascular complications. This finding was against several studies (Black et al., In the subgroup analysis, major depression with recurrent episodes had greater associations with macrovascular complications and all-cause mortality than mild depression. These severity-response relationships further support the hypothesis between depression and diabetes complications. In addition, we found that women had a greater risk for mortality and macrovascular complications associated with depression than men. Previous studies have shown that the effect of diabetes on the risk of coronary disease is significantly greater for women than men (Lee et al., et al., Several limitations should be considered in this study. First, we identified patients with depressive disorders based on claims records. However, some patients with depression were not diagnosed or treated and could be misclassified into the comparison group; therefore, it would introduce bias towards the null. The effect of depression on diabetes complications and mortality might be underestimated. The duration between the diagnosis of depression and diabetes mellitus was unknown; therefore, we could not explore the effect of duration of depression on the study association. Second, only a few patients with type 1 diabetes mellitus were included because the age of onset was generally before 20 years. Our findings could not be concluded for those with type 1 diabetes mellitus due to the limited statistical power. Third, the accuracy of the diagnosis of microvascular complications of diabetes was not yet validated in the NHIRD; however, we used procedural claims data to confirm ambulatory diagnostic codes, or we only used inpatient claims data to minimise the possibility of misclassification. Fourth, several important factors, such as smoking, body weight, exercise, diet control and family history of depression and/or diabetes are not available in the NHIRD. Although we tried to use chronic pulmonary disease, dyslipidemia, hypertension and alcohol or substance use disorders as proxy measures for smoking, obesity and unhealthy lifestyle behaviours, there were still residual confounding effects. Especially, the lifestyle behaviours are time-variant and would be influenced by depression; therefore, these factors need to be adjusted by advanced methodology (Fewell The strengths of this study are the novelty of analysing the associations between depression and diabetes complications among incident patients with diabetes, the elimination of confounding by duration of illness and pre-existing complications, the use of a nationwide representative cohort with clear temporal relationships, a very large sample and a well-defined method for identifying complications of diabetes.In conclusions, we found that patients with diabetes mellitus had a higher rate of macrovascular complications and all-cause mortality when they had comorbid depressive disorders. However, we found a lower adverse effect of depression than the findings of previous studies. This might be owing to the inclusion in our study sample of only incident patients with diabetes, thereby eliminating confounding owing to the duration of illness and preexisting complications. Depression is a modifiable risk factor of diabetes outcome. Further research should focus on evaluating the effect of depression treatment on advanced complications and mortality among patients with diabetes mellitus."}
+{"text": "Protein quality control (PQC) systems play essential roles in the recognition, refolding and clearance of aberrant proteins, thus ensuring cellular protein homeostasis, or proteostasis. Especially, continued proliferation and differentiation of stem cells require a high rate of translation; therefore, accurate PQC systems are essential to maintain stem cell function. Growing evidence suggested crucial roles of PQC systems in regulating the stemness and differentiation of stem cells. This review focuses on current knowledge regarding the components of the proteostasis network in stem cells, and the importance of proteostasis in maintaining stem cell identity and regenerative functions. A complete understanding of this process might uncover potential applications in aging intervention and aging-related diseases. Stem cells serve as the origin of a multicellular organism. They can divide to give rise to daughter cells that remain as stem cells or become differentiated with a specific function. The multi-differentiation potential gives stem cells unparalleled advantages in regenerative medicine. Originally, stem cells can be categorized into two main groups: embryonic stem cells (ESCs) and adult stem cells (ASCs). Yet with the development of reprogramming technologies, somatic cells can also be reprogrammed into ESC-like cells, termed as induced pluripotent stem cells (iPSCs). Collectively, ESCs and iPSCs are referred to as pluripotent stem cells (PSCs) because of their high capacity for self-renewal and their ability for multipotent differentiation, offering far-reaching potential in disease modeling and transplant therapies , while such high levels of expression diminish during differentiation  is activated to cope with misfolded proteins, either facilitating their proper re-folding or delivering them for degradation via the proteasome or autophagy pathways  is a central cellular organelle in proteostasis. It is involved in the synthesis, modification, and delivery of proteins to their target sites in the secretory pathway and the extracellular space  is a central regulator, as it plays a vital role in protein folding, ER calcium binding, and regulating the activities of transmembrane ER stress sensors. Consistently, Grp78 homozygous knockout mouse embryos failed to hatch from zona pellucida, and exhibited proliferation defects and extremely high levels of apoptosis in the inner cell mass, demonstrating that Grp78 is crucial for embryonic cell growth and pluripotent cell survival  enhances ER protein folding, thereby increasing the repopulation capacity of hematopoietic stem cells (HSCs) in xenograft assays, connecting the UPR to the maintenance of HSC properties  also plays an important role in the maintenance of stem cell characteristics and homeostasis  increase  plays a crucial role in the self-renewal and differentiation of HSCs and NSCs (Matsumoto et al., Sel1L, reduced self-renewal and resulted in HSC depletion (Liu et al., Taken together, the UPS is essential for maintaining stemness in both PSCs and ASCs, and dysfunction of the UPS may contribute to perturbed stem cell function and fate control. The main differences between UPS-related cellular reactions in stem cells and those in differentiated cells were summarized in Fig. Misfolded and aggregated proteins can also be degraded by a separate autophagy-mediated pathway. Autophagy is a highly conserved intracellular process, in which damaged or unwanted proteins, cytosolic fractions, and organelles are degraded by the lysosome (He and Klionsky, Despite extensive research on autophagy in somatic cell physiology, relatively little is known about the roles of autophagy in stem cell biology. Recent studies report that autophagy is crucial for ESCs and for various ASCs, i.e. HSCs, MSCs, NSCs, and gut stem cells, although with different requirements for its activity (He et al., Apg5 in mESCs causes defects in autophagosome formation and consequent accumulation of proteins in the cytoplasm (Mizushima et al., beclin-1, a mammalian ortholog of the yeast autophagy-related gene 6, die early in embryogenesis, and the autophagic response in mESCs is significantly altered as a result of the beclin-1 deficiency (Yue et al., Ambra1, an autophagy gene, are impaired for neuronal generation (Vazquez et al., In contrast to the high levels of proteasome activity observed during self-renewal, high levels of\u00a0autophagy activity was exhibited during early differentiation of ESCs\u00a0and NSCs (Tra et al., Atg7 or Fip200 in the hematopoietic system results in the loss of normal HSC function and death of the mice, suggesting that both autophagy genes are necessary for adult HSC maintenance (Liu et al., Atg3 or Atg7 can inactivate autophagy and restore the expression of 6-photofructo-2-kinase/frutose-2,6-biphosphatase 3, which can in turn restart cell proliferation (Flynn et al., Atg5 plays a key role in the maintenance of HSCs, and the reconstitution ability of Atg5-deficient HSCs in bone marrow of chimeric mice is significantly impaired (Jung et al., Atg5, Atg7, and Atg12 can mediate the self-renewal, differentiation, and regeneration of the muscle and hematopoietic system, and the overexpression of Atg7 can rejuvenate aged satellite cells and HSCs and restore their regeneration ability (Garc\u00eda-Prat et al., Different from ESC sand NSCs, in which autophagy activity is required during differentiation, autophagy activity is decreased during the differentiation of MSCs, HSCs, dermal stem cells, and epiblast stem cells (Mortensen et al., Likewise, autophagy is essential for iPSC reprogramming. A distinguishing feature of iPSCs is that the existing number and mass of mitochondria in the somatic cell origins are strikingly diminished during reprogramming. Hence, their metabolic pattern is switched from oxidative phosphorylation to glycolysis and this is considered as an important mechanism in iPSC reprogramming. ATG3-dependent autophagy can act as an executor for mitochondrial clearance during somatic cell reprogramming (Liu et al., Oct4 mRNA (Bradley et al., Previous studies have revealed that genomic and epigenetic stability is essential for stem cell identity. Yet recent years have seen increasing evidence that supported a pivotal role for proteostasis in regulating pluripotency and differentiation of stem cells as well. Under physiological conditions, the proteostasis network is equipped with high versatility in response to distinct stimuli (Balch et al., Furthermore, defects in proteostasis lead to the dysfunction of somatic stem cells, and eventually result in impairment of organismal development and aging, which encourages studies of PQC in search of treatment of aging and aging-related diseases. Pathological conditions, environmental and metabolic stresses, and aging contribute to the production of aberrant proteins in addition to the normal and physiological sources of misfolded proteins (Haigis and Yankner, Study of the regulatory network in proteostasis will also provide new aspects in understanding embryonic development, aging, and pathogenesis. For instance, misfolded proteins have been linked to many neurodegenerative diseases such as Huntington\u2019s disease, Parkinson\u2019s disease, and Alzheimer\u2019s disease, in which aberrant protein aggregates overwhelm the cellular clearance machinery (Bosco et al.,"}
+{"text": "Small interfering RNA (siRNA) is a class of nucleic acid-based drugs (NABDs) able to block gene expression by interaction with mRNA before its translation. Small interfering RNAs (siRNAs) therefore present extraordinary potential due to their ability to silence the expression of disease-causing genes. Even if the mechanism of action has been successfully investigated (Nobel Prize in Physiology or Medicine 2006 to Andrew Z. Fire and Craig C. Mello \u201cfor their discovery of RNA interference \u2013 gene silencing by double-stranded RNA\u201d) and siRNA drugs can be candidates to fight, in principle, any diseases. However, the practice of siRNA-based therapies is restricted because of relevant inconveniences. SiRNAs are negatively charged large macromolecules and this entails difficult crossing of cell membranes; they undergo rapid degradation by plasma enzymes and are easily subjected to fast hepatic/renal clearance sequestration. These features seriously hinder siRNAs\u2019 usability in therapeutics. Currently, the scientific community focused on gene therapy research is developing studies to overcome the obstacles related to siRNA\u2019s features.Pharmaceutics titled \u201cDrug Delivery of siRNA Therapeutics\u201d aims to present the state of the art of siRNA delivery, embracing investigation strategies of international research groups with different experiences and skills. The Special Issue will thus be devoted to presenting the current connections between experimental and in silico approaches for therapies based on siRNA delivery, accounting for all the most promising techniques based on liposomes, polymeric and inorganic nanoparticles, aptamers, chemical modification of siRNAs, and so on.This Special Issue of Reviews (five) and research papers (eight) constitute this Special Issue. A representative international scientific community focused on gene-therapies researches is represented by 12 different countries involving 75 scientists with multidisciplinary skills.In the reviews, different research activities cover several disciplines of investigation mainly focused on approaches of siRNA therapies to combat several kinds of cancer in laboratory conditions and the current state of siRNA\u2013lipid delivery systems in clinical trials.In Marson et al.,  studies Research papers deal with experimental new strategies to design and develop innovative suitable and effective vectors for siRNA delivery such as liposomes, dendrimers, aptamers, polymer\u2013lipid systems, polymeric, co-polymeric and magnetic nanoparticles.3O4 nanoparticles prepared for the delivery of therapeutic siRNAs to contrast oral cancer cells\u2019 growth. Craparo et al., [Stiina Kontturi et al.,  aimed th et al.,  studied"}
+{"text": "The factors associated with suicidal ideation among adolescents have been extensively characterised, but the mechanisms underlying the complexities of the relationship between experiences of childhood trauma and suicidal ideation have been less studied. This study examined the direct effect of childhood trauma on suicidal ideation on the one hand and whether school bullying victimisation and Internet addiction mediate the association between childhood trauma and suicidal ideation on the other hand.This school-based mental health survey was carried out in Qinghai Province in Northwest China in December 2019. We employed standardised questionnaires to collect sociodemographic and target mental health outcomes. Hierarchical multiple logistic regression and structural equation modelling were performed for the data analyses.p < 0.001). School bullying victimisation and Internet addiction mediated the relationship between childhood trauma and suicidal ideation. Internet addiction played a mediating role between school bullying and suicidal ideation.This study included 5864 university students. The prevalence of lifetime suicidal ideation and Internet addiction were 34.7% and 21.4%, respectively. Overall, 16.4% and 11.4% of participants reported experiences of childhood trauma and school bullying victimisation, respectively. There were direct effects of childhood trauma, school bullying victimisation and Internet addiction on suicidal ideation. The total effect of childhood trauma on suicidal ideation was 0.201 (Childhood trauma had both direct and indirect effects on suicidal ideation; these effects were mediated by school bullying victimisation and Internet addiction in Chinese university students. Elucidating these relationships will therefore be useful in developing and implementing more targeted interventions and strategies to improve the mental well-being of Chinese university students. In each university or college, a stratified (according to the majors) random sampling method was used to select the classes, and cluster sampling was then used in each class.Questionnaires were distributed to participants and collected after completion by our study investigators who were uniformly trained prior to the on-site survey. Students who were fully enrolled in the universities were included. A total of 6500 questionnaires were distributed, and 6200 questionnaires were returned, yielding a response rate of 95.4%. Students from Qinghai University, Qinghai Nationalities University, Qinghai Institute Of Health Sciences and Xining Urban Vocational & Technical College accounted for 30.0%, 27.5%, 26.9% and 15.7% of the sample, respectively. Finally, data from 5864 participants were analysed in this study after cases with \u2a7e 20% missing data were deleted.et al., The Ethics Committee of the Medical College of Qinghai University approved the study protocol. The survey process followed the principles of anonymity and voluntariness, and all university students involved in this survey provided the informed consent. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to report this study , sex , place of residence prior to entering the university (non-plateau/plateau area), ethnicity (Han/others), self-perceived family economic level , only-child status (no/yes), self-perceived weight , self-perceived health , whether in a dating relationship (no/yes) and relationships with classmates, teachers and family (poor/fair/good), was collected.et al., et al., et al., Suicidal ideation (SI) was assessed using the fourth and fifth items of the Beck Scale for Suicidal Ideation (BSS)  , which has satisfactory psychometric properties (Cronbach's ) Young, , 2008, hn) and percentage (%) or the mean and standard deviation (s.d.), as appropriate. Hierarchical multiple logistic regression was carried out to examine the associations between experiences of childhood trauma and suicidal ideation. In step 1, the model was unadjusted by setting suicidal ideation as the dependent variable and childhood trauma as the independent variable. In step 2, adjustments were made for age (years), sex, place of residence prior to entering university, ethnicity, self-perceived family economic level, only-child status, self-perceived weight, self-perceived health status, whether in a dating relationship, relationships with classmates, relationships with teachers or relationships with family. In step 3, school bullying victimisation was added, and Internet addiction was added in the last step. At each step, the R2 change (\u0394R2) was used to indicate the predictive power of each group of predictor(s) when adjustments were made for previous predictor(s). A post hoc analysis was performed by reversing steps 3 and 4. The results were expressed with odds ratios (ORs) and their 95% confidence intervals (CIs).The sociodemographic and clinical characteristics were described with the number  .We performed a structural equation model (SEM) to evaluate the hypothesis of the mediating effects of Internet addiction and school bullying victimisation in the relationship between childhood trauma and suicide ideation. Sociodemographic and clinical characteristics that showed statistical significance in step 4 in hierarchical multiple logistic regression were adjusted in the SEM. We used the R lavaan package Rosseel, , and a cs.d.\u00a0=\u00a01.52) were included in this study. Among the participants, 62.4% were (3657) female, 44.8% (2629) were of Han ethnicity and 79.4% (4656) lived in high-altitude areas prior to entering the university. A total of 5864 university students with an average age of 19.9 years  and 21.4% , respectively. Overall, 16.4%  and 11.4%  of university students reported experiences of childhood trauma and school bullying, respectively.R2\u00a0=\u00a00.201, \u0394R2\u00a0=\u00a00.148). School bullying victimisation, tested in step 3, captured an additional 0.8% of variance in suicidal ideation beyond the effects of basic sociodemographic and clinical factors and the experiences of childhood trauma . When Internet addiction was added in the last step, it yielded an additional 0.8% of the variance , showing that experiences of childhood trauma , Internet addiction  and school bullying victimisation  were positively associated with suicidal ideation. When we reversed the order of entry in the regression model, entering Internet addiction in the third step, school bullying victimisation predicted suicide ideation over and above Internet addiction in the fourth step .\u03b2\u00a0=\u00a00.160, p\u00a0<\u00a00.001), school bullying victimisation  and Internet addiction  on suicidal ideation. The total effect of childhood trauma on suicidal ideation was 0.201 (p\u00a0<\u00a00.001). The final SEM also revealed the mediating effects of school bullying victimisation and Internet addiction on the association between childhood trauma and suicidal ideation . School bullying victimisation also had an indirect effect on suicidal ideation which was mediated by Internet addiction . Goodness-of-fit indices  indicated satisfactory fit of the SEM.This study, based on a sample of 5864 university students from parts of the Chinese Tibetan Plateau (i.e. Qinghai Province), allowed us to identify the following: (1) our mental health problems of interest were common among Chinese university students; (2) childhood trauma, school bullying victimisation and Internet addiction had associations with suicidal ideation among the population of interest; (3) there were indirect effects of childhood trauma on suicidal ideation, which were mediated by school bullying victimisation and Internet addiction; and (4) Internet addiction played a mediating role in the relationship between school bullying victimisation and suicidal ideation.et al., et al., et al., et al., et al., et al., At present, suicidal ideation among adolescents is widely concerned around the world (Mortier et al., et al., et al., et al., et al., After adjustments were made for the control variables, hierarchical regression models indicated that childhood trauma, school bullying victimisation and Internet addiction increased the likelihood of having suicidal ideation. We thus conducted SEM by adjusting for sociodemographic factors, personal health factors and dating status, and we identified the direct effect as well as the indirect effect of childhood trauma on suicidal ideation, the latter of which was mediated by school bullying victimisation. Consistently, the direct effect of childhood trauma on suicidal ideation was demonstrated in another Chinese study including 922 freshmen (Shi et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Internet addiction also played a mediating role in the relationship between childhood trauma and suicidal ideation. Childhood trauma and its subtypes, such as emotional, physical and sexual abuse, were reported as factors associated with Internet addiction or Internet gaming disorders in different populations (Dalbudak et al., et al., The findings underscore the importance and necessity of implementing suicide intervention strategies and preventing adverse childhood events and invisible or visible on-campus bullying and Internet addiction. Professional levels of psychological counselling and guidance, mental health education courses, campus safety management and other interventions should be considered and practically implemented (Jimerson and Furlong, In conclusion, this study extended the findings of previous literature by elucidating the direct effects of childhood trauma, school bullying victimisation and Internet addiction on suicidal ideation among university students, as well as the mediating roles of school bullying victimisation and Internet addiction in the relationship between childhood trauma and suicidal ideation. Integrally targeted interventions and strategies that can eliminate and alleviate school bullying events, Internet addiction and the influences of childhood trauma should be developed and implemented to reduce the risk of suicidal ideation and improve the comprehensive mental well-being of Chinese university students."}
+{"text": "P < 0.01) and a significant dilution effect (P < 0.01). When considering a subsample of horses treated with macrocyclic lactones only, young horses grazed with cattle had 50% fewer strongyle eggs excreted in their faeces than horses grazed in equine-only pastures (P < 0.01). This is the first evidence of the benefits of mixed grazing with cattle as an alternative to control strongyle infection in horses, although this promising alternative remains largely unknown by horse breeders.Strongyle infection is an important issue in horse breeding. It impairs horse health and performance, with young horses being the most sensitive. Strongyle control has long relied on the systematic use of chemical treatments. However, expanding anthelmintic resistance among strongyles calls for alternative options. Mixed grazing is assumed to reduce strongyle load on the pasture as the result of a dilution effect. This has been shown in small ruminants grazing with cattle, but the putative benefits of co-grazing between horses and cattle have not yet been evaluated. Here, we conducted field surveys and face-to-face interviews on 44 farms from two contrasted saddle-horse production areas, Normandy and northern Massif Central, to compare equine strongyle management practices between specialized systems and mixed horse-cattle systems. Our goals were (i) to quantify breeders\u2019 awareness of the putative benefits associated with the co-grazing of horses and cattle, (ii) to establish whether mixed farming was associated with different strongyle management strategies and (iii) to test whether strongyle egg excretion was reduced in horses grazed with beef cattle. Every breeder relied on systematic calendar treatments, and only 8 out of the 23 mixed breeders were aware that co-grazing of horses with cattle could be used as part of their strongyle control strategy. Management practices were similar across both systems in Normandy. In Massif Central, mixed breeders formed a distinct cluster from their specialized counterparts: deworming was less frequent and stocking density was higher in mixed farms, while specialized breeders seemed more willing to integrate herd and plot management into control strategies. Faecal egg counts measured in horses from Massif Central were significantly reduced when horses were grazed with cattle. This was the result of an increased reliance on macrocyclic lactones in mixed farms ( Horse breeders are increasingly challenged by drug resistance when controlling strongyle infection. Although largely unknown by mixed breeders, alternate grazing or co-grazing with horses and cattle is assumed to reduce strongyle load in pastures as the result of a dilution effect. Here, we reveal a decrease in strongyle egg excretion in young saddle horses grazing with beef cattle. This dilution effect is likely to decrease treatment frequency and thus veterinary costs and environmental side-effects of drug metabolites on dung beetle assemblages.et al., et al., et al., et al., Parasitic infection by strongyle nematodes (mostly cyathostomins) is common in grazing horses. High levels of infection affect horse welfare and performance and can eventually lead to death  to establish if horse breeders integrate herd and grassland management as part of their strongyle control strategy, (ii) to analyse if horse deworming and grazing management differ between mixed horse-cattle and specialized horse farms, and (iii) to quantify strongyle egg excretion in both types of system to determine putative benefits of co-grazing horses with beef cattle.The study was conducted on 44 farms producing saddle horses with or without beef cattle that were selected according to three additional criteria: at least three mares were kept on a farm, farms were located in lowlands  and grasslands represented more than 80% of the agricultural area. Normandy and northern Massif Central were considered as two contrasted case studies: in Normandy, high-level sport horses are bred and grazed on productive grasslands, while in Massif Central, horses are mainly bred for leisure and grazed on less productive grasslands.Face-to-face interviews were carried out on 23 farms from Normandy  and 21 farms from northern Massif Central . Interviews (1 to 2.5-h long according to farm size and the complexity of pasture management) focused on farmer beliefs and practices related to grazing, plot cleaning and animal health management.(i)LU) per hectare, intermediate between 0.6 and 1.0 LU/ha and high between 1.0 and 1.4 LU/ha . To obtain three balanced classes for statistical analyses, annual mean stocking rate was considered low between 0.2 and 0.6 livestock unit ((ii)The proportion of total grassland area in both cut and grazed management  was partitioned into three categories: lower than 30%, intermediate (between 30% and 45%) or higher than 45% of grassland area. Grazing horses on mixed grasslands can strongly decrease numbers of infective larvae in pastures none when strongyle control only relied on a systematic calendar treatment; yes_livestock when additional practices were based on herd management, for example, reducing stocking rate ); (iii) the person in charge of parasite control  and (iv) the anthelmintic class given to young horses and mares.The implemented deworming strategy was also addressed during the interviews. Four variables were covered: (i) the number of anthelmintic treatments administered to young horses , or mares ; (ii) the strategy used for deworming , or systematic plus additional treatments based on faecal egg counts (ERP) indeed varies across anthelmintic classes . A farm was considered of excellent genetic merit when at least one of the mares was registered with a score higher than +9 for one of the genetic indices. A farm was considered of high genetic merit when at least one of the mares was registered with a positive score for one index. All other farms were considered to produce horses for leisure.To test whether FEC was reduced in horses from mixed systems, faeces were sampled in autumn in horses at greater risk of infection (18 to 42 months old). For logistical reasons and according to breeders\u2019 willingness to participate, the sampling took place on Massif Central farms only.n = 23 horses, 6 farms) or alone in a specialized farm . Fresh individual faeces were collected on the ground and kept at 4\u00b0C for less than 48 h; eggs were counted (test sensitivity: 15 eggs/g) at the official local veterinary services (DDCSPP du Puy de D\u00f4me), based on sedimentation and concentration by a flotation technique  on farming system (two classes), the number of treatments (three classes), the proportion of time each horse spent on mixed grasslands, grassland stocking rate and time since the end of the ERP. A variable selection procedure was implemented with the stepAIC function of the MASS package that retained the farming system, the time since the end of ERP and stocking rate.To establish whether FEC was significantly associated with the farming system, a linear regression was performed. We built a full model regressing FEC  and mixed systems (n = 19). For all statistical analyses, effects were considered significant when the P-value was lower than 0.05.In a second analysis, we considered a subsample of 28 horses treated with macrocyclic lactones only. A two-sample n = 33 farms; moxidectin n = 22 farms). Additional herd and grassland management practices were implemented and considered as part of breeders\u2019 strongyle control strategy in a total of 18 farms, 11 from Massif Central and 7 from Normandy.Face-to-face interviews were also undertaken to evaluate the general beliefs and awareness regarding parasite control management in both mixed and specialized systems. Strongyle control relied on a systematic calendar treatment in all 44 farms surveyed. The most commonly used anthelmintics were fenbendazole (in 36 farms) and macrocyclic lactones  and included pasture liming (n = 5), use of rotary slashers (n = 5) or dung-spreading harrows (n = 4), avoiding rapidly returning herds to the same pasture (n = 3) and removing dung from pastures (n = 1). The sum is higher than 14, as some breeders used 2 of these grassland management practices.Plot-cleaning practices were the most common , two-thirds of which were mixed cattle-horse farms and one-third specialized horse farms. Remaining clusters, named MC-mix and MC-spe, were mostly composed of mixed (70%) or specialized (83%) farms from northern Massif Central, respectively. This suggests that practices were different between mixed and specialized systems in Massif Central, whereas practices were much more similar across systems in Normandy.Following the analysis of breeders\u2019 awareness, we attempted to summarize their strategies in order to establish whether mixed farming systems were associated with particular practices. Multiple correspondence analysis applied to management practice data revealed three clusters separated along two axes explaining 13.0% and 10.6% of total variance, respectively. The first cluster, named Nor, included 22 farms, mainly in Normandy  but not stocking rate . Farming system was also associated with a significant difference in FEC , with horses from the mixed farming systems excreting half as many eggs than their counterparts from specialized farms.FEC was conducted on 46 horses from mixed and specialized farms to establish whether farming system was impacting horse excretion and what variables underpinned this variation. Our regression model found that time since the end of ERP was significantly driving observed variation in FEC (P < 0.01; Figure A second analysis was performed on a subsample of 28 horses last treated with macrocyclic lactones. It confirmed that young horses grazed with cattle had 50% fewer strongyle eggs excreted in their faeces than horses grazed in equine-only pastures (et al., et al., et al., The purpose of our study was to compare specialized saddle horse farms with mixed horse-cattle farms and to establish whether any difference in parasite control could be found. The limited awareness of the putative beneficial effects associated with the co-grazing strategy was striking, especially because mixed grazing is a key pillar of integrated parasite management in agroecological grassland-based systems (Dumont et al., et al., et al., et al. This lack of awareness regarding mixed grazing was also associated with the widespread use of fenbendazole, despite high prevalence of resistant strongyle populations in France (Traversa et al., et al., A key finding from our surveys is that specialized horse breeders from Massif Central seemed more willing than the mixed breeders to integrate herd and plot management into their control strategies. In these farms, the proportion of grasslands under both cut and grazed management was also the highest, and early cuts under mixed management are known to strongly decrease the number of infective larvae in pastures (Martin-Rosset, et al., et al., et al., et al., et al., et al., While our results are thus likely influenced by regional context, they also provide the first indication that the co-grazing of horses and cattle has beneficial effect for equine strongyle control. Our results are consistent with previous observations in ruminant farming, showing that simultaneous grazing by cattle and sheep (Southcott and Barger, We provide the first evidence of a decrease in the parasite burdens of young saddle horses grazing the same pastures as cattle in mixed farms, compared with horses grazing alone in specialized systems. This opens a promising alternative for controlling horse parasitic infection that remains largely unknown by horse breeders. Association between horses and cattle at pasture is facilitated through the use of the same type of fencing for the two species, with possible limitations due to injury risks which could be solved through alternate grazing. This suggests a diversity of more sustainable agroecological parasite management strategies in horse farms as alternatives to repeated chemical treatment, which raises serious resistance issues."}
+{"text": "The current status and ongoing development of 3D electron diffraction and microcrystal electron diffraction in macromolecular crystallography are reviewed. Microcrystal electron diffraction (MicroED) has recently emerged as a promising method for macromolecular structure determination in structural biology. Since the first protein structure was determined in 2013, the method has been evolving rapidly. Several protein structures have been determined and various studies indicate that MicroED is capable of (i) revealing atomic structures with charges, (ii) solving new protein structures by molecular replacement, (iii) visualizing ligand-binding interactions and (iv) determining membrane-protein structures from microcrystals embedded in lipidic mesophases. However, further development and optimization is required to make MicroED experiments more accurate and more accessible to the structural biology community. Here, we provide an overview of the current status of the field, and highlight the ongoing development, to provide an indication of where the field may be going in the coming years. We anticipate that MicroED will become a robust method for macromolecular structure determination, complementing existing methods in structural biology. However, the rate-limiting step in macromolecular crystallography inhibiting structure determination is often crystallization  can make use of such small protein microcrystals by outrunning the radiation damage using a diffraction-before-destruction scheme. SFX data are collected using an X-ray free-electron laser (XFEL), which generates brief and highly intense X-ray pulses on a femtosecond timescale, taking single still diffraction snapshots of partial reflections from individual hydrated microcrystals before the sample is destroyed micrometre-sized crystals can be obtained from proteins that are well below 50\u2005kDa  was determined in 2013  occur more frequently with increasing crystal thickness and will affect structure determination  milling  cannot be separated from kinematic scattering. Because of dynamical scattering, weaker reflections on average will appear more intense. As a result, the first-order kinematic approximation that is used in structure refinement is no longer valid. An effective way to minimize dynamical scattering is to carefully select thin crystals  for data collection. The crystal thickness ideally should not exceed much more than about 200\u2005nm (Subramanian 4.3.et al., 2018et al., 1999et al., 2015et al., 1996et al., 1999et al., 2015Electrons are charged particles and interact with the electrostatic potential of the crystal (Cowley, 19954.4.ab initio phasing of short peptide fragments (Sawaya et al., 2016et al., 2018et al., 2020de novo phasing of protein structures using electron diffraction has not yet been achieved. The anomalous signal may be too insignificant for experimental phasing using anomalous dispersion (Cowley, 1995To date, all structural models of proteins determined by MicroED have been phased using molecular replacement. Direct methods can be used for electron diffraction data (Dorset & Hauptman, 19764.5.et al., 1999et al., 2005et al., 1984et al., 1990et al., 1992et al., 1996et al., 1998et al., 2003et al., 2013et al., 2020In 2D electron crystallography, reconstructions from TEM images can be combined with high-resolution electron diffraction patterns for structure determination (Unwin & Henderson, 19754.6.et al., 2019et al., 2020et al., 2018et al., 2020et al., 2019et al., 2020\u2212\u2005\u00c5\u22122 was found to have an optimal signal-to-noise ratio (B\u00fccker et al., 2020In macromolecular crystallography, the total electron dose limits the maximum attainable resolution and data quality. Using the continuous-rotation method in MicroED, the critical accumulated dose is spread out over an entire tilt series to sample a substantial wedge in reciprocal space. In contrast, in SFX only single snapshots are recorded from tens of thousands of individual crystals (Schlichting, 2015et al., 2013et al., 2020et al., 2019In SerialED, only a single still diffraction pattern of a randomly orientated crystal is acquired, lacking information about unit-cell parameters owing to the large Ewald sphere. This limitation can be overcome by automation, collecting and integrating data from many thousands of randomly oriented crystals (White 5.de novo phasing through experimental phasing and/or high-resolution imaging may be realized in the years to come. We anticipate that with these advances, MicroED will play an ever more important role in macromolecular crystallography.Here, we illustrate the various achievements made by MicroED in the past years, and discuss the novel opportunities that it may bring for structural biology. Recent successes include determining increasingly challenging structures, resolving ligand-binding interactions and enabling structure determination of membrane proteins from microcrystals embedded in lipidic mesophases. The field is still evolving, and improvements in specimen preparation, optimization of TEM hardware and accurate modelling of the electrostatic potential are needed. Even more so,"}
+{"text": "Antimicrobial resistance (AMR) is a threat to public health O'Neil, . AMR occDrug\u2010resistance infections contribute to longer hospital stays, higher medical costs and increased incidence of morbidity , 23,000 deaths and two million illnesses were caused by antibiotic\u2010resistant bacterial infections (Centers for Disease Control, (Zetts et al., . Researchers have found that approximately 154 million primary care visits in the United States result in an antibiotic prescription and approximately 30 per cent, or 47 million, of these prescriptions are not necessary (PEW, One of the main risk factors for AMR in the United States is inappropriate prescription of antimicrobial therapies by primary care providers ary PEW, .(Zetts et al., . However, people in extremely rural communities in the United States tend to wait longer before seeing a provider for treatment for upper respiratory symptoms (Morgan & Hart, Researchers have shown that patients\u2019 demand for antimicrobial therapies varies depending on cultural background and geographic location (Larson et al., 2Interventions at the primary level are needed long term to prevent the spread of AMR (Centers for Disease Control, Appropriate nursing interventions at the primary level are also needed to overcome cultural and geographic barriers (Hicks et al., 3Researchers have demonstrated that the primary level of prevention of AMR has a clear impact and is cost\u2010effective (Ball, Dains, Flynn, Solomon, & Stewart, All authors contributed equally to this article."}
+{"text": "Breast cancer is the most frequently diagnosed cancer type and the second leading cause of cancer-related deaths among women worldwide. The causes of breast cancer are not yet fully known, although a number of risk factors have been identified. Tumor biomarker is a term used to describe potential markers of cancer development and progression. As we explore these biomarkers further, we must try to understand the underlying mechanisms of tumor development, as we move along the path to discovery of novel therapies that will increase our ability to offer personalized patient care in the future. With the migration of advanced high throughput technologies, such as Next Generation Sequencing from clinical practice, biomarker research and discovery are poised to explode once again. Translation of novel biomarkers into clinical practice and diagnostic laboratories is coupled with regulatory and administrative requirements that must be met, while collaboration between research institutions, industry, and the private sector drives further advancements in the field of breast cancer biomarker discovery and application.N-Acetyltransferase 1 Knockout Elevates Acetyl Coenzyme A Levels and Reduces Anchorage-Independent Growth in Human Breast Cancer Cell Lines\u201d by Stepp et al., \u201cOverexpression of Kynurenine 3-Monooxygenase Correlates with Cancer Malignancy and Predicts Poor Prognosis in Canine Mammary Gland Tumors\u201d by Chiu et al., \u201cNotch Signaling Activation as a Hallmark for Triple Negative Breast Cancer Subtype\u201d by Giuli et al., and \u201cHuman Mitotic Centromere-Associated Kinesin is Targeted by MicroRNA 485-5p/181c and Prognosticates Poor Survivability of Breast Cancer\u201d by Lu et al. contributed different biomarkers of breast cancer which may help to assess prognosis or predictive indicators. The focus of the third group of articles is on genetic mutations in breast cancer. The paper titled \u201cAssociation of ESR1 Mutations and Visceral Metastasis in Patients with Estrogen Receptor-Positive Advanced Breast Cancer from Brazil\u201d by Reinert et al. observed an association of ESR1 mutations with metastasis. The paper titled \u201cRole of Four ABC Transporter Genes in Pharmacogenetic Susceptibility to Breast Cancer in Jordanian Patients\u201d by AL-Eitan et al. proposed the ABCB1 mutation associated with breast cancer in Jordanian Arabs. The paper titled \u201cA Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci and the Role of Nontraditional Genetic Elements\u201d by Ellsworth et al. described genes and genetic elements, which have been associated with increased risk of triple negative breast cancer. The paper titled \u201cPregnancy Hypertension and a Commonly Inherited IGF1R Variant (rs2016347) Reduce Breast Cancer Risk by Enhancing Mammary Gland Involution\u201d by Powell et al. observed that statistically significant decrease in terminal duct lobular unit counts signifies increased breast epithelial involution in women with prior hypertension who inherited the TT genotype of IGF1R SNP (rs2016347).The aim of this special issue is to provide new findings regarding molecular pathways and biomarkers that could improve the diagnosis and the prognostic classification of breast cancers, their application in the clinical setting, and their potential utility in personalized patient therapy. The total of submissions is 50. After single-blind peer review by at least two reviewers, 14 papers were finally accepted to be published. The accepted rate is 28%. The average number of authors for each accepted paper is 7. The affiliated institutes of the authors are from Brazil, China, Italy, Iraq, Jordan, Portugal, Spain, Saudi Arabia, Taiwan, the UK, and the USA. These accepted papers can be organized in different groups. The focus of the first group of articles is on prognosis and therapy in breast cancer. The findings of the paper titled \u201cExploring the Role of Breast Density on Cancer Prognosis among Women Attending Population-Based Screening Programmes\u201d by Domingo et al. reveal that increased breast density was associated with worse survival outcomes among women participating in breast cancer screening. The paper titled \u201cAttenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) Spectroscopy Analysis of Saliva for Breast Cancer Diagnosis\u201d by Ferreira et al. showed ATR-FTIR spectroscopy can be used in saliva samples to discriminate breast cancer patients from benign patients and healthy subjects. The paper titled \u201cDovitinib Triggers Apoptosis and Autophagic Cell Death by Targeting SHP-1/p-STAT3 Signaling in Human Breast Cancers\u201d by Chiu et al. has provided the evidence for anticancer effect of dovitinib to suggest it as a potential target for breast cancer therapy. The focus of the second group of articles is on biomarkers in breast cancer. The paper titled \u201cA Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer\u201d by Wilkinson et al. investigated the expression profile of Cathepsin S in breast cancer patients. The paper titled \u201cIdentification of Cell-Free Circulating MicroRNAs for the Detection of Early Breast Cancer and Molecular Subtyping\u201d by Souza et al. identified the molecular signature miRNA as noninvasive biomarkers in patients with breast cancer. The paper titled \u201cCD133 in Breast Cancer Cells: More Than a Stem Cell Marker\u201d by Brugnoli et al. reviewed the value of CD133 as prognostic factor of malignant progression of breast cancer. The other four papers titled \u201cIn summary, the research papers cover a wide range of applications including potential diagnostics, predictions, and treatment. Furthermore, this special issue also includes regional genetic mutation, breast density on cancer prognosis, small RNA as a biomarker, surface marker of cancer stem cells, potential marker of cancer metastasis, and spectroscopy predicting the rate of cancer. This may be helpful in assessing prognostic or predictive indicators, as well as developing new therapies and new insights aimed at improving breast cancer.Chia-Jung LiHui-Ming ChenJi-Ching Lai"}
+{"text": "Critical comment on the review by Okada et al. on the effect of early versus delayed mobilization because of their definition of early mobilization as mobilization within a week of ICU admission in contrast to current evidence. In their systematic review and meta-analysis, Okada et al. investigate the impact of early versus delayed mobilization for in-hospital mortality and health-related quality of life among critically ill patients, including 11 studies in their meta-analysis [Aware that there is no uniform definition of \u201cearly mobilization\u201d in the ICU yet, to use 1\u2009week as cut-off point seems unreasonable for various reasons. So far, only studies starting early mobilization within 72\u2009h have been able to improve patient outcomes, as summarized in published narrative reviews . SchweicAnother current meta-analysis using different definitions was able to show an effect of early mobilization . FinallyIn conclusion, as timing seems crucial for patient-centered outcomes, early mobilization should be consistently defined as mobilization within 72\u2009h of ICU admission."}
+{"text": "M\u0101ori and Pacific Islander people are a priority population originating from Australasia. M\u0101ori and Pacific Islander children exhibit greater risk of obesity and associated morbidities compared to children of other descent, secondary to unique cultural practices and socioeconomic disadvantage. Despite these known risk factors, there is limited synthesised evidence for preventing and treating childhood obesity in this unique population. The objective of this systematic review was to identify and evaluate global prevention or treatment interventions for overweight or obesity that targeted M\u0101ori and Pacific Islander children and adolescents (aged 2\u201317\u2009years).The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The databases PubMed, EMBASE, Scopus, Web of Science and CINAHL were searched from inception to August 2018. Study quality and risk of bias was assessed using a modified Downs and Black Quality Checklist for Health Care Intervention Studies. Studies were included if RCT/intervention/case control/ or prevention study designs. The study group was defined under the search term \u2018Oceanic Ancestry Group\u2019.Of the initial 94 articles identified, six were included describing two prevention and three treatment interventions. Interventions were heterogenous in setting, design, length and outcomes. Four interventions were implemented in New Zealand. Most studies were of \u2018fair\u2019 quality. One study recruited an exclusive population of M\u0101ori and Pacific Islander participants. In the five studies that recruited mixed populations, one performed sub-group analysis on M\u0101ori and Pacific Islander participants. No study reported an improvement in anthropometric outcomes post-intervention in complete or sub-group analysis. Improvements in cardiometabolic or psychological secondary outcomes were inconsistent across all studies.There is a lack of evidence to recommend specific intervention characteristics to optimise obesity prevention or treatment outcomes for M\u0101ori and Pacific Islander children. Future research requires greater consideration of cultural values and beliefs, community engagement, exclusive targeting of M\u0101ori and Pacific Islander children and families, and sub-group analyses for mixed-population studies. Incorporating co-design principles during study design and implementation can maximise the cultural specificity of interventions and may contribute to improved health and weight-related outcomes for this at-risk, priority population.CRD42019121790 (26 March 2019).PROSPERO  The authors concluded that a co-design approach empowered the target population by enabling active, participatory action throughout each phase of design [In their recently published article, Verbiest et al.  describef design .Whilst standalone trials are essential in building an evidence-base for appropriate childhood overweight/obesity prevention and intervention characteristics in M\u0101ori and Pacific Islander peoples, a coordinated whole-of-government, policy-level and healthcare systems response is paramount in contributing to a reduction in prevalence. In response to the growing prevalence of obesity and congruent with the World Health Organization (WHO) Report of the Commission on Ending Childhood Obesity , New ZeaA localised example of a culturally-tailored, integrated health system approach to improving M\u0101ori and Pacific Islander child and adolescent health is the \u2018Good Start Program\u2019, a statewide, schools-based, nutrition and physical activity initiative embedded within the Queensland Health system, Australia. A qualitative evaluation of its implementation concluded that building a system-wide workforce of M\u0101ori and Pacific Islander Health Workers was a significant contributor to enabling high-level community engagement, cultural specificity of interventions, community member satisfaction and trust with the Good Start Program, and ultimately positively shifting M\u0101ori and Pacific Islander community members\u2019 attitudes to and knowledge of health .There were a number of observed strengths of included studies. Project Energize, the New Zealand schools-based prevention intervention described by Rush et al. , 26 in tn\u2009=\u200918) and the participants of SWITCH trial of Maddison et al. [n\u2009=\u00a0116), which may have limited the generalisability of findings to the larger population of Hawaii. Most interventions were described as stand-alone, and there was little evidence of attempted integration within a broader, health system to maximise reach, impact, and sustainability.The primary limitation of the current literature is the lack of exclusive recruitment of M\u0101ori and Pacific Islander participants and limited sub-group analysis in mixed participant demographics. Descriptions of intervention intensity and intervention fidelity could have been strengthened; this may have contributed to the modesty of reported results, especially anthropometric outcomes. The intervention of Chansavang et al.  was impln et al.  were offn et al. . Anothern et al. , 25\u201327 an et al.  and 5-yen et al.  analysedThe primary strength of this review is its novelty, being the first known to synthesise global evidence of prevention and treatment interventions for the unique, at-risk population of M\u0101ori and Pacific Islander children and adolescents. Findings of this review are potentially transferable to priority populations from various developed countries, including the USA and Canada, where young Alaska Native and American Indian children, and First Nations and Inuit peoples, respectively, exhibit high obesity prevalence rates . As an en\u2009=\u00a06) to prevent or treat obesity in M\u0101ori and Pacific Islander children and adolescents generated minimal impact in improving anthropometric indicators of weight or improving cardiometabolic or psychological secondary outcomes. There is a lack of evidence to recommend specific intervention characteristics that will optimise overweight/obesity prevention or treatment interventions in M\u0101ori and Pacific Islander children and adolescents. These results are possibly secondary to a lack of intervention intensity and specificity to M\u0101ori and Pacific Islander peoples. The authors propose the following recommendations for future research:Cultural-tailoring of interventions, preferably utilising a co-design approach, with adequate methodological reporting;Implementation of interventions that exclusively target M\u0101ori and Pacific Islander children and adolescents; fostering community engagement, leadership and ownership at every stage of the proposed intervention i.e. from conception to evaluation;Performing intervention sub-group analysis on M\u0101ori and Pacific Islander participants in mixed-population studies; andIntegrating and evaluating, where possible, long-term, mixed-methods interventions within an existing healthcare system to maximise reach and sustainability for policy- and population-level impactOverall, previously reported studies (Consideration of these recommendations in future research will optimise interventions to tackle childhood overweight/obesity in the unique priority population of M\u0101ori and Pacific Islanders, who exhibit a significantly higher prevalence of childhood overweight/obesity in Australia and New Zealand, as well as demonstrate substantial socioeconomic and health disadvantage that inherently increases population risk for long-term overweight/obesity and its comorbidities.Additional file 1. PRISMA checklist.docxAdditional file 2. Search strategy in EMBASE according to the PICO format.docxAdditional file 3. Individual quality assessment and risk of bias results for included studies.docx"}
+{"text": "Cannabis Sativa plant, interacts with the endocannabinoid system by inhibiting fatty acid amide hydrolase (FAAH) activity (the rate-limiting enzyme for anandamide hydrolysis), allosterically modulating CB1 and CB2 receptors, and activating components of the \u201cextended endocannabinoid system.\u201d Congruently, CBD has shown prominent pro-neurogenic effects, and, unlike \u03949-tetrahydrocannabinol, it has the advantage of being devoid of psychotomimetic effects. Here, we first review pre-clinical studies supporting the facilitating effects of CBD on adult hippocampal neurogenesis and available data disclosing cannabinoid mechanisms by which CBD can induce neural proliferation and differentiation. We then review the respective implications for its neuroprotective, anxiolytic, anti-depressant, and anti-reward actions. In conclusion, accumulating evidence reveals that, in rodents, adult neurogenesis is key to understand the behavioral manifestation of symptomatology related to different mental disorders. Hence, understanding how CBD promotes adult neurogenesis in rodents could shed light upon translational therapeutic strategies aimed to ameliorate psychiatric symptomatology dependent on hippocampal function in humans.During the last decades, researchers have investigated the functional relevance of adult hippocampal neurogenesis in normal brain function as well as in the pathogenesis of diverse psychiatric conditions. Although the underlying mechanisms of newborn neuron differentiation and circuit integration have yet to be fully elucidated, considerable evidence suggests that the endocannabinoid system plays a pivotal role throughout the processes of adult neurogenesis. Thus, synthetic, and natural cannabinoid compounds targeting the endocannabinoid system have been utilized to modulate the proliferation and survival of neural progenitor cells and immature neurons. Cannabidiol (CBD), a constituent of the  During the last half-century, considerable progress has been made to understand, prevent, and treat such conditions. However, treatment options are still far from optimal in terms of efficacy and specificity, and there remain important untreatable maladaptive phenotypes and treatment-resistant patients. To solve this issue, basic and applied research has tried to identify new altered neuropsychological mechanisms suitable to promote new therapeutic strategies , CBD is devoid of psychotomimetic and rewarding effects , transient potential vanilloid 1 (TRPV1), G-protein 55 (GPR55) and peroxisome proliferator-activated gamma (PPAR\u03b3) receptors, as well as the antagonism of adenosine reuptake  of the dentate gyrus . Moreover, the authors reported an interesting opposition to the effects of THC on this measure. Months later, Demirakca et al. (Considering that the endocannabinoid (eCB) system exerts important functions in the regulation of neuronal generation and survival  and BrdU/NeuN. Due to the prolonged presence of both markers in different stages of the neurogenesis process (for a review see Kempermann et al., in vitro, Campos et al. (in vivo. Inverted U-shaped dose-response curves usually suggest the participation of multiple pharmacological mechanisms. In this way, it has already been described that CBD also exerts a similar anxiolytic dose-response curve (for a review see Jurkus et al., 1A and TRPV1 mechanisms (Campos and Guimar\u00e3es, 1A receptors. However, CBD-induced proliferation in HiB5 hippocampal progenitor cells was not blocked by a 5-HT1A antagonist (Campos et al., CBD pro-neurogenesis also shows great consistency across doses. Literature findings report increases in neuronal proliferation and differentiation after CBD doses ranging from 3 to 30 mg/kg, usually after prolonged treatments (\u226510 days; s et al.  describes et al.  showed t\u2212/\u2212 mice (Aguado et al., The eCB system stands out as a key regulator of newborn neuron generation, survival, maturation, and functional integration in the adult hippocampus. Neural progenitor cells, and their descendants, express a functional eCB system and are subject to the effects of endocannabinoid signaling (Prenderville et al., in vitro and in vivo evidence has suggested such interplay. The first evidence was given by Wolf et al. (\u2212/\u2212 mice. The seminal work of Campos et al. (in vitro. CB1 and CB2 antagonists prevented the pro-neurogenic effect of CBD in hippocampal HiB5 progenitor cells. Furthermore, CB1 and CB2 receptor agonists, as well as eCB degradation inhibitors mimicked the pro-neurogenic effects of CBD. Interestingly, CBD effects were abrogated when the FAAH was inhibited. Combined, these results imply that the pro-neurogenic effects of CBD depending on the increase of AEA concentration. Crucially, CBD is an inhibitor of the FAAH and is well known to increase AEA concentration (Bisogno et al., in vivo. After a CBD treatment in chronically stressed mice, neuronal differentiation, and late survival were found to be increased in CBD-treated mice (Foga\u00e7a et al., Given the mechanistic interactions between CBD and eCB system, a plausible hypothesis originated stating that CBD increases adult neurogenesis by modulating the eCB system. Accordingly, f et al. . In theis et al.  further A considerable number of studies have reported the pro-neurogenic effects of CBD, and some among them have even related these with an eCB mechanism of action. But, can the pro-neurogenic effects of CBD account for some of its therapeutic applications? Answering this question requires specialized experimental strategies designed to rule out CBD pro-neurogenesis, leaving intact its other pharmacological mechanisms and so, fewer experiments have been conducted. Nonetheless, a handful of studies have addressed this question, presenting evidence for a potential implication in the protection against neurodegenerative diseases (Esposito et al., Neurodegenerative and ischemic conditions are among the circumstances in which hippocampal function can manifest greater impairments (Shah et al., A significant amount of animal and human data has emerged relating the neuro-modulatory role of adult hippocampal neurogenesis, its interactions with broader hippocampal circuits, and its implications on altered behaviors in different neuropsychiatric disorders (Beckervordersandforth and Rolando, ML and OV were responsible for the study concept and design. Both authors drafted the manuscript and approved the final version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cell death (CD) is a fundamental biological process that is indispensable in all living organisms Ameisen, . Phloem + outward rectifying conductances (KORC) was recorded in response to various CD-inducing microbe-derived molecules, such as harpins , cell shrinkage (Yekkour et al., + efflux channel were also shown to have fewer autophagosomes compared to the wild-type plant upon ROS-induced CD (Demidchik, + efflux through KORC is supposed to result in dramatic K+ loss from plant cells and promotes CD (Demidchik et al., + loss was effectively shown to be involved in tobacco cell death induced by palmitoleic acid and ceramide (Peters and Chin, Nicotiana benthamiana plants undergoing oxidative stress and transiently expressing CED-9, an anti-apoptotic gene from the bcl-2 family (Craig, + efflux and maintaining intracellular K+ homeostasis (Shabala et al., An increase in Ky Craig, , are capIn response to ozone or DON, plant cells rapidly activate anion currents, followed by a delayed activation of KORC (Tran et al., In plant the vacuolar collapse seems a key step in cell shrinkage but to our knowledge the role of vacuolar conductances is poorly documented. Therefore, further studies are needed to decipher the role of vacuolar channels in this process.+ channels and is prevented by application of blockers of Cl\u2212 or K+ channels (Okada and Maeno, As a whole, these data are reminiscent of those described in numerous studies in animal cells and show that plant CD could involve specific modifications of ion transporter activities that could be significant and crucial in the successful propagation of CD . ActivatFB, DR, DT, and PL conceived and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Anorexia nervosa and bulimia nervosa are two severe eating disorders associated with high premature mortality, suicidal risk and serious medical complications. Transition between anorexia nervosa and bulimia nervosa over the illness course and familial co-aggregation of the two eating disorders imply aetiological overlap. However, genetic and environmental liabilities to the overlap are poorly understood. Quantitative genetic research using clinical diagnosis is needed.N = 782 938) of randomly selected full-sisters and maternal half-sisters born in Sweden between 1970 and 2005. Structural equation modelling was applied to quantify heritability of clinically diagnosed anorexia nervosa and bulimia nervosa and the contributions of genetic and environmental effects on their overlap.We acquired a clinical diagnosis of anorexia nervosa  and bulimia nervosa  in a large population-based sample  (36\u201350%)] and 41% (31\u201352%), respectively, in the study population, with the remaining variance explained by variance in unique environmental effects. We found statistically significant genetic  and unique environmental correlations [0.55 (0.43\u20130.66)] between the two clinically diagnosed eating disorders; and their overlap was about equally explained by genetic and unique environmental effects [co-heritability 47% (35\u201358%)].Our study supports shared mechanisms for anorexia nervosa and bulimia nervosa and extends the literature from self-reported behavioural measures to clinical diagnosis. The findings encourage future molecular genetic research on both eating disorders and emphasize clinical vigilance for symptom fluctuation between them. Anorexia nervosa is characterized by significantly low body weight and intense fear of weight gain  of bulimia nervosa compared to the same types of relatives of individuals without anorexia nervosa, and In the current work, we used clinical diagnoses of anorexia nervosa and bulimia nervosa in a large Swedish female cohort containing full-sisters  and maternal half-sisters . The application of diagnostic information considerably expands the clinical significance of the results. Using non-twin siblings significantly increased sample size and improved precision in estimating the underlying morbidity liabilities. We quantified the contribution of genetic and environmental effects on anorexia nervosa and bulimia nervosa and their overlap and estimated the genetic and environmental correlations between the two eating disorders.The current study was approved by the Regional Ethics Review Board in Stockholm, Sweden.et al., et al., et al., et al., et al., We acquired information from several Swedish national registers linked by the unique individual identification number. The Swedish Population Register provided birth year and month, death date and migration information  from the treatment quality registers. We were unable to distinguish between restricting and binge-eating and purging anorexia nervosa from the ICD diagnosis in the NPR. Bulimia nervosa diagnosis was identified with ICD-10 codes F50.2 or F50.3 from the NPR, or meeting DSM-IV-TR criteria for bulimia nervosa or sub-threshold bulimia nervosa in EDNOS from the treatment quality registers. Bulimia nervosa was not an independent eating disorder category in the Swedish version of ICD-9 . Therefos.d.)\u00a0=\u00a09.3]. We then randomly selected one pair of full-sisters per mother in the remaining mothers after excluding mothers of the selected maternal half-sisters. We excluded twin pairs from full-sister pairs, resulting in 334\u00a0433 pairs of full-sisters for analysis . No individual was included in more than one pair. The selected full-sisters and maternal half-sisters comprised the study population, where 6104 (0.91%) individuals among the full-sisters and 938 (0.82%) among the maternal half-sisters had been diagnosed with anorexia nervosa; 3142 (0.47%) among the full-sisters and 579 (0.51%) among the maternal half-sisters had been diagnosed with bulimia nervosa; 679 (0.10%) among the full-sisters and 122 (0.11%) among the half-sisters had been diagnosed with both disorders  and maternal half-sisters (sisters born to the same mother but different fathers) who were born in Sweden between 1970 and 2005. We excluded individuals who emigrated or died before age 6, adopted individuals and individuals whose biological parents were not identifiable from the registers. We did not have access to information on race and ethnicity; however, being born in Sweden might suggest that our study population was comprised primarily of individuals of Scandinavian/Nordic ancestry. We then randomly selected one pair of maternal half-sisters per mother  in full-sisters and 0.03 (s.e.\u00a0=\u00a00.06) in maternal half-sisters; the cross-sister-within-trait correlation for bulimia nervosa was estimated as 0.20 (s.e.\u00a0=\u00a00.03) in full-sisters and 0.13 (s.e.\u00a0=\u00a00.07) in maternal half-sisters . The AE model was selected for interpretation because it had the lowest AIC , illustrating the diagnostic transition between the two eating disorders within individuals regardless of the type of siblings. The cross-sister-cross-trait correlation further characterizes the nature of the association between the disorders across the individuals in a pair. A higher cross-sister-cross-trait correlation was observed in full-sister pairs  than in maternal half-sisters , suggesting genetic effects on the overlap between the two eating disorders ] of the phenotypic correlation of the two disorders was explained by their genetic covariance and the remaining 54% [95% CI (42\u201365%)] was explained by their environmental covariance . We founet al., s.e. 1%) in the most updated genome-wide association study (GWAS) ] and environmental correlations [0.55 (0.43\u20130.66)] suggest an aetiological overlap between anorexia nervosa and bulimia nervosa and underscore the importance of vigilance for transitions between the two eating disorders during treatment. Using large population data, we significantly improved the precision of the estimates. We reported heritability for clinically diagnosed anorexia nervosa as 43% (36\u201350%) and bulimia nervosa as 41% (31\u201352%), which was slightly lower than, but within the confidence interval of, the heritability found in the twin study based on self-reported questionnaire data [57% (0\u201381%) for anorexia nervosa and 62% (8\u201370%) for bulimia nervosa] ] and between anorexia nervosa and major depression (around 0.5 in multiple studies) (Wade et al., et al., et al., et al., In addition, we reported significant unique environmental effects, both disorder-specific and common to the two eating disorders. Previous research suggested various potential environmental risk factors for eating disorders, such as dieting and events that trigger mood change and thin-ideal internalization (Chua et al., et al., et al., Using extended familial relatedness drastically increased the available sample size of the models in our study, and the use of clinical diagnostic information increased the clinical significance of the results. Our results are consistent with the prior twin study on the overlap between anorexia nervosa and bulimia nervosa based on self-reported measures of eating behaviours (Bulik et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Limitations of the current study would arise if there are violations of basic assumptions of the models, such as the assumption of equal shared environmental factors across different types of siblings [equal environment assumption, EEA (Plomin To our knowledge, this is the first quantitative genetic study on clinically diagnosed anorexia nervosa and bulimia nervosa and their overlap. The moderate and statistically significant genetic and environmental correlations between the two eating disorders might suggest aetiological overlaps and emphasize clinical vigilance of the transition between the two disorders."}
+{"text": "In modern biotechnological and medical research, RNA-guided nucleases (RGNs) continue to be highly effective in targeted modification of genomes and the manipulation of gene expression (Sander and Joung CRISPR-Cas proteins are non-specific endonucleases that bind a protospacer adjacent motif (PAM) located in the proximity of the genomic target  nuclease concentration and features and (ii) target site accessibility, functionality, and uniqueness. The occurrence of complementary sites within the genome, which form highly stable duplexes to guide oligonucleotide, is one of the important determinants of off-target activity. Cas9 and Cas12a (Cpf1) activity can be modulated by chromatin states to varying degrees. Off-targeting is expected to be context dependent because chromatin states and DNA accessibility is tissue/cell- or condition-dependent  RISC complex formation, several key measurements including association kinetics, equilibrium binding energies, and single turnover cleavage rates allows revealing of important rules for binding and cleavage of targets. Becker and co-authors (Becker et al. A comparison of Cas9- and Cas12a-binding experiments showed variable binding kinetics responses to target sequence mutations, which explained why Cas12a enables the selection of DNA sequences more precisely than Cas9 (Strohkendl et al. For Cas nucleases, targeting rules were empirically established by different groups (Klein et al. Several models and approaches based upon thermodynamics and kinetics have the potential to explain off-targeting patterns for CRISPR-Cas and AGO2, as well as for other systems. To go beyond binding energetics, Klein and co-authors (Klein et al. Bisaria and co-authors (Bisaria et al. Attenuating DNA cleavage kinetics can be successfully applied for enhancing gene editing specificity and reducing off-targeting not only to CRISPR systems but also to different engineered nucleases (Becker et al."}
+{"text": "Ichihashi et al reported that 43% of patients had antipsychotic polypharmacy. Number of antipsychotics used in patients with schizophrenia in Japan was the greatest among Asian countries. However, the antipsychotic polypharmacy rate in Japan decreased gradually. Recent systematic review, meta\u2010analysis and meta\u2010regression analysis demonstrated that antipsychotic augmentation was superior to monotherapy. However, several cohort studies have suggested a significant association between antipsychotic daily dose and mortality. In addition, most pharmacokinetic interactions with antipsychotics occur at the metabolic level and usually involve changes in the activity of the major drug\u2010metabolizing enzymes involved in their biotransformation. Thus, avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and possibly plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving antipsychotics. Ichihashi et alAntipsychotics are not always effective in schizophrenia patients. There are still patients with treatment\u2010resistant schizophrenia (TRS), which has led to a growing trend of resorting to atypical antipsychotic polypharmacy due to fewer side effects.Number of antipsychotics used and psychotropic drug loading in patients with schizophrenia in Japan was the greatest among Asian countries.A recent systematic review, meta\u2010analysis and meta\u2010regression analysis demonstrated that antipsychotic augmentation was superior to monotherapy regarding total symptom reduction, although the superiority was only apparent in open\u2010label and low\u2010quality trials and not in double\u2010blind and high\u2010quality trials.On the other hand, several guidelines consistently recommend monotherapy of antipsychotic agents. For example, the Maudsley Prescribing Guidelines in Psychiatry states that we should concern ourselves with the addition of an antipsychotic to another antipsychotic solely to increase efficacy. From a theoretical point of view, since all antipsychotics block D2 receptors , there is limited rationale for additional antipsychotics. In addition, many clinical trials studying the side effects of polypharmacy have associated polypharmacy with an increased incidence of side effects, although most have been uncontrolled studies or observational studies.Several cohort studies have suggested a significant association between antipsychotic daily dose and mortality.Mortality associated with antipsychotic polypharmacy has not yet been concluded. Previous reports have suggested that significant mortality risks are 2.46 Thus, although evident disadvantage of antipsychotic polypharmacy has not yet been concluded, avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and possibly plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving antipsychotics.Norio Yasui\u2010Furukori has been a speaker for Otsuka Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Dainippon\u2010Sumitomo Pharmaceutical Co., and MSD Co. Kazutaka Shimoda has received research support from Novartis Pharma KK, Dainippon Sumitomo Pharma Co., Astellas Pharma Inc, Meiji Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc, Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., and Takeda Pharmaceutical Co., Ltd., and honoraria from Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical KK, Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Daiichi Sankyo Co., and Pfizer Inc The funders did not have any role in data collection or in the study design, analysis, decision to publish, or preparation of the manuscript. The remaining authors declare that they have no competing interests to report.NYF designed the study and wrote the initial draft of the manuscript. KS contributed to supervision of the draft."}
+{"text": "On page 288, \u2018recent reports have shown that CAII can also reduce nitrite (NO2\u2212) to nitric oxide (NO), and thus, may play a role in vasodilation and regulation of blood pressure  to nitric oxide (NO), and thus, may play a role in vasodilation and regulation of blood pressure  On pages 288\u2013299, \u2018However, when dialyzed with ethylenediaminetetraacetic acid (EDTA), the enzyme retained its carbonic anhydrase activity yet lost its nitrite reductase activity  And on page 291, \u2018... indicating that a metal cofactor within the bovine blood was needed for the CAII-dependent nitrite reductase activity (Andring et al., 2018et al., 2018et al. (2018et al., 2018( al. 2018 and shou"}
+{"text": "A discussion of recent discoveries in the etiolation/de-etiolation field, focusing on post-transcriptional processes and ultrastructural changes, along with comments on usage of the term \u2018etiolation\u2019, and of common etiolation/de-etiolation systems. The state of etiolation is generally defined by the presence of non-green plastids (etioplasts) in plant tissues that would normally contain chloroplasts. In the commonly used dark-grown seedling system, etiolation is coupled with a type of growth called skotomorphogenesis. Upon illumination, de-etiolation occurs, marked by the transition from etioplast to chloroplast, and, at the seedling level, a switch to photomorphogenic growth. Etiolation and de-etiolation systems are therefore important for understanding both the acquisition of photosynthetic capacity during chloroplast biogenesis and plant responses to light\u2014the most relevant signal in the life and growth of the organism. In this review, we discuss recent discoveries (within the past 2\u20133 years) in the field of etiolation and de-etiolation, with a particular focus on post-transcriptional processes and ultrastructural changes. We further discuss ambiguities in definitions of the term \u2018etiolation\u2019, and benefits and biases of common etiolation/de-etiolation systems. Finally, we raise several open questions and future research possibilities. Etiolation involves prolonged growth in the absence of light that results in the development of etioplasts in tissue that would have chloroplasts if subjected to light. Etioplasts do not contain chlorophyll or stacked thylakoid membranes, but rather have a paracrystalline lipid\u2013pigment\u2013protein structure known as the prolamellar body (PLB). The PLB consists largely of the plastid lipids monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG), and an association of the chlorophyll precursor protochlorophyllide (Pchlide), the light-dependent protochlorophyllide oxidoreductase (LPOR) that is responsible for its conversion, and the cofactor NADPH  germination and growth of seedlings in complete darkness, the term \u2018etiolated\u2019 is commonly defined additionally by the presence of a skotomorphogenic phenotype of elongated hypocotyls, shortened roots, and small, closed cotyledons . In thesThe majority of the data discussed in this Expert View refer to work undertaken in such seedling-based etiolation/de-etiolation systems. The various limitation of these systems and possible alternative or complementary systems are also discussed (in the section \u2018New systems required and new lessons learned\u2019).\u00e9tiolier (i.e. straw), is still used as a descriptor for a range of pale or yellowing phenotypes. These include nitrogen-deficient rice  albostrians mutant  are 20\u201324 nt-long molecules that regulate gene expression via RNA-dependent DNA methylation, translation inhibition, or mRNA cleavage (reviewed in Zea mays) to understand the establishment of photosynthesis in C3 versus C4 species. These studies, which defined several specific sRNA roles, such as the repression of photomorphogenic growth by miR396 via members of the Growth Regulating Factors family  is an evolutionarily conserved protein kinase that acts as a central hub to control cellular- and organism-level development : RNA\u2013protein complexes that are conserved in eukaryotes and regulate gene expression by degradation or translational arrest of mRNA (reviewed in Genomes uncoupled (gun) mutants defective in plastid-to-nucleus retrograde signaling (gun2\u20136) have defects in genes for enzymes involved in tetrapyrrole biosynthesis. More recently, a role for the enigmatic GUN1 in regulating protein import via the cytosolic heat shock protein 90 (HSP90) chaperone was clarified using a de-etiolation system  is produced early during greening as a by-product of tetrapyrrole biosynthesis  and lipid to protein ratios change with greening . The rolin vitro system recently used to show the requirement for MGDG and charged lipids in regulating LPOR complex formation and activity . These issues argue for alternative systems, such as the ues e.g. .Phaseolus coccineus) and pea (Pisum sativum) (Landoltia punctate), a flat-leafed aquatic monocot  requires limited growth time and space yet provides sufficient material compared with other experimental systems such as the shoot apical meristem, and (ii) is highly customizable by use of different timing and lighting regimes and introduction of different substances to the growth medium (sativum) . PLBs hasativum) . The pro monocot , and in Cucumis sativus; Persea americana; Phaseolus vulgaris) (Nicotiana tabacum)  thylakoid membranes, early studies in cucumber (ulgaris) , varioustabacum) . These fThe benefits of the standard seedling etiolation and/or de-etiolation systems means that they have been used often in recent years to study diverse topics including gravitropism  changes during greening in Arabidopsis , acts downstream of the COP1\u2013auxin cascade during de-etiolation  in the dark . Soluble1O2; 1O2 retrograde signaling mediates de-etiolation via the EXECUTER1 pathway (The early assembly of the PSII oxygen evolving complex results in the (damaging) formation of singlet oxygen (Three recent studies investigated the effect of decreased MGDG ("}
+{"text": "Recent years have seen the idea of a close association between nutrition and the modulation of cancer development/progression reinforced. In fact, an increasing number of experimental and epidemiological evidence has been produced, supporting the concept that many different bioactive components of food  may be implicated in either the promotion of or the protection against carcinogenesis. At the cellular level, such compounds can have an impact on different but sometimes intertwined processes, such as growth and differentiation, DNA repair, programmed cell death, and oxidative stress. In addition, compelling evidence is starting to build up of the existence of primary epigenetic targets of dietary compounds, such as oncogenic/oncosuppressor miRNAs or DNA-modifying enzymes, which in turn impair gene expression and function. This editorial aims to summarize the themes of the 31 papers  published in the Special Issue \u201cRole of Natural Bioactive Compounds in the Rise and Fall of Cancers\u201d presenting the latest findings on the intracellular pathways and mechanisms affected by selected natural molecules influencing the fine-tuning of cancer phenotype.Plant polyphenols have been among the most studied natural compounds by the contributors to this issue.In the original article group, Polonio-Alcal\u00e0 et al.  showed tOther natural phenolic compounds whose activity is discussed in the original articles of this issue are:\u2013Gallic acid , widely distributed in natural plants, fruits, and green tea, whose tumor-suppressive effect via the p53-mediated downregulation of the transmembrane protein PD-L1 was demonstrated by Kang et al. [\u2013Olea europaea L., whose presence in enriched extracts from olive leaves was proven to reduce the glycolytic rate of a wide range of solid and liquid tumor cells via the downregulation of the three key effectors of the glycolytic pathway, GLUT-1, PKM2 and MCT4, likely resulting in a decreased glucose entrance and biomass production [Oleuropein, the main bioactive phenolic component of oduction ;\u2013Oleacein , the main secoiridoid contained in extra virgin olive oil, able to elicit significant anti-tumor activity by promoting cell cycle arrest and apoptosis in multiple myeloma cells due to its histone deacetylase inhibitory properties ;\u2013Dadzein , present in soybeans, whose 4-sulphate metabolite produced by gut microbiota was found to exert an anti-estrogenic effect on ER\u03b1-positive breast cancer cells via the downregulation of the anti-apoptotic neuroglobin protein thus rendering cells more prone to the paclitaxel treatment [\u2013Gigantol, a bibenzyl compound from orchid species, whose ability to destabilize tumor integrity via the suppression of the PI3K/AKT/mTOR and JAK/STAT pathways was demonstrated by Losuwannarak et al.  in non-s\u2013Lonchocarpus sericeus, proven to be a powerful inhibitor of the Wnt/\u03b2-catenin pathway able to selectively suppress the migration and proliferation of a panel of colorectal cancer cell lines in vitro and in a preclinical colorectal cancer mouse model [Lonchocarpin, a chalcone isolated from se model ;\u2013Isorhamnetin, , a flavonol aglycone found in some medicinal plants, able to exert an anti-proliferative effect on human bladder cancer cells via the induction of cell cycle arrest during the G2/M phase and apoptosis, accompanied by the activation of the AMPK signaling pathway and ROS overproduction ;\u2013Piper genus plants, whose ability to inhibit XIAP protein, involved in the regulation of caspase-dependent/independent cell death pathways, was reported by Mu\u00f1oz et al. [Erioquinol, eriopodol A and gibbilimbol B, derived from z et al.  in breas\u2013Calocedrus formosana Florin leaves extract, proven to interfere with cell cycle and microtubule dynamics in lung adenocarcinoma cells, also inhibiting tumor growth in a xenograft mouse model [Vatein, isolated from se model .Magnolia-derived polyphenol honokiol based upon its ability to impair cell cycle progression, inhibit epithelial\u2013mesenchymal transition, and suppress cell motility, invasion, metastasis and angiogenesis. Zhou et al. [In the Review section, Perrone et al.  discusseu et al.  summarizu et al.  reviewedu et al.  focused \u2013Malva pseudolavatera leaves, which showed a promising selective anti-proliferative and pro-apoptotic effect on acute myeloid leukemia cell lines, determining PARP cleavage, cytochrome-c release, Bax/Bcl-2 ratio increase and ROS overproduction [The methanolic extract of oduction ;\u2013Eicosapentaenoic acid, an \u03c9-3 polyunsaturated fatty acid, which played a protective role, both alone and in combination with angiotensin-converting enzyme inhibitors, in attenuating adipocyte-induced proinflammatory cytokine expression and the migration of breast cancer cells in an in vitro model of obesity-induced breast cancer ;\u2013Fucoidan, a sulphated polysaccharide derived from brown seaweed, whose combination with gemcitabine determined an enhanced pro-apoptotic and cell cycle-inhibitory activity on selected uterine carcinosarcoma and stromal sarcoma cell lines ;\u2013Nicotin, whose mechanisms underlying the promotion of melanoma cell proliferation and migration mediated through \u03b19-nAChR-initiated carcinogenic signaling and PD-L1 expression were reported by Nguyen et al. ;\u2013Streptomyces sp. MUM256, isolated from mangrove soil in Malaysia, and the cyclic dipeptides contained whose ability to induce cell cycle arrest and apoptosis was demonstrated by Tan et al. [The ethyl acetate fraction of the crude extract of n et al.  in colon\u2013Luffariella variabilis, which preferentially inhibits the proliferation of oral cancer cells inducing apoptosis and DNA damages via oxidative stresses, such as intracellular ROS and MitoSOX/MitoMP [Manoalide, an antibiotic sesterterpenoid isolated from the marine sponge X/MitoMP ;\u2013\u03bb-carrageenan, a family of linear sulfated polysaccharides, proven to enhance the effect of radiotherapy by suppressing the survival and invasiveness of different cancer cell lines in vitro and in vivo through the Rac GTPase-activating protein 1 pathway ;\u2013Ethanol, which was found to trigger a pro-survival autophagic response following the induction of oxidative and endoplasmic reticulum stress in colon cancer cells, and the activation of Nrf2 and HO-1 also leading to the acquisition of a more aggressive phenotype ;\u2013Colchicum autumnale, whose enhanced anticancer effects and reduced cytotoxicity on colon cancer cells when delivered in the nanoformulated form was reported by AbouAitah et al. [Colchicine, an alkaloid present in the medicinal plant h et al. .The other articles and reviews addressed further cancer-related issues relevant to types of compounds of a different nature, specifically:In the Review section, Del Corn\u00f2 et al.  discusseThe number of manuscripts published in this Special Issue indicates an active interest in research about the molecular/pharmacological mechanisms used by natural products exerting anti-tumoral effects which deserve further and deeper studies. I wish to thank all the contributors of this issue for sharing with us their experimental or reviewed data which will surely attract readers\u2019 attention and encourage the publication of other high-quality papers in this field."}
+{"text": "This Special Issue containing seminal contributions from international experts highlights the current understanding of Rho GTPases in cancer, with an emphasis on recognizing their central importance as critical targets for cancer therapy and for chemosensitization of current therapeutic strategies. A comprehensive review by Jung et al.  gives anNew regulatory mechanisms for Rho GTPases are presented in a review by Humphries et al. , who desNovel directions for Rho GTPase guanine nucleotide exchange factors (GEFs) are also highlighted in a number of peer-reviewed research articles. Using in silico analyses and in vitro experimental studies in keratinocytes, Lorenzo-Martin et al.  implicatTwo articles by Dr. Hendrick Ungefroren\u2019s group contribute to the role of the constitutively active Rac1B splice variant in transforming growth factor (TGF\u03b2) signaling ,9. The aFinally, Dyberg et al. implicate the downstream effector of Rho, Rho kinase (ROCK), in EMT and medulloblastoma growth by demonstrating that ROCK mRNA is preferentially expressed in metastatic tumors . They usIn summary, herein, you will find timely articles on the ubiquitous role of Rho GTPases in cancer and how understanding their mechanisms of action can lead to the design and development of targeted therapeutic strategies."}
+{"text": "The worldwide increase of human life expectancy (\u201clifespan\u201d) along with the concomitant rapid population aging represents the major social phenomena of the last century. This has substantially impacted our societies by virtue of the huge economic implications and public health challenges  definition of reference values; (2) identification of reference standards specific for the disease of interest ; (3) proper inclusion and contextualization within the diagnostic process; and (4) statistical processes supporting the whole framework. They concluded that various methodological issues remain to be addressed in order to perform an adequate and complete clinical validation of candidate CSF biomarkers for AD.Using cerebrospinal fluid (CSF) biomarkers for AD as a paradigmatic example, D'Anca et al. explored the current understanding of role of exosomes in physiological aging and age-related neurodegenerative diseases such as AD, Parkinson's Disease (PD) and frontotemporal dementia. Insights from the study of exosomes and their genetic cargo  have elevated their role beyond mere waste disposal function to fundamental mediators of intercellular communication, akin to the proverbial double-edge sword serving as Trojan horses of neurodegeneration vis-\u00e0-vis providing neuroprotection from neurodegeneration. Exosomes can be detected in many biological fluids, enhancing their appeal as potential sources of biomarkers suitable for use in clinical practice.Five papers in this Research Topic shed precious insights into emerging biomarkers from readily available biological samples. In their comprehensive review, Tay et al. prospectively studied serum levels of Dickkopf-1 (Dkk-1) in older adults with mild cognitive impairment (MCI) and mild-to-moderate AD. The findings revealed that Dkk-1 increased significantly from baseline amongst progressors, while non-progressors exhibited decremental Dkk-1 at 1 year, alluding to the putative role in MCI and AD progression of dysfunctional Wnt signaling through Dkk-1 antagonism. Sun et al. demonstrated that cofilin 2 expression was significantly increased in AD patients and different AD models , with good discriminatory ability that distinguish AD from healthy subjects and in differential diagnosis of AD from vascular dementia. By studying 391 cognitively normal subjects aged 23\u201391 years from Asia, USA and Europe, Lue et al. characterized the relationship between age and three plasma AD core biomarkers , provided the normal ranges of A\u00df species and t-Tau in plasma, and explicated the development of a dynamic relationship between these biomarkers from middle to old age. Lastly, Falconi et al. investigated the transcriptional regulation of the Adenosine A2A receptors (A2ARs) gene in human peripheral blood mononuclear cells obtained from PD patients and in the striatum of the 6-hydroxydopamine-induced PD mouse model. They reported an increase in A2AR mRNA expression and protein levels in both human cells and mice that is accompanied by histone acetylation and DNA methylation, paving the way for therapeutic interventions in future.Similarly, Li et al. shed light on the neural mechanisms of working memory deficits in MCI. By combining static and temporal dynamic examination of amplitude of low-frequency fluctuations (ALFF) from functional magnetic resonance imaging, they reported background network changes especially in the parietal and temporal lobes during working memory states in MCI. Similarly, Pur et al. enhanced understanding by demonstrating the moderating effect of cortical thickness on blood oxygen level-dependent (BOLD) signal variability age-related changes and highlight the importance of considering these effects when evaluating BOLDSD alternations across the lifespan. Kobayashi et al. examined whether dementia with Lewy Bodies (DLB) follows an AD-type trajectory whereby amyloid-\u00df deposition begins considerably before onset of dementia. They observed a low amyloid load in REM sleep behavioral disorder, a prodromal symptom of DLB, suggesting that this phenomenon does not always precede the onset of cognitive decline in DLB. Lastly, through the use of MRI voxel studies to examine neural substrates, Wu, Geng et al. implicated the left-precentral cortex and left inferior frontal gyrus areas that accounted for olfactory impairment in a cohort of AD and MCI patients in the Chinese Han population.Another prominent theme in this Research Topic was the contribution of advanced neuroimaging biomarkers. For instance, in terms of explicating mechanisms that underpin underlying pathophysiological processes, Wang, Hatashita et al. examined [18F]-flutemetamol (FMM), a fluorinated derivative of the prototypic [11C]-Pittsburgh Compound B (PIB), and demonstrated that [18F]-FMM PET imaging can track longitudinal changes in A\u03b2 deposition across the AD spectrum, similarly to [11C]-PIB PET. Notably, they reported that the increase in A\u03b2 deposition is not constant across the AD spectrum but faster in the predementia stage . Using dynamic [18F] florbetapir PET, Verfaillie et al. investigated the possibility that self-perceived cognitive decline (SCD), generally associated with a three- to six-fold increased risk of AD, may reflect an early symptom of A\u03b2 related pathology. They concluded that A\u03b2 load was associated with SCD related worries rather than subjective cognitive functioning per se .Other papers in this Research Topic illuminated the knowledge gap in our understanding about the role of misfolded protein accumulation in neurodegenerative diseases. The extracellular accumulation of amyloid beta (A\u03b2) peptide is the paradigmatic example, with recent neuroimaging capabilities in tracking A\u03b2 deposition a fascinating way to distinguish if the observed A\u03b2 accumulation is characteristic of the aging process or conversely, an etio-pathogenetic mechanism of AD . Furthermore, the study by Wu, Xu et al. provides proof-of-concept evidence that a topological examination of the structural connectivity networks with different parcellation schemes can provide important complementary AD-related information and thus contribute to a more accurate and earlier diagnosis of AD. Another promising technique involved amide proton transfer (APT) imaging as an imaging modality to detect tissue protein. In fact, Wang, Chen et al. adopting a modified APT method  in animal models, demonstrated that APT imaging could potentially provide molecular biomarkers for non-invasive diagnosis of AD. Using direct non-invasive brain network electrophysiological imaging, Zifman et al. established that this new technique can be used both to monitor brain aging and for early detection of abnormal changes leading to neurodegeneration.Other papers highlight advances in neuroimaging techniques that pave the way for fresh perspectives in early diagnosis of AD. Utilizing sophisticated measurements of cortical thickness with 3.0-Tesla MRI in a large population of cognitively normal individuals and patients with AD continuum, Lorio et al. described how the combination of these imaging modalities can be used as biomarkers of PD severity and prognosis which can be potentially useful for clinical trials. Likewise, Pelizzari et al. proposed the concomitant use of DTI to detect brain tissue microstructural alterations, together with arterial spin labeling (ASL) MRI to analyse abnormal cerebral perfusion patterns in PD. The study showed that DTI is a more sensitive technique than ASL to detect alterations in the basal ganglia in the early phase of PD, suggesting that a relationship between microstructural integrity and perfusion changes in the caudate may be present .Bioimaging techniques are also useful for the differential diagnosis of PD. Dopamine-transporter SPECT (DAT-SPECT), diffusion tensor imaging (DTI), and structural magnetic resonance imaging (sMRI) provide unique information about neurotransmitters and microstructural properties in PD. The longitudinal study of Chen et al. developed an innovative predictive model to evaluate white matter burden in hypertensive patients using metrics in 24-h ambulatory BP monitoring (systolic blood pressure [SBP] and daytime SBP standard deviation) and carotid ultrasound IMT. Leveraging upon the diagnostic potential of diabetic retinopathy (DR) afforded by its time-course which precedes the occurrence of T2DM cognitive impairment, Lu et al. verified the correlation between DR from fundus examination and T2DM cognitive impairment. They further established using magnetic resonance spectroscopy (1H-MRS) that this may be attributed to bilateral changes in hippocampal brain metabolism, alluding to the potential role of 1H-MRS for early diagnosis of T2DM cognitive impairment .Papers in this Research Topic also addressed the issue of age-associated co-morbidities, particularly cardiovascular diseases, and related risk factors such as Type II diabetes mellitus (T2DM), which often confound the measurement and interpretation of neurodegenerative biomarkers. Exploring the association between white matter hyperintensities with higher Intima-media thickness (IMT) and blood pressure variability, Bandera et al. suggested an omics approach  to accelerate the discovery of reliable biomarkers of HIV-associated neurocognitive disorders in the current era of virological suppression with modern anti-retroviral therapy. Similarly, persistent inflammation has been implicated as a cardinal mechanism of neurocognitive impairment and neurodegenerative features in Multiple Sclerosis (MS). Jakimovski et al. reported the novel finding that almost half the elderly subjects with MS are impaired on tests of cognitive processing speed or verbal fluency. Since the deficit in verbal fluency is not a typical hallmark of the cognitive profile associated with MS, it may represent a unique trait of old persons with MS neurocognitive profile .A major pathogenetic influence of co-morbidities or their treatment that have emerged in recent years is that of concomitant inflammatory processes that may alter disease manifestation and confound biomarker interpretation. An example is the cognitive decline observed in some HIV subjects during ART-mediated viral suppression, a phenomena which has been ascribed to cytokine-mediated inflammation. Barha et al. underlined the role of biological sex as a potential moderator in the relationship between physical activity and brain health in older adults. They suggested that different neurobiological mechanisms  as well as physiological adaptations to physical activities could be responsible for the differences in trajectories of decline observed in men and women . This highlights the importance of taking into consideration the potent moderating influence of sex differences for both cognitive and neural outcomes in future therapeutic and rehabilitative interventions involving physical activity in older adults.Lastly, there is growing interest in the role of physical activity and exercise as \u201cmedicine\u201d that can be prescribed for brain health. In their comprehensive review, As guest editors for this Research Topic, we commend this collection of 23 articles to our readers as a timely addition and important contribution to the field. We are confident that this will spur further discourse and open avenues for further research into the rapidly evolving and fascinating area of biomarkers to disentangle physiological from pathological brain aging.FG, WL, and BA conceived the manuscript. FG and WL drafted the paper. BA critically appraised and edited the manuscript. All authors read and approved the final version of the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Background: Growing evidence points out that a disturbance of gut microbiota may also disturb the gut\u2013brain communication. However, it is not clear to what extent the alteration of microbiota composition can modulate brain function, affecting host behaviors. Here, we investigated the effects of gut microbiota depletion on emotional behaviors.Methods: Mice in the experimental group were orally administered ceftriaxone sodium solution  for 11 weeks. The open-field test and tail-suspension test were employed for the neurobehavioral assessment of the mice. Fecal samples were collected for 16s rDNA sequencing. The serum levels of cytokines and corticosterone were quantified using enzyme-linked immunosorbent assays. The immunohistochemistry method was used for the detection of brain-derived neurotrophic factor (BDNF) and c-Fos protein.Results: The gut microbiota for antibiotic-treated mice showed lower richness and diversity compared with normal controls. This effect was accompanied by increased anxiety-like, depression-like, and aggressive behaviors. We found these changes to be possibly associated with a dysregulation of the immune system, abnormal activity of the hypothalamic-pituitary-adrenal axis, and an alteration of neurochemistry.Conclusions: The findings demonstrate the indispensable role of microbiota in the gut\u2013brain communication and suggest that the absence of conventional gut microbiota could affect the nervous system, influencing brain function. Gut microbiota, known as a reservoir of bacteria, not only plays an essential role in host digestion and energy metabolism but shapes host immunity  and given either sterile saline solution  or ceftriaxone sodium solution   intragastrically once a day for 11 consecutive weeks  were maintained (ten mice per cage) under a specific-pathogen-free (SPF) condition at 22\u201326\u00b0C, 40\u201360% humidity, and 12-h light-dark cycle. The mice were given 1 week to acclimate. All mice were fed with adequate food and clean water. At the end of adaptive phase, all mice  were randomly divided into two groups : open-field test (OFT) \u2192 tail-suspension test (TST). The OFT, which involves a low stress level, preceded the TST, which involves a high stress level  was used to extract fecal DNA. Then, the extraction was eluted using elution buffer and stored at \u221280\u00b0C until PCR amplification detection by LC-Bio . The V3-V4 region of the prokaryotic 16S rRNA gene was amplified with primers 338F (5\u2032-ACTCCTACGGGAGGCAGCAG-3\u2032) and 806R (5\u2032-GGACTACHVGGGTWTCTAAT-3\u2032)  axis in rodents. Rising corticosterone levels suggest increases in HPA axis activity  in the hippocampus and c-Fos in the amygdala. The whole process consisted of brain collection, sectioning, and immunolabeling. The details referred to previous literatures . The staining extent was divided into five grades according to the percentage of positive cells in the region: negative, 0\u201325, 26\u201350, 51\u201375, and 76\u2013100%   regions of the hippocampus . Similarly, semi-quantification of c-Fos was performed by calculating the intensity score and fraction score in the CeC, CeL, and CeM regions of the amygdala. The immunohistochemical analysis was performed blind.P-values less than 0.05 were considered statistically significant.Data were expressed as the mean \u00b1 standard deviation or median (IQR) and analyzed by one-way ANOVA or Wilcoxon rank sum test in SPSS 22.0 software . p < 0.05)  .OFT is usually performed to assess locomotor activity and exploratory behavior  after gavage for 11 weeks  in the AB group   . In addiA slight decrease of BDNF in the CA1, CA3, and DG regions of the hippocampus was observed in the AB group compared to the CT group , Table 3The gut, a vulnerable but vital organ, is affected by different factors easily. Antibiotics are one of the common causes leading to gut disturbance, especially given the broad spectrum of antibiotics. Consistently, little is known about adverse effects of these antibiotics on health except for drug resistance. But, recently, medications with antibiotic have been reported to enhance the risk of allergies, inflammatory bowel diseases, obesity, and even mental diseases (Harris and Baffy, Ceftriaxone administration caused significant weight loss in the study. This is consistent with the previous finding that the weight gain of mice was delayed significantly following the ceftriaxone treatment (Miao et al., Proteobacteria became a dominant phylum, and the abundance of Bacteroidetes, Firmicutes, Actinobacteria, and Deferribacteres decreased. This result is supported by studies that ceftriaxone could characteristically decrease the alpha-diversity of the fecal microbiota accompanied with more Proteobacteria and less Bacteroidetes (Cheng et al., Proteobacteria is perceived as a diagnostic characteristic since it is closely related to colon epithelial oxygenation as well as the disruption of the gut anaerobic environment (Zhu et al., Firmicutes has become a controversial strain as some studies identified an increase in Firmicutes after ceftriaxone treatment, but others have demonstrated a declined Firmicutes in the ceftriaxone group (Cheng et al., Firmicutes (Huang et al., Firmicutes led to a reduction in short-chain fatty acids, which are an important physiological basis for low-level inflammation during depression (Huang et al., Bacteroidetes, as an important microbe for short-chain fatty acids, almost disappeared from the feces of the mice during exposure to ceftriaxone (Miao et al., Porphyromonadaceae, Escherichia, and Parabacteroides dominated the gut microbiota of the AB group mice, while Lactobacillus, Clostridiales, Acetatifactor, Bacteroidetes, Barnesiella, Helicobacter, Prevotella, Bacteroidales, and Alistipes were lowered. In line with this, some researchers have proposed that decreased Barnesiella after ceftriaxone gavage is a common and sensitive gut microbiota of the BALB/c mice and can be used as an indicator for assessing the balance of the gut microbiota (Zhao et al., Bacteroidetes is closely associated with digestion and interacts with the host's immune system, affecting the growth of other bacteria (Karlsson et al., Escherichia prevalence after oral antibiotic treatment has been reported for vancomycin and imipenem (Stokes, Escherichia could be beneficial or harmful as Escherichia is both a commensal and pathogenic inhabitant of a host's gastrointestinal tract. But most of the time, Escherichia is considered a potential pro-inflammatory bacteria (Liu et al., Porphyromonadaceae associates with mental deficits and cognitive disorders as well as anxiety-like behaviors in mice (Scott et al., Lactobacillus is known as a protective species against long-lasting metabolic disturbances and prevents gut dysbiosis, but was suppressed by ceftriaxone (Robles-Vera et al., Parabacteroide relates to the etiology of depression (Cheung et al., Ceftriaxone could result in a significant gut microbiota dysbiosis by killing most of the normal flora and providing the living space for other potential pathogens (Cheng et al.,  Stokes, , amoxici Stokes, , and met Stokes, . It is dBifidobacterium and Lactobacillus (Logan and Katzman, Lactobacillus fermentum strain NS9 administration not only normalized the composition of gut microbiota but reduced the anxiety-like behavior induced by ampicillin (Wang et al., Bifidobacterium infantis has also been identified in the rat separation model of depression (Desbonnet et al., Alterations in gut microbiota were accompanied by behavioral changes in the mice, including anxiety-like, depression-like, and aggressive behaviors. These behavioral changes cannot necessarily be a result of the direct toxic effect of ceftriaxone on the brain, since ceftriaxone is a non-absorbable antibiotic and usually given by injection. Previous studies have demonstrated the complex interaction between gut microbiota and the CNS; this is what is known as the MGB axis (Wang and Wang, Schistosoma mansoni showed a reduction in behaviors such as exploration and grooming (Sulaiman et al., Immune dysregulation was demonstrated by high levels of serum cytokines. This is supported by the evidence that inflammatory factors associate with a profile of behavioral changes (Capuron and Miller, Bifidobacterium species, have been demonstrated to be efficient in restoring HPA axis function (Moya-P\u00e9rez et al., Elevated corticosterone, one marker of HPA axis activation, was observed in the mice of the AB group (Borrow et al., Bifidobaterium adolescentis shows a promising anxiolytic and antidepressant property as it up-regulated BDNF expression by restoring the balance of gut microbiota (Guo Y. et al., Campylobacter jejuni (Goehler et al., The BDNF level showed a decreasing trend in the hippocampus of the AB group. According to the previous study, BDNF can maintain and promote development, differentiation and regeneration of neurons as well as affect learning and memory (Bercik et al., In general, we found that mice exposed to 11 weeks of ceftriaxone sodium treatment had a lower diversity and abundance of gut microbiota and showed more behavioral changes as compared to mice that were given normal saline. Dysregulation of the nerve-endocrine-immunological network may be a potential mechanism underlying abnormal behaviors induced by impaired gut microbiota. The study revealed the unknown side effects of antibiotics to a certain extent. Follow-up studies rebalancing the gut dysbacteriosis are required to further confirm the relationship between gut microbiota and brain function.PRJNA592623.The datasets generated for this study can be found in the NCBI, SRA accession: The animal study was reviewed and approved by Animal Care Advisory Committee of Sichuan University.ZZ and HY put forward the hypothesis, and BW, CT, LZ, and ML guided and supervised the experimental investigation and practices. LM, HW, and JL were responsible for data collection and analysis. YY provided pathologic diagnosis. ZZ was the main executer and involved in the entire research process, from proposal, planning and execution to implementation and composition. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Alzheimer's disease (AD) is the most common form of dementia. Its prevalence will significantly increase in the coming decades, whereas no efficient treatment is currently available. AD has two main neuropathological lesions: amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are composed of amyloid \u00df (A\u00df) peptides cleaved from the Amyloid Precursor Protein (APP) . Although genetic factors are estimated to represent 60% of the risk to develop LOAD, they remained largely unknown for a long time except for APOE  accounts for <5% of AD cases and is well characterized by mutations in three genes (The endolysosomal proteins listed above play critical roles at various steps of dynamin-dependent endocytosis and further steps . EndocytDynamin-dependent endocytosis is regulated by the interplay of the interactions between PRD of dynamin and SH3 domain-containing proteins (Ferguson and De Camilli, in vitro (Talaga et al., post-mortem brain tissues of AD and other tauopathies (Nishikawa et al., In vitro phosphorylation of tau by GSK3\u00df, a kinase abnormally activated in AD brains (Leroy et al., Given that endocytic proteins such as SHIP1, SHIP2, and SYNJ1 are PI-5-phosphatases involved in PI metabolism (Ramos et al., Many of the endocytic machinery proteins implicated in AD risk possess SH2, SH3 domains, and/or PRD and are involved in actin dynamics as well as in regulation of PIs. Because the endocytic machinery needs fine-tuned regulation of PIs and endocytic protein-protein interactions, the endocytic pathway must be highly vulnerable. Dysregulation of even one of these endocytic proteins could lead to significant endocytic abnormalities. Hyperphosphorylation of tau may further accelerate endocytic dysregulation. Genetic risk factors and tau pathology might well have profound impacts on synaptic functions, endolysosomal/autophagic pathways, and APP processing via dysfunction of endocytosis, actin network, and PI metabolism . EndolysKA constructed the main concept of the manuscript by exchanging opinions with the other authors. All authors participated in writing the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ion channels are expressed throughout nervous system development. The type and diversity of conductances and gating mechanisms vary at different developmental stages and with the progressive maturational status of neural cells. The variety of ion channels allows for distinct signaling mechanisms in developing neural cells that in turn regulate the needed cellular processes taking place during each developmental period. These include neural cell proliferation and neuronal differentiation, which are crucial for developmental events ranging from the earliest steps of morphogenesis of the neural tube through the establishment of neuronal circuits. Here, we compile studies assessing the ontogeny of ionic currents in the developing nervous system. We then review work demonstrating a role for ion channels in neural tube formation, to underscore the necessity of the signaling downstream ion channels even at the earliest stages of neural development. We discuss the function of ion channels in neural cell proliferation and neuronal differentiation and conclude with how the regulation of all these morphogenetic and cellular processes by electrical activity enables the appropriate development of the nervous system and the establishment of functional circuits adapted to respond to a changing environment. Nervous system development is a complex process in which neural cells undergo a transformation from neural stem cells to highly specialized neurons and glia to form different brain structures and spinal cord and establish circuitry that facilitates simple to advanced neural functions.Many cues have been recognized as drivers of the first steps in nervous system development. Morphogenetic proteins and growth factors regulate the number and type of neural cells as well as the morphogenesis of the neural tube. These include Sonic hedgehog (Shh), Bone Morphogenetic Proteins (BMPs), Wnts and trophic factors such as EGF, IGF, NGF, BDNF to mention few. Most of these factors are not exclusive to the organogenesis of the brain and spinal cord but instead support growth and act as morphogens of every tissue and organ in the developing embryo. Mechanistically, these developmental cues trigger a transcriptional combinatorial code that accompanies cells through their cell cycle progression and exit, differentiation and maturation  and IP3 receptor-operated Ca2+ release from stores in ventral domains of the spinal cord  and CaNeural activity is a feature of the maturing and mature nervous system, which during development facilitates the refinement of neural connections. The expression of ion channels in mature neurons is intrinsic to neuronal function. Diverse ion conductances are indispensable for neurotransmission, thus, the roles of different ion channels in synaptic function and neuronal excitability have been extensively studied. In contrast, the neurophysiological features of neural cells before synapse formation and before neuronal differentiation has not been as strong a focus of attention as those of mature neurons. Nevertheless, studies have argued that other forms of neural activity are present in neural cells throughout nervous system development Spitzer, .This activity may not be structured under a classical chemical synapse, but it is certainly dependent on ion channels gated by diverse mechanisms. Expression of voltage- and neurotransmitter-gated ion channels as well as transient receptor potential (TRP) channels, among others, is apparent in neural stem cells as early as neural plate stages (Abdul-Wajid et al., Here, we review studies addressing the pattern of expression of ion channels during development in neural cells before and during synapse formation. We compile investigations demonstrating a role for ion channels in neural cell proliferation, neural tube formation, and neuronal differentiation and discuss the consequences of having neural activity functioning in the early stages of nervous system development.Xenopus laevis spinal cord neurons are first recorded 8 h after exiting the cell cycle, when, these events manifest spontaneously, are Ca2+-dependent and long in duration (Spitzer and Lamborghini, + channel contributes to shorten the action potential duration and shifts it from Ca2+- to Na+-mediated (Barish, 2+, Na+ and K+ voltage-gated channel subunits for which their expression is developmentally regulated have been investigated (Harris, + current as development advances (Gurantz et al., 2+ currents are dominant at the earliest embryonic stage of chick limb motor neuron development, while later T currents decrease and N and L Ca2+ currents increase (McCobb et al., + and K+ currents in these motor neurons during embryonic development result in changes in action potential amplitude and duration, respectively, which in turn, modify the instructions of motor neurons to the muscle (McCobb et al., The excitable nature of neurons and muscle cells is dependent on the specific expression of ion channels and their subcellular localization in these cells. Seminal studies have investigated the developmental appearance of excitability in neurons and muscle cells through the progressive and differential expression of ion channels. Embryonic spinal cord neurons have served as a powerful model for the study of the ontogeny of excitability during development. Action potentials in  Barish, . The ide Harris, . In partXenopus spinal cord neurons and their activation contributes to the spontaneous Ca2+ spike activity in these cells before and during synapse formation (Root et al., In addition to voltage-gated ion channels and their fundamental role in contributing to the excitability of developing neurons and muscle cells, other types of ion channels are also present at the early stages of embryonic development. These channels are gated by diverse mechanisms, including notably, neurotransmitter-operated channels. GABA and glutamate receptors are expressed in immature Xenopus embryo (Spencer et al., Our recently published study shows that the cold-sensitive channel TRPM8 is expressed in the developing Xenopus neuroectodermal cells exhibit Ca2+ transients (Abdul-Wajid et al., 2+ channels (Abdul-Wajid et al., Expression of these diverse types of channels appears to start at even earlier stages of neural development, before the neural tube is formed. At neural plate stages, Transcripts and proteins for glutamate (Root et al., The process of neural tube formation consists of transforming a flat layer of cells known as the neural plate into a tubular structure from which the brain and spinal cord originate. The cellular events encompassing neural tube morphogenesis, all of which are tightly regulated, include neural plate cell proliferation, apicobasal polarization, apical constriction, elongation, cell intercalation, migration and differentiation (Wallingford et al., Xenopus laevis embryos. We demonstrated that during neural tube formation neural plate cells exhibit Ca2+ transients partly mediated by NMDA receptors. Inhibiting glutamate signaling, through pharmacological inhibition of NMDA receptors or downregulation of the GluN1 subunit, induces NTDs (2+ dynamics in the neural plate to a similar extent as inhibition of NMDA receptors. Moreover, preincubating embryos with NMDA partially rescues both the number of Ca2+ transients in the folding neural plate and the valproic acid-induced NTD phenotype (Sequerra et al., Our recently published study (Sequerra et al., ces NTDs . Valproices NTDs , also in2B interferes with mouse neural tube closure and morphogenesis (Choi et al., Many other neurotransmitter signaling systems have been identified as participants in the process of neural tube formation. Inhibiting serotonin receptors 5HTA and GABAB receptor ligands to pregnant rats alters embryos\u2019 neural tube formation leading to NTDs (Briner, A receptors. Another chloride conductance-mediated neurotransmitter system that affects neural tube formation is glycine. Blocking glycinergic signaling by administering strychnine to pregnant rats results in embryos with anencephaly, anterior NTD (Garc\u00eda-Alcocer et al., Administering GABA Briner, . The fac Briner, , which mSimilarly, enhancing or inhibiting NO levels by enhancing BMP signaling or inhibiting NO synthase in chicken embryos induces NTDs (Traister et al., Noradrenaline promotes neuronal differentiation by upregulating expression of N-tubulin in noggin-expressing neural plate cells, which is prevented by inhibiting \u03b1-adrenergic receptors (Messenger et al., 2+ signaling is a plausible common denominator for the action of diverse neurotransmitter systems on neural tube formation. Sources of Ca2+ can be intracellular from stores or extracellular through Ca2+ influx. Early studies in cultured rat embryos during cephalic neural fold elevation and neural tube closure assessed the role of Ca2+ influx and found that reducing it causes opening of the elevated neural folds (Smedley and Stanisstreet, 2+ transients in the neural plate, suggesting that additional mechanisms other than these ionotropic glutamate receptors contribute to neural plate cell Ca2+ dynamics during folding (Sequerra et al., Xenopus laevis embryos consisting of a Na+-dependent inward current which is stronger in the mid-lateral neural plate and decreases near the midline of the neural groove (Robinson and Stump, 2+ currents with characteristic kinetic parameters to transduce the signaling required for neural tube morphogenesis. Indeed, T-type Ca2+ channels are involved in neural tube formation and loss of them impairs neural fold closure in Xenopus laevis and Ciona embryos. Ca2+ influx through these channels is necessary for the regulation of cell adhesion during neural tube formation by ephrin signaling (Abdul-Wajid et al., 2+ transients seem to regulate apical actin dynamics in superficial neural plate cells of Xenopus laevis embryos, which, in turn, regulates neural plate cell apical constriction necessary for neural tube formation (Christodoulou and Skourides, Ca2+ signaling and downstream effectors recruited for neural plate folding and neural tube formation. The elucidation of these mechanisms will contribute to the delineation of safe therapies for the treatment of epilepsy during pregnancy.Further investigation is needed to identify the molecular mechanisms eliciting CaThe generation of the appropriate number of neurons and glial cells is essential not only during nervous system development but also in the adult brain where neurogenesis occurs in the hippocampus and olfactory bulb, and the peripheral nervous system during regeneration and remodeling. Thus, this is a highly regulated process because the dysregulated proliferation of neural stem cells can lead from tumors to neurodevelopmental disorders and birth defects like NTDs.2+ channels have all been implicated in regulating neural plate cell proliferation.The expression of ion channels during the early stages of development supports a role for them in the relevant cellular processes pertinent to these stages including neural cell proliferation. Different types of ion channels including voltage-gated, neurotransmitter-gated, TRPC and store-operated CaXenopus embryos, and, likely as a consequence, impairs lateromedial migration leading to NTDs. An increase in neural plate cell proliferation is also apparent by incubating embryos with the AED valproic acid (Sequerra et al., The action of glutamate-mediated regulation of neural plate cell proliferation is apparent as early as neural plate stages. We found that blocking NMDA receptor signaling increases neural plate cell proliferation in 2+ channels (LoTurco et al., In vitro studies on embryonic rat hippocampal neural progenitors reveal that stimulating glutamate signaling enhances neural cell proliferation or neuronal differentiation depending on the temporal pattern of NMDA receptor activation (Joo et al., Regulation of neural plate cell proliferation by glutamate-gated ion channels is present at later developmental stages during corticogenesis in the rodent brain. The effects of glutamate signaling on neural progenitor proliferation vary depending on the nervous system structure, the developmental stage and the type of model system and manipulation used in specific studies. Glutamate decreases the number of proliferating embryonic rat cortical cells through an AMPA/Kainate receptor-dependent mechanism that leads to depolarization of neural progenitors in the ventricular zone and activation of voltage-gated CaA receptor. In vivo studies in the neonatal mouse subventricular zone (Young et al., in vitro studies in cerebellar granule cells (Fiszman et al., A receptor-induced depolarization enhances neural progenitor cell proliferation. In contrast, activation of this receptor in the ventricular zone of the rat embryonic neocortex (LoTurco et al., 2+ channels and inhibits cell cycle progression. Even in the adult mouse brain, the GABAA receptor seems crucial in regulating neurogenesis by controlling hippocampal neural progenitors. GABAA receptor \u03b32 subunit-mediated signaling is responsible for controlling the experience-dependent transition between quiescence vs. proliferative states of the mouse hippocampal neural stem cell niche (Song et al., A receptor favors the quiescence of adult neural stem cells (Song et al., A receptor signaling (Dumitru et al., Another important neurotransmitter-gated ion channel that participates in neural progenitor cell proliferation is the GABAvia membrane depolarization. In particular, voltage-gated Ca2+ channels are pivotal for the regulation of neural progenitor proliferation and mouse embryonic cortical layer formation (Malmersj\u00f6 et al., 2+ channels enable Ca2+ transients that propagate through a network of neural progenitors connected by gap junctions. Inhibiting this electrotonic transmission decreases neural progenitor proliferation suggesting that correlated Ca2+ transients are necessary for the regulation of neural progenitor proliferation (Malmersj\u00f6 et al., 2+ channels in embryonic neural cells increases neural cell proliferation that has detrimental consequences to brain morphogenesis (Pai et al., 2+ channel-mediated signaling has, depends on developmental timing and location.Other ion channels directly involved in regulating neural cell proliferation include the voltage-gated ion channels. Moreover, some actions of the neurotransmitter receptor-gated ion channels seem to converge into the recruitment of voltage-gated ion channels 2+ channels, voltage-gated K+ and Na+ channels are involved in regulating neural cell proliferation. The voltage-gated Na+ channel \u03b21 subunit is necessary for inhibiting granule cell precursor proliferation during the first week of mouse postnatal dentate gyrus development (Brackenbury et al., + channels was discovered recently in Drosophila larvae, where the single pore-forming voltage-gated Na+ channel \u03b1 subunit, paralytic, regulates neural progenitor proliferation and survival (Piggott et al., + channel regulates neural stem cell proliferation in the subependymal zone and consequently neurogenesis in the mouse olfactory bulb (Petrik et al., + channel \u03b1-subunit Kv6.4 regulates the proliferation of cells lining the embryonic brain ventricles (Shen et al., v6.4 increases it. Moreover, the Kv6.4 action appears antagonized by the expression of a homolog to the delayed rectifier K+ channel subunit Kv2.1, for which gain and loss of function manipulations cause the opposite effects on neural progenitor proliferation and ventricular brain development (Shen et al., In addition to Ca2+-dependent mechanism (Fiorio Pla et al., 2+ release-activated Ca2+ channels that enable store-operated Ca2+ entry in these cells mediated by Orai1 and STIM1. Downregulating the expression of these molecules decreases in vitro and in vivo proliferation of neural stem cells (Somasundaram et al., Non-voltage-gated ion channels have also been implicated in regulating neural cell proliferation. For instance, TRPC1 participates in bFGF/FGFR1-mediated proliferation of embryonic rat neural stem cells through a Ca+ channels and membrane depolarization, oligodendrocyte progenitor proliferation is regulated by controlling the progression of the cell cycle at the G1 phase, likely through a cAMP and cyclin-dependent kinase inhibitors p27Kip1 and p21CIP1 mechanism (Ghiani et al., A receptor-triggered hyperpolarization in embryonic and neural crest stem cells, S-phase checkpoint kinases of the phosphatidylinositol-3-OH kinase-related kinase family and, subsequently the histone variant H2AX, regulate proliferation (And\u00e4ng et al., + channel by fluid flow elicits Ca2+ dynamics through Ca2+ release-activated channels that activate ERK, regulating neural cell proliferation in the mouse subependymal zone in the olfactory bulb (Petrik et al., in vivo activates ERK in neural plate cells during Xenopus neural tube formation. In turn, constitutive activation of ERK during neural plate folding completely rescues the NTD phenotype induced by dysregulated neural plate cell proliferation due to blocking NMDA receptors or incubation with the AED valproic acid (Sequerra et al., The specific effect that is triggered downstream of all these ion channels on cell proliferation varies among these studies. This is likely due to differences in downstream signaling, recruitment of molecular partners, environmental milieu and maturational status of the cells subjected to these ion channel-triggered signaling mechanisms. There are many downstream signaling effectors reported to mediate ion channel-dependent regulation of neural cell proliferation. For instance, downstream of voltage-gated K+ channel, which in turn assigns a functional neuronal identity to developing nervous system cells (Maue et al., 2+ spikes generated by voltage-gated Ca2+ and Na+ channels in embryonic neurons (Gu et al., Xenopus laevis development (Gu and Spitzer, 2+ spikes that embryonic neurons exhibit is important for the type of neurotransmitter spinal cord neurons express, following a homeostatic rule by which higher spike frequency leads to expression of inhibitory neurotransmitters while suppression of these spikes results in expression of excitatory neurotransmitters (Borodinsky et al., 2+ waves, dependent on both extracellular Ca2+ and Ca2+ release from ion channels present in intracellular Ca2+ stores such as ryanodine receptors, are apparent in growth cones of developing neurons (Gu et al., It has been long recognized that expression of ion channels and prominently voltage-gated ion channels, their density, clustering, and subcellular localization are at the core of what distinguishes a neuron from other cell types. This fundamental question was addressed by pioneering studies from the Mandel lab when they cloned the transcription factor REST and identified it as a silencer element active in nonneuronal cells. In contrast, the absence of REST in neurons allows for the expression of the type II Na+ channels have been at the center of the process of neuronal differentiation in a variety of central nervous system structures and species. Weaver mice carry a mutation in a G-protein coupled inward rectifier K+ channel, GIRK2, that affects the pore-forming domain of the protein and impairs cerebellar granule neuron differentiation immediately after cell cycle exit (Patil et al., + channels, in turn, is a key determinant of the spontaneous Ca2+ activity that developing neurons exhibit. For instance, K+ channels like the small conductance Ca2+-activated K+ channel SK2 are expressed in immature Purkinje cells in the postnatal rat cerebellum and establish a feedback loop with Ca2+ influx and activation of Ca2+ channels to regulate the spatiotemporal features of Ca2+ transients in developing neurons (Cingolani et al., + channel during a critical period of development (Ribera and Spitzer, K2+ activity that differentiating neurons exhibit during development either directly or indirectly. Another instance of direct regulation of Ca2+ activity in developing neurons that connects the process of differentiation with the environment in which embryos develop is represented by the role of TRPM8, cold-sensitive channel, in spinal cord neuron differentiation (Spencer et al., 2+ spike frequency in ventral spinal cord neurons of Xenopus laevis embryos. In turn, Ca2+ spike activity regulates the expression of Hb9 (Spencer et al., +, Ca2+, and K+ channels and the downstream interaction between Ca2+ and cAMP dynamics (Peng et al., While all these studies are focused on specific ion channels and their role in different aspects of neuronal differentiation, they converge on shaping the spontaneous Ca2+ dynamics downstream of neurotransmitter receptor activation. NMDA receptor function is necessary for the development of dendritic arbors in differentiating retinotectal neurons and to establish appropriate retinotectal topographic maps (Cline and Constantine-Paton, 2+ channels to regulate neuritogenesis (Maric et al., Neurotransmitter-gated channels that regulate neuronal differentiation also involve Ca2+ channel-dependent mechanism that results in a higher number of calbindin-expressing mouse hippocampal pyramidal neurons when Neurotrophin-3 signaling is enhanced and lower when it is decreased (Boukhaddaoui et al., 2+]i in growth cones of rat cerebellar granule cells and Xenopus spinal cord neurons through the recruitment of TRPC channel activity (Li et al., Neurotransmitter modulation of neuronal differentiation through direct or indirect regulation of ion channel activity is a function shared by neurotrophic factors. Neurotrophin 3 signaling regulates the specification of neuronal phenotype through a voltage-gated CaXenopus retinal ganglion cells that direct their growth towards softer tissue (Koser et al., Ion channels can be mechanically gated and participate in the differentiation of developing neurons. Piezo 1, a mechanosensitive channel, mediates axonal growth and pathfinding of + channels are involved in regulating axonal outgrowth and morphology. In zebrafish, knockdown of the Nav1.6a alters axonal outgrowth and morphology of dorsally and ventrally projecting secondary motor neurons (Pineda and Ribera, Voltage-gated Na2+ transients recruit activity-dependent transcription factors like CREB (Belgacem and Borodinsky, 2+ channels are recruited downstream of the clustering of the neural cell adhesion molecule 2, inducing submembrane Ca2+ spikes that in turn activate the protein tyrosine kinase c-Src, which results in CaMKII activation and increases in filopodia density, neurite outgrowth and branching (Sheng et al., Downstream of channel activity local and whole-cell effectors are recruited to change, for example, directionality and growth rate of neurites and neurotransmitter specification, respectively. Cav1.2 that translocates to the nucleus and acts as a transcription factor controlling rat neuronal differentiation (Gomez-Ospina et al., 2+ permeation and is dependent on localized RhoA activation (Krey et al., 2+-dependent imbalance in the numbers of subtypes of differentiated cortical neurons (Panagiotakos et al., Alternatively, ion channels may trigger downstream signaling relevant for neuronal differentiation independently of ion permeation. For example, in some instances, the channel itself regulates transcription, as shown for the C-terminal fragment of Ca2+ dynamics in developing neural cells. The participation of neural activity via ion channel expression throughout neural development poses the question of whether this makes the developing nervous system more vulnerable to \u201chijacking\u201d of the necessary signaling mechanisms by exogenous unwanted factors. For instance, we have shown that incubating embryos with the AED valproic acid interferes with Ca2+ dynamics in neural plate cells and results in NTDs (Sequerra et al., 2+ activity-dependent mechanism operating in embryonic spinal cord neurons, exhibit an enhanced escape locomotor performance compared to siblings grown at warm temperatures when tested at cold temperatures (Spencer et al., The studies presented demonstrate that ion channels are expressed from the very first stages of neural development. Furthermore, the signaling mechanisms triggered by these ion channels participate in all the relevant cellular processes of early development including neural cell proliferation and neuronal differentiation, mostly through imprinting specific spatiotemporal CaRG, KS and LB wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,Hi CD8+ peripheral T-cells for a cytolytic gene signature. Expression of cytotoxic genes in the peripheral blood was associated with worse prognosis, which may be explained by persistent micrometastatic disease that finally leads to recurrence . The aual., 2020). Numerous studies have analyzed the association of breast cancer with outcome, including the spontaneous course of disease and response to chemotherapy (Sparano et al., 2018; Wang etThe author declares no conflict of interest."}
+{"text": "By utilizing high-throughput technologies, precision medicine is being developed as a preventative, diagnostic and treatment tool to combat complex human diseases. It is therefore necessary to investigate how to integrate these multi-scale \u2018omics datasets to distinguish the novel individual-specific disease causes from conventional cohort-common disease causes. Currently, machine learning plays an important role in biological and biomedical research, especially in the analysis of big \u2018omics data. This Research Topic focuses on the application of wet \u2018omics technology and dry machine learning approaches together to further develop precision medicine.Liu, R. et al. proposed a single-sample-based hidden Markov model approach to detect the dynamical differences between a normal and a pre-disease states, to detect the immediately upcoming critical transition from the pre-disease state. Lee et al. implemented a deep learning-based python package for multimodal longitudinal data integration, especially the numerical data including time series and non-time series data. Yu et al. implemented an adjusted individual-specific edge-network analysis (iENA) method when a limited number of samples from one individual are available, and made a proof-of-concept study on individual-specific disease classification based on microbiota compositional dynamics.Chen et al. analyzed the miRNA expression profiles in whole plasma, Extracellular Vesicle (EV) and EV-free plasma of lung cancer patients and identified several discriminative miRNAs and classification rules as potential non-invasive biomarkers by Monte-Carlo feature selection method and Repeated Incremental Pruning to Produce Error Reduction method. Liu, Z. et al. conducted a genome-wide analysis of allele-specific expression (ASE) in colorectal cancer patients, providing a systematic understanding of how ASE is implicated in both tumor and normal tissues. Hu et al. used RNA sequencing data to identify and quantify the circRNAs in atrial fibrillation (AF) by bioinformatics analysis and characterized their potential functions through the competing endogenous RNA network and protein-protein interaction network. Shi, X. et al. screened a cohort of Total anomalous pulmonary venous connection cases and healthy controls for rare copy number variants by whole exome sequencing, providing candidate genes associated with rare congenital birth defect. Wu et al. performed whole exome sequencing on seven members of an HSCR family, making a first report on the in-frameshift variant p.Phe147del in RET responsible for heritable HSCR. Xie et al. investigated rare Copy number variants (CNVs) in a recruited cohort of unrelated patients with pulmonary atresia and a population-matched control cohort of healthy children by whole-exome sequencing, helping elucidate critical disease genes and new insights of pathogenesis. Meng et al. made a brief research report on the driver gene mutations in Chinese patients with non-small cell lung cancer by target sequencing and Hotspot3D computational approach together.Ho et al. provided a review of polygenic risk scoring and machine learning in complex disease risk prediction with tissue-specific targets, expecting their power to manage complex diseases for customized preventive interventions. Li et al. identified target genes at Juvenile idiopathic arthritis risk loci in neutrophils by an integrated multi-omics approach, constructing a protein-protein interaction network on the basis of a machine learning approach. Dai et al. applied the mega-analysis of Odds Ratio (MegaOR) method to prioritize candidate genes of Crohn's Disease, based on a comprehensive collected multi-dimensional data. Wang, C.H. et al. detected differentially expressed lncRNAs and mRNAs in atherosclerosis by analyzing public datasets with the weighted gene co-expression network analysis, and this bioinformatics study would provide potential novel therapeutic and prognostic targets for atherosclerosis. Jiang, S. et al. collected and profiled the circRNA expressions of heart tissues from Atrial fibrillation patients and healthy controls, providing new insights of the circRNA roles in AF with highly potential interaction mechanisms among circRNAs, microRNAs, and mRNAs.Gu et al. reused the Surveillance, Epidemiology, and End Results registry database to conduct stratification analyses, univariable and multivariable analyses, indicating surgery is an important component of multidisciplinary treatment and sublober resection is not inferior to lobectomy for the specific patients. Zhang, J. et al. exploited the largest crohn's disease dataset and ulcerative colitis dataset by a two-step approach, exhaustively searching for epistasis with dense markers and exploiting marker dependencies. Du et al. analyzed the genome-wide splicing data in 16 cancer types with normal samples by a network-based and modularized approach and captured the pan-cancer splicing and modularized perturbation, which support the dominant patterns of cancer-associated splicing. Zhao et al. assessed the prognostic value of Apolipoprotein E and explored the potential relationship with tumor progression in colorectal cancer (CRC), by collecting the microarray data from the Gene Expression Omnibus and exploring the gene with prognostic significance from the TCGA database. Tang et al. proposed an effective data integration framework HCI (High-order Correlation Integration) to realize high-dimensional data feature extraction with extensive flexibility and applicability on sample clustering with RNA-seq data on bulk and single-cell levels. Chang et al. identified new susceptibility genes and causal sub-networks in schizophrenia by an integrated network-based approach, and reported the N-methyl-D-aspartate receptor interactome highly targeted by multiple types of genetic risk factors. Wang and Liu recognized potential diagnostic biomarkers of Alzheimer's disease by integrating gene expression profiles from six brain regions in a machine-learning manner and validating marker genes in multiple cross-validations and functional enrichment analyses. Xu et al. provided an effective way for the annotation of nuclear non-coding and mitochondrial genes and the identification of new steady RNAs, making a pan RNA-seq analysis to suggest the ubiquitous existence of both 5' and 3' end small RNAs.Yang et al. presented a new pathogen detection and strain typing method UltraStrain for Salmonella enterica based on whole genome sequencing data, which includes a noise filtering step, a strains identification step on the basis of statistical learning, and a final refinement step. Tan et al. conducted comprehensive and systematic experiments, including in vitro genetic assessments and an in vivo acute toxicity study, aiming to study safety issues associated with Bacteroides ovatus ELH-B2. Qiu et al. set up an in-silico model emerging or re-emerging dengue virus (DENV) based on possible antigenicity-dominant positions of envelope (E) protein, so that, the DENV serotyping may be re-considered antigenetically rather than genetically. Zhang, B. et al. collected and re-analyzed the published fecal 16S rDNA sequencing datasets to identify biomarkers to classify and predict colorectal tumors by random forest method, and the trained random forest model has good AUC performance for CRC when combined all samples, although the predication performed poorly for advance adenoma and adenoma.Luo et al. proposed a manifold learning-based method to predict disease-gene associations by assuming that the geodesic distance of related disease-gene pairs should be shorter than that of non-associated disease-gene pairs. Tkachev et al. proposed a heuristic technique termed FLOating Window Projective Separator (FloWPS) for data trimming with SVM and applied it for personalized predictions based on molecular data. Wang, W. et al. developed a new multiple-instance leaning algorithm derived from AdaBoost and accessed this algorithm on annotating proteins that bind DNA and RNA. Xiao et al. proposed a method called BPLLDA to predict lncRNA-disease associations from a heterogeneous lncRNA-disease association network assuming the association paths on network with fixed lengths. Zou et al. used decision tree, random forest and neural network to predict diabetes mellitus by the hospital physical examination data, and the best prediction could be achieved by random forest after dimensionality reduction by principal component analysis and minimum redundancy maximum relevance.Guo et al. proposed a new approach SGL-LMM for mining multivariate associations of quantitative traits by combining sparse group lasso and linear mixed model together, which can consider confounding effects and groups of SNPs simultaneously. Zhang, W. et al. developed a new calling method for differentially expressed genes as DECtp by integrating tumor purity information into a generalized least square procedure and a follow-up Wald test. Cheng et al. utilized a Mendelian randomization (MR) to test the influence of body mass index (BMI) on the risk of T2DM based on GWAS data, validating the causal effect of high BMI on the risk of T2DM. Feng et al. utilized one analysis procedure of feature selection and classification on both transcriptomes and methylomes cancer data, suggesting age should be an essential factor rather than confounding factor in the training and optimization of disease diagnosis model.Qin et al. developed a new joint gene set analysis statistical framework, aiming to improve the power of identifying enriched gene sets by integrating multiple similar disease datasets when the sample size is limited. Shi, Q. et al. proposed a new computational framework of \u201cMulti-view Subspace Clustering Analysis\u201d to capture the underlying heterogeneity of samples from multiple data types, by first measuring the local similarities of samples in the same subspace and then extracting the global consensus sample patterns. Jiang, P. et al. developed a new variants mining algorithm based on trio-based sequencing data, and applied this method on a Ventricular septal defect (VSD) trio and identified several genes and lncRNA highly related to VSD.Finally, we sincerely thank the reviewers for their great efforts to ensure the high quality of all contributing articles, and we hope this Research Topic can attract wide attention in these topics of precision medicine based on machine learning and omics data.TZ drafted the manuscript. TZ, TH, and CL revised the manuscript.This study was supported by the National Natural Science Foundation of China (11871456), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the Natural Science Foundation of Shanghai (17ZR1446100).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this review, we discuss the prevalence, molecular mechanisms, and functional evidence for androgen-regulated prostate cancer fusion genes and transcripts. We also discuss the clinical relevance of especially the most common prostate cancer fusion gene TMPRSS2-ERG, as well as present open questions of prostate cancer fusions requiring further investigation.Androgens are steroid hormones governing the male reproductive development and function. As such, androgens and the key mediator of their effects, androgen receptor (AR), have a leading role in many diseases. Prostate cancer is a major disease where AR and its transcription factor function affect a significant number of patients worldwide. While disease-related AR-driven transcriptional programs are connected to the presence and activity of the receptor itself, also novel modes of transcriptional regulation by androgens are exploited by cancer cells. One of the most intriguing and ingenious mechanisms is to bring previously unconnected genes under the control of AR. Most often this occurs through genetic rearrangements resulting in fusion genes where an androgen-regulated promoter area is combined to a protein-coding area of a previously androgen-unaffected gene. These gene fusions are distinctly frequent in prostate cancer compared to other common solid tumors, a phenomenon still requiring an explanation. Interestingly, also another mode of connecting androgen regulation to a previously unaffected gene product exists via transcriptional read-through mechanisms. Furthermore, androgen regulation of fusion genes and transcripts is not linked to only protein-coding genes. Pseudogenes and non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) can also be affected by androgens and  Androgens are steroid hormones governing the development of male reproductive tract organs and secondary male sex characteristics, as well as functioning in the regulation of muscle mass, fat deposition, and function of steroid hormone-sensitive neurons , also referred to as prostein, as a 5\u2032 partner . The KLK4-KLKP1 fusion is formed either by a trans-splicing mechanism or an in-frame fusion due to a microdeletion, leading to the fusion of the first two exons of KLK4 with exon 4 and 5 of KLKP1. The resulting chimeric sequence predicts a 164\u2013amino acid protein, of which the latter third is derived from KLKP1, leading to a conversion of the non-coding pseudogene to a protein-coding gene. Utilizing cell culture and chicken chorioallantoic membrane (CAM) assay, the expression of KLK4-KLKP1 fusion transcript was shown to affect cell proliferation, cell invasion, intravasation, and tumor formation  in prostate cancer. LncRNAs are >200 bp long RNAs that do not encode for protein end-products. They are known to play important roles in the regulation of gene expression and to be dysregulated in several types of human malignancies, including prostate cancer  was shown to be strongly correlated with ERG expression in ERG-positive primary tumors, as well as CRPCs  developed prostatic adenocarcinoma, whereas Pten+/\u2212 mice only showed HGPIN lesions. Moreover, two genes involved in promoting cell migration and invasion (CXCR4 and ADAMTS1) were found to be upregulated in the context of ERG overexpression , showed a significant reduction in tumorigenicity, concomitant reduction in the expression of the oncogene C-MYC and upregulation of prostate epithelial differentiation genes KLK3 and SLC45A3  in LNCaP and VCaP cells. The results revealed that ERG and AR can co-occupy the same target genes and ERG functions as a repressor of AR-driven lineage-specific differentiation program. ERG also directly regulates the expression of the histone methyltransferase EZH2, by binding to its promoter and activating EZH2-mediated cell de-differentiation program  transcriptional program, whereas ETV1 was found to upregulate genes involved in AR signaling and cooperates in its activation.Carver and colleagues also showed that in vitro and in vivo and pointed to a role of the ETV1 transcriptional program in the development of more aggressive disease and poorer clinical outcome . These authors, in contrast to what reported by Tomlins and colleagues  is a direct target of ERG in VCaP cells and that PAI-1 inhibited the invasion of VCaP cells  treatment of VCaP and LNCaP cells showed increased expression of both ERG and CXCR4 in VCaP, but not LNCaP, suggesting that, indeed, the androgen-mediated ERG overexpression caused by the TMPRSS2:ERG fusion drives CXCR4 expression in VCaP cells, confirmed by the lack of CXCR4 induction when siERG-VCaP cells were treated with R1881. Androgen-induced CXCR4 overexpression was also shown to increase invasiveness of VCaP cells . Moreover, ERG overexpression was shown to activate the Wnt signaling pathway via increased expression of the Wnt receptor FZD4  and upregulation of the EMT mediator integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1  lesions  and TMPRSS2:ERG has been shown to improve the sensitivity for prostate cancer diagnosis , derived from PC-3, to assess the role of the TMPRSS2:ERG fusion transcript in the formation of bone metastases. They used PC3c clones that overexpress the most common TMPRSS2:ERG transcript variant (TMPRSS2 exon 1 and ERG exon 4) at variable levels and also including the 72 bp exon 11 previously shown to be associated with more advanced stages of the disease . These genes were confirmed to be directly regulated by ERG overexpression. Knock-down experiments confirmed that PLXNA2 is directly involved in the increased migration and invasion capabilities of prostate cancer cells  and Endothelin-1 (ET-1), responsible for improved acquisition of a bone-like phenotype in cancer cells (osteomimicry), helping the cancer cells survive in the bone microenvironment  in separated foci of prostate cancers revealed interfocal heterogeneity and intrafocal homogeneity, indicating that individual foci are the result of clonal expansion (Mehra et al., Prostate cancer is a heterogeneous disease which very often harbors multiple cancer foci within the same gland. It is well-established that different foci are histologically and molecularly heterogeneous, suggesting that they are clonally independent (Wise et al., SPINK1 had been reported in a subset of ETS-negative prostate cancer samples exclusively (Tomlins et al., ERG and SPINK1 overexpression were mutually exclusive in all tumor foci (Fontugne et al., ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci, but not in the same tumor cells (Lu et al., CHD1 and MAP3K7, and mutations in SPOP, FOXA1, and IDH1 were also found to be associated with the ETS-fusion negative subtype (Liu et al., SKIL fusions described in Annala et al. (ERG. For example, correlative analysis with other ETS gene fusions showed that KLK4-KLKP1 expression is associated with ERG but not ETV1, ETV4, or ETV5 (Chakravarthi et al., Profiling studies of fusion genes in multifocal disease are also important to evaluate co-occurrence of these alterations. Other FISH analyses of recurrent ETS gene rearrangements in multifocal prostates showed complex patterns of alterations, with both rearranged and un-rearranged foci and multiple ETS rearrangements within the same gland (Clark et al., a et al.  and the a et al.  were idea et al. , the ERGTumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors. For example, gene fusions involving ETS transcription factors have been utilized in diagnostic applications, such as with detection of TMPRSS2-ERG fusion transcripts in urine samples or CTCs from patients or ERG protein by immunostaining in biopsies [reviewed recently in Kumar-Sinha et al. , Berg 2, and Garin silico methods, demonstrating that a small molecule targeting the ERG-ETS domain suppressed its transcriptional activity and reverse transformed the characteristics of prostate cancers aberrantly expressing ERG (Butler et al., in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures, and inhibited growth of ERG-positive tumors in mouse xenograft models (Wang et al., As the TMPRSS2-ERG fusion is the most common alteration in prostate cancer, molecular targeting of it has gained attraction as a potential therapeutic strategy. Recent examples include the work of Wang and colleagues, who identified a series of peptides that interact specifically with the DNA binding domain of ERG, leading to proteolytic degradation of the ERG protein, and attenuation of ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth (Wang et al., TNIK as a potential therapeutic target in ERG-fusion gene positive prostate cancer (Lee et al., On the basis of the interaction of ERG and other ETS fusions with the DNA repair proteins PARP1 and DNA-PKc, use of PARP inhibitors has shown initial promise and is being tested in ETS fusion-positive prostate cancers [reviewed in Kumar-Sinha et al.  and PedeSLC45A3 with FGFR2 in which the SLC45A3 non-coding exon 1 is fused to the intact coding region of FGFR2 has been found from a brain metastasis of a prostate cancer patient (Wu et al., While the therapeutic targeting of transcription factor oncogenes remains challenging, tumors with fusions involving therapeutically targetable genes, most often kinases, often have the strongest implications in personalized treatment of cancer patients. Amongst prostate cancer fusion genes, especially the effects of androgen-regulated SLC45A3-BRAF and a non-androgen-regulated ESRP1-RAF1 are targetable. The effects of ectopic expression of these fusion genes were studied in RWPE benign immortalized prostate epithelial cells and resulted in increased proliferation, invasion and anchorage-independent growth, which were sensitive to RAF and MEK inhibitors (Palanisamy et al., in vivo environment and is thus valuable in developing new drugs and selecting appropriate treatment strategies for prostate cancer patients. In terms of prostate cancer fusion genes, the expression of ERG has been shown to be retained in the PDXs along with other molecular, histopathologic, and genomic characteristics (Palanisamy et al., Prostate cancer xenografts play a central role in pharmacological testing of potential drugs. The VCaP cell line, due to the TMPRSS2-ERG fusion gene it harbors, has been widely utilized in xenograft drug studies. For example, TMPRSS2-ERG harboring VCaP bone xenograft models were shown to better respond to enzalutamide treatment, suggesting that ERG expression status in tumors could help stratify patients for enzalutamide therapy (Semaan et al., de novo expression of a cancer driver protein, for some fusions the advantage seems not as straightforwardly explained nor convincingly supported by functional data. Especially, despite a lot of effort, the field has yet to pinpoint why and how TMPRSS2-ERG fusion is an early event in prostate cancer development, yet the most significant functions of it seem concentrated in the phase of metastatic disease. The PCAWG Consortium recently reported that, amongst their 3,540 fusion events identified in 1,188 pan-cancer samples studied, 82% were associated with specific genomic rearrangements (PCAWG Transcriptome Core Group et al., The frequent gene fusions in prostate cancer are a curiosity amongst solid tumors. Why and how this particular tumor type benefits so much from these rearrangements for them to be so frequent are still open questions. While the benefit with certain fusions may clearly result from de novo structures and functions, it is possible that also some of the other fusion transcripts may have non-coding functions yet to be discovered. This is supported by the notion that up to 20% of expressed prostate cancer fusion transcripts are non-canonical, with one or both transcripts in antisense orientation (Vellichirammal et al., The case of SLC45A3-ELK4 fusion has proven that it is possible for a chimeric RNA to function as a ncRNA, even though the 3\u2032 fusion partner is initially protein-coding. Considering that chimeric transcripts may have acquired MS and LL wrote the manuscript. SK designed the figures. MS, LL, and SK edited the manuscript. All authors have approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors and metastatic lesions and provide significant information about tumor progression and metastasis. CTCs contribute to tumor metastasis through the epithelial-to-mesenchymal transition (EMT). CTC clusters and stem-like phenotypes lead to a more aggressive and metastatic potential. CTCs retain the heterogeneity and imitate the nature of corresponding primary tumors. Therefore, it is important to use single-cell based analysis to obtain information on tumor heterogeneity and biology. CTCs are also good candidates for building preclinical models  for drug screening, disease modeling, genome editing, tumor immunity research, and organ-like biobank establishment. In this article, we summarize the current CTC capture technology, dissect the phenotypes associated with CTC metastasis, and review the progress in single-cell based analysis and preclinical modeling of the pattern and kinetics of CTCs. In particular, we discuss the use of CTCs to assess the progression of hepatocellular carcinoma (HCC). Circulating tumor cells (CTCs), which carry valuable tumor information, arise from the hematogenous diffusion of metastatic tumors in vitro and in vivo CTC culture approaches have provided significant insights into tumor development and metastasis With emerging technological developments, CTC research is not limited to enumeration. Different CTC phenotypes have been analyzed, including the epithelial, mesenchymal, and stem cell types and CTC clusters, which were associated with distinct kinetics and functions Hepatocellular carcinoma (HCC) is the seventh most common cancer and the second leading cause of cancer-related deaths worldwide In recent years, a series of \u201cliquid biopsy\u201d techniques have been developed to evaluate HCC biomarkers  Figure 1.CTCs, first discovered by Thomas Ashworth 150 years ago, can be obtained multiple times from tumor patients without an invasive approach. The recent development of new and powerful technologies has remarkably facilitated the precise capture of CTCs et al.et al. developed a novel Labyrinth microfluidic device, offering unique features over other inertial devices to efficiently isolate CTCs from the peripheral blood of HCC patients CTCs from HCC patients are primarily isolated based on their unique biological or physical properties. The biological methods include immune magnetic bead capture and nucleic acid aptamer capture. Court et al., \u201cCTC-iChip\u201d, an inertial focusing-enhanced microfluidic CTC capture platform, is capable of isolating CTCs with or without tumour membrane epitopes et al. proposed an on\u2010chip strategy combining multiplex SERS nano-vectors and multivariate analysis for in situ profiling of circulating tumor cell phenotypes on microfluidic chips et al. reported a magnetically assisted surface\u2010enhanced Raman scattering (SERS) biosensor for HCC CTC detection et al.Currently, nanomaterials and microfluidic chips are widely used for CTC capture. According to the study by Ozkumur et al. showed that tumor cells undergo gradual or complete EMT  that is associated with slow proliferation, loss of epithelial cell adhesion molecule EpCAM expression, and increased migration et al. showed that mixed CTCs might be vital for intrahepatic metastasis, and mesenchymal CTCs could predict extrahepatic metastasis et al. revealed that total CTC count and the proportion of M-CTCs are negative factors for postoperative HCC recurrence et al. mapped the distribution and characterized the biological features of HCC CTCs along the transportation route EMT is a process that initiates metastasis et al. that CTC clusters originate from oligoclonal tumor cell groupings rather than cell aggregation in the blood vessels et al. prospectively measured CTCs at five key vascular sites in patients with localized HCC  et al.Besides EMT, CTC clusters have been proposed to indicate the initiation of tumor metastasis et al. showed that ICAM-1 is a marker of HCC stem cells. They quantified circulating CD45-ICAM-1+ tumor cells from 60 HCC patients using flow cytometry and found that higher frequencies of circulating CD45-ICAM-1+ cells in HCC patients correlated with more aggressive tumor behavior and worse clinical outcomes et al. found that EpCAM+ CTCs show stem cell characteristics and indicate poor prognosis of HCC after curative resection It has been more than a century since Cohnheim proposed the \u201cembryonic theory\u201d of cancer. The cancer stem cell (CSC) hypothesis argues that cancers arise from a subset of malignant cells that possess stem cell characteristics et al.et al.et al.In animal models, CD90+CXCR4+ HCC cells could be CTSCs, as reported by Zhu et al. systematically investigated the clinical significance of diverse subtypes of CTCs and showed that the presence of EpCAM+ multiploid CTSCs (cut-off: \u22651 cell in 6 ml of blood), EpCAM- small triploid CTCs (\u22655 cells), CTM (\u22651), and increased triploid CTCs, were highly relevant for poor prognosis Although the tumor metastasis mechanism remains unclear Figure 2.Single-cell sequencing technology has been a major breakthrough in sequencing history. CTCs can be processed and analyzed as single cells and then subjected to single-cell sequencing. Given the considerable heterogeneity of CTCs, it is essential to analyze the molecular and genetic characteristics of single CTCs et al. developed a new technology combining image flow cytometry and high-density single-cell mRNA sequencing to identify CTCs in HCC patients et al. collected blood from the peripheral vein, peripheral artery, hepatic vein, inferior hepatic vena cava (IHIVC) and portal vein (PoV) before tumor resection. They analyzed the EMT phenotypes of CTCs using the 4-channel immunofluorescence CellSearch assay and microflow quantitative RT-PCR. The study demonstrated the heterogeneity of EMT status in CTCs across different vascular compartments With advances in the next-generation sequencing (NGS) and single-cell sequencing (SCS) technology, it is possible to obtain the complete genomes of CTCs and compare them with the corresponding primary and metastatic tumors. Several clinically relevant genomic alterations have been discovered, such as single nucleotide variations (SNV), microsatellite instability, and copy-number variations, providing valuable information for the companion diagnostics et al. established a CTC line using the peripheral blood from a mouse HCC model Epigenetic events, including histone modification and DNA base modifications (such as methylation and hydroxy-methylation), also contribute to tumor cell heterogeneity. ChIP-seq (Illumina) is used for studying histone modifications at the single-cell level et al. developed a microchip-assisted single-cell proteomic method for profiling CTC surface antigens facilitating the phenotypic and functional analysis of single CTCs Single-cell protein analysis identifies the heterogeneity of seemingly similar tumor cells, providing critical insights into the mechanisms underlying tumor heterogeneity et al. isolated CTCs from 31 patients and cultured them into spheroids Although the techniques mentioned above have provided abundant information about CTCs, their functions still need to be validated in preclinical models. CTC-based preclinical models include 2D cultures, CTC spheroids, CTC-derived organoids, and xenografts in vivo model in which CTCs enriched from patient blood are injected into immunocompromised mice to generate tumors and expand the number of original tumor cells et al. had developed a xenograft assay and shown that primary human luminal breast cancer CTCs contain metastasis-initiating cells (MICs) that cause metastasis in the bone, lung, and liver. These MIC-containing CTCs expressed EpCAM, CD44, CD47, and MET +CD44+CD47+MET+ CTCs correlated with increased metastatic sites and a poor survival rate. Recently, Vishnoi et al. established a novel triple- negative breast cancer (TNBC) liver metastasis\u2010specific CDX model that selectively recapitulates CTC biology for four sequential generations of mice CTC-derived xenograft (CDX) is an et al. was a significant advance et al.in situ capture method for ex vivo CTC expansion in a 3D co-culture model simulating tumor microenvironment. They successfully expanded CTCs from 14 out of 19 early-stage lung cancer patients and revealed several mutations, including TP53 in both cultured CTCs and primary lung cancer. This strategy sets the stage to further characterize CTC biology and metastatic factors in patients with early-stage cancers. Although CDOs have not been established from HCC patients yet, we propose a strategy for analyzing HCC CDOs .The establishment of CDX models is time-consuming and inapplicable to large-scale drug screening. CDO is the alternative that allows quick molecular analysis and high-throughput drug screening. An organoid is a special 3D culture model harboring a semisolid extracellular matrix supplemented with growth factors for tissues et al. used an advanced CanPatrol CTC-enrichment technique and in situ hybridization to sort and classify CTCs from blood samples and found 90.18% of HCC patients to be CTC positive, even at the early stage of HCC  et al. implicated CTCs in tumor staging There is considerable evidence for a crucial role of CTCs as initiators of metastasis, suggesting CTCs as a biomarker for the early detection of HCC. In previous CTC studies, early detection of HCC was mainly based on the assessment of CTC numbers, showing a significant positive correlation between the CTC number and the standard Barcelona Clinic Liver Cancer (BCLC) stage as well as the serum AFP level et al.et al. also reported the association of increased postoperative CTC numbers with worse prognosis of HCC patients et al., CTCs were classified using EMT markers and the presence of mesenchymal CTCs, together with mixed phenotypic and epithelial CTCs predicted the shortest relapse-free survival In patients diagnosed with HCC, CTCs not only contribute to neoplasm staging but are also useful for prognosis et al. used CanPatrol\u2122 system to count CTCs 1 day prior to and 30 days after surgical excision of HCC et al. to detect the preoperative levels of EpCAMmRNA+ CTCs and CD4+CD25+Foxp3+ Treg cells in 49 HCC patients. The data showed that elevated CTC/Treg levels implied a higher risk of postoperative recurrence Since CTC numbers may change after anti-tumor treatment, they could be used for predicting or evaluating therapeutic efficacy before or after treatments. Ye et al. presented a novel system to provide quantitative information of sorafenib-related targets through simultaneously detecting phosphorylated ERK (pERK) and Akt (pAkt) in HCC CTCs Mutation profiles and drug-resistant molecular expression profiles have been widely identified in many solid tumors. In this context, CTC analysis allows the determination of therapeutic targets and resistance mechanisms to cancer therapies at the DNA, RNA, and protein levels and has great potential to identify the patient population most likely to respond to specific treatments. Li et al. that evaluation of PD-L1+ CTCs discriminated between HCC patients with early-stage and advanced/metastatic disease Table Immune checkpoint inhibitors have launched a new era in immunotherapy, with exceptional long-term remissions in some patients across diverse tumor entities. However, only a few patients respond to this modality, with many experiencing severe side effects Supplementary Figure.CTCs offer valuable diagnostic and therapeutic information on HCC, although some challenges still exist in their identification, quantification, and/or characterization. Currently, new CTC capture technologies are emerging, while the CellSearch system is still the only FDA-approved CTC detection and quantification method. So, we urgently need novel and certified tools for quick isolation and characterization of CTCs. There are various sources of CTCs including primary tumors and metastatic lesions. Identifying of the sources of captured CTCs is beneficial for a more in-depth analysis. For a comprehensive understanding of CTC biology, multiple omic disciplines should be combined for single-cell analysis. With the development of CDO approaches, we can co-culture CTCs with immune cells to simulate the tumor microenvironment to monitor tumor progression and associated molecular events. Furthermore, as part of liquid biopsy, CTC testing should be combined with other liquid biopsies such as analysis of ctDNA and exosomes to promote the efficiency of clinical CTC tests. Ongoing and future research on CTC capture technology, molecular profiling, sing-cell analysis, and preclinical models are expected to considerably improve CTC testing for early diagnosis, efficacious treatment, and effective prognostic management of HCC. The overview of CTC research is showed in the Supplementary figures and tables.Click here for additional data file."}
+{"text": "Tau is a microtubule-associated protein (MAPT) that is highly expressed in neurons and implicated in several cellular processes. Tau misfolding and self-aggregation give rise to proteinaceous deposits known as neuro-fibrillary tangles. Tau tangles play a key role in the genesis of a group of diseases commonly referred to as tauopathies; notably, these aggregates start to form decades before any clinical symptoms manifest. Advanced imaging methodologies have clarified important structural and functional aspects of tau and could have a role as diagnostic tools in clinical research. In the present review, recent progresses in tau imaging will be discussed. We will focus mainly on super-resolution imaging methods and the development of near-infrared fluorescent probes. Tauopathy is a general term referring to a group of disorders characterized by the accumulation of misfolded tau protein. Highly heterogeneous from a clinical perspective, tauopathies can be further divided into primary tauopathies (where tau is the leading cause of neurodegeneration) and secondary tauopathies (where a tauopathy is associated with other pathologies). Progressive supranuclear palsy (PSP), Pick\u2019s disease (PiD), and fronto-temporal dementia (FTD) are examples of primary tauopathies while, Alzheimer\u2019s disease (AD), Lewy\u2019s body disorder (LBD), and Down\u2019s syndrome (DS) belong to the second group  STED experiments, revealed that in FTD neurons, an aberrant microtubular organization was responsible for the deformation of the nuclear lamina , and [11C]PBB3. These compounds represented a \u201cproof of concept\u201d in the process of tau PET imaging and their properties have extensively been examined  in the whole brain; in addition, MAO-B correlated with glial fibrillary acid protein (GFAP) a marker for astrocytes, and therefore they concluded that [18F]THK5351 PET could be useful to evaluate tau-associated neuroinflammatory states in AD rather than tau pathology. PET scanning using the tracer [18F]AV-1451 was performed on a 76-year-old female patient carrying the MAPT R406W mutation. This mutation leads to the presence of tau aggregates similar to those found in AD. Clinically, the patient presented a long history of cognitive deficits and behavioral abnormalities. Postmortem immunohistochemical staining for hyperphosphorylated tau protein showed a strong positive correlation between in vivo [18F]AV-1451 retention and the density of tau aggregates . In this study, no significant correlation was reported between in vivo PET and autoptic examination of tau deposits; therefore, the authors conclude that [18F]-AV-1451 may not be suited to detect tau aggregates in these non-AD tauopathies . Another big obstacle is represented by the heterogeneous structural organization of tau aggregates in AD and non-AD-related tauopathies. The need for dyes with better selectivity, affinity, and specificity is opening the door for the development of a second generation of tau tracers . In vitro experiments confirmed its ability to label intracellular tau aggregates; however, no experiments on mouse models of tauopathies nor on postmortem human AD tissues have been performed  with better fluorescence emission upon tau aggregates binding (\u03bbem = 650 nm) have been proposed  and a large Stokes shift (110 nm). When incubated with AD human brain slices, the probe 2e displayed a staining pattern that resembled that which was obtained with an antibody against ptau epitopes  experiments allowed a strong and stable signal from the brain of both JNPL3 and htau/PS1 mice to be detected. Very little signal was observed in control animals. Moreover, older mice from both genotypes showed higher signals compared with younger mice further suggesting the specificity of the scFv 235 antibody (Krishnaswamy et al., Several research groups are actively involved in developing affordable probes/methodologies that could be potentially used for the diagnosis of tau-based neurodegenerative disorders. A plethora of approaches using different chemical strategies have been proposed (Verwilst et al., in vitro aggregation of misfolded proteins in particular (Cosentino et al., in vitro and in vivo. Tau aggregates have recently been described in the retina of AD patients (Sch\u00f6n et al., Advanced imaging methodologies are providing valuable information about tau structure, interaction with proteins and organelles, localization, and mechanisms of self-aggregation. Far from being definitive, these techniques are still under active development as several limitations need to be overcome. A critical step for improvement is represented by protein labeling with fluorescent probes (Wang et al., All authors reviewed and discussed relevant literature, wrote sections, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this editorial, we briefly summarized the International Conference on Intelligent Biology and Medicine 2019 (ICIBM 2019) that was held on June 9\u201311, 2019 at Columbus, Ohio, USA. We further introduced the 19 research articles included in this supplement issue, covering four major areas, namely computational method development, genomics analysis, network-based analysis and biomarker prediction. The selected papers perform cutting edge computational research applied to a broad range of human diseases such as cancer, neural degenerative and chronic inflammatory disease. They also proposed solutions for fundamental medical genomics problems range from basic data processing and quality control to functional interpretation, biomarker and drug prediction, and database releasing. The International Conference on Intelligent Biology and Medicine 2019 (ICIBM 2019) was co-hosted by the International Association for Intelligent Biology and Medicine (IAIBM) and the Department of Biomedical Informatics at The Ohio State University on June 9\u201311, 2019 in Columbus, OH. A total of 164 researchers attended the conference, of which 79 were faculty/staff and 84 were trainees. The conference included four keynote lectures, four eminent scholar talks, five tutorials and workshops, twelve concurrent regular scientific sessions, and one poster session. It covered a board range of topics, including but not limited to next-generation sequencing, single cell analyses, deep learning, metabolomics, genomics, and other omics research, systems biology, medical applications and translational research involving high-throughput data, computational methods and novel applications of computational tools, and others. Among 105 original manuscript submissions, 19 research articles of interests to computational method development and applications in medical genomics were selected for the ICIBM 2019 BMC Medical Genomics Supplement Issue after with careful peer reviews. The proposed computational methods and applications cover a broad range of biomedical topics and are innovative with significant biological and clinical implications. A more detailed summary of the conference arrangement, scientific programs, and achievements were published elsewhere [This supplement issue includes five papers that propose computational methods to  predict Li et al. developed a new computational method, namely SIMCCDA (Speedup Inductive Matrix Completion for CircRNA-8 Disease Associations prediction), which is the first work that apply the recommendation system based inductive matrix completion to predict circRNA-disease associations . The cirLi et al. developed a novel computational workflow for customized neoantigen prediction and selection . The worMostavi et al. conducted a novel application of convolutional neural network model for cancer type prediction by using gene expression data . Novel CCai et al. developed a new association test, namely weighted Adaptive Fisher (wAF) to test the association of common and rare SNVs and detect dense and sparse signals in GWAS . wAF is Foroughi pour et al. developed a new computational capability to conduct binary classification based on high dimensional SNP data . Binary Three genomics analysis are included in this supplement issue, two utilized network-assisted methods to explore new SNPs in multiple sclerosis and Cleft lip with/without cleft palate, while the other focused on somatic mutations in genetic regulatory elements in melanoma. Each of the two genomics data based study identified significant sets of biological and clinical associated genetic events.Zhang et al. explored the landscape of somatic synonymous mutations in genetic regulatory elements in melanoma . This stManuel et al. conducted a network-assisted search in two multiple sclerosis GWAS data sets to identify the gene networks that were associated with the disease . With apYan et al. conducted a integrative network-assisted GWAS study of the Cleft lip with/without cleft palate (CL/P) . By usinFour biological network based studies, including two differential co-expression analysis and two network based drug prediction, are included in this supplement issue. Two studies identified variations in co-expression networks through different disease stages of Alzheimer\u2019s disease and chronic kidney disease, which can be potentially used as biomarkers of disease progression. Two novel network based drug prediction method was developed by predicting variations in signaling pathway activities in patient subgroups and applied to identify novel drug and targets in pancreatic and ovarian cancer.Upadhyaya et al. conducted a differential gene co-expression analysis of gene expression data collected from patients\u2019 plasma samples of Alzheimer\u2019s disease . The autnuclear SMAD2/3 signaling and signaling events mediated by focal adhesion kinase, 27 including Regulation of nuclear SMAD2/3 signaling. The study also identified a list of vanishing hub genes and disrupted correlations within and between key signaling pathways, on the pathophysiological mechanisms of CKD progression.Yu et al. conducted a differential co-expression analysis of the RNA-seq data of chronic kidney disease (CKD) collected from patients at different disease stages . Kidney Liu et al. conducted a network based study to identify possible drug targets in pancreatic ductal adenocarcinoma . A novelZhang et al. conducted an integrative network analysis to identify potential drug targets of ovarian cancer . In theiA substantial part of this supplement issue is composed by biomarker predictions, including seven works with utilizing  deep leaHuang et al. developed a novel auto-encoder based model, namely AECOX, to identify prognostic marker genes from cohort transcriptomics data . CompariLiu et al. developed a novel computational pipeline to predict colon cancer prognosis by using gene expression level of transcriptional factors . UnivariDong et al. developed a new computational pipeline to identify breast cancer patients\u2019 prognosis associated transcriptional regulatory factors (TFs), by using estimated activity level of TFs . Data seSmerekanych et al. conducted a systematic identification of gene expression, pseudogene expression, miRNA expression, and pseudogene-gene interactions and clinical factors that were predictive to breast cancer patients\u2019 prognosis . Based oAdnan et al. established a comparative evaluation of network features to predict the metastasis of breast cancer on data collected in 12 cohorts . The autZhang et al. conducted a pan-cancer study to demonstrate the clinical implication of class-3 semaphorins in the treatment of cancer . By compByun et al. conducted a study of the differential alternative splicing in HIV infected T cells . ApplicaICIBM conferences provide a friendly forum for researchers to present and publish cutting-edge biomedical studies. Stimulated by state-of-the-art biotechnologies, therapeutic strategies, biological hypotheses and interdisciplinary capabilities, computational scientists developed models to link biomedical data with biological hypothesis from different perspectives. Here, the 16 selected works illustrating innovative computational ideas or applications of new computational methods on important biomedical questions. Even though the high complexity of some models may limit their application in a broader domain and some observations still need further experimental validations, we anticipate some of these biomedical studies and computationally derived results can contribute in real clinical applications, as is discussed in this supplemental issue."}
+{"text": "Oxidative stress plays an important role in the pathogenesis of several different neurodegenerative diseases (NDDs), such as Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), Huntington\u2019s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) ,2. In paLin et al.  performeOther manuscripts reviewed the emerging role of oxidative stress-responsive proteins, such as sestrins, in various neurological diseases, protein DJ-1 in PD and mitofusin-2 (Mfn2) in AD. Chen et al.  reportedAmong neurodegenerative events, chronic inflammation can exacerbate the oxidative stress in the cells, leading to oxidation and damage of cellular components, increased inflammation and activation of neuronal death pathways . In thisAs previously highlighted, the identification and use of oxidative stress biomarkers in NDDs could be useful for the development of new drugs as well as for the early diagnosis and demonstration of drug efficacy in clinical studies. Padureanu et al.  evaluateAmong the research manuscripts of this Special Issue, some papers evaluated the antioxidant and anti-inflammatory effects of different molecules in several in vivo models of neurodegeneration. Hong et al.  evaluateIn conclusion, the manuscripts published in this Special Issue highlight recent advances in knowledge of the oxidative stress\u2019s contribution to various NDDs as well as novel antioxidant strategies of neuroprotection for NDDs."}
+{"text": "Recently, Ebmeyer and colleagues published a 28-day feeding study with six pyrrolizidine alkaloids in rats (Ebmeyer et al. Hepatotoxicity represents a major focus in current toxicological research (Jansen et al. Often risk evaluation is hampered by a lack of carefully performed subchronic or chronic animal studies with human relevant doses. Therefore, the present study of Ebmeyer et al. represents an important milestone in the current research on the hepatotoxicity of pyrrolizidine alkaloids."}
+{"text": "Ficus elastica using transmission electron microscopy. As depicted in a model, an inner polysaccharide-rich layer and an outer cutin (or cutan)-rich layer may support the composite, heterogeneous concept of the leaf cuticle.Two distinct layers in terms of texture and electron density were observed in the leaf cuticle of  The cuticle represents the outermost surface structure of a variety of organisms such as plants and insects. As the interface between plants and their environment, the plant cuticle plays a number of roles mostly associated with\u00a0protection against biotic and abiotic stresses including pathogen infection and water loss (Dom\u00ednguez et al., Ficus elastica were fixed, dehydrated, and embedded in LR white resin (Kim, Leaves of the rubber tree sin Kim, . Energy-sin Kim, . Two difThe heterogeneous cuticle structure was strikingly similar to that of the model depicted by Heredia-Guerrero et al. . They pr"}
+{"text": "The ability to rapidly detect viable pathogens in food is important for public health and food safety reasons. Culture-based detection methods, the traditional means of demonstrating microbial viability, tend to be laborious, time consuming and slow to provide results. Several culture-independent methods to detect viable pathogens have been reported in recent years, including both nucleic acid\u2013based (PCR combined with use of cell viability dyes or reverse-transcriptase PCR to detect messenger RNA) and phage-based  methods. Some of these newer methods, particularly phage-based methods, show promise in terms of speed, sensitivity of detection and cost compared with culture for food testing. This review provides an overview of these new approaches and their food testing applications, and discusses their current limitations and future prospects in relation to detection of viable pathogens in food.\u2022 Cultural methods may be \u2018gold standard\u2019 for assessing viability of pathogens, but they are too slow.\u2022 Nucleic acid\u2013based methods offer speed of detection but not consistently proof of cell viability.\u2022 Phage-based methods appear to offer best alternative to culture for detecting viable pathogens. Salmonella spp., Campylobacter spp., Listeria monocytogenes, Staphylococcus aureus and pathogenic Escherichia coli are the main pathogens that cause the highest number of outbreaks linked to food sources , for example. Tests for foodborne pathogens have historically been culture-based, which is still considered the gold standard  methods.As stated earlier, culture-based methods are generally regarded as the \u2018gold standard\u2019 for microbiological analysis of food. Traditional culture relies on the ability of bacteria to grow and multiply on laboratory media and form visible colonies. These methods still represent the first choice for many food testing laboratories as they are sensitive, inexpensive, easy to use, and give either qualitative or quantitative information on the number and type of viable microorganisms present in the food samples Doyle . HoweverThere are essentially two culture-independent approaches that represent promising alternatives to culture-based approaches for detection of viable foodborne pathogens, namely nucleic acid\u2013based and bacteriophage-based detection methods. The advantages and limitations of these culture-independent methods are summarised in Table Nucleic acid\u2013based methods operate by detecting specific DNA or RNA sequences of the target pathogenic organism. Polymerase chain reaction, or PCR, is the most commonly used nucleic acid amplification method for detecting pathogenic microorganisms, and over the last two decades, many different advances on the original PCR protocol have been described  is considered a better indicator of cell viability than DNA, since this molecule is only present in metabolically active cells (Sheridan et al. The high specificity and natural affinity of bacteriophages, or simply phages, for their host cells make phage-based methods an attractive proposition. Bacteriophages can only replicate inside living cells, meaning that phage-based methods can be tests to demonstrate cell viability (Richter et al. . In this method samples are incubated with seed bacteriophages to start the lytic cycle. Just before the end of the latent period, a chemical virucide (McNerney et al. Salmonella Typhimurium and Staphylococcus aureus (Stewart et al. Salmonella Enteritidis and Escherichia coli 0157:H7 (Favrin et al. Listeria monocytogenes (Oliveira et al. Mycobacterium avium subsp. paratuberculosis (Foddai et al. Most phage-based tests employ lytic phages as lysing agents, and detection of the new progeny phages or intracellular material released from target bacterial cells provides the indication of cell viability. One of the simplest lytic phage-based tests is called the phage amplification assay or simply the plaque assay (Stewart et al. Listeria monocytogenes within 8\u00a0h (Stambach et al. Faster phage-based detection can be achieved by combining the lytic part of the plaque assay and an alternative end-point detection method, such as immunological (Stewart et al. A third type of lytic phage\u2013based method to detect intracellular components released from bacteria also exists. After phage lysis, the quantity of released compounds is monitored through a bioluminescence assay using an enzyme and a substrate. The amount of light generated is proportional to the quantity of intracellular compound released and to the bacterial concentration originally present in samples. Examples of intracellular markers are adenosine-5 triphosphate or ATP (Griffiths More rapid and sensitive tests for detection of viable pathogens in food are continually being sought. Culture-based methods are becoming too laborious and time consuming to apply, and might have limited detection capability if pathogens in a VBNC state are present in food. Molecular tests, particularly mRNA-based tests, represent a potential solution for the rapid detection of living microorganisms. However, the perishable nature of mRNA still represents a barrier to the large-scale use of reverse transcriptase PCR for food testing purposes. A range of lytic phage\u2013based methodologies have emerged over the last two decades, which are exhibiting high detection sensitivity for several foodborne pathogens in many different matrices including food and water. The combination of phage amplification and lysis with PCR/qPCR, immunoassay or enzyme assay endpoint detection approaches seems to be the most promising rapid alternative to cultural methods for detection of viable pathogens in food. Providing host cell metabolism is occurring, phage amplification will take place and pathogen cells will eventually burst to release measurable intracellular components such as ATP, enzymes, host DNA or progeny phages."}
+{"text": "Irisin is a PGC-1\u03b1-dependent myokine that causes increased energy expenditure by driving the development of white adipose tissue into brown fat-like tissue. Exercise can improve irisin levels and lead to its release into the blood. In ischemic stroke, neurons are always sensitive to energy supply; after a series of pathophysiological processes, reactive oxygen species that are detrimental to cell survival via mitochondrial dysfunction are generated in large quantities. As a protein associated with exercise, irisin can alleviate brain injury in the pathogenesis of ischemic stroke. It is thought that irisin can upregulate the levels of brain-derived neurotrophic factor (BDNF), which protects nerve cells from injury during ischemic stroke. Furthermore, the release of irisin into the blood via exercise influences the mitochondrial dynamics crucial to maintaining the normal function of nerve cells. Consequently, we intended to summarize the known effects of irisin during ischemic stroke. The incidence of stroke has increased rapidly over the past few decades, causing it to become one of the main causes of death and long-term disability worldwide  in various ways by regulating sugar, lipid, and protein metabolism (Febbraio and Pedersen, The role of FNDC5/irisin in learning and memory is mediated by BDNF expression, which plays an important role in neural remodeling in conditions such as Alzheimer's disease (Wrann et al., in vivo (Peng et al., in vitro (Yu et al., A recent study has reported that irisin protects the blood-brain barrier from ischemic injury by decreasing the expression of MMP-9 (Guo et al., Notably, although Li et al.  have fouAs previously described, the discovery of irisin provides an alternative direction for studying the potential treatment methods for ischemic stroke. In 2017, Lidongjie et al. found that irisin synthesis reduces the infarct volume and the degree of brain edema and improves the neurobehavioral score in an oxygen-glucose deprivation model (Li et al., Mitochondrial dynamics mainly consist of fission and fusion. Fission is mediated by the proteins Drp1, Fis1, and MFF. Drp1 is recruited from the cytosol to the outer membrane of mitochondria and interacts with its receptor proteins MFF and Fis1 to create the fission complex. Drp1 is then oligomerized into filaments that wrap around mitochondria, leading to mitochondrial constriction and sequential separation of the inner and outer membrane. Drp1 reportedly has a crucial role in ischemic stroke; brain edema, the infarct area, and other neuronal injuries are alleviated following Drp1 downregulation (Anzell et al., Three different GTPases mediate fusion, including Opa1 and Mfn1/2. Mfn1/2 are anchored to the outer membrane of mitochondria, while inner membrane fusion is mediated by Opa1. A lack of mitofusins prevents fusion of both the outer and inner membrane of the mitochondria, while the loss of Opa1 only blocks fusion of the inner membrane. Mitochondrial fusion proteins are less studied in ischemic stroke. Mfn2 is reported to exert an anti-apoptotic effect, and its expression decreases in the presence of ROS. Opa1 can attenuate infarct volume in ischemic stroke, and its expression is increased after exercise (Anzell et al., In ischemic stroke, cell survival and pathobiology are involved in mitochondrial dynamics. As mitochondrial dynamics processes, fission and fusion are crucial to mitochondrial function. Fusion is presumed to be beneficial to cell survival, but studies show that fission facilitates cell death (Li and Liu, It is reported that mitochondrial homeostasis is closely related to AMPK upregulation associated with altered cell energy metabolism (Siteneski et al., AMPK is a heterotrimer including an \u03b1-subunit and two regulatory subunits, \u03b2 and \u03b3. The \u03b1-subunit is the main catalytic part of AMPK, containing a kinase domain and the key residue Thr172. When the ratio of ATP-AMP decreases, the AMPK complex is activated by phosphorylation on Thr172 in the \u03b1-subunit. The activated AMPK affects the mitochondrial dynamics by activating downstream substrates. When stresses, such as ischemia or hypoxia, are applied, the phosphorylated AMPK directly phosphorylates MFF. MFF then recruits Drp1 to the mitochondrial membrane, selectively causing fission of the damaged mitochondria and protecting normal mitochondrial function (Wang and Youle, It has been reported that exercise is a potential activator of AMPK, demonstrating the possibility that AMPK can affect mitochondrial dynamics via exercise (Trewin et al., Although treatment strategies for stroke have been explored over several decades, intravenous thrombolysis remains the primary and most effective method (Keizman et al., Irisin is reportedly induced by physical exercise to augment energy expenditure, according to the initial report (Bostr\u00f6m et al., Irisin protects against endothelial injury and ameliorates atherosclerosis in Apo-E knockout mice (Lu et al., Many scholars have also suggested that irisin is an exercise-induced muscle factor, with exercise promoting its large-scale expression in skeletal muscles, the heart, and the brain. These brain regions include Purkinje cells in the cerebellum (Varela-Rodr\u00edguez et al., Evidence suggests that irisin levels are affected by a large number of stressors. It is well-established that acute exercise increases the levels of blood irisin (Jedrychowski et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Childless older adults may be at risk for poorer health cross-nationally, yet most studies on this topic analyze only a small number of countries and only 1 or 2 health outcomes. To our knowledge, two papers exist that explore associations between childlessness and multiple indicators of health using data from a large number of regionally diverse countries , but neither study includes an examination of socioeconomic resources. The level of health risk faced by childless older adults is likely to be distinctly shaped by older adults\u2019 socioeconomic resources . Associations between childlessness, socioeconomic resources, and health may also differ by country context. Using harmonized, cross-national data for adults aged 50 and older across 20 high- and middle-income countries (United States (HRS), European Union (SHARE), Mexico (MHAS), and China (CHARLS) from the Gateway to Global Aging data repository), we explore if and how individual-level socioeconomic resources  moderate associations between childlessness and five health indicators . Results suggest that associations between childlessness and health outcomes vary by individual socioeconomic resources in some country contexts, but not in others. We discuss these findings in light of the impact of individual-level socioeconomic resources on older adults\u2019 support options and health outcomes cross-nationally."}
+{"text": "B. Ngor et al.; Scientific Reports 10.1038/s41598-018-27340-1 (2018).3.As one of the richest sources of fisheries-related data in the lower Mekong basin, the Tonle Sap dai fishery has received considerable attention in the literature in recent years as concerns grow over the impacts of hydropower dams on fisheries, which are important for livelihoods and food security4 reported a decline since 2000 in the catch of larger species which tend to occupy higher trophic levels; compensatory increases in the catch of smaller species; and declines in the mean body weight (and length) of common species in the Tonle Sap dai fishery, as evidence of the effects of indiscriminate fishing or \u201cfishing-down\u201d of the multi-species fish assemblage in the lower Mekong basin. We provide evidence below that suggest that these apparent recent changes are more likely to reflect changing hydrological conditions than fishing-down effects, possibly caused by climate change and recently also by hydropower development.Ngor et al.6  of monitoring data which include one of the driest fishing seasons on record (1998\u201399). The authors thereby created a time series beginning with the three wettest seasons (largest floods) since monitoring began (2000\u20131 to 2002\u20133) that were followed by 12 seasons of variable, but decreasing flows caused by hydropower dam construction, low rainfalls possibly resulting from climate change, and abstractions for agricultureWithout reference to hydrological variation, Ngor et al. reported a temporal decline in the catch of larger, high-trophic level species; compensatory increases in the catch of smaller species; and declines in the mean body weight (and length) of six common species. The authors reported these findings as evidence of the effects of indiscriminate fishing (fishing-down) in the lower Mekong basin, without considering alternative explanations for the observed patterns.2. Moreover, the fishery itself is not standardised, with net types, mesh sizes and flow rates through the gears varying inter and intra-annually. Catches may therefore not reflect changes in underlying abundance7. Despite this, we re-examined the analysis of Ngor et al. at face value.Ngor et al. describe their dataset as being generated from a \u201cstandardized biological catch assessment\u201d. In reality, this assessment is complex having undergone numerous changes through time, including to sampling efforte-transformed catch time series of larger species (TL\u2009>\u200945\u00a0cm) excluding those with zero catch in any year. These 28 species formed approximately 16% of the total catch during the study period. We also found negative regression coefficients for all 28 species, supporting the findings of Ngor et al. However, the combined annual catch of these 28 species did not decline significantly through time .Using the 15-season dataset that accompanied Ngor et al., we re-fitted regression models to the log2\u2009=\u20090.46; p-value\u2009<\u20090.01) \u2014a measure of flood extent and duration  with the FI. Rle Table . The fivHenicorhynchus, that formed 42% of the total catch during the study period, exhibited no significant trend through time .Contrary to Ngor et al. we found no clear evidence of a compensatory response by small species. The annual catch of the three most prolific small species of the genus 2. The time series analysis of mean fish weight illustrated in Figure\u00a04 of Ngor et al. was subject to sampling-related bias because the number of observations of fish weight in each month varied significantly each year.The growth of species of fish caught by the dai fishery is non-linear and seasonale-transformed body weight using \u2018year\u2019 and the FI as alternative independent explanatory variables. To aid model comparisons we first standardised both independent variables.To avoid this bias, and minimise any gear selectivity effects, we examined how the mean body weight of the six common species examined by Ngor et al. varied in both December and January each year corresponding to the end of the flood, when any flood-related effects on fish growth would manifest. We compared regressions of mean logThe FI explained more of the variation in mean fish weight than \u2018year\u2019 in 9 of the 12 regressions compared  in Cambodia in 201213, we suspect that since then, an already fished-down assemblage has been further impacted by periods of low flow and limited flooding, possibly caused by climate change and hydropower dams6.While fishing pressure undoubtedly caused some fishing-down between 1970 and the 1990s corresponding to strong population growth and the spread of modern fishing methods"}
+{"text": "N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring  N-arachidonoylethanolamide  family, also termed fatty acid ethanolamides. NAEs differ in the length and saturation of the hydrocarbon chain and their receptor affinity  are emerging as an intriguing class of neuromodulators, although largely uncharacterized so far  at physiologically relevant concentrations, the others display an affinity for peroxisome proliferator-activated receptor-\u03b1 .Very little is known about the biosynthesis of N-acyl amino acids are hydrolyzed to free fatty acids and ethanolamine or amino acids  are synthesized following activation of metabotropic glutamate, muscarinic, or dopamine D2 receptors . Very little is known about the functional relevance of N-acyl amino acids and their receptors such as GPR18, GPR55, or GPR92; this topic is discussed in Burstein  evokes an increase in Ca2+ permeability and a rise in intracellular Ca2+, which is necessary for the activity of the Ca2+-dependent NAT isoform  .An extensive literature substantiates the role of the dopamine system in addiction and SUD. Dopamine facilitates the development of long-lasting forms of synaptic adaptations that determine the effectiveness of reward and reward predictors to control subsequent seeking behavior  depends on increased eCB levels within mesolimbic dopamine regions  were elevated in the plasma (Best et al., The role of NAEs in alcohol dependence has been extensively explored by studying the catabolic enzyme FAAH, both in rodents and humans. Several studies stress out the importance of FAAH genetic variants (Zhou et al., PPAR\u03b1 is upstream of diverse genes that are modulated by ethanol or involved in ethanol-induced effects (Ferguson et al., Tobacco use is associated with high morbidity and mortality, it being the most preventable cause of death in the world (World Health Organization, Both tobacco smoke and nicotine can affect the eCB system. Tobacco smoke alters FAAH, NAPE-PLD, and MAGL levels in the striatum (Torres et al., The involvement of the eCB system in nicotine dependence was demonstrated by the effect of FAAH inhibitors. FAAH inhibitors suppress many reward-related effects of nicotine in rats and non-human primates, such as nicotine self-administration and reinstatement of nicotine seeking (Scherma et al., via \u03b17-nAChRs, and subsequent increase of intracellular Ca2+ (Melis et al., in vivo and in vitro strategies, Melis et al. (N-oleoyl glycine was shown by Donvito et al. (N-acyl amino acid is synthesized in dopamine cells and acts as an endogenous neuromodulator in a similar fashion of other NAEs with a dopamine moiety such as N-arachidonoyldopamine or N-oleoyldopamine (Ferreira et al., Besides the effect of the major eCBs, there is increasing evidence of the involvement of PEA and OEA in nicotine addiction, as they have a crucial role as endogenous modulators of cholinergic transmission (Melis et al., s et al.  confirmeo et al.  to countBased on the mechanisms described, the suppression of nicotine-induced responses of dopamine neurons by PPAR\u03b1 agonists raised the interest on these ligands as a promising strategy to prevent nicotine relapse (Melis and Pistis, A way to circumvent the limited brain permeability of fibrates is to increase brain levels of endogenous PPAR\u03b1 agonists, such as PEA and OEA. The recent development of brain-permeant selective NAAA inhibitors offers the advantage to modulate levels of PEA and OEA selectively, and not AEA, therefore concurrently limiting psychiatric side effects due to eCB-CB1 alteration. Similar to direct PPAR\u03b1 agonists, also NAAA inhibitors display potential as anti-smoking medications, as they block nicotine-induced excitation of dopamine cells, dopamine elevations in the nucleus accumbens, and conditioned place preference in a PPAR\u03b1-dependent manner (Sagheddu et al., The expanded eCB system, the \u201cendocannabinoidome,\u201d is a hotbed for a large number of lipid signaling molecules, enzymes, and receptors and represents a Pandora\u2019s box for drug discovery (Cristino et al., This review article summarizes evidence suggesting that NAE/PPAR\u03b1 signaling shows promise as a target in the treatment of SUD, particularly alcohol and nicotine use disorder. A parsimonious unifying hypothesis for this effect is NAE/PPAR\u03b1\u2019s ability to modulate dopamine cell activity by specifically dampening stress-evoked excitatory drive from cholinergic afferents on VTA dopamine cells. Hence, a heightened cholinergic transmission has long been postulated to contribute to detrimental effects induced by stress, such as depression (Janowsky et al., N-acyl amino acid family suggest that analogs of these lipid neuromodulators could become potential drug candidates.SUD represents an unmet clinical need, with drugs currently in use that show limited efficacy or untoward side effects. Indeed, results reported for members of the NAE and CS, LT, TM, and MP wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Genes. The topics of the selected manuscripts cover a wide range of current topics in biomedical research including cancer informatics, transcriptomic, computational algorithms, visualization and tools, deep learning, and microbiome research. In this editorial, we briefly introduce each of the manuscripts and discuss their contribution to the advance of science and technology.The International Association for Intelligent Biology and Medicine (IAIBM) is a nonprofit organization that promotes intelligent biology and medical science. It hosts an annual International Conference on Intelligent Biology and Medicine (ICIBM), which was established in 2012. The ICIBM 2019 was held from 9 to 11 June 2019 in Columbus, Ohio, USA. Out of the 105 original research manuscripts submitted to the conference, 18 were selected for publication in a Special Issue in  Genes were further reviewed by a minimum of two additional external reviewers. In the end, 18 manuscripts were selected for publication in the Special Issue, which covered the topics of cancer research, gene expression, single cell sequencing, novel computational algorithms, and microbiome research. In this editorial, we introduce the 18 selected research manuscripts.The International Conference on Intelligent Biology and Medicine ICIBM 2019) was organized and hosted by the International Association for Intelligent Biology and Medicine (IAIBM) and the Department of Biomedical Informatics at Ohio State University from 9 to 11 June 2019 in Columbus, Ohio, USA. The detailed description of the conference and its organization and achievements is summarized in [9 was orgChen et al. published \u201cComputational Cancer Cell Models to Guide Precision Breast Cancer Medicine\u201d . In thisA pathway is a summary of a set of genes that can be connected via their biological process, regulation, mechanism. or phenomenon. Pathways of important function can be alternatively activated in cancer. Wang et al. published \u201cIdentification of Alternatively-Activated Pathways between Primary Breast Cancer and Liver Metastatic Cancer Using Microarray Data\u201d, in which the authors proposed an alternatively-activated pathway mining method  based onCirculating tumor DNA (ctDNA) has been found in the bloodstream which originated from cancerous cells. Research on ctDNA has been expanding over the last decade resulting in substantial advancement in the identification of single nucleotide variants from ctDNA. Copy number variation (CNV), which is also considered to be an important cancer biomarker, has been very difficult to detect from ctDNA due to the low amount and complex CNV features. Peng et al. published \u201cCNV Detection from Circulating Tumor DNA in Late-Stage Non-Small Cell Lung Cancer Patients\u201d to address the critical issue of CNV identification in ctDNA . Their mDNA methylation plays a variety of roles in cancer, including a critical role in the control of gene activity, which helps to convert gene expression in normal tissue to a cancerous pattern. Utilizing deep learning techniques, Liu et al. published \u201cDNA Methylation Markers for Pan-Cancer Prediction by Deep Learning\u201d, in which they studied the prognostic value of DNA methylation . Using dFOXO1 and PAX3/7 and observed substantial restructuring of co-expression networks related to fusion status and fusion type.Gene fusion describes hybrid genes that are formed from two independent genes. Gene fusion has been a common feature in cancer genomes and has served as a molecular target in therapeutic development. In Helm et al.\u2019s \u201cGene Co-Expression Networks Restructured Gene Fusion in Rhabdomyosarcoma Cancers\u201d, the authors studied gene fusion features in rhabdomyosarcoma . In thisTumor-infiltrating leukocytes (TILs) are immune cells surrounding tumor cells, and several studies have shown that TILs are potential survival predictors in several types of cancers including liver cancer, which is highly associated with a hepatitis virus. Hsiao et al. studied TIL abundance and compositions concerning hepatocellular carcinomas survival in their manuscript, entitled \u201cTumor-Infiltrating Leukocyte Composition and Prognostic Power in Hepatitis B- and Hepatitis C-Related Hepatocellular Carcinomas\u201d . The autNetwork and biomarker analyses have been heavily utilized for cancer research. Liu et al. combined the concept of both a network and biomarker approach in their paper entitled \u201cNetwork as a Biomarker: A Novel Network-Based Sparse Bayesian Machine for Pathway-Driven Drug Response Prediction\u201d . The autIn the paper entitled \u201cKinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer\u201d, Buiga et al. focused on the analysis of dual-specificity phosphatases (DUSPs) in HER2-positive breast cancer , a highlCompelling evidence has shown that microRNAs (miRNAs) can regulate genes and be associated with various cancers through a post-transcriptional suppression regulation mechanism. The dysregulation of miRNA can substantially alter the landscape of the transcriptome level of messenger RNAs (mRNAs). Dai et al. published \u201cIdentifying Interaction Clusters for miRNA and mRNA Pairs in TCGA Network\u201d, which describes a novel cluster scoring method to identify mRNA and miRNA interaction pairs . Their aCryogenic electron microscopy (cryoEM) is an electron microscopy technique applied on samples cooled to cryogenic temperatures and embedded in an environment of vitreous water. It is often used to study structural biology. The analysis of cryoEM often involves a clustering algorithm. Al-Azzawi et al. published \u201cA Super-Clustering Approach for Fully Automated Single Particle Picking in Cryo-EM\u201d, a manuscript that describes a newly developed fully automated super-clustering algorithm for single particle picking in cyroEM micrographs. The authors focused on identifying, detecting, and picking particles of the complex and irregular shapes in micrographs with extremely low signal-to-noise ratio .While single cell sequencing has quickly emerged as a powerful technology for measuring DNA variants or transcriptome abundance at the single cell resolution, numerous challenges currently remain in this new field. One of the major shortcomings of single cell RNA-seq is the excessive zero counts, because only a small fraction of the transcripts sequenced in each cell. This problem can be alleviated by sequencing more, but it is at a high financial cost and also a lack of enough cells available for sequencing. The sparsity of the gene expression for each cell creates additional downstream analysis challenges such as cell type identification. Zand et al. introduced a network-based method, netImpute  to battlIn the era of big data, data visualization tools are essential for analyzing massive amounts of information and making data-driven decision. This is no difference in transcriptomic data analysis. Al-Ouran et al. published \u201cA Portal to Visualize Transcriptome Profiles in Mouse Models of Neurological Disorders\u201d, in which they described a new web-based platform for visualizing mouse transcriptome data . The webNon-coding RNA has been the focus of many research studies over the last decade. Porto et al. published \u201cLong Non-Coding RNA Expression Levels Modulate Cell-Type-Specific Splicing Patterns by Altering Their Interaction Landscape with RNA-Binding Proteins\u201d, a study  in whichLepisosteus oculatus)\u201d [nfil3 and cry families are different between spotted gar and humans. These findings help decipher the repertoires of the spotted gar\u2019s circadian system and shed light on how the vertebrate circadian clock systems have evolved.A circadian rhythm is a natural internal process that regulates the sleep-wake cycle. While the canonical circadian clock genes and their regulatory mechanisms appear highly conserved, the evolution of clock gene families is still unclear due to several rounds of whole genome duplication in vertebrates. Sun et al. studied circadian clock genes in spotted gar, a non-teleost ray-finned fish, and published their findings in the manuscript \u201cThe Molecular Evolution of Circadian Clock Genes in Spotted Gar (ulatus)\u201d . PhylogeIn data science, a large dataset is often assembled from multiple smaller datasets with heterogeneity. The missing variable has become a common problem when combining datasets, which poses a major challenge for downstream analysis. Bartlett et al. published \u201cForming Big Datasets through Latent Class Concatenation of Imperfectly Matched Databases Features\u201d, to address this problem . The autGenotyping data has been aiding researchers for large genetic association studies for the last two decades. Imputation is an important preprocessing step for combining genotyping data or increasing coverage. Traditional genotype imputation methods are typically based on haplotype-clustering algorithms, hidden Markov models (HMMs), and statistical inference. Chen et al. described their new deep learning-based imputation method  in theirThe microbiome studies many microorganisms in a particular environment. Microbiome research has been greatly enhanced by the advancement of 16S rRNA high throughput sequencing. Liu et al. published \u201cChanges in the Microbial Community Diversity of Oil Exploitation\u201d, a study on microbiome in several offshore petroleum production sites . The autICIBM is an annual international conference, which has been held every year since 2012 (except 2017). It promotes a highly interactive and friendly platform for both young and senior researchers to exchange their research, foster collaboration, as well as expand educational activities. Approximately one hundred and seventy researchers and trainees from around the world joined the 2019 conference and contributed to a rich conference program, which included four keynote lectures, four eminent scholar talks, five tutorials and workshops, twelve concurrent sessions, a poster session, and other conference activities. Among the 105 original research manuscripts, we selected 18 for the Special Issue after two rounds of peer reviews. These 18 manuscripts describe innovative, computational works in the field. We expect these manuscripts to promote further investigation in the same or similar topics, and lead to more research toward translational clinical applications."}
+{"text": "Objective: Mild cognitive impairment (MCI) is an important risk state for dementia, particularly Alzheimer\u2019s disease (AD). Depression, anxiety, and apathy are commonly observed neuropsychiatric features in MCI, which have been linked to cognitive and functional decline in daily activities, as well as disease progression. Accordingly, the study\u2019s objective is to review the prevalence, neuropsychological characteristics, and conversion rates to dementia between MCI patients with and without depression, anxiety, and apathy.Methods: A PubMed search and critical review were performed relating to studies of MCI, depression, anxiety, and apathy.Results: MCI patients have a high prevalence of depression/anxiety/apathy; furthermore, patients with MCI and concomitant depression/anxiety/apathy have more pronounced cognitive deficits and progress more often to dementia than MCI patients without depression/anxiety/apathy.Conclusions and Implications: Depression, anxiety, and apathy are common in MCI and represent possible risk factors for cognitive decline and progression to dementia. Further studies are needed to better understand the role and neurobiology of depression, anxiety, and apathy in MCI. Mild cognitive impairment (MCI) represents a transitional stage between healthy aging and dementia. Subjects with MCI complain about cognitive impairments, have documented cognitive deficits relative to age- and education-matched controls\u2014although they are less impaired than patients with dementia\u2014and have largely intact activities of daily living Sanford, . Dependiin vivo by biomarkers in the National Institute on Aging and Alzheimer\u2019s Association Research Framework in Jack et al.  presented a reanalysis of subpopulations already included in other studies; (b) reported a patient population of less than 10 patients; or (c) were commentaries, technical notes, or review articles summarizing the results of previous studies.We included original studies from tertiary referrals and population-based studies written in English that examined populations with MCI, depression, anxiety and apathy. A systematic literature search was performed using the PubMed database. Search terms were via depression  compared to MCI patients without depression (13.5%; Lee G. J. et al., However, there is research that demonstrated contrary conclusions. A 3-year prospective study of MCI outpatients demonstrated no increased risk of AD in patients with symptoms of depression (Palmer et al., Vascular factors play an important role in depression within preclinical dementia. In MCI patients, new onset of depression was associated with deep subcortical cerebral white matter hyperintensity severity (Kim et al., The reported prevalence of apathy in MCI is between 10.7% and 44.8% (Palmer et al., Patients with MCI with apathy have an increased risk of dementia, independent of depression. A systematic review found that apathy was associated with an approximately two-fold increased risk of dementia in memory clinic patients (van Dalen et al., Anxiety symptoms have been studied less than depression, and the relationship between anxiety and cognition is complex. The reported prevalence of anxiety in MCI patients ranged between 9.9%\u201352% (Lyketsos et al., Generalized anxiety disorder is the main anxiety disorder associated with poor global cognitive functioning, and this association is moderated by sex but not by the presence of depressive episodes (Potvin et al., Anticipatory anxiety is significantly associated with earlier conversion to AD, but this association does not remain significant following an adjustment for cognitive status at the baseline; anxiety for upcoming events and purposeless activity frequently co-occur, which indicates anticipatory anxiety may be a marker of severity rather than an independent predictor of disease progression (Gallagher et al., Other investigators have failed to find an association between anxiety symptoms in patients with MCI and an increased risk of conversion to AD (Robert et al., Depression, anxiety, and apathy are common in MCI patients and are important indicators in the progression to dementia in MCI patients, which emphasizes the importance of assessing depressive symptoms as well as anxiety and apathy in the early stages of cognitive impairment. Further studies are needed to better understand the role and neurobiology of depression, anxiety, and apathy in MCI. Indeed, further studies on observation of larger patient populations and long follow-up are needed.LM designed and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Meanwhile, the Editors became aware of adenouncement published by independent journalists from the \u201cFor Better Science\u201d websiteincluding this paper. This denouncement consisted of potential data falsification and/orinaccuracy of results in western blots and flow cytometry plots.As per consensus between the Authors and the Editors-in-Chief of the Brazilian Journal ofMedical and Biological Research (BJMBR), the article titled \u201cEffect of lncRNA HULCknockdown on rat secreting pituitary adenoma GH3 cells\u201d that was published in year 2019,volume 52, issue 4,  has been retracted."}
+{"text": "APOE) is the best-known and has the strongest association with AD development. AD probability decreases in carriers of the e2 variant of the APOE gene (APOE-e2), whereas APOE-e4 is believed to be a strong risk factor  is a neurodegenerative condition that inevitably impairs cognitive functions and influences a patient's behavior, mood, and self-reliance. Due to demographic changes, AD and other age-associated diseases have become increasingly common and burdensome for families, as well as entire societies. It is extremely important that we learn more about specific mechanisms that can be linked to the development of the disease. The main symptoms of AD, observed in the central nervous system, are brain atrophy and loss of neurons and synapses. They are believed to result from excessive aggregation of tau protein and amyloid plaques (composed of \u00df-amyloid). However, neither the initial cause nor the detailed chain of events that lead to this type of neurodegeneration are known. No deterministic genes were identified for late-onset Alzheimer's disease (LOAD), but several risk genes seem to be involved in its pathogenesis. The gene coding apolipoprotein E  of negative impact on human brain function in AD. Results indicating enhanced APP synthesis are in agreement with studies showing higher levels of A\u03b2 in brains of APOE-e4 carriers, examined post-mortem  and other risk-genes. Moreover, it was shown that neurons need astrocytes and microglia to eliminate redundant synapses  homeostasis and synaptic stability maintenance, with APOE-e4 having the most negative impact on the brain. APOE-e4 limits the astrocytes' ability to recycle and clear extracellular cholesterol (Fernandez et al., APOE-e4 showed accumulation of cholesterol and could not efficiently fulfill their role related to clearance of A\u03b2 (Lin et al., The question arises: how is it possible to link these cell-level studies with the same ranking (g et al. , and preg et al. , showed g et al. . APOE haAPOE-e4 that leads to an increase in toxic A\u03b2 forms and impairs astrocytes' function, which can initiate the whole cascade of changes related to later loss of synapses and cognitive functions. It may indicate that, in the brains of APOE-e4 carriers, AD risks begin to accumulate from early developmental stages when too many synapses are formed and not enough of them are pruned (Chung et al., APOE-e4 risk related to loss of cognitive functions is predominant for persons older than 50 years of age, people homozygous for APOE-e4 may experience the risk much earlier, just after 40 years of age (Liu et al., APOE-e4 could affect the brain even earlier, changing its structure, function and neurochemistry (see DiBattista et al., APOE-e4 young carriers perform equally well or even much better in a variety of cognitive tasks compared to non-carriers (Mondadori et al., APOE-e4 on neuronal signaling pathways throughout the lifespan may help us to identify early biomarkers and target therapy against AD in the future.Perhaps it is the initial higher number of synapses and APP in neurons with PD wrote the first draft. EK critically edited and improved the manuscript. PD and EK read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Exosomes (EXs) and extracellular microvesicles (EMVs) represent a diverse assortment of plasma membrane-derived nanovesicles, 30\u20131000 nm in diameter, released by all cell lineages of the central nervous system (CNS). They are examples of a very active and dynamic form of extracellular communication and the conveyance of biological information transfer essential to maintain homeostatic neurological functions and contain complex molecular cargoes representative of the cytoplasm of their cells of origin. These molecular cargoes include various mixtures of proteins, lipids, proteolipids, cytokines, chemokines, carbohydrates, microRNAs (miRNA) and messenger RNAs (mRNA) and other components, including end-stage neurotoxic and pathogenic metabolic products, such as amyloid beta (A\u03b2) peptides. Brain microglia, for example, respond to both acute CNS injuries and degenerative diseases with complex reactions via the induction of a pro-inflammatory phenotype, and secrete EXs and EMVs enriched in selective pathogenic microRNAs (miRNAs) such as miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155, and others that are known to promote neuro-inflammation, induce complement activation, disrupt innate\u2013immune signaling and deregulate the expression of neuron-specific phosphoproteins involved in neurotropism and synaptic signaling. This communication will review our current understanding of the trafficking of miRNA-containing EXs and EMVs from astrocytes and \u201cactivated pro-inflammatory\u201d microglia to target neurons in neurodegenerative diseases with an emphasis on Alzheimer\u2019s disease wherever possible.  As sucl., 2014 ; Rodrigul., 2014 ).(i) were first characterized about ~40 years ago as a heterogeneous group of cell cytoplasm-derived intracellular micro-particles (MPs) of endosomal origin ; (ii) are variable in their content and morphology, ranging in size from about ~30 to ~100 nm in diameter; (iii) are released by a variety of central nervous system (CNS) cells whose function was originally described as a cytological basis for intercellular signaling and communication : al. 1981 ; Columboal. 1981 ; Jiang eal. 1981 ; Mathewsal. 1981 ; Arbo etal. 1981 ; Martinsal. 1981 ). EXs oral. 1981 ; Arbo etal. 1981 ). Extracal. 1981 ; Webers al. 1981 ). Similaal. 1981 . Astrocyal. 1981 ; Leidal al. 1981 ). Some oal. 1981 ; Serpental. 1981 ; Vanherlal. 1981 ; Mathieual. 1981 ; Arbo etal. 1981 ; Seyedraal. 1981 ; Upadhyaal. 1981 ). As mosal. 1981 ; Urbanelal. 1981 ; Federical. 1981 ; Groot aal. 1981 ; Stahl eal. 1981 ; Upadhyaal. 1981 ; VanherlEscherichia coli and Bacteroides fragilis, species of the family Brassicaceae such as Arabidopsis thaliana, Protists, protozoa such as Amoeba proteus and slime molds such as Dictyostelium discoideum, nematodes such as Caenorhabditis, and up the evolutionary scale to a wide range of mammals including humans. The biogenesis, secretion and the release of EXs, MPs and/or EMVs into the extracellular space or external environment for the purpose of mediating intercellular communication or transmitting DNA- or RNA-encoded genetic information between different cell types and the environment is therefore a very ancient and conserved evolutionary process  tract bacteria such as l., 2014 ; Arbo etl., 2014 ). From wl., 2014 ; Cong etl., 2014 ; Avsar el., 2014 ).(i) are released under normal physiological conditions, but are also discharged from parent cells upon cellular activation, hypoxia and/or hyperoxia, senescence, apoptosis and disease via a paracrine- and endocrine-type type action to their target cells; (ii) represent one of the major biological mechanisms for genetic exchange, immune signaling and the spread of inflammation and disease between cells of the host; (iii) EX and EMV trafficking in the mammalian CNS is a particularly robust, active and dynamic process . The hul., 2007 ; Seyedral., 2007 ; Song etl., 2007 ). Indeedl., 2007 ; Vanherll., 2007 ).extracellular directional strategy\u201d for vesicular sorting and translocation over both short and long distances . Many ol., 2015 ; Serpentl., 2015 ).(i) that these vesicular organelles consist of a unique repertoire of cytoplasmic components representing cellular, molecular and genetic information that is a direct reflection of the unique biological condition of the parent cell\u2019s cytoplasm at the time of vesicular release; (ii) that these microparticles play important roles as enveloped proteolipids, a nucleic acid-enriched \u201cinformation packet\u201d in a complex extracellular communication network; (iii) that EXs and EMVs may reprogram recipient, adjacent cells and/or distant tissues as CNS-resident cells involved in immune-surveillance and the maintenance of normal cellular homeostasis, while also contributing to neuropathology during disease; (iv) that the molecular content and rates of production and secretion of EXs and EMVs vary greatly depending on the cell-type and physiological state of the cells of vesicular origin . Attestl., 2018 ; Barnes l., 2018 ; Leidal l., 2018 ).Atropa belladonna) and higher animals (Homo sapiens) over many billions of years of evolution  are the smallest known gene information-carrying nucleic acids yet discovered; (ii) are important posttranscriptional and epigenetic regulators of mRNA abundance, speciation and complexity in aging, development, neurological health and disease processes; (iii) play pivotal roles in the initiation, development and propagation of many human CNS disorders including progressive terminal cancers and lethal, age-related neurological syndromes with an inflammatory component; (iv) are loaded into both EXs and EMVs and are a typical component of their vesicular cargoes are soluble, amphipathic, single-stranded non-coding RNAs (sncRNAs) 18- to 25-ribonucleotides (nt) in length whose RNA sequences have been very highly selected. Some miRNAs, such as the neurologically relevant miRNA-378, are very highly conserved, and their core ribonucleotide sequence has remained virtually unchanged in plants . Abundal., 1990 ; Lukiw 2l., 1990 ; Lukiw 2l., 1990 ; Zhao etl., 1990 ; Hosaka l., 1990 ; Slota el., 1990 ; Swarbril., 1990 ; Briand Homo sapiens while only about 25\u201330 individual miRNA species, or fewer, are abundant and easily detected in the human brain and retina . The upl., 2016 ; Lukiw 2l., 2016 ; Zhao etl., 2016 ; Wang etl., 2016 ; summaril., 2016 ). Importl., 2016 ; Zhao anl., 2016 ).pro-inflammatory miRNAs\u201d, including miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and others in the parenchyma of the temporal lobe neocortex (Lukiw 2007 [(i) from the microarray analysis of mast cells involved in innate and adaptive immunity, autoimmunity, and inflammation  from studies of specific miRNAs, mRNAs and angiogenic proteins in glioblastoma and neuroblastoma tumor cells that have released EXs and EMVs , Huntington\u2019s disease (HD), stroke and other neuro-inflammatory degenerative conditions. This indicates a definitive role for EX and EMV miRNA cargoes in neurological disease processes with an inflammatory component which may have considerable diagnostic, prognostic and/or therapeutic value  brains (Lukiw 2007 ) This inkiw 2007 ; Valadi kiw 2007 ; Hunter kiw 2007 ; Sethi akiw 2007 ; Zhao etkiw 2007 ; Hammondkiw 2007 ). The fil., 2007 ); (ii) fl., 2008 ; Briand l., 2008 ; Skog etl., 2008 ). As disl., 2018 ; Mathieul., 2018 ; Li et al., 2018 ; Serpentl., 2018 ; Upadhyal., 2018 ). Becausl., 2018 ; BarbagaAccumulating evidence continues to implicate secreted miRNAs, including EX and EMV-encapsulated miRNAs, in the pathogenic spreading of progressive, age-related and incapacitating neurodegenerative diseases with an uncontrolled or deregulated inflammatory component and synaptic deficits. These include Alzheimer\u2019s disease (AD), age-related macular degeneration (AMD), Parkinson\u2019s disease (PD), Huntington\u2019s disease (HD), prion disease (PrD), multiple sclerosis (MS), Japanese and viral-induced encephalitis and many related amyloidopathies, tauopathies and synucleinopathies , hypoxil., 2016 ), by coml., 2016 ) and micl., 2016 ; Lukiw el., 2016 ; Alexandl., 2016 ). As obsl., 2016 ; Ludwig l., 2016 ).(i) the signals and pathways essential for stimulation and the origin of their formation, as well as the mechanism of their release from many different cell types in the CNS and their proficiency for modulating functions of target cells; (ii) the molecular-genetic injury and/or environmental factors which stimulate their release for this evolutionarily-conserved type of information communication system amongst astrocytes, microglia and neurons; (iii) their increased production and release during the initiation and spread of progressive age-related inflammatory neurodegeneration; (iv) the actual molecular contents, stoichiometry and packaging of the contents in the vesicles themselves; (v) the magnitude and signaling impact of their plasma membrane-packaged vesicular cargo; (vi) the regulation of their trafficking and targeting to neuronal cells via plasma membrane-mediated cell-surface reception mechanisms; (vii) the lipidomic, proteomic and transcriptomic profiles of these vesicles and what miRNA and/or mRNA encoded information these vesicles may be carrying; (viii) whether or not EXs and/or EMVs can transfer their miRNA-enriched intraluminal cargoes to other cell types and/or to other species; (ix) the role of circular RNA (circRNA) which have been shown in some cases to act as natural \u201canti-miRNA sponges\u201d of specific miRNA activities , microparticles (MP), exosomes (EX) and extracellular microvesicles (EMV), the nature of their vesicular cargoes and miRNA composition. These include: kiw 2013 ; Zhao etkiw 2013 ; Fakhourkiw 2013 ; Pogue akiw 2013 ; Zhao ankiw 2013 ; Avsar ekiw 2013 ; Groot akiw 2013 ; Hou et kiw 2013 ; Li et akiw 2013 ; Ma et akiw 2013 ; Serpentkiw 2013 ). A singThe neurobiology of EX and EMV genesis, release, translocation and uptake by target cells, and their containment of select miRNA populations enriched in the CNS, indicate that they are significant components of a highly dynamic system of intercellular communication via extracellular translocation and targeting in brain cell health, aging and disease. Multiple independent studies indicate that while vesicle-mediated intercellular signaling is important in the homeostatic maintenance of brain cell functions, they have a substantial role in the proliferation of injury, cancer and inflammatory neurodegeneration signaling, as is observed in the AD brain. Many of the details of the mechanisms by which EXs and EMVs and their miRNA cargoes are generated and released by the activation of astrocytes and microglia and their trafficking to target brain cells, primarily neurons, remain to be further clarified. A greater understanding of the mechanisms underlying EX and EMV biogenesis, cargo selection and loading, vesicle release, translocation exterior to the cells of origin and targeting to adjacent or distant neural cells remains critical for unlocking the immense neurobiological and therapeutic potential for these ubiquitous organelles. Not only could an increased understanding of EX and EMV systems and their containment of miRNAs in the brain be useful in the treatment of CNS injuries and progressive age-related inflammatory neurodegeneration, but may also prove useful as delivery vehicles for therapeutic miRNAs, anti-miRNAs and both bioactive and neuroactive pharmaceuticals."}
+{"text": "Phase-contrast enhanced micro-computed tomography reveals huge discontinuities at the interfaces between dental fillings and the tooth substrate. Despite the complex micromorphology, gaps in bonding could be visualized and quantified in 3D. ImageJ. PCE-CT at sub-micrometre resolution provided images with an impressive increased contrast and detail when compared with laboratory micro-computed tomography. The interface between the dental adhesive and the tooth was often strongly disrupted by the presence of large debonded gaps . The thickness of the gaps spanned 2\u2005\u00b5m to 16\u2005\u00b5m. There was a large variability in the distribution of gaps within the bonding area in each sample, with some regions around the canal exhibiting up to 100% discontinuity. Although only several micrometres thick, the extensive wide gaps may serve as gateways to biofilm leakage, leading to failure of the restorations. They can also act as stress-raising \u2018cracks\u2019 that are likely to expand over time in response to cyclic mechanical loading as a consequence of mastication. The observations here show how PCE-CT can be used as a non-destructive quantitative tool for understanding and improving the performance of clinically used bonded dental restorations.Bonding of resin composite fillings, for example following root-canal treatment, is a challenge because remaining gaps grow and lead to failure. Here, phase-contrast-enhanced micro-computed tomography (PCE-CT) is used to explore methods of non-destructive quantification of the problem, so that countermeasures can be devised. Five human central incisors with damaged crowns were root-filled followed by restoration with a dental post. Thereafter, the crowns were rebuilt with a resin composite that was bonded conventionally to the tooth with a dental adhesive system (Futurabond U). Each sample was imaged by PCE-CT in a synchrotron facility  with a pixel size of 650\u2005nm. The reconstructed datasets from each sample were segmented and analysed in a semi-automated manner using  To fix this, the dentist restores the tooth shape and function using a combination of bonded composite materials that need to tightly adhere to the substrate. Biomaterials are typically chosen for mechanical durability and for aesthetic considerations, while matching the mechanical behaviour to the remaining tooth structure. Such dental biomaterials are used to return the tooth into function for patient satisfaction, and specifically to make sure the reconstruction withstands the repeating loads of mastication for many years. In fact, a main objective of contemporary dental treatment is to establish strong and continuous bonds between the filling and the tooth substrate. Current treatment protocols advocate bonded sealing for a variety of reasons. These include increased mechanical stability of the restoration due to an improved distribution and resistance to stresses, as well as prevention of bacterial percolation at the interface  of the crown  to attributes of the bonding system    to increase contrast. 3D measurements of whole, root-treated teeth have previously been demonstrated using PCE-CT, revealing different density dental materials at micrometre resolution  accentuates interfaces due to the combined effects of high flux \u2018partial-coherence\u2019 X-rays. This facilitates the differentiation between materials with similar density  by the Ethical Review Committee of the Charit\u00e9 Universit\u00e4tsmedizin Berlin, Germany, and were stored in an antiseptic solution prior to the experiment. Each tooth had its root canal treated following a standardized protocol  each tooth was restored using a fibreglass dental post. This was cemented into the root canal with a self-adhesive resin cement, following manufacturers recommendations . Such d2.4.Each tooth crown was restored immediately after post cementation. For that, the exposed tooth cervical area was acid etched for 10\u2005s, followed by rinsing and air drying. A dental adhesive system was applied following manufacturers recommendations, including light curing for 10\u2005s Table 1. A stand2.5.After tooth restoration, each sample was mounted in a transparent vial , padded with wet foam to maintain humidity and to avoid dehydration during imaging.ImageJ 1.52d, National Institute of Health, USA; Amira ZIB-Edition, Konrad-Zuse-Zentrum f\u00fcr Informationstechnik Berlin, Germany). The cervical areas, including the rim between root and the crown restoration were\u00a0selected for imaging by PCE-CT in a synchrotron. Each sample was scanned on beamline ID19 of the European Synchrotron Radiation Facility  using inline propagation-based contrast microtomography   was used to first image each specimen . Following reconstruction  the architectures of the restorations were examined in both 2D and 3D ]. The resulting binary images had their different sets of connected pixels and voxels individually numbered and labelled using the \u2018Connected components Labelling\u2019 algorithm. The different components localized to the adhesive layer were then visually selected, discarding the irrelevant (outside of the interface) labels by using the \u2018Select Labels\u2019 function of MorpholibJ. The final Boolean volume comprising only the interfacial gaps between adhesive and tooth was overlaid onto the original volume , is due to the cutting lines, used to remove excess soft cement during restoration construction: a sharp straight scalpel was used to clear overflow prior to crown construction. Thus PCE-CT even reveals laying steps during restoration fabrication. With 2D slices containing the conditioned tooth area and gap, the percentage of gaps at the interface was calculated. Radial, orientation-specific variations in the non-bonded regions were quantified to assess the distributions of gaps at the interface. With the centre of the restoration/post defined as a pivot, the tooth and gap areas were divided in 18 equal segments (sectors) spanning 360\u00b0 around the tooth long axis, each extending 20\u00b0 on the tooth surface. For each sector, the ratio of gaps to the area of bonding was quantified and plotted against the azimuthal angular axis.To isolate debonding and interfacial gaps, the datasets were processed using the free extension package me Fig. 5 to verifme Fig. 5. The ext3.Laboratory \u00b5CT scans generated datasets that reproduced the approximate geometry and the main components of the tooth restoration within the root and the reconstructed crown. In such data, however, there was no difference in contrast between the resin composites used for crown reconstruction and the resin cement Fig. 5, nor wasPCE-CT at sub-micrometre resolution provided 3D datasets with an impressive contrast and a remarkable amount of detail . The micromorphology of the tooth and restoration were fully visible, revealing micrometre-diameter dentin tubules, highlighting the presence of fillers in the different resin composites and well reproducing the layout of single fibres within the fibreglass post. Example overviews and slices in the datasets are shown in a longitudinal slice in Fig. 6e.g. Fig. 6The enhanced contrast brought about with PCE-CT highlights gaps between the adhesive Fig. 6, tooth sThe results from the analysis of 18 sections of each sample, shown in the graphs of Fig. 74.in\u00a0vitro, it is extremely difficult to produce a predictable sealed bonded interface. From a biological standpoint, establishing a continuous interface between tooth and adhesive is a major objective of treatment. It is a clinical objective aimed at preventing damages associated with water sorption, infiltration of bacteria and bacterial by-products, reportedly associated with secondary caries and/or re-infection of the root canal system  at the interfaces in adhesively restored human teeth. Of great concern is the observation that in each tooth at least 50% of the visible section of the outer imaged rim exhibited some form of gap, as seen\u00a0in the central column of Fig. 7et al., 2019et al., 2004et al., 2005et al., 2019et al., 2014et al., 2015et al., 2019et al., 2014et al., 2014et al., 2019Due to the lack of contrast and resolution in the laboratory \u00b5CT images, it was not possible to observe the adhesive layer or the interfaces between materials. PCE-CT resolved this problem as it is extremely effective and may be the only possible means to non-destructively image interfacial gaps between the low-density polymer material and other structures within the tooth restorations (Soares et al., 2004et al., 2005et al., 2019et al., 2014et al., 2015et al., 2019Discontinuities at the interface between restorative materials and tooth substrate have been reported using high-contrast dyes such as silver nitrate. This radiopaque liquid has been widely used in dental research due to its high contrast in radiographs (Mollica et al., 2015et al., 2011et al., 2019et al., 2018The use of semi-automated image segmentation presented here will benefit from further improvements but already has many advantages. Since the data are obtained non-destructively, effects of artefacts and filtering can be tested and the 3D data can be quantified in a repeatable, quantitative operator-independent way (Carrera et al., 1996et al., 2007et al., 2004et al., 2005et al., 2011et al., 2014et al., 2016et al., 2016et al.,\u00a02016et al., 2019et al., 2011et al., 2018et al.,\u00a02020Synchrotron \u00b5CT imaging is an effective tool for examining different biological samples. The high photon flux density and almost parallel beams with a wide range of energies is suited for imaging both low- and high-density structures. Phase-contrast imaging (Cloetens et al., 2017in vitro performance record, comparable with other universal adhesive systems (Chen et al., 2015et al., 2015et al., 2010The adhesive used for testing here was Futurabond U, a clinically used universal adhesive system. It can be deployed either with or without prior acid etching of the tooth substrate (Sofan 5.in vitro. It is also a valuable tool for imaging interfacial gaps between thin polymer adhesives and tooth substrate in restored hydrated, treated teeth in 3D. Flaws in the thin polymer bonding layer were quantified non-destructively. Although a possible quantitative data processing pipeline was proposed, much more can be done for improved image segmentation and analysis. The use of PCE-CT will assist efforts to systematically assess the integrity of contact between different clinically used dental materials.The present work provides details about steps needed to measure gaps and the areas that they affect, without the use of any tracer dye and while strictly adhering to clinically used materials and procedures allowing reproducibility and comparability. The observations here clearly establish the use of PCE-CT for advancing our understanding about the ability of clinically used dental adhesive systems to form continuous interfaces with tooth tissues when measured"}
+{"text": "Background: CrossFit\u00ae training is a high-intensity functional training program that aims to increase physical functional performance through biochemical responses, i.e., hormonal, metabolic, and inflammatory responses. Most hormonal, metabolic, and inflammatory changes induced by CrossFit\u00ae training have been reported in isolated clinical studies. The purpose of this review was to systematically explore the existing literature on characterization of hormonal, metabolic, and inflammatory responses resulting from CrossFit\u00ae training.Methods: A systematic search of the literature was conducted in PubMed, Web of Science and Scopus from August 2019 to October 2019. Studies were selected through critical review of the content. Using specific keywords, 623 articles were found, of which 597 were excluded for ineligibility, and 25 were eligible. The papers were separated according to subject area: hormonal (n = 8), metabolic (n = 19), and inflammatory (n = 6) changes. All were published between 2015 and 2019.Results: This review reveals potential effects of CrossFit\u00ae training on hormonal, metabolic, and inflammatory responses. However, studies had low levels of evidence and reliability due to methodological limitations.Conclusion: In summary, the results showed a greater volume and intensity of workouts accentuate the responses, that are of paramount importance for improving understanding of the effects of CrossFit\u00ae training and serve as a basis for prescribing future exercise protocols. The training consists of a combination of different exercise elements: cardiovascular (CV), gymnastic and weightlifting exercises , is structured into joint mobility, warm-up, a technical portion, and the main portion. WODs are performed with short or no breaks between exercises, repetitions, and rounds  is a training program that emphasizes functional movements. HIFT uses a combination of movements, and self-selected time periods of work and rest , exercise modalities , methods (for time or AMRAP), and intensities (absolute or relative load). In reviewing the literature, it was observed that most of the hormonal, metabolic, and inflammatory changes related to CrossFit\u00ae training have been reported in isolated clinical studies.Studies on the physiological changes resulting from CrossFit\u00ae training.To date, no systematic review of such changes has been performed. The purpose of this review was to systematically review the existing literature on characterization of hormonal , insulin-like growth factor 1 (IGF-1), adrenaline, noradrenaline, metabolic , and inflammatory  responses associated with CrossFitA systematic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , metabolic  and inflammatory (IL-6 and IL-10) parameters. CK, that is biomarkers of muscle damage, was included in inflammatory responses.\u00ae training interventions.Study design: Randomized and non-randomized trials, using either cross-over or parallel groups, comparing different types of CrossFit\u00ae training; (3) a sample of men and women; (4) studies that investigated at least one hormonal, metabolic, or inflammatory/muscle damage variable relevant to the analysis in the present study. Studies were excluded in the following cases: (1) duplicate articles; (2) articles that were not in the English language; (3) articles that presented training protocols not based on CrossFit\u00ae training; (4) articles with special populations; (5) articles that were systematic reviews, conference abstracts, dissertations, theses, and book chapters.The specific inclusion criteria were as follows: (1) articles that were original research; (2) intervention based on CrossFitThe systematic literature search was carried out until October 2019 using the following databases: PubMed, Web of Science and Scopus. The articles were searched using a combination of keywords corresponding to the theme of the review: CrossFit OR \u201chigh-intensity functional training\u201d OR HIFT. Medical Subject Headings (MeSH) was consulted to check possible entry terms related to the keywords. After combining the research results and discarding duplicate studies in the databases, two researchers (NJ and MRD) independently selected titles and abstracts to identify relevant studies. The included articles were retrieved, read in full (full text) and independently assessed for eligibility by the same two researchers (NJ and MRD) according to the criteria described above. A meeting was held, and in the case of disagreement regarding the selection of articles, a third author (JN) was consulted to resolve the disagreement.\u00ae training protocols, and main conclusions was extracted (see Standardized data extraction forms were completed by two researchers (NJ and MRD) and verified by another researcher (JN). Information on the type of study design, characteristics of the participants, sample size, time of experience in the profile, data collection, CrossFitcted see \u20133. The eThe Cochrane Collaboration's risk of bias assessment tool was used to evaluate the internal validity of the studies  were selected for a complete full-text review. Finally, 25 articles were selected . All were published between 2015 and 2019, and most were of a cross-sectional design.n = 21; pre-training and post-training or comparison between groups), longitudinal  or descriptive of a cross-sectional cohort .The study design was described as acute  assessment, in which the HR remained between 85.9 and 97.4% of the maximum HR . There was a consensus that lactate levels are high immediately after a CrossFiti et al. , when evGlycemia was often investigated (8 studies). Similar to lactate, several studies showed an increase after independent WOD (Tibana et al., \u00ae training (Cadegiani et al., Cholesterol, creatinine, GOT and GPT were each investigated in only one study. Cholesterol showed no differences after training (Shaw et al., Six studies (Tibana et al., CK seemed to increase after training (Durkalec-Michalski et al., IL-6 increased after WOD-independent training, while IL-10 increased as a function of WOD characteristics (Tibana et al., \u00ae training. The results of this systematic review showed that there are still few studies for each observed variable. Of the 25 studies analyzed, all had different training protocols regarding the training stimulus administered. This methodological difference was found because CrossFit\u00ae training is constantly varied and consists of a combination of different exercise elements: CV, gymnastic and weightlifting exercises (Glassman, \u00ae training seem to be related to the training variables, and the protocols with more volume and intensity provided greater biochemical responses. In addition, psychological factors, such as pre-competitive anxiety, can alter the physiological status of athletes (Mangine et al., The purpose of this review was to systematically examine the existing literature on characterization of hormonal, metabolic, and inflammatory responses associated with CrossFit\u00ae training practitioners and create an environment conducive to an increase in cortisol (Mangine et al., The studies demonstrated that increases in testosterone and cortisol levels occurred after WODs, with longer recovery intervals (Mangine et al., \u00ae training.Some limitations were observed in the study by Mangine et al. , who eva\u00ae training, while cortisol levels decreased (Poderoso et al., Chronically, testosterone levels in men rose after 6 months of CrossFitThe training dose required to cause hormonal changes is difficult to determine. Notably, training with a greater volume promoted increases in GH concentrations (Kliszczewicz et al., \u00ae training practitioners have higher levels of testosterone and GH and lower levels of noradrenaline than practitioners with overtraining syndrome. The higher levels of noradrenaline in practitioners with overtraining syndrome may be a compensatory attempt to maintain performance during exercise due to reduced conversion of catecholamines to metanephrines (Cadegiani et al., \u00ae training has a high metabolic component may explain the increases in GH levels (Kliszczewicz et al., On the other hand, increases in testosterone levels may be closely related to the health of the participants. In a descriptive cross-sectional study, Cadegiani et al.  showed tCatecholamines showed acute elevations after WODs (Kliszczewicz et al., \u00ae practitioners with other sport athletes, the responses may differ. From this perspective, Arruda et al. (\u00ae training (Poderoso et al., When comparing the chronic hormonal responses of CrossFita et al.  observed\u00ae training studies was blood lactate. An acute increased lactate concentration response was observed after training sessions (Fernandez-Fernandez et al., \u00ae training, WODs generally do not have a standard break time, i.e., as the training is \u201cfor time\u201d or AMRAP, the intervals are self-selected according to the suitability of the participants. Therefore, this characteristic can keep lactate elevated for a longer duration after the session (Goto et al., The main metabolic marker evaluated in CrossFit\u00ae training practitioners are inconclusive.As for chronic metabolic responses, the lack of change in lactate response may be the result of the intensity utilized for each WOD. It must also be considered that pre-training lactate was not registered (Murawska-Cialowicz et al., \u00ae training session due to increased catecholamines. The increase in the glycemic rate in response to a training session is due to the need for greater utilization of glucose to meet the energy required for the sport, which has the particular characteristic of always being performed at high intensity (Glassman, Blood glucose was another variable observed. According to Tim\u00f3n et al.  and Klis\u00ae training session (Shaw et al., Cholesterol response does not appear to be affected by a CrossFit\u00ae training performance and aerobic capacity. Although the primary objective of the study was to examine the effectiveness of a sodium bicarbonate supplementation protocol, the CK response was similar, regardless of the supplement, increasing after the WOD. Another study found an increase in CK level after different WODs, which continued for up to 24 h (Tim\u00f3n et al., Acute muscle damage responses through CK were investigated in three studies (Durkalec-Michalski et al., \u00ae training practitioners to a higher volume and intensity of training for successive days may expose the practitioner to the risk of damage associated with muscle cell necrosis.In addition to being an indicator of muscle damage, CK levels have been shown to be high in people with rhabdomyolysis (Honda et al., \u00ae competition. In contrast, Heavens et al. (IL-6 and IL-10 were evaluated in two studies (Tibana et al., s et al.  showed ts et al.  used mens et al.  studied s et al. .\u00ae training on hormonal, metabolic and inflammatory factors. However, studies evaluating such aspects have a low level of evidence and reliability due to methodological limitations and biases that hinder the convergence of results. Apparently, hormonal, metabolic, and inflammatory stress marker levels increase after CrossFit\u00ae training, regardless of the protocol used. However, a greater volume and intensity of workouts accentuate the responses. Some parameters are inconclusive, such as blood glucose and IL-6 and IL-10 levels, due to different results and the small number of studies. Thus, this review sheds light on specific knowledge gaps that should be further investigated. Nevertheless, the results are of paramount importance for improving understanding of the effects of CrossFit\u00ae training and serve as a basis for prescribing future exercise protocols.The present review demonstrates the potentially significant effect of CrossFitAll relevant data is contained within the article. Further inquiries can be directed to the corresponding author.NJ structured and designed the research. NJ and MD carried out the review of studies. JGV and MD realized risk of bias. NJ, JN, JGV, MD, and JV contributed to the conception and writing of the article, reviewing, and editing the manuscript. DB corrected the final version and English grammar. All authors approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Various bacteria, archaea, and microbial eukaryotes also evolve H2 as a diffusible end product during fermentative metabolism through the activity of [FeFe]- or [NiFe]-hydrogenases (Horner et al., 2 is a facultative trait that is regulated through the expression and maturation of hydrogenases (Schwartz et al., 2 represents a substrate that organisms utilize to supplement their energy metabolism, thereby allowing for an expansion of their niche space in ecosystems where other sources of reductant are low or variable in supply (e.g., Amenabar et al., Approximately a third of sequenced microorganisms, spanning at least 70 microbial phyla, encode hydrogenases and are thus predicted to be capable of interconverting H2 in ecosystem level processes is increasingly being realized in both environmental and biomedical settings. A wide range of ecosystems have now been described where H2 cycling supports the bulk of primary production and where it forms the basis by which species interact, leading to ecologically structured communities. Much of the research on H2 metabolism to date has focused on ecosystems where H2 is present at elevated concentrations due to biological activity (e.g., anoxic sediments, gastrointestinal tracts; S\u00f8rensen et al., 2 can serve as source of reductant for aerobic soil microorganisms and that this can influence the composition of the atmosphere (Conrad, 2 metabolism is critical for the virulence of numerous pathogens, including Helicobacter, Clostridia, and Enterobacteriaceae (Kaji et al., The implications of H Conrad, . In para2 metabolism from the molecular to the ecosystem scale. In the area of anaerobic metabolism, there are articles exploring the metabolism of H2-metabolizing bacteria capable of sulfate reduction, acetogenesis, halorespiration, and fermentation. Two articles investigate H2 oxidation in sulfate-reducing bacteria using the model system Desulfovibrio vulgaris (Fauque et al., Smith et al. present a mathematical model of the growth and metabolism of this bacterium, whereas L\u00f6ffler et al. investigate the kinetic isotope fractionation associated with its H2 oxidation activity. A comprehensive review led by Schuchmann et al. covers recent advances in understanding clostridial H2 metabolism; it details the discovery and characterization of multimeric electron-bifurcating [FeFe]-hydrogenases, including those associated with formate dehydrogenases (Schut and Adams, Dragomirova et al. focuses on heterologous expression of a [NiFe]-hydrogenase from dehalogenating Chloroflexi (Kublik et al., Pinske explores a third type of formate dehydrogenase-linked hydrogenase, namely the classical formate hydrogenlyase complex of Enterobacteriaceae (McDowall et al., This special issue, featuring 10 articles from 46 different authors, explores microbial H2 metabolism. Islam et al. report two other novel iron-sulfur proteins in mycobacteria, demonstrating that they are essential for the activity of the two high-affinity hydrogenases described in this lineage (Greening et al., Carere et al. meanwhile, build on the recent discovery that verrucomicrobial methanotrophs are facultative mixotrophs (Carere et al., Methylacidiphilum varies depending on H2 availability. Three articles also explore H2 metabolism at the ecosystem level. Adam and Perner explore the diversity of aerobic and anaerobic H2 metabolism in deep-sea hydrothermal vent systems, whereas Meyer-Dombard et al. investigate the influence of H2 on biogeochemical cycling in serpentinizing springs in the Philippines. Teng et al. review the previously underexplored area of H2 metabolism in bioremediation, including in the reduction of organohalides, nitroaromatic compounds, and heavy metals (Chardin et al., Several articles also investigate aerobic H2 in microbial metabolism and uncovers novel enzymes and pathways that mediate this process. This body of work highlights the intricate linkages between H2 cycling and the cycling of various other compounds, including methane, formate, carbon dioxide, sulfate, and organohalides, among others. In turn, these findings pave way for future studies on the biochemistry, physiology, ecology, and industrial applications of microbial H2 metabolism.In summary, this special Research Topic sheds light on the diverse role of HCG and EB drafted this editorial together and approve its submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Salmonella enteric serovar Typhimurium (ST), by oral consumption of a genetically modified (GM) probiotic strain in mice , and a significantly improved preventive effect was displayed. However, successful probiotic intervention of ST, one of the most prevalent foodborne pathogens, is challenging, and more work is necessary. We know that many probiotic strains have an inhibitive effect on ST by different mechanisms .ST is a Gram-negative, non-spore-forming, facultative anaerobic bacterium and can infect any warm-blooded animal  ST is rapidly expanding (Obaidat and Stringer, L. casei promotes overall bacterial species diversity and increases the abundance of Lactobacillus and Bifidobacterium in the cecum in mice (Peng et al., Lactobacillus spp. is mainly in the small intestine, and Bifidobacterium spp. is mainly in the large intestine (Donaldson et al., In chickens, ST first attaches to the cecal epithelial cells and then spreads to the liver, spleen, and oviduct. In pigs, early ST infection disrupts microbiome composition and functionality principally at the ileum (Arg\u00fcello et al., Probiotics play important roles in human health. As normal commensals, they exert their prophylactic and therapeutic properties against ST in four main ways (Gut et al., L. casei modulates host immunity by regulating the expression of intestinal inflammation-related cytokines [e.g., suppressing pro-inflammatory cytokines and provoking anti-inflammatory cytokines after ST infection (Peng et al., Lactobacillus spp. modulate ST by regulating gene expression related to colonization and virulence (Muyyarikkandy and Amalaradjou, L. pentosus AT6 and its cell-free culture supernatants inhibit ST growth and its adhesion as well as invasion (Liu et al., In fact, probiotics can be modulators, producers, and residents after being administered. As modulators, probiotics effectively modulate either the host or the pathogen. L. casei or the GM counterpart has displayed a significant protective effect on ST infection (Peng et al., Salmonella enteritidis infection is efficacious in broilers, but data on prophylactic treatment timing regarding ST is not available (Higgins et al., Pre-administration of probiotics is an effective method demonstrated in animal studies. For example, 1-week pre-administration of either wild-type Bacillus spp., Bifidobacterium spp., Clostridium spp., Escherichia coli Nissle 1917, and Lactobacillus spp., yeast, and so on (Kanmani et al., Bifidobacterium spp. and Lactobacillus spp., harbor most of the well-characterized probiotic strains and are widely commercialized. These probiotics reduce more than 90% of caecal ST load, prevent invasion of organs, and even completely eradicate ST (Gut et al., Akkermansia muciniphila, Eubacterium hallii, and Faecalibacterium prausnitzii (Almeida et al., Probiotics are any non-pathogenic microorganisms that confer health-promoting properties when administered in adequate amounts (Hill et al., E. coli inhibits ST growth with improvement in fitness (Palmer et al., L. casei improves the protective effect on ST more than the wild-type strain by increasing CLA (Peng et al., Besides the traditional application of wild-type probiotics, GM probiotics are also studied. Although there are safety issues, GM probiotics attracted much interest due to their extra advantages and strengthened effects (Barra et al., Pseudomonas aeruginosa and reducing vancomycin-resistant Enterococcus by GM probiotic E. coli Nissle 1917, similar approaches might be also promising for ST prevention (Hwang et al., Along with the rapid development of synthetic biology, interest has increased on the design and construction of GM probiotics as live biotherapeutics for a range of medical applications (Chua et al., 6 CFU/g or CFU/mL viable cells may be an acceptable way. Considering the GRAS status, consumption of them can be without control. However, to cure ST infection, NG or GM probiotics are more promising. These probiotics can be formulated as concentrated pills or capsules containing more than 109 CFU/g or even more cells. They may be more suitable as over-the-counter drugs. Nevertheless, for any purposes, release of both conventional and GM probiotics as live biotherapeutical products in the market needs full assessment of safety (O'Toole et al., As pointed out, formulation of viable probiotics while enabling cost-effective biomass yield is a critical step toward product development of translational application (Almeida et al., ZS conceived the opinion. YS and JL wrote the draft manuscript. YS collected reference and drawn the figure. ZS finalized the manuscript and acquired funding. All authors discussed the content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Resveratrol is a natural polyphenol that has anti-aging and anti-inflammatory properties against stress condition. It is reported that resveratrol has beneficial functions in various metabolic and central nervous system (CNS) diseases, such as obesity, diabetes, depression, and dementia. Recently, many researchers have emphasized the connection between the brain and gut, called the gut\u2013brain axis, for treating both CNS neuropathologies and gastrointestinal diseases. Based on previous findings, resveratrol is involved in glucagon-like peptide 1 (GLP-1) secreted by intestine L cells, the patterns of microbiome in the intestine, the 5-hydroxytryptamine (5-HT) level, and CNS inflammation. Here, we review recent evidences concerning the relevance and regulatory function of resveratrol in the gut\u2013brain axis from various perspectives. Here, we highlight the necessity for further study on resveratrol's specific mechanism in the gut\u2013brain axis. We present the potential of resveratrol as a natural therapeutic substance for treating both neuropathology and gastrointestinal dysfunction. Resveratrol is a polyphenol that is secreted by grapes and berries -activated protein kinase (AMPK) pathway  and phosphodiesterases (PDEs) Chung,  Figure .SIRT1 gene, considered an anti-aging related gene, in the duodenum and also rescues insulin resistance and improves neuronal networks in the brain , an incretin hormone and a major hormone of the gut\u2013brain axis, is linked to the control of energy homeostasis and the development of obesity , and finally lead to improved cognitive function  is expressed in both the CNS and gastrointestinal tracts, and currently 5-HT has been considered as an important target in the gut\u2013brain axis.5-HT is a growth factor, a paracrine factor, and an enteric neurotransmitter  synthesis through 5-HT receptors (Prasad et al., Considering previous data, 5-HT derived from gut and brain contributes to nervous systems globally, and the circulation of 5-HT in the body mediates the gut\u2013brain axis (Yano et al., 2C receptor-dependent signaling (Peng et al., A current study proved that resveratrol regulates the gut\u2013brain axis by controlling the 5-HT-dependent pathway in an irritable bowel syndrome rat model and specifically that resveratrol influences various organs including brain hippocampus, ileum, and colon through 5-HT axis (Yu et al., Another recent study demonstrated that resveratrol could increase the expression of 5-HT, leading to the improvement of brain function (Nabavi et al., Several studies have mentioned the neurological role of resveratrol in depression and anxiety (Yu et al., One current study reported that the inhibition of 5-HT release attenuates the activation of GLP-1 receptor signaling and highlighted the relationship between GLP-1 and 5-HT serotonin system (Anderberg et al., Another study mentioned that GLP-1 receptor agonist liraglutide could reduce the expression of 5-HT2A receptor and subsequently reduces body weight and inhibits serotonin synthesis in mice model (Nonogaki and Kaji, Ripken et al. suggested that serotonin treatment could boost GLP-1 release, and the blocking of 5-HT receptor could affect the production of GLP-1 (Ripken et al., A recent study proved that 5-HT enterochrnomaffin cells in gut regulates gut microbial metabolism and homeostasis and is affected by the activation of GLP-1 (Lund et al., Further, ghrelin, known as a hormone for regulation of motivation and reward system among brain function, has been interacted with GLP-1 and the monoamine transmitter 5-HT (Currie et al., GLP-1 derived from brain mainly is produced by the nucleus tractus solitarius in brain (Alhadeff et al., Given previous evidences, resveratrol can control 5-HT and its receptor and also modulate release of 5-HT through GLP-1 regulation. Ultimately, resveratrol could control the neuropathology of neurological diseases such as depression and stress-induced anxiety. Also, resveratrol can regulate gut dysfunction in irritable bowel syndrome via 5-HT. Thus, we emphasize the necessity for further study of the specific mechanism and cellular pathways regulated by resveratrol and mediated by 5-HT to fully understand the gut\u2013brain axis.Resveratrol is involved in the gut\u2013brain axis through another mode in addition to the GLP-1 pathway and 5-HT system.Recently, gut microbiota is emerging as an important node in the gut\u2013brain axis (Louwies et al., trans-stilbene have been reported to be the major microbiota-derived metabolites made from resveratrol (Juan et al., Resveratrol administration could be metabolized by the liver, intestinal tract, and gut microbiota Walle, . A recenBifidobacteria infantis and Lactobacillus acidophilus are strongly linked to piceid production from resveratrol (Basholli-Salihu et al., Enterococcus faecalis and increasing the Lactobacillus and Bifidobacterium populations (Qiao et al., Specifically, dihydroresveratrol as a metabolite of resveratrol is produced in the intestines such as the cecum, colon, and rectum through fermentation by the gut microbiota (Amri et al., Recently, resveratrol has been reported to improve gut microbiota in bowel diseases under harsh oxidative stress (Hu et al., A clinical study has reported that resveratrol treatment exerts cardiovascular and anti-obesity effects by ameliorating gut microbiota diversity (Bird et al., These previous findings demonstrate that resveratrol and gut microbiota influence each other. Furthermore, resveratrol could enhance the gut microbiota diversity and the gut barrier's homeostasis. These effects of resveratrol should be investigated further to determine the specific gut bacteria that affect the gut\u2013brain axis.Here, we reviewed previous significant evidence of the effect of resveratrol on the gut\u2013brain axis . We summJC, J-HJ, and JS contributed to the writing of the text. JC and J-HJ made and revised all figures. JS wrote and finalized the revised manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ten years ago, Archives of Toxicology has issued an Editorial by R.D. Combes  entitledIn the following, important research lines of computational toxicology were the development and refinement of computational models for relevant toxicological endpoints, such as liver injury, cardiotoxicity, renal toxicity and genotoxicity Ekins . Best prAs far as regulatory acceptance is concerned, a decisive breakthrough was the integration of (Q)SAR methodologies into the guideline ICH M7 \u201cAssessment and control of DNA-reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk\u201d, issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use (Amberg et al. Advanced computational methodologies (Kusko and Hong Perspectives are emerging for computational approaches to predict the toxicity of nanomaterials Buglak  and of cComputational toxicology continues to assist in refining PBPK modelling (Savvateeva et al. A burst in manuscript submissions to \u201cArchives of Toxicology\u201d covering the in silico/computational field is noticed since 2019, signaling both increased scientific importance and regulatory relevance in the twenty-first century of this research area (Krewski et al. A current tendency, both in the United States (Kosnik et al. Given this exciting development, further submissions of manuscripts from these fields to Archives of Toxicology are highly encouraged!"}
+{"text": "This is one of the few polymers that the Food and Drug Administration (FDA) has approved for human administration due to its biocompatibility and biodegradability [Poly/poly(lactic acid) (PLGA/PLA) carriers were prepared through spray-drying to incorporate the microcrystals that were previously prepared by ultra-sonication. In vivo testing in rat models was demonstrated to prolong drug retention in joints. The TA remained there for over 28 days, which was more 21 days compared with the TA-free group. Furthermore, these nanocarriers were demonstrated to be stable for one year.In the first research study presented in this Special Issue, Ho et al. developed polymeric microspheres which contain micronized triamcinolone acetonide (TA) in order to increase the drug retention time in joints after intra-articular administration . Poly(laThe group of Peula-Garc\u00eda used PLGA nanoparticles to carry bone morphogenetic protein (BMP-2) . The nanIn another study, Hwang et al. fabricated PLGA carriers combined also with a hydrogel matrix. They produced oxaliplatin-loaded PLGA microparticles using a double emulsion technique and then loaded them into hyaluronic acid and carboxymethyl cellulose sodium-based cross-linked hydrogels . This drKim et al. developed an original system to be used in the topical delivery of trolamine salicylate (TS), a topical anti-inflammatory analgesic used for the treatment of small joint pain . Here, tDuse et al. used PLGA nanoparticles to encapsulate curcumin, a well know natural compound that present anticancer benefits . It was Another interesting study proposed by Varga and colleagues, who contributed with an interesting study of nanoparticle design and optimization where the (\u00b1)-\u03b1-Tocopherol (TP) with vitamin E activity was encapsulated in PLA and PLGA nanoparticles . To stab2) cells.Morelli et al. improved paclitaxel delivery in the gastro-intestinal tract by encapsulating the drug in PLGA nanoparticles coated with PEG . The nanWith the objective to overcome the undesired lag time of the commercially available risperidone, Janich et al. encapsulated this drug in PLGA\u2013lipid microcapsules and PLGA\u2013lipid microgels . The carA research work using PLGA nanoparticles for ocular application was also collected. Ryu et al. produced rapidly dissolving dry tablets containing alginate and dexamethasone-loaded PLGA nanoparticles . These nAn interesting approach based on a combination of cell and drug delivery for the treatment of Huntington\u2019s disease (HD) was proposed by Andr\u00e9 et al. . The autTwo works lead by Roing and Wacker present new theranostic PLGA-based nanoparticles. In the first one, biodegradable and photoluminescent polyester (BPLP) with PLGA polymer was used to fabricate biocompatible photoluminescent nanocapsules . AdditioPLGA toxicity was investigated by Bakhaidar et al. . Here, tAnother relevant study was performed by Operti et al., who used microfluidics technology as a tool to manufacture particles in a highly controllable way . In theiFinally, a research study regarding the importance of new techniques to characterize PLGA nanoparticles was included in this special edition. Shmool et al. investigated the dynamics of PLGA microspheres prepared by freeze-drying . The watThe papers presented in this Special Issue represent a small part of the research that is ongoing in the field of PLGA nanocarriers all over the world. The huge potential of PLGA nanoparticles make them a promising drug delivery system with outstanding properties and with much more potential for exploring in the coming years. With this Special Issue, the editors expect that the readers from the field find it stimulating and contributing more ideas or methodologies for their future work."}
+{"text": "Parkinson\u2019s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a \u201cfalse\u201d transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD. Parkinson\u2019s disease (PD) is one of the most common neurodegenerative disorders, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra compacta (SNc). Dopamine replacement therapy using the precursor L-DOPA is the main treatment for the disease. However, long-term use of L-DOPA leads to the development of dyskinesias and non-motor manifestations  contains the largest group of serotonin-producing neurons, and changes in DRN function have been implicated in neuropsychiatric diseases and movement disorders Hornung, . Classic1\u20137) and at least 15 receptor subtypes have been identified  may have a constitutive activity, which may be associated with pathophysiological conditions  appear particularly interesting for PD , which was reduced by dopaminergic and serotonergic lesions and suppressed by NMDA glutamate receptor antagonists, suggesting that stimulation of glutamate receptors is essential for the observed neuronal response , which is the main brain neurotransmitter mediating inhibitory signals. Deficiency in brain serotonin results in alterations in the GABAergic system  in striatal dopaminergic terminals. However, in advanced stages of the disease, the dopaminergic denervation is almost complete and other cell types showing AADC activity convert exogenous L-DOPA into dopamine, including serotonergic terminals (Arai et al., 2A antagonists (Meco et al., 1A agonist have been shown to reduce LID without compromising L-DOPA efficacy (Meadows et al., Compounds acting through the serotonin system such as anpirtoline, (B\u00e9zard et al., 1A agonists such as buspirone (Politis et al., 3 receptors also reduced LID (Kwan et al., 1 agonists with drugs that modulate the glutamatergic function (Tison et al., Clinical trials with serotonergic drugs are ongoing, revealing the promising antidyskinetic effects of 5HT1A receptor agonist buspirone produced significant dampening of GID in grafted patients. However, this effect could also be explained by the dopamine D2 receptor partial antagonistic effects of the drug (Politis et al., 1A and 5-HT1B agonists, suggesting that the effect of these drugs on GID is mediated by the activation of presynaptic host-derived receptors (Shin et al., 6 receptors (Aldrin-Kirk et al., Clinical trials using transplants of fetal dopamine neuroblasts have shown promising results, although many patients have developed GID (Freed et al., Interactions between serotonergic and other neurotransmitter systems reveal that serotonin plays a crucial role in the control of movement by the basal ganglia. These interactions are of great interest for understanding the pathophysiology of PD and to develop novel therapeutic strategies. Manipulation of the serotonergic system represents a valuable target to treat LID and GID in PD patients. However, further investigation is required to clarify mechanisms of neurotransmitter interactions and to determine optimal compounds and doses for effective therapies.All authors have contributed to this work and approved its final version for submission. AM developed the idea for this review and wrote the manuscript. AL-L, CL, and JL-G prepared the figure and were involved in the literature review and preparation and revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Preclinical models for the definition of anti-cancer drug safety and efficacy are constantly evolving. Indeed, tumor development in humans is not always fully reproducible and predictable in other animals. In turn, two-dimensional (2D) cultures, used for many years to test drug effects, are limited by the lack of tissue structure and architecture, which can influence both pharmacokinetics and pharmacodynamics, thus impairing the prediction of anticancer drug efficacy. An interesting and reliable alternative is represented by three-dimensional (3D) culture systems, including spheroids and matrix-based collagen or synthetic scaffolds, which have been validated by the EU Reference Laboratories as preclinical models to overcome at least some of the above-mentioned drawbacks.This thematic issue collects studies involving both advances in the techniques used to create and analyze some 3D culture systems and their applications in different cancer models for drug combination testing. The switch from 2D to 3D culture changes several conditions for cell growth, the first being a reduced surface for direct targeting, with the inner cell layers being protected from the external environment. At the same time, inner cells can suffer a reduced nutrient or oxygen supply, drastically changing their metabolism to a hypoxic one, causing the transcription of genes typically involved in drug resistance. This picture is even more complicated when co-cultures of different cell types are generated.A. R. Holub et al.  used an The bioprinting approach tested by Seokgyu Han et al.  allowed Ezequiel Monferrer et al.  comparedAlthough these models of scalable complexity allow us to investigate the interactions between tumor spheroids and the tissue microenvironment, their analysis is usually confined to classic microscopy approaches. Optical microscopy shows intrinsic limits that can be usually outdone only by high cost instruments. However, Eliana Steinberg et al.  have demAnother approach to increasing the information derived from 3D models has been described by Tarapong Srisongkram et al. , applyinAlthough new techniques allow researchers to extract an increasing amount of data from 3D cultured cells, the more immediate application of these models is still drug testing. This goal was pursued by Sadaf E. Pustchi et al. , testingA combined therapeutic regimen was also investigated by Layla Mohammad Hadi et al.  in 2D anIn summary, 3D cultures have contributed deeply to improving the reliability of in vitro pre-clinical models in anti-cancer drug testing. Moreover, with the establishment of organoids from various types of epithelial cancers, co-cultures of cancer organoids and immune cells have become a highly informative strategy for the development and testing of cancer immunotherapy, representing an additional useful application of 3D culture systems in cancer treatment."}
+{"text": "Bacterial proteins exhibiting two or more unrelated functions, referred to as moonlighting proteins, are suggested to contribute to full virulence manifestation in pathogens. An expanding number of published studies have revealed the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to be a multitasking protein with virulence impact in a number of pathogenic bacteria. This protein can be detected on the bacterial surface or outside the bacterial cell, where it interacts with host proteins. In this way, GAPDH is able to modulate various pathogenic processes. Moreover, it has been shown to be involved in non-enzymatic processes inside the bacterial cell. In this mini review, we summarize main findings concerning the multiple localization and protein interactions of GAPDH derived from bacterial pathogens of humans. We also briefly discuss problems associated with using GAPDH as a vaccine antigen and endeavor to inspire further research to fill gaps in the existing knowledge. Although bacterial glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme catalyzing the conversion of glyceraldehyde-3-phosphate to 1, 3-bisphosphoglycerate , two distinct pathways participate in GAPDH secretion. In cells grown in Dulbecco's modified Eagle's medium, the GAPDH secretion was mediated by the type III secretion system generally involved in translocation of various effector proteins into the infected cells. Additionally, the interaction of GAPDH with CesT, a specific chaperone for type III effectors, was established. The associated chaperone may stabilize the GAPDH molecules and prevent them from interacting with other cytosolic partners, thus enabling their targeting to the type III secretion apparatus. The other secretory pathway has not been further described and is responsible for GAPDH secretion in EPEC and in probiotic E. coli strains grown in Lysogeny broth medium . Its binding specificity differs among individual pathogens, but plasminogen is the most common target . PathogeMycobacterium tuberculosis secrets iron-binding molecules known as siderophores  that compete with the host's iron-transport proteins (De Voss et al., M. tuberculosis utilizes surface-localized GAPDH to capture the human transferrin and then internalizes the transferrin\u2013GAPDH complex. Three years later, the same research group (Malhotra et al., M. tuberculosis has even greater binding affinity to lactoferrin. M. tuberculosis GAPDH thus acts as dual receptor for both transferrin and lactoferrin. The ability of surface-localized GAPDH to bind transferrin has newly been demonstrated for Streptococcus agalactiae (Nagarajan et al., Staphylococcus ssp. Whereas, Modun and Williams (Streptococcus pneumoniae utilizes hemoglobin or heme instead of transferrin or lactoferrin as an iron source. GAPDH of this pathogen can bind both these proteins and has been proposed to participate in iron scavenging for bacterial needs (Yang et al., The ability of an invading bacterial pathogen to survive and proliferate within a host organism also depends on the availability of several trace elements, such as iron, an essential cofactor for diverse biochemical reactions. In a healthy mammalian organism, almost all the iron is bound to the transport proteins transferrin or lactoferrin or is stored in ferritin, because free iron catalyzes the production of toxic free oxygen radicals. The free ionic iron both in extracellular fluids and inside the cells is thus far too low to support bacterial growth. Bacterial pathogens have developed several strategies, however, to exploit iron from those iron-binding proteins (Cornelissen and Sparling, Williams  identifiWilliams . StreptoListeria monocytogenes. The surface-localized GAPDH interferes with the host Rab5a protein (Alvarez-Dominguez et al., Listeria monocytogenes escapes rapidly from the phagosomal compartment to the cytosol, where it replicates (V\u00e1zquez-Boland et al., L. monocytogenes GAPDH evidently has the ability to ADP-ribosylate the Rab5a protein, thus blocking its function in phagosome\u2013endosome fusion. As a consequence of this strategy, L. monocytogenes delays the phagosome maturation and gains time for escape from the vacuole prior to its fusion with endolysosome that would result in the pathogen's destruction (Alvarez-Dominguez et al., Extracellular localization of GAPDH has also been demonstrated for bacteria with intracellular life cycles. One can therefore assume that intracellular bacteria might use GAPDH for manipulating some host cellular processes in order to customize the host cell milieu for their successful survival and proliferation. So far, the only study supporting this hypothesis was performed on intracellular Gram-positive S. agalactiae, S. pyogenes, and Staphylococcus aureus was reported to induce apoptosis in murine macrophages (Oliveira et al., GAPDH derived from extracellular pathogens seems to affect host cellular processes, too, as GAPDH secreted by Streptococcus pyogenes is one of few known bacteria able to bind and inhibit the C5a component of the complement system. As an integral part of the innate immunity, the complement system acts in early defense against pathogens prior to the activation of acquired immune response. It promotes cell killing by the formation of a membrane attack complex and production of molecules that stimulate the function of phagocytic cells and contribute to the inflammation manifestation. The C5a component is a potent anaphylatoxin and chemoattractant for neutrophils and macrophages (Kajita and Hugli, 2O2 production in neutrophils (Terao et al., S. agalactiae, the secreted GAPDH exerts a stimulatory effect on B lymphocytes and to a lesser extent also on T cells. GAPDH-induced production of the anti-inflammatory cytokine interleukin-10 suppresses neutrophil recruitment in mice, which finally contributes to successful host colonization by this pathogen (Madureira et al., Immunomodulatory activities of surface proteins represent another strategy for promoting a pathogen's survival in its host organism. S. agalactiae (Madureira et al., S. pneumoniae (Sun et al., Bacillus anthracis (Matta et al., L. monocytogenes (Calderon-Gonzalez et al., L. monocytogenes, the GAPDH peptide was tested as a component of a cell-based vaccine against listeriosis. Dendritic cells were used as adjuvants for immunostimulation. Despite those promising results, the high GAPDH sequence homology between the bacterial strains and humans should be taken into consideration in vaccine development. Homologous sequences can be responsible for inducing cross-immune responses that result in deleterious effects on human health (Perez-Casal and Potter, S. agalactiae or suffering from autoimmune diseases which excludes as potential candidates for a subunit vaccine (Razim et al., Surface localization plus its role in virulence together with the binding to ECM proteins make GAPDH a suitable vaccine candidate for preventing infectious diseases. The host immune responses triggered by bacterial GAPDH have been studied extensively, and as a vaccine component GAPDH was able to induce protection against several pathogenic bacteria (Argiro et al., In summary, it is evident that our current knowledge concerning bacterial GAPDH remains quite limited and provides much space for further research. It is indisputable that this protein has other functions unrelated to its enzymatic role, and it meets the criteria to be included into the family of moonlighting proteins. Data from previously published studies indicate that multiply localized GAPDH participates in other non-glycolytic processes : CytosolAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Parkinson\u2019s disease (PD) is the second most common neurodegenerative disorder characterized by age-dependent motor dysfunction and degeneration of the midbrain dopaminergic neurons. The deposition of neuronal inclusion, named Lewy body (LB), in the affected regions is a pathological feature of PD and related disorders such as dementia with LB (DLB). Lewy body formation is thought to begin with \u03b1-synuclein aggregation and fibrillation. Experimental studies based on the knowledge obtained by epidemiological and genetic studies continue challenging researchers to make PD risk predictable and surmountable. In this context, the development of experimental models of PD has contributed to the understanding of PD etiology and the development of therapeutics. The current 11 contributions that comprise this Special Issue highlight the PD-associated phenotypes and their evaluation methods and the development of therapeutic strategies using animal models of PD .+) by glial monoamine oxidase B is transported to dopaminergic neurons probably through the dopamine transporter and inhibits the mitochondrial respiratory complex I subunits [+ and its precursor, MPTP, to make animal or cellular models of PD. Kinoshita et al. [The discovery of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) focused the spotlight on the roles of mitochondria in dopaminergic neurons [a et al. . Another neurotoxin, 6-hydroxydopamine (6-OHDA), is a dopamine analogue which produces selective damage to dopaminergic neurons by generation of reactive oxygen species (ROS). Unlike MPTP, 6-OHDA does not cross the blood\u2013brain barrier and is used to induce the degeneration of the nigrostriatal pathway by intracerebral stereotactic injection. 6-Hydroxydopamine-induced rodent models are generally unilateral lesion models and exhibit a rotation response by apomorphine. Rosa et al.  reportedThe pesticide rotenone is known to inhibit the mitochondrial complex I, generating ROS. Chronic systemic exposure to rotenone has been reported to reproduce selective nigrostriatal dopaminergic degeneration with LB-like \u03b1-synuclein-positive inclusions in rat . HoweverHyposmia, constipation, and rapid eye movement sleep behavior disorder are considered prodromal symptoms of PD that often precede motor symptoms. These phenotypes are particularly important in developing disease-modifying therapies that prevent the onset or control progression of PD. Taguchi et al.  reviewedA synaptic vesicle-binding protein, \u03b1-synuclein, is a key protein to produce PD symptoms, forming LBs in the associated neurons. Recent cellular and animal model studies have revealed that \u03b1-synuclein has a prion-like property, ascending from peripheral to central neural circuits. Mori et al.  reviewedPINK1 and Parkin genes cause early-onset familial PD [Mutations of ilial PD ,15. The ilial PD . Torii eilial PD  reviewedDrosophila is a powerful tool for genetics and has revealed the molecular relationship between PINK1 and Parkin in mitochondria [Drosophila is now commonly used as PD models to evaluate genetic association. Elvira et al. [Drosophila. Historical perspective of overall PD models was also well summarized by Chia et al [chondria . Drosopha et al.  reportedia et al .In summary, all articles appearing in this Special Issue cover the interesting and current topics in PD model studies. Although most PD models do not faithfully reproduce all aspects of this disease, PD model studies would advance our knowledge and promote the development of drugs and therapeutic strategies, receiving new inputs from clinical studies. This Guest Editor would like to thank all of the authors for their contributions to this Special Issue and expects significant advancement to our knowledge of PD in future studies."}
+{"text": "Mounting evidence shows genetic overlap between multiple psychiatric disorders. However, the biological underpinnings of shared risk for psychiatric disorders are not yet fully uncovered. The identification of underlying biological mechanisms is crucial for the progress in the treatment of these disorders.We applied gene-set analysis including 7372 gene sets, and 53 tissue-type specific gene-expression profiles to identify sets of genes that are involved in the etiology of multiple psychiatric disorders. We included genome-wide meta-association data of the five psychiatric disorders schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. The total dataset contained 159 219 cases and 262 481 controls.We identified 19 gene sets that were significantly associated with the five psychiatric disorders combined, of which we excluded five sets because their associations were likely driven by schizophrenia only. Conditional analyses showed independent effects of several gene sets that in particular relate to the synapse. In addition, we found independent effects of gene expression levels in the cerebellum and frontal cortex.We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders. We used precomputed LD scores that were provided by LD score regression, which were calculated using the European panel of the 1000 Genomes Project. No constraining of the intercept was applied.SNP heritability  gene sets (n\u00a0=\u00a05917) and canonical pathways (n\u00a0=\u00a01329). The GO gene sets contain genes annotated by the same GO term and cover biological processes, cellular components, and molecular functions. The canonical pathways are representations of biological processes that are compiled by domain experts. Second, we selected 126 expert-curated gene sets that have been tested to date for one of the five disorders in studies based on whole genome approaches . These gene sets cover different types of expert-curated sets: sets of functionally related genes, sets of co-expressed genes, and sets representing protein complexes or networks (online Supplementary Table S1). Third, we obtained gene-expression values of 53 tissues from the GTEx project v7 . The expression values of all genes were Winsorized at 50 reads per kilobase of transcript per million reads mapped (RPKM) and subsequently log2 transformed with pseudocount 1  derived from publicly available databases, and (2) expert-curated, i.e., genes annotated by experts in a specific research field that commonly involves an extensive experimental or methodological design and interpretation. In addition, we investigated tissue-specific gene-expression values as gene properties . First, we selected from the molecular signature database . Considering the significantly associated gene sets, the three calcium channel sets and the gene set involved in membrane depolarization showed equal association strengths, while the other gene sets present small to moderate reduced associations when taking the direction of SNP effects into account. This implies that the effects of SNPs related to calcium channels, or more broadly related to action potentials and depolarization, increase the risk on the different disorders in the same direction, while the effects of genetic variants related to the other identified functions partly act in opposite directions across disorders. In addition to this post hoc analysis, we performed a gene-set and gene-property analysis weighting the disorders according to sample size. These results were highly consistent with the initial unweighted analysis .We compared the results of these analyses \u2013 which are based on meta-analyzing gene-based associations of the individual disorders \u2013 with a gene-set and gene-property analysis including as input the meta-analyzed SNP associations of the five disorders. Hence, the direction of the SNP effects is taken into account. The results of these analyses and the initial analyses showed strong correlations [Pearson's correlation of logTo investigate the contribution of the association signal of the individual disorders to the cross-disorder association, we performed the gene-set and gene-property analyses for the individual disorders as well , indicating that the associations of the identified gene sets are not merely because they comprise genes expressed in the brain.FMRP targets (Darnell et al., GO high voltage gated calcium channel activity, GO postsynapse, MIR137 targets (Lewis et al., GO modulation of synaptic transmission, GO membrane depolarization during cardiac muscle cell action potential, GO gamma aminobutyric acid signaling pathway, and GO transcription factor activity RNA polymerase II core promoter sequence specific showed independent effects. However, the associations with the gene sets GO synapse part, GO synapse, GO neuron spine, GO voltage gated calcium channel complex, and GO excitatory synapse could fully be accounted for by the other identified gene sets. The large overlap of genes in these sets with the other identified gene sets (Third, we applied the forward selection procedure to the gene sets to shed light on the relations between their associations. We excluded the highly-brain-expressed gene set from this step as gene expression levels are already captured by conditioning on the average, cerebellum and frontal cortex tissue expression levels included in the previous step. The eight gene sets ene sets  clearly et al., et al., et al., The current gene-set analyses revealed various new sets of genes \u2013 in particular related to the synapse and neuronal functions \u2013 and gene-expression profiles of multiple brain tissues that play a role in shared genetic risk across five psychiatric disorders. The most strongly associated gene set was the highly-brain-expressed genes, which has previously been related to ASD (Pinto et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., de novo mutations (Iossifov et al., et al., et al., et al., et al., et al., et al., In addition, we identified multiple gene sets related to the synapse, which aligns with synaptic functions of several identified genes for multiple individual psychiatric disorders (Schizophrenia Working Group of the Psychiatric Genomics Consortium, Of note, the biological annotations of gene sets comprise a complex and challenging process, e.g., due to the multiple functions of many genes and incomplete knowledge. The construction of gene sets is in general based on different approaches such as shared cellular mechanism, co-expression patterns, protein-protein interaction, or co-localization. Hence, sets of genes may be based upon different inclusion criteria, creating an overlap between gene sets, as also illustrated by the current study. Clearly, it is important to recognize the impact of particular annotations on gene-set analysis results and their biological interpretation.et al., et al., To address this issue of confounding and redundancy in gene sets, we applied conditional analyses. This provided insight in how different gene-set associations relate to each other, and whether identified functions may not be biologically relevant to the disorders but rather induced by confounding factors (de Leeuw et al., Our cross-disorder gene-set and gene-property analyses are built on a meta-analysis of the gene-based associations with the individual disorders, therefore possible opposite effects of genetic variants are not taken into account. To explore if genetic variants are related to multiple disorders but with opposite effects, we performed an SNP-based meta-analysis of the five disorders and conducted a gene-set and gene-property analysis based on those results. In this analysis, genetic variants with opposite effects across disorders are cancelled out. Although these results showed strong correlations with the original analysis, we detected differences in association strength that point to partial differences in direction of SNP effects between the disorders for most identified gene sets. Interestingly, the effects on calcium channel activity are unidirectional across disorders. The outcome of different effects across disorders is supported by the recent finding that the highly correlated disorders SCZ and BD are differentiated by several genetic loci with opposite directions of effects (Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, et al., et al., We note that the associations of our identified gene sets were to a large extent driven by SCZ. This is in line with previous studies that reported multiple gene sets associated with SCZ (Ripke In conclusion, the current study provides novel evidence for shared biological mechanisms that act across psychiatric disorders based on gene-set and gene-property analyses. We showed that several gene sets that previously only had been associated with individual disorders also play a role in a broader range of psychiatric disorders, supporting the view of a common pathogenesis across disorders. This indicates that the genetic overlap between disorders is not randomly distributed, but can be explained by specific biological mechanisms. The strongest evidence in our results was for the involvement of synaptic functions, and gene expression profiles of the cerebellum and frontal cortex. The genetic data collection of additional psychiatric disorders is rapidly increasing and will make it possible to extend our analyses to other disorders in the near future. Understanding the shared biological mechanisms between psychiatric disorders may provide a hint towards a general vulnerability for multiple psychiatric disorders, and could result in potential treatment for a broad spectrum of psychiatric disorders."}
+{"text": "Annals of Intensive Care about the dose adjustments of vitamin C in critically patients undergoing renal replacement therapy [We have read with interest the manuscript from Honore et al. in  therapy . After aMedicine  journal in 2019 (online: 2019 November 27) [The authors included in their study the Wu et al.\u2019s case report of a patient with hemolytic jaundice induced by pharmacological dose of ascorbic acid in glucose-6-phosphate dehydrogenase (G6PD) deficiency . This mamber 27) , becauseThe authors searched for studies and used studies published in 2020, like Fujii et al.\u2019s study , so the We conclude that the exclusion of Wu et al.\u2019s study does not probably affect the overall conclusions of Honore et al.\u2019s study, but it affects directly the particular conclusion exposed previously because Wu et al.\u2019s study failed to provide valid scientific evidence.We recommend to exclude it, but a good and accurate literature review is a key element in high-quality original studies."}
+{"text": "Mutations in the encoding genes in patients and mouse models underlie severe phenotypes including kidney stones with CLCN5 and osteopetrosis or hypopigmentation with CLCN7. Dysfunction of those intracellular CLCs that are expressed in neurons lead to neuronal defects. Loss of endosomal ClC-3, which heteromerizes with ClC-4, results in neurodegeneration. Mutations in ClC-4 are associated with epileptic encephalopathy and intellectual disability. Mice lacking the late endosomal ClC-6 develop a lysosomal storage disease with reduced pain sensitivity. Human gene variants have been associated with epilepsy, and a gain-of-function mutation causes early-onset neurodegeneration. Dysfunction of the lysosomal ClC-7 leads to a lysosomal storage disease and neurodegeneration in mice and humans. Reduced luminal chloride, as well as altered calcium regulation, has been associated with lysosomal storage diseases in general. This review discusses the properties of endosomal and lysosomal Cl\u2212/H+ exchange by CLCs and how various alterations of ion transport by CLCs impact organellar ion homeostasis and function in neurodegenerative disorders.The regulation of luminal ion concentrations is critical for the function of, and transport between intracellular organelles. The importance of the acidic pH in the compartments of the endosomal-lysosomal pathway has been well-known for decades. Besides the V-ATPase, which pumps protons into their lumen, a variety of ion transporters and channels is involved in the regulation of the organelles' complex ion homeostasis. Amongst these are the intracellular members of the CLC family, ClC-3 through ClC-7. They localize to distinct but overlapping compartments of the endosomal-lysosomal pathway, partially with tissue-specific expression. Functioning as 2Cl Data from patients, mouse models and cell biophysical measurements highlight an important role for Cl\u2212 which is accumulated in a secondary active transport by CLC Cl\u2212/H+ exchangers  possess a further glutamate, referred to as \u201cproton glutamate,\u201d whose mutation abolishes or strongly diminishes the transport of both protons and chloride  display similar transport properties but differential subcellular localization  and the loss of VGLUT1, SV acidification was not impaired   in primary neurons from ClC-3-deficient mice was reported to be reduced, suggesting that glutamate toxicity due to excessive glutamate release contributes to the neurodegeneration  pointed to the activity of ClC-7 as a ClClcn7\u2212/\u2212 mice , displayed conspicuous loss of hippocampal and cortical neurons. Starting in the CA3 region of hippocampus neuronal loss progressed into the dentate gyrus and by the age of 1.5 years no hippocampal structures in Clcn7lox/lox;EMX1cre mice could be detected  revealed slowed lysosomal degradation of endocytosed protein  in humans (Kornak et al., CLCN7 mutations (Cleiren et al., CLCN7-related ARO in about 50% of the cases, as well as OSTM1-related ARO, are also neuropathic with primary neurodegeneration manifesting in developmental delay, hypotonia, retinal atrophy and seizures (Steward, CLCN7 mutations, which may lead to subcellular mislocalization of the ClC-7/Ostm1 complex or the impingement of the dysfunctional subunit on the ion transport properties of the unaffected subunit (Schulz et al., Clcn7\u2212/\u2212 mice with death after only a few weeks and neurodegeneration (Alam et al., PM/Ostm1 (Leisle et al., Clcn7+/G213R ADO2 mice also presented fibrosis in non-skeletal tissues such as lung and muscle; their brains exhibited perivascular fibrosis, \u03b2-amyloid accumulation and astrogliosis, and the animals showed behavioral abnormalities (Maurizi et al., Mutations in Steward, , which iSteward, . DominanPM/Ostm1 (Leisle et al., During the first electrophysiological analysis of osteopetrosis-causing ClC-7 missense mutations, it was surprisingly found that, besides loss-of-function mutations due to impaired ER exit or reduced ion transport, several pathogenic ClC-7 mutations accelerated the voltage-dependent activation of ClC-7de novo mutation of ClC-7 was identified in two children with hypopigmentation and delayed development (Nicoli et al., Y715C led to a drastic enlargement of late endosomal/lysosomal compartments (Nicoli et al., Y553C mutant (Polovitskaya et al., Y715C, the enlarged compartments were reported not to be acidified in contrast to surrounding smaller, hyperacidified lysosomes, which was attributed to the hyperactivity of the ClC-7 mutant (Nicoli et al., Recently, a heterozygous \u2212/H+ exchangers on distinct, but overlapping organelles of the endosomal-lysosomal pathway (Stauber et al., Loss-of-function and in some cases also gain-of-function of the intracellular CLCs, ClC-3/ClC-4, ClC-6 and ClC-7/Ostm1, lead to neuropathies, often neurodegeneration. They all function as Cl\u2212 export from endosomes/lysosomes. At membrane voltages in the range of those measured for endosomal/lysosomal compartments, which can be up to inside-positive 100 mV (Koivusalo et al., \u2212 accumulation by CLCs and the necessity of their ion transport. Mutation of the \u201cgating glutamate\u201d does not only convert the exchanger into a pure Cl\u2212 conductor, but also abolishes its voltage dependence. Therefore, such a mutation may indeed represent a gain of function in respect to Cl\u2212 transport. Interestingly, while the uncoupling mutation of ClC-5 or ClC-7 leads to effects that are similar to the respective knock-out in mouse models, the heterozygous mutant of ClC-6 results in a much more severe disorder in patients than in the murine gene knock-out model (Po\u00ebt et al., In some cases, it has been proposed that the CLC serves as a structural protein that functions to recruit other proteins such as components of the transport machinery by direct protein-protein interaction. Amongst others, the existence of different missense mutations which unlikely all prevent the same interactions argues against this. Although a role a role for protein-protein interactions of intracellular CLCs in vesicular trafficking cannot be excluded, the most straight-forward explanation for the importance of CLCs is their role in the regulation of the vesicular ion homeostasis. In this respect, the pronounced outward rectification of the vesicular CLCs remains enigmatic, because it would strongly favor Cl\u2212 by their Cl\u2212/H+ exchange mechanism is pivotal \u2013also for ClC-5, in addition to the acidification- (Novarino et al., \u2212 concentration rises to > 100 mM in the lysosome (Saha et al., \u2212 concentrations, but a normally low pH, have been found in nematode models of various neurodegenerative lysosomal storage diseases including Gaucher and Nieman-Pick A and B (Chakraborty et al., \u2212 concentration has been shown to influence the enzymatic activity of the lysosomal protease cathepsin C (Cigi\u0107 and Pain, \u2212 affects vesicular function is elusive (Stauber and Jentsch, The luminal pH is of undisputed importance for endosomes and lysosomes and impaired acidification is linked to neurodegeneration (Mellman et al., \u2212/H+ exchanger does not only \u2013if at all\u2013 affect the luminal Cl\u2212 concentration and pH, but ion homeostasis in general, including the transmembrane voltage and concentrations of other ion species (Ishida et al., 2+ (Chakraborty et al., The presence of a Cl\u2212/H+ exchangers impinges on the trafficking, function and possibly signaling of endosomal and lysosomal organelles and interconnected pathways such as autophagy, which in turn leads to cell death of vulnerable neurons. Future work is required to uncover in detail the molecular mechanism by which these CLCs contribute to the functioning of the endosomal-lysosomal pathway.In summary, dysfunction of the intracellular CLC ClSB, HH, and TS wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Nursing workforces are strengthened in COVID-19 units to enable closer monitoring of patients\u2019 vitals and personalized care. Yet, the healthcare teams confronted with COVID-19 are particularly strained and require active psychological support from psychologists and unit managers . Although benzodiazepines are often used as first-line treatments in case of acute agitation, after ruling out any somatic cause , randomized control trials don\u2019t support their use (McDermott and Gruenewald, et al., Unfortunately, in case of a drug shortage, alternative treatments must be considered. Midazolam can be used either orally or by subcutaneous injection to treat acute behavioral symptoms (McDermott and Gruenewald, et al., et al., Good clinical practice for the prescription of psychotropic drugs (Livingston et al., If chemical restraint is not possible, physical restraint may exceptionally be prescribed preferably with abdominal and pelvic straps (Livingston The COVID-19 outbreak is overwhelming all healthcare systems and we need to provide new guidelines for better medical management of elderly BPSD patients and their families and preserve hospital staff by streamlining their procedures."}
+{"text": "With an enormous prevalence worldwide, diseases of the oral cavity and respective tissues are a highly relevant global health issue . Beside n = 23) with or without depression based on the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMDs) Axis II, respectively. All study participants underwent an electromyographical examination to assess their bioelectrical resting activity of temporal and masseter muscles. The resting activity of selected masticatory muscles did not differ between the two groups. The authors concluded that these preliminary findings should lead to further research with larger sample size to gain insight the psychological factors related to bioelectric parameters in masticatory muscles. A Polish study by Gerreth et al. [The high variety and complexity of oral-systemic interactions is displayed by ten excellent articles in this special issue \u201cOral Health and Systemic Diseases\u201d. Thereby, seven studies are reported, complemented by three systematic reviews. A case-control study by Gerreth et al.  compreheh et al.  examinedh et al.  examinedh et al.  was perfThree systematic reviews are part of this special issue. The systematic review by P\u00e9rez-Losada et al.  also appAltogether, the ten articles in the special issue \u201cOral Health and Systemic Diseases\u201d show different aspects of oral and systemic disease interaction and provide several implications for dental care of these patients. One main conclusion is the necessity of further research, especially large-scaled prospective studies to get a better understanding of the needs of respective patient groups. Furthermore, patient centered dental special care appears recommendable for different patient groups, which were examined in the different studies. The special issue \u201cOral Health and Systemic Diseases\u201d gives the reader an interesting and clinically relevant insight into oral and systemic disease interactions, an emerging field of dental and medical research."}
+{"text": "Escherichia coli chromosome by forming a filamentous axial core from which DNA loops emanate, similar to the action of condensin in mitotic chromosome formation. MukBEF action, along with its interaction with the partner protein, MatP, also facilitates chromosome individualization by directing opposite chromosome arms (replichores) to different cell halves. This contrasts with the situation in many other bacteria, where SMC complexes organise chromosomes in a way that the opposite replichores are aligned along the long axis of the cell. We highlight the similarities and differences of SMC complex contributions to chromosome organization in bacteria and eukaryotes, and summarize the current mechanistic understanding of the processes.Structural maintenance of chromosomes (SMC) complexes are ancient and conserved molecular machines that organize chromosomes in all domains of life. We propose that the principles of chromosome folding needed to accommodate DNA inside a cell in an accessible form will follow similar principles in prokaryotes and eukaryotes. However, the exact contributions of SMC complexes to bacterial chromosome organization have been elusive. Recently, it was shown that the SMC homolog, MukBEF, organizes and individualizes the  Escherichia coli MukB was the first SMC protein to be identified through its role in chromosome segregation  complexes, play multiple important roles in chromosome organization and individualization [reviewed in  plays an essential role in determining the axial core shape. Deletion of matP led to formation of uniform circular axial cores, because MatP displaces MukBEF from ter, while MatP+ cells have linear cores as a consequence of MatP-directed displacement of MukBEF complexes from ter  in wild-type cells, while MukBEF clusters localize equally with all genetic regions tested in MatP\u2212 cells.By modestly increasing E. coli chromosome placed randomly within a cell? Early imaging studies showed that in new-born E. coli cells that have not initiated replication, the left and right replichores are organized into separate cell halves, while oriC is at midcell . Indeed, MukBEF complexes and MatP-matS are largely confined to \u03b3-proteobacteria (Br\u00e9zellec et al. oriCs located at the old pole in new borne cells and ter at the new pole (Fig. \u2212E.coli exhibit a similar organization (Danilova et al. S systems that are the main driving force behind chromosome segregation in many bacteria and which additionally recruit SMC complexes to the chromosome at specific parS sites near oriC (Fig. Vibrio cholerae encodes for two types of ParABS system, each directed to a specific one of the two separate chromosomes, despite encoding MukBEF and MatP-matS (David et al. The action of MukBEF-MatP in individualization of chromosome arms, by directing left and right arms to opposite cell halves, contrasts with the situation in many bacteria that encode SMC\u2013ScpAB complexes rather than MukBEF (e.g., ole Fig. e. IntrigriC Fig. . IntriguB. subtilis arms could be explained by higher order SMC action. The first in vitro single-molecule studies of loop extrusion by condensin showed asymmetric loop extrusion (Ganji et al. The mechanistic and functional differences between MukBEF and SMC\u2013ScpAB complexes remain elusive, but in our opinion, it is likely that they both act through ATP hydrolysis-driven loop extrusion. The requirement of MukBEF dimers of dimers for function (Badrinarayanan et al. matS, along with other proteins (Br\u00e9zellec et al. \u2212 and Gm+ bacteria (Petrushenko et al. SMC complexes also have co-evolved with other chromosome binding proteins that can cooperate their activity with prospective loop formation; for example, MukBEF and MatP-As in most biological systems, investigation of how SMC complexes function has been limited by the available assays. Early studies primarily exploited classical genetics and biochemistry, while later on new imaging techniques, particularly FISH-painting techniques, along with ensemble techniques like ChIP-seq and chromosome conformation capture techniques began to play important roles; in the latter case these can now be applied to single-cells [reviewed in (McCord et al."}
+{"text": "Individuals who exercise regularly are protected from type 2 diabetes and other metabolic syndromes, in part by enhanced gene transcription and induction of many signaling pathways crucial in correcting impaired metabolic pathways associated with a sedentary lifestyle. Exercise activates Calmodulin-dependent protein kinase (CaMK)II, resulting in increased mitochondrial oxidative capacity and glucose transport. CaMKII regulates many health beneficial cellular functions in individuals who exercise compared with those who do not exercise. The role of exercise in the regulation of carbohydrate, lipid metabolism, and insulin signaling pathways are explained at the onset. Followed by the role of exercise in the regulation of glucose transporter (GLUT)4 expression and mitochondrial biogenesis are explained. Next, the main functions of Calmodulin-dependent protein kinase and the mechanism to activate it are illustrated, finally, an overview of the role of CaMKII in regulating GLUT4 expression, mitochondrial biogenesis, and histone modification are discussed. In developing countries, around 50 % of people with diabetes are undiagnosed. As a result, many do not receive adequate treatment and care to manage the disease, putting them at greater risk of serious complications and even death. According to the International Diabetes Federation (IDF) , the number of people with type 2 diabetes is increasing in every country. In 2019, diabetes affected at least 463 million people worldwide and is expected to reach 700 million by 2045 (IDF). The economic impact of diabetes is expected to continue to grow by 2045 as there is no effective cure to prevent or treat diabetes.Type 2 diabetes is one of the fast moving public health problems in both developed and developing countries. According to the World Health Organization (WHO), developing countries will likely suffer from diabetes epidemics in the 21Regulation of carbohydrate and lipid metabolism is very important in patients with insulin resistance and type 2 diabetes. Glucose is most commonly utilized for energy production in mammals. The regulation of glucose metabolism is very important to ensure glucose availability for the central nervous system, which almost entirely depends on glucose for its fuel. Under hyperglycemic conditions, glycogen synthesis is the major pathway in glucose metabolism, and muscle glycogen synthesis rate decreases by 50 % in type 2 diabetes as compared with healthy subjects . SkeletImpairment of insulin-mediated glucose uptake correlates with altered fatty acid metabolism as the biochemical pathways of fatty acid and glucose metabolism are fully integrated . Lipids2+) is an important second messenger involved in the regulation of many cellular events . Raisinal., 2000). It is al., 2000; Raney aal., 2000; Wu et aal., 2000). This pExercise or physical activity is one of the cornerstones for the prevention and management of type 2 diabetes in both men and women . SeveraRegular exercise also reduces the risk of ectopic (non-adipose tissue) lipid accumulation and type 2 diabetes through increased lipid oxidation and lipid oxidative capacity . A studWith regards to insulin sensitivity, exercise also shows a beneficial effect on insulin sensitivity in normal as well as insulin-resistant populations. Individuals with insulin resistance and type 2 diabetes are characterized by impaired insulin-stimulated glucose uptake in skeletal muscle . HoweveReduction in the risk of diabetes by exercise is owing to increased glucose transport capacity . GlucosPlasma membrane GLUT4 content correlated with glucose transport activity in both rat and human skeletal muscle . A studSeveral studies show that exercise increases glucose transport and GLUT4 expression in skeletal muscle. A vigorous 7-day exercise program increased insulin sensitivity and muscle GLUT4 content in younger and older people . Again,A study by McGee et al. (2009) shows tRegular exercise induces mitochondrial biogenesis, resulting in increased lipid oxidation capacity and turnover and improved glucose transport . MitochFewer and smaller-sized mitochondria are found in skeletal muscle of insulin-resistant, obese, or type 2 diabetes subjects, and the size of mitochondria correlates with mitochondrial oxidative capacity  as well as in oxidative capacity   and increases markers of mitochondrial biogenesis, which include PGC-1, mitochondrial transcriptional factor a (Tfam), and citrate synthase . Increaal., 2010; Ojuka eal., 2010). Activaal., 2010). Increaal., 2010). Increa2+/Calmodulin-dependent serine/threonine-specific protein kinase . It act Figure 2 . A typiman, 2002). When Tal., 1989; Hanson al., 1989).2 max) cycling exercise increases phosphorylation of CaMKII at Thr286. Another study by Serpiello et al.  and in al. (2011) also shal. (2011). Besideal. (2011) indicat2+, AMP, and ROS . Increaal., 2003 McConellal., 2003). PGC-1 A study by Mukwevho et al. (2008) reporte3+ groups of lysine amino acid residues. Acetylation is regulated by a factor called Histone acetyltransferases (HATs). HATs help the transfer of an acetyl group from a molecule of acetyl Coenzyme-A to the NH3+ group on lysine. Deacetylation of lysine is facilitated by a factor called Histone deacetylases (HDACs), which catalyzes the removal of the acetyl group with a molecule of H2O . The splis, 1998; Grunstelis, 1998).A study by McGee and Hargreaves (2004) showed"}
+{"text": "In this mSphere of Influence article, he reflects on how two papers, \u201cLong-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium\u201d by Sato et al.  and \u201cT helper cell cytokines modulate intestinal stem cell renewal and differentiation\u201d by Biton et al. , have influenced his research by describing the development of intestinal organoid cultures and implementation of high-throughput sequencing analysis. The combination of these forefront technologies has expanded opportunities for mechanistic interrogation of host immunity to enteric pathogens.Jose Lemme-Dumit works in the field of mucosal immunology and vaccines. In this mSphere of Influence article, he reflects on how two papers, \u201cLong-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium\u201d by Sato et al. (T. Sato, D. E. Stange, M. Ferrante, R. G. J. Vries, et al., Gastroenterology 141:1762\u20131772, 2011,  Although their use is practical, the genetic modifications and aberrant behavior of immortalized cells render results unreliable and nongeneralizable. Other models involve ex vivo primary cultures. The limited viability of human primary cells restricts and limits their use. A major advancement in tissue culture technology was achieved by the identification of the \u201cstemness\u201d marker Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) at the intestinal crypts  human intestinal stem cells and for establishment of long-term organoid cultures. These factors included ligands for Wnt signaling  and epidermal growth factor, both of which are necessary for intestinal stem cell proliferation, as well as Noggin (a bone morphogenetic protein inhibitor), an inducer of cell expansion. The authors found that gastrin and nicotinamide improved culture efficiency, with nicotinamide being essential for prolonging culture viability for up to 1\u2009month. Further, inhibition of MAPK (p38) and transforming growth factor \u03b2 (TGF-\u03b2) type 1 (Alk4/5/7) signals increased intestinal stem cell stability and expansion, extending the duration of cultures by at least 6\u2009months. Besides identifying essential factors for intestinal stem cell expansion, Sato and colleagues showed that organoids retain essential aspects of the tissue from which they were derived, including aspects such as architecture, cell type composition, self-renewal dynamics, and normal karyotype. Organoids can be biobanked, which adds practicality. The technology described in that seminal paper has been broadly applied to produce organoids from other polarized epithelial organs such as stomach, lung, bile duct and pancreas, and prostate and mammary gland. Since the original publication of that paper, conditions appropriate for use in establishing 2D organoids  have been described. Advantages of working with polarized epithelial cells in a steady monolayer include ease of handling and direct access to apical and basolateral compartments for treatment and analysis.Homeostasis and host defenses in the human gut are finely regulated. The intestinal epithelium provides a physiological and immunological barrier that protects the host from pathogens and harmful agents while maintaining a peaceful coexistence with nutrients and the gut microbiota. A variety of epithelial cell culture models have been used to study biological processes in the human gut. The majority of these l crypts . This brthelium\u201d , CleversThe discoveries by Clevers\u2019 group detailed in their report and follow-up studies have inspired and catalyzed not only my research but an entire field of study. Avoiding the drawbacks represented by cancer cell lines and the difficulty of working with animals and their host restriction, their approach opened a new avenue to the investigation of gut physiology and, in my case, of host-pathogen interactions and mucosal immunity. The organoid system as originally described still lacks the major cells and components that support and interact with the intestinal epithelium and that have important functional roles: innervation, fibroblasts and extracellular matrix components, and immune cells. My work has focused on the development and characterization of human enteroid-immune cell cocultures and the interrogation of immune mechanisms of host defense against enteric pathogens.+ intestinal stem cell subsets with different proliferative capacities capable of interacting with and activating naive Th cells via major histocompatibility complex class II (MHCII) antigen presentation. Treg and interleukin-10 (IL-10) were found to promote organoid expansion, while Th1, Th2, and Th17 cells and derived cytokines  depleted intestinal stem cells and induced organoid differentiation. In addition, luminal signals (bacteria or parasite) influenced the intestinal stem cell-Th axis and shaped epithelial cell composition, increasing levels of MHCII-expressing stem cells. While the work was conducted using murine organoid and intestinal mouse crypts, the report highlights an important form of epithelial and immune cell cross talk as a regulated response for maintenance of epithelial self-renewal or for promotion of its differentiation. These results challenge the prevailing paradigm of adaptive immune cell function by showing that they not only contribute to antimicrobial surveillance but also support intestinal tissue growth and differentiation. The role of Th cells activated by intestinal stem cells in host immunity and tolerance is wide open for investigation. Single-cell analysis is the \u201cgold standard\u201d for discerning cell responses and interaction. The approach of Biton and colleagues stimulated ideas that I am applying in my own research to decipher interactions between the human intestinal epithelium and immune cells in the steady state, in response to infection, and during the phase of recovery, facilitating tissue repair.The topic of the complexity of the molecular and cellular processes involved in mucosal immunity to enteric organisms brings me to my second selected paper, which illustrates the unprecedented opportunity offered by recent technological advances to fill important knowledge gaps. Cutting-edge tools, including cell imaging, gene editing, and molecular analyses such as single-cell RNA sequencing (scRNA-seq), are now available for deep mechanistic interrogation of coordinated multicellular host responses. In the research article \u201cT helper cell cytokines modulate intestinal stem cell renewal and differentiation\u201d , the autThe two elegant publications discussed here illustrate the impact of cutting-edge technologies and their potential to advance translational research. Organoids and single-cell analyses could be powerful tools for personalized medicine; they would allow evaluation of drugs or therapies, understanding of genetic risks or disease susceptibility, and even correction of inherited defects."}
+{"text": "Scientific evidence shows that food consumption is one of the main causes that increases the risk of developing a non-communicable disease (NCD). One of the mechanisms introduced to ensure more informed food purchases that lead to healthier diets is the introduction in the marketplace of functional food products to provide information on the nutritional and health properties that certain foods possess. This information is transmitted to consumers via different nutritional and health claims. Two studies investigated the prevalence of front-of-package (FoP) claims in Brazilian packaged food. Duran et al.  found thTwo studies explored the context of foods and drinks with healthy and nutritious attributes in the United Kingdom (UK). Cesar Revoredo-Giha et al.  indicateFour studies focused on consumers\u2019 preferences and willingness to pay (WTP) for functional food products, while one study examined the role of functional food in disease prevention. Vischeccia et al.  analyzedTwo studies investigated consumers\u00b4 preferences for food products carrying sustainable and nutritional labels simultaneously. Almli et al.  observedTwo lines of investigation analyzed how consumers ranked different nutritional claims. Gracia and Barreiro-Hurl\u00e9  reportedTwo studies explored consumers\u2019 choices for health information. Sogari et al.  tested tFour studies focused on psychological factors affecting consumers\u2019 preferences for NCs. Guzek et al.  determinThe last two studies investigated new determinants influencing purchase intention for functional foods. Berhaupt-Glickstein et al. , investiThe present Special Issue focused on the role of nutritional properties and/or health-related claims of food products and functional food products on choice preferences, choice behavior, healthy eating/healthy diet and the willingness to pay for certain foods."}
+{"text": "Mercury (Hg) is a well-recognized biohazard for the nervous system. Methylmercury (MeHg) is an organic methylated form of Hg, highly toxic to humans, targeting the brain, as MeHg is rapidly absorbed, and easily reaches and crosses the blood-brain barrier , and related intricate mechanisms during homeostasis and disease states. In addition, we discuss possible ways how MeHg may affect hippocampal neurogenesis and the potential lasting consequences for brain neurodegeneration.In mammals, the intestinal microbiota is first acquired either by contact with maternal skin (if a cesarean labor) or directly maternal microbiota transfer  immediately after birth  intestinal barrier function. Impaired intestinal barrier function has been associated with increased MeHg intestinal absorption  in the large intestine  ; stage 2, containing transition cells/progenitor cells type 2a  and type 2b  and stage 3 . After stage 3, NSCs reach neuronal maturity by the extension of dendritic and axon processes and functional synaptic activity into neural circuitry   7 (Falluel-Morel et al., A reduction of 22% of hilus cells and 27% of granular layer cells, without affecting CA1 to CA3 hippocampal fields, after the MeHg challenge, has been found in mice, suggesting that MeHg preferentially affects SGZ's NSC (Sokolowski et al., E. coli, Clostridium, Staphylococcus spp., and hemolytic bacteria, could affect redox-sensitive transcription factor HIF1\u03b1 and ERK1/2 MAP kinase and intestinal barrier function (Holota et al., Falluel-Morel work also documented a decrease in the extracellular signaling of ERK1/2, required for the transition from G1 to S phase and inhibition of Bmi-1 gene expression, responsible for controlling the self-renewal potential of NSC. Genes linked to cell senescence have also been shown to be altered by MeHg, such as increased expression levels of HP1-\u03b3 and HMGA-1 (Falluel-Morel et al., Actinobacteria and decreases in the class Clostridia (Dunphy-Doherty et al., Interestingly, early life stress, such as social isolation, can impact neurogenesis and the intestinal microbiota. Socially isolated rats early in life show significantly fewer BrdU/NeuN positive cells in the dentate gyrus than controls and altered microbiota composition with increases in One possible crosstalk pathway between intestinal microbes and the brain may involve the vagal nerve. Vagotomy has been implicated in impaired hippocampal neurogenesis and BDNF levels (O'Leary et al., The better understanding how the MeHg-altered gut microbiota affects the hippocampal neurogenic niche, by tracking neurogenic biomarkers during NSC maturation in critical time windows of brain development, is in most need for novel therapeutic strategies to ameliorate these deleterious effects that may have lasting consequences for human health.This opinion paper discussed the role of the intestinal microbiota on MeHg neurointoxication with potential consequences for the hippocampal neurogenic niche. Novel breakthrough findings are much supportive of human neurogenesis even in elderly (Boldrini et al., Accumulating evidence implies the gut-brain axis as a pathway for MeHg harmful neurotoxic effects and a potential factor for later neurodegenerative disorders. The MeHg may induce a hormesis-related neuronal toxicity. Hormesis is an important redox dependent aging-associated neurodegenerative/ neuroprotective issue (Calabrese et al., All authors have read and approved the manuscript. All authors have equally contributed to the opinion paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "L. de Swart et al.  and \u201cLong-term measles-induced immunomodulation increases overall childhood infectious disease mortality\u201d by M.Rory de Vries works in the field of viral pathogenesis and focuses on interactions between respiratory viruses (or corresponding vaccines) and the host immune system. In this mSphere of Influence article, he reflects on how the articles \u201cPredominant infection of CD150 + lymphocytes and dendritic cells during measles virus infection of macaques\u201d by R. L. de Swart et al.  and \u201cLong-term measles-induced immunomodulation increases overall childhood infectious disease mortality\u201d by M. J. Mina et al.  made an impact on him. These articles studied interactions between measles virus and the host and influenced him by making two important points. (i) It is crucial to use nonadapted (recombinant) viruses in disease-relevant model systems when studying virus-host interactions. (ii) Studying viral pathogenesis requires a combination of in vitro, ex vivo, and in vivo studies, and a group of researchers with multiple expertises. He learned that only when all these aspects are combined, can one truly answer the question: \u201cHow does a virus cause disease?\u201dRory de Vries works in the field of viral pathogenesis and focuses on interactions between respiratory viruses (or corresponding vaccines) and the host immune system. In this mSphere of Influence article, he reflects on how the articles \u201cPredominant infection of CD150 I have implemented these lessons in our current studies on virus-host interactions of human respiratory syncytial virus (HRSV), where we make use of recombinant viruses directly based on clinical isolates and study their behavior in respiratory organoids or differentiated primary airway epithelial cells cultured at the air-liquid interphase , and scientists should always remain vigilant and \u201ccritical.\u201d If one has a hypothesis that deviates from the current dogma, you should be ambitious and perform the experiments to either prove or disprove that hypothesis with perseverance and indomitable spirit.Both articles described here were game-changers in the field of measles research; combined with follow-up studies, they led to revisions of the textbooks. Shaping me as a researcher, this is one of the \u201clife lessons\u201d I have taken from these articles: what you read in textbooks or articles is not right"}
+{"text": "An algorithmic strategy to design stoichiometric quaternary and solid-solution quinary solids is described. The strategy involves recognition of structural inequivalences to generate ternary and quaternary cocrystals which can then be extended to five-component solid solutions through matching of suitable interactions. Ever since Gerhard Schmidt 1971 proposedet al., 2000et al., 2005et al., 2020et al., 2009et al., 2021et al., 2020et al., 2020From early work in the design of molecular crystal structures . Multidrug cocrystals can be expected to produce a synergistic therapeutic effect, while crystal engineering of the molecular packing and dominant non-covalent interactions may allow the modulation of physicochemical properties to improve drug formulation and delivery. To date, the only approaches to succeed in preparing ternary API solids have been the \u2018drug\u2013bridge\u2013drug\u2019 strategy developed by Liu  al. 2018 and the IUCrJ , tetramethylpyrazine (TMP), either 2,2\u2032-bipyridine (22BP) or 2,2\u2032-bithiophene (22TBP), and 1,2-di(4-pyridyl)ethane (DPE). A flowchart approach (see Fig. 1Aside from the intrinsic beauty of the resulting structures, this is an elegant example of a retrosynthetic approach being applied to systems built on noncovalent interactions. While hydrogen bonding is the dominant interaction in the examples reported here, the approach lends itself to use with other forms of supramolecular interactions such as halogen bonding, coordination bonding and \u03c0\u2013\u03c0 interactions.An algorithmic approach, such as that described here, is a positive step in the direction of developing an understanding of non-covalent interactions and their influence on synthesis of multicomponent crystals. This is essential for the advancement of crystal engineering into the new era of true design of functional materials."}
+{"text": "In addition, microfluidics platforms enable us to measure the mechanical properties of cells by establishing defined flow or confined microstructures through viscoelastic particles/cells focusing and droplet microfluidics. Finally, the flexible microdevices have become widely employed.Microfluidics has proven to be a useful platform to understand the material properties and technical applications of soft matter, including emulsions, polymer solutions, hydrogels, and cellulose papers. The study of the characteristics of soft matter, like viscoelasticity, non-Newtonian fluid mechanics, and deformation, has greatly benefitted from using microfluidics to accurately control conditions in time and space. Microfluidics has also served as a useful platform to study biological cell and tissues systems, including mechanobiology. Using microfluidics, external mechanical stress is regulated in physiologically-relevant systems for studying cells, tissues and organisms to understand how mechanical cues are sensed and transduced into biochemical and electrical signals that influence mechano-transduction. Furthermore, the characteristics of soft matter are exploited when combined with microfluidic platforms to mimic in-vivo microenvironment mimics and (6) mechanobiology research.In this Special Issue, we highlight recent progress in microfluidics with research papers and review articles that focus on novel methodological developments and applications of microfluidics devices for soft matter and mechanobiology. It contains ten research papers and two review articles on the following aspects of microfluidic application regarding soft matter and mechanobiology: (1) droplet generation and its application (2) viscoelasticity-based handling of particles/cells (3) paper-based assays (4) flexible devices (5) Droplet generation and its application: S\u00e1nchez et al.  reviewedC. albicans [Viscoelasticity-based handling of particles/cells: Cho et al.  found thalbicans  in sheatPaper-based assays: Kim et al.  reviewedFlexible devices: Lee et al.  demonstrin-vivo microenvironments: Yue et al. [Mimic of e et al.  engineerMechanobiology research: Feng et al.  discusseWe wish to thank all authors who submitted their manuscripts to this Special Issue. We would also like to acknowledge all the reviewers for dedicating their time to provide careful and timely reviews to ensure the quality of this Special Issue."}
+{"text": "Dear Editor,Recently, Gao and colleagues published a study about the role of Kupffer cells in hepatotoxicity . The au3 . IntereKupffer cells are known as important modifiers of hepatotoxicity (Kessler et al., 2014; Reif etThe authors declare no conflict of interest."}
+{"text": "Although climate change is altering the productivity and distribution of marine fisheries, climate-adaptive fisheries management could mitigate many of the negative impacts on human society. We forecast global fisheries biomass, catch, and profits to 2100 under three climate scenarios  and five levels of management reform to (1) determine the impact of climate change on national fisheries and (2) quantify the national-scale benefits of implementing climate-adaptive fisheries reforms. Management reforms accounting for shifting productivity and shifting distributions would yield higher catch and profits in the future relative to today for 60\u201365% of countries under the two least severe climate scenarios but for only 35% of countries under the most severe scenario. Furthermore, these management reforms would yield higher cumulative catch and profits than business-as-usual management for nearly all countries under the two least severe climate scenarios but would yield lower cumulative catch for 40% of countries under the most severe scenario. Fortunately, perfect fisheries management is not necessary to achieve these benefits: transboundary cooperation with 5-year intervals between adaptive interventions would result in comparable outcomes. However, the ability for realistic management reforms to offset the negative impacts of climate change is bounded by changes in underlying biological productivity. Although realistic reforms could generate higher catch and profits for 23\u201350% of countries experiencing reductions in productivity, the remaining countries would need to develop, expand, and reform aquaculture and other food production sectors to offset losses in capture fisheries. Still, climate-adaptive management is more profitable than business-as-usual management in all countries and we provide guidance on implementing\u2013and achieving the benefits of\u2013climate-adaptive fisheries reform along a gradient of scientific, management, and enforcement capacities. Marine fisheries provide a vital source of food for over half the world\u2019s population and support the livelihoods of over 56 million people globally . HoweverThe response of fishers and managers to these changes could either exacerbate or mitigate the impacts of climate change on human society and must be considered in forecasts of climate impacts on marine fisheries ,14. For Gaines et al.  providedHere, we use the Gaines et al.  climate-MSY) determined by aggregating values from Costello et al. [We used the Gaines et al.  climate-o et al.  S1 Fig)MSY) deteo et al. . Projecto et al.  species o et al.  bioeconoo et al.  and the The modified Garc\u00eda Molinos et al.  species K), intrinsic growth rate (g), and a shape parameter (\u03d5) that determines the proportion of carrying capacity at which production is maximized. Parameters were developed for species-stocks following the procedure detailed in Gaines et al. [The modified Costello et al.  bioeconos et al.  and are s et al.  sourced s et al.  and catcs et al.  fit to ts et al. . The shas et al. , which ms et al.  for a des et al.  which pos et al. \u201334 and ts et al. . AlthougThe harvest rate is based on the following five management scenarios: business-as-usual , productivity shift adaptation only, range shift adaptation only, full adaptation, and \u201crealistic\u201d adaptation  revenues were calculated as catch multiplied by species-specific ex-vessel prices  and (2) We evaluated the impact of climate change and management reform on the fisheries of 156 coastal sovereign countries summing across their domestic and territorial exclusive economic zones (EEZs). We scaled the projections of Gaines et al.  from theMSY, the biomass that produces MSY when fished at FMSY, by century\u2019s end (2091\u20132100). This is a common target for fisheries management . This performance metric better reflects the goals of fisheries management than percent change in biomass. For example, decreasing biomass in a previously undeveloped fishery is an expected consequence of economically optimal management and should only be perceived negatively when the decrease reduces biomass below the target.For Approach 1, we compared the percent difference in harvests and profits in 2100 relative to today  under each management scenario. While Gaines et al.  performeMaximum sustainable yield (MSY) of the evaluated stocks is forecast to decrease by 2.0%, 5.0%, and 18.5% from 2012\u20132021 to 2091\u20132100 under RCPs 4.5, 6.0, and 8.5, respectively . Note thMSY \u2264 1.2 and 0.8 \u2264 F/FMSY \u2264 1.2) in the initial year  management results in both lower catches and profits in the future relative to today under all three emissions scenarios . In contial year ; thus, rWhile business-as-usual management results in lower catches and profits relative to today for the majority of countries (82\u201385% of countries), full adaptation yields higher catches and profits for a majority of countries in all but the most severe emission scenario . In thisOverall, our results indicate that climate change will dramatically alter the distribution and productivity of marine fisheries, but plausible climate-adaptive management reforms could minimize or eliminate negative impacts in most countries. This reinforces and expands upon the work of Gaines et al.  in two iOur model predicts shifts in productivity that are consistent in both pattern and magnitude with a recent ensemble model  that aveImportantly, however, our approach differs from these studies, because, in addition to forecasting the impact of climate change on the biological potential of fisheries, we consider the impact of alternative human responses to these changes, which could either exacerbate or alleviate the impacts of changing biological potential . Indeed,The development and implementation of stock assessment methods and management strategies necessary to achieve benefits in the face of climate change is nascent but rapidly developing. For example, Skern-Mauritzen et al.  reviewedFurthermore, achieving the benefits of climate-adaptive fisheries reform will require accounting for shifting productivity and distributions along a gradient of scientific, management, and enforcement capacities. Many countries lack the monitoring programs required to detect and describe shifts in distribution and productivity, the scientific capacity for conducting either climate-agnostic or climate-adaptive stock assessments, and the management capacity for setting and enforcing fisheries regulations ,42,43. TFortunately, a growing body of literature provides guidance on accounting for shifting distributions and productivity in fisheries assessment and management ,17,45,46Historically, well-managed fisheries have been among the most resilient to climate change , and ourAdapting to climate change will require dynamic, flexible, and forward-looking management. This can be achieved by aligning management policies with the spatio-temporal scales of climate change, ecosystem change, and socioeconomic responses . In highShifting distributions are already generating management challenges and the rates of these shifts and associated conflicts are expected to increase with climate change ,18,70. NThe impact of climate change on fishing communities can be reduced through measures that increase socioeconomic resilience and adaptive capacity to environmental variability and changing fisheries ,76,77. AEven the best climate-adaptive management will be unable to maintain current catch and profits in most tropical developing countries. Although these countries should still pursue climate-adaptive reforms to maximize catch and profits from capture fisheries, they will also need to develop, expand, and reform other sectors to compensate for capture fishery losses and meet growing production demands . Marine Although climate change is expected to reduce the productivity of marine fisheries globally , climateS1 Table* See Table S1 in Gaines et al.  for eart(DOCX)Click here for additional data file.S1 FigMSY \u2264 1.2 and 0.8 \u2264 F/FMSY \u2264 1.2).The transparent grey box indicates near optimal fisheries management Click here for additional data file.S2 Fig(TIFF)Click here for additional data file.S3 FigThe percentage labels indicate the percentage of countries falling in each quadrant of catch and profit outcomes.(TIFF)Click here for additional data file.S4 FigThe percentage labels indicate the percentage of countries falling in each quadrant of catch and profit outcomes.(TIFF)Click here for additional data file."}
+{"text": "Mycobacterium abscessus (Mab) is a fast-growing cousin of the infamous Mycobacterium tuberculosis. Both bacteria cause difficult-to-cure lung disease. In contrast to the slow-growing obligate pathogen M. tuberculosis, Mab is an opportunistic pathogen. Ubiquitously present in soil and water, Mab typically causes disease in vulnerable populations, including immune-compromised patients and people suffering from lung disorders such as cystic fibrosis and chronic obstructive pulmonary disease. Whereas, a drug regime that cures tuberculosis within 6 months is available, cure rates for Mab with the currently recommended combinations are 50% at best (Kwak et al., in vitro potency. Instead, the cornerstone of Mab disease therapy is a macrolide, either azithromycin or clarithromycin. It is plausible that the lack of a rifamycin in Mab regimens contributes to unfavorable outcomes (Ganapathy et al., A key drug in the regimen against tuberculosis is rifampicin. Inclusion of this rifamycin in anti-tuberculosis therapy in the 1960's resulted in dramatic treatment shortening and formed the basis of the 6-month curative regimen still in use today (Ganapathy et al., in vitro (Aziz et al., In a screen of approved drugs against Mab, we were surprised to find that the rifampicin analog rifabutin (Crabol et al., To provide additional preclinical data supporting repurposing of rifabutin, we recently measured its efficacy in a murine model of Mab lung disease. Rifabutin was as efficacious as the first line drug clarithromycin, both administered at the mouse equivalent of their clinically approved doses. As expected, rifampicin lacked efficacy (Dick et al., in vitro results are emerging suggesting that rifabutin is not only active as a single agent, but also appears to suppress inducible macrolide resistance, an intrinsic resistance mechanism frequently encountered in Mab isolates (Nash et al., whiB7-erm41 system (Hurst-Hess et al., in vivo, this finding, would support a one-two punch attack against the infection.Interestingly, Concomitant to these encouraging preclinical data, a first clinical success story was recently reported (Cheng et al., Our preclinical results, together with these early clinical data suggest that rifabutin may improve outcomes of refractory Mab disease. Just as inclusion of a rifamycin was a game changer in the treatment of tuberculosis, rifabutin may both improve cure rates and reduce treatment duration of largely incurable Mab lung disease.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Aspergillus, Cryptococcus, Candida, Histoplasma, Blastomyces, and Coccidioides, and discuss potential strategies to manipulate monocyte responses in order to enhance anti-fungal immunity in susceptible hosts.Monocytes and their derivatives, including macrophages and dendritic cells, play diverse roles in the response to fungal pathogens. Sensing of fungi by monocytes triggers signaling pathways that mediate direct effects like phagocytosis and cytokine production. Monocytes can also present fungal antigens to elicit adaptive immune responses. These monocyte-mediated pathways may be either beneficial or harmful to the host. In some instances, fungi have developed mechanisms to evade the consequences of monocyte activation and subvert these cells to promote disease. Thus, monocytes are critically involved in mediating the outcomes of these often highly fatal infections. This review will highlight the roles of monocytes in the immune response to some of the major fungi that cause invasive human disease, including  Lineage tracing studies suggest that non-classical monocytes develop directly from classical monocytes  or a monocyte-dendritic cell progenitor (MDP) , including C-type lectin receptors (CLRs), Toll-like receptors (TLRs), and NOD-like receptors (NLRs), can detect pathogen-associated molecular patterns (PAMPs) like \u03b2-glucan, chitin and mannose in the fungal cell wall and trigger downstream signaling pathways to coordinate the innate immune response  production , and reactive nitrogen species (RNS) produced by inducible nitric oxide synthase (iNOS or NOS2) in response to pro-inflammatory stimuli  macrophages or anti-inflammatory, alternatively-activated (M2) macrophages  macrophages and monocytes, activation of these cells with cytokines, including IFN\u03b3 and GM-CSF, restricts the intracellular growth of H. capsulatum, in part by sequestering nutrients like zinc ions that are needed for fungal growth  can survive within unstimulated macrophages in vitro, but the addition of IFN\u03b3 or TNF enables fungal killing  requires stimulation by pro-inflammatory cytokines  cells to secrete GM-CSF that is required for neutrophil fungicidal activity  to prime T cells and induce adaptive immune responses that promote fungal clearance (Roy and Klein, C. neoformans or bind cryptococcal antigens, resulting in DC maturation and the subsequent activation and proliferation of T cells (Syme et al., H. capsulatum antigen can dampen harmful Th2 responses by reducing IL-4 production by CD4+ T cells (Szymczak and Deepe, H. capsulatum antigen acquired from apoptotic macrophages to promote CD8+ T cell cytotoxic responses under conditions where CD4+ T cells are absent or low, as might be found in HIV/AIDS patients (Lin et al., B. dermatitidis and H. capsulatum, robust CD4+ T cell priming is dependent on monocyte recruitment to the immunization site (Wuthrich et al., C. immitis antigen can induce T cell proliferation and IFN\u03b3 secretion (Richards et al., A. fumigatus conidia to the draining mediastinal lymph nodes and trigger beneficial CD4+ T cell responses (Bozza et al., C. gattii, but concurrently, the fungus is able to prevent further DC maturation that would lead to a robust adaptive immune response (Huston et al., In a murine model of chronic cryptococcosis, monocytes can differentiate into DCs that mediate the generation of a Th1 adaptive response that aids in clearance of the fungus (Osterholzer et al., The adaptive immune response, which includes the generation of memory T and B cells, is the classic mechanism by which the immune system retains memory of foreign antigens to ensure a rapid and specific response upon re-exposure. However, recent studies indicate that monocytes and other innate immune cells can also contribute to immunological memory through the process of trained immunity (Netea et al., C. albicans can cause histone modifications and metabolic changes in monocytes and macrophages (Quintin et al., C. albicans, these trained monocytes and macrophages had enhanced cytokine production and improved survival of the infected mice (Browder et al., Staphylococcus aureus (Di Luzio and Williams, Saccharomyces cerevisiae can enhance monocyte responses to C. albicans as well as gram-positive and gram-negative bacteria (Rizzetto et al., Fungal antigens have been found to induce trained immunity in monocytes and their derivative cells. Exposure to \u03b2-glucan and to heat-killed or sublethal doses of the commensal fungus C. neoformans indicate that splenic DCs undergo histone modifications that enhance cytokine responses upon rechallenge with a virulent strain of C. neoformans (Hole et al., S. aureus, and C. albicans. The fungal component of C. neoformans that may be involved in stimulating this DC memory also remains to be identified.There is some evidence that DCs may also have memory-like capabilities. Studies using a vaccine strain of C. albicans infection (Saz-Leal et al., Strides are being made to further enhance the effects of trained immunity. For example, deleting SHIP-1 in trained macrophages increases their production of pro-inflammatory cytokines and improves their protection against lethal + macrophages vs. moDCs (Menezes et al., Pneumocystis jirovecii, Fusarium spp., the Zygomycetes like Rhizopus spp. and Mucor spp., and emerging pathogens like Candida auris (Friedman and Schwartz, The multiple roles of monocytes and their derivative cells in the host response to fungal pathogens highlight their importance in mediating the outcomes of infection. Dissecting the specific mechanisms by which monocytes carry out these functions may enable us to develop novel therapeutics that can target these pathways to improve the mortality rates from invasive fungal infections. With the current intense focus on the role of the microbiome in human health, it will be interesting to further uncover the roles that commensal organisms may play in the trained immunity of monocytes as a key defense mechanism against pathogenic fungi. There is ongoing work to determine whether the heterogeneity of monocyte responses may be tied to their origins in the hematopoietic tissues. For instance, there is evidence that the fate of monocytes is predetermined in the bone marrow and may originate from differences in expression of the transcription factor PU.1, which can dictate their eventual differentiation into iNOSLH conceptualized, wrote, and edited the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the field of Neuroelectronic Interfaces it seems as though the lines between reality and science-fiction/fantasy are often blurred. One of the inspirations for our most recent Gordon Research Conference in March 2018 aimed at \u201cBridging the Gap in Neuroelectronic Interfaces\u201d dates back to 1999 when Chapin et al. , very muUnfortunately, after this very promising start two decades ago, these technologies were \u201clost in translation\u201d  useful to further explore the foreign body responses or nano-particle based stimulations. The prospects of bioactive, so called \u201cliving electrodes\u201d were discussed by Adewole et al., who points out several differing approaches to \u201ctrick\u201d the brain into incorporating artificial implants. The biomechanics of neuronal adhesion may play an important role in this context and can be assessed by frequency analysis of quartz crystal oscillators, as is pointed out by Khraiche et al.. As important as microscopic biomechanics is in our field of research, it is equally difficult to quantify in brain tissue. Help is offered from localized probing of biomechanics by Atomic Force Microscopy (AFM) as is briefly reviewed by Viji Babu and Radmacher. Another exciting review by Aplin and Fridman extensively discusses the rarely used constant current (DC) stimulation of neural tissue, a potential new field of neuromodulation enabled by recent developments in microfluidics.Several insightful reviews support our conference's look outside the box and give an overview into microfluidic based model systems . They were able to show optogenetic stimulation of muscles in non-human primates! It goes without saying, flexibility was not a feature expected from silicon probes successfully used in large animals as reported by Ulyanova et al..As one common denominator, several groups reported on recent approaches to a long-standing idea to use of flexible or compliant substrates. For example, Electrode composition and performance was an issue investigated in several articles.Meijs et al. deposited different layers of Boron Doped Diamond (BDD) on TiN electrodes and compared them electrochemically, identifying good candidates for further in vivo testing. The article from Ferlauto et al. demonstrates a reduction of electrical noise by inserting conductive polymers as compliant intermediary on Pt-electrodes. Whereas, the work by Neto et al. informed us to stop worrying about impedances\u2014at least of recording micro-electrodes in the usual range (0.1 to 2 M\u03a9)\u2014as long as they exhibit a low shunting capacity. In contrast, potentiostatic experiments done by Harris et al. concluded that the use of Ohm's law to describe electrical stimulation over Pt-electrodes is an unwarranted oversimplification, ignoring the electrically complex, spatially varying tissue-electrode interface. In order to further the quality control with MEAs Suarez-Perez et al. introduced spectral definitions of SNR based on cortical slow oscillations (SO) providing a less disputable \u201csignal\u201d (LFP UP state) over a \u201cnoise\u201d state.Several articles dealt with improvements for artificial sensing front ends:Losada et al. took the well-known mushroom electrodes . A novel simulation tool was presented by Al Abed et al. to shed light on in vivo electroporation in context of gene therapeutic improvements of the cochlea-electrode-interface.Improvements of optical techniques were presented by several other articles.Nambiar et al. demonstrated an algorithmic pipeline to reconstruct brain tissue surrounding explanted \u201chybrid\u201d array electrodes. Esquibel et al. employed the label free, optical sectioning method of second harmonic generation to examine implanted brain slices and showed unusual collagen fiber patterns not found in normal brains. Quite remarkably, by applying a custom made optoacoustic imaging setup Gottschalk et al. monitored neuronal calcium dynamics under blood-free conditions deep in an ex vivo maintained whole mouse brain. It will not be the last we are going to hear from genetically encoded calcium indicators (GECI). Improvements in 2-photon imaging presented in the review by Dorand et al. show a complicated and dynamic response to BBB-rupturing, substantial immune activation and microglia participation which might warrant a systematic application of different medications. Wellman et al. further supports the quest to widen the circle of usual suspects around brain implanted devices as they reveal an involvement of a wealth of other players like oligodendrocytes or even pericytes. A view shared by Bedell et al. and Hermann et al. poihc who not only vote for minimizing the cross sectional area of implants, but propose benefits from targeting the TLR/CD14 pathway as a therapeutic mechanism\u2014in particular focusing on infiltrating peripheral immune cells, while allowing the resident microglia to facilitate neuroprotection.As hoped for while organizing the conference, several overarching cutting-edge topics were presented to the community for the first time. The conference organizers then crystalized the momentum from the meeting into in the subsequent articles reported in this virtual issue. Unfortunately, the COVID-19 pandemic postponed the most recent installment of our meeting. Please continue to check the Gordon Research Conference website for information about the rescheduled conference.UH and JC both wrote and edited this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,st century. Individuals with COVID-19 are at an increased risk of developing lower respiratory tract disorders, such as pneumonia, acute respiratory distress syndrome (ARDS), and even death , a novel coronavirus infection, is fast becoming the epidemic of the 21al., 2020). To stoRecently, the use of vitamin D as a preventive/therapeutic intervention against COVID-19 infection has received much attention . It hasal., 2011). In addal., 2011; Moise aal., 2011; Li, 201al., 2011; Manasekal., 2011; Remmeltal., 2011). For inal., 2011). COVID-al., 2011; Sun et al., 2011). Conseqal., 2011). Vitamial., 2011), which al., 2011; Suh et al., 2011). If theal., 2011), may inin vitro and in vivo vitamin D-mediated ACE2  metabolism and its interactions with other ACE2-inducing drugs. Finally, until further data regarding the efficacy of vitamin D on the COVID-19 infection is available, clinicians should exercise caution in the overuse of vitamin D, especially in the elderly patients who also use other drugs which may alter ACE2 expression. Until further studies can fill these gaps, the single daily dose of 800-1000 IU vitamin D may be sufficient to meet the needs of most of the population. To summarize, first, the review of literature on the beneficial effects of vitamin D against COVID-19 infection leads to some doubts and controversies; therefore, well-designed clinical trials are needed to assess the potential risk-benefit of vitamin D supplementation for the prevention and/or treatment of COVID-19 infection. Second, although appropriate vitamin D doses may show some benefits in reducing the respiratory tract infections, higher doses may be harmful. Third, limited information is available on the None of the authors have any conflicts of interest or financial ties to disclose.Not applicable."}
+{"text": "This research provides a guide to sweetpotato breeders for developing and deploying appropriate sweetpotato cultivars capable of meeting targeted consumer needs for sweetpotato fries and other fried sweetpotato products in distinct segments. It will also enable stakeholders in the sweetpotato value chain strategise in order to increase sweetpotato adoption. Prepared foods are increasing in popularity in West Africa alongside rapid urbanisation. Growing demand for fried products calls for targeted breeding efforts to meet consumer needs, but little is known regarding consumer preferences. This research identified the sensory attributes of fried sweetpotato preferred by different consumer groups using a combination of consumer acceptance testing and descriptive sensory analysis. Market and community surveys identified three consumer segments in Ghana and Nigeria with contrasting preferences for fried sweetpotato sensory attributes. One group preferred crispy, crunchy, mealy and sweet fried sweetpotato; another preferred characteristic yam flavour and dry texture; and the third preferred uniform orange colour appearance, ripe plantain flavour and palm nutty flavour. Such consumer segmentation can help emerging West African fried sweetpotato industries identify target markets and provides valuable information to breeders, growers and retailers to prioritise attributes in their breeding, growing or product sourcing decisions. Sweetpotato is a nutritionally important crop and increased consumption has been attributed to several factors. Though primarily a starchy staple, it is also rich in antioxidants, vitamins and minerals in both its roots and leaves. Orange\u2010fleshed, provitamin A\u2010rich types have been well\u2010established for their ability to combat vitamin A deficiency, when combined with a nutrition education component . The market survey set included five contrasting sweetpotato cultivars from breeding trials of the Crop Research Institute and Savanna Research Institute of the Council for Scientific and Industrial Research, Ghana and the International Potato Center. These included both released cultivars, and clones at the advanced stage of the varietal selection process Table\u00a0; Fig.\u00a01.et al. . Oil was heated to a temperature of 180\u00b0C before frying for about 8\u201310\u00a0min. Samples were placed on a white paper towel inside a clean disposable bowl to drain excess oil for about 2\u00a0min before wrapping them with aluminium foil. Sensory evaluation was conducted within 10 mins after frying with initial inner strip temperature of about 80\u00b0C. Samples for the consumer sensory tests in the community survey were prepared by expert fryers at each community using local common practices that varied slightly as described by Ssali et al. . The majet al., Eight panellists were used to profile the two sets of sweetpotato materials Table\u00a0 using a Consumer preference tests of the five varieties in the market survey were carried out in four major Ghanaian regional markets purposively selected. Three of these regions  are known to have major sweetpotato producing communities. Bawku in the Upper East Region, Cape Coast in the Central Region and Akatsi in the Volta Region were selected for being the major regional markets and Agbogbloshie, Malata, Kaneshie and Accra Mall markets in the nation\u2019s capital, Accra, were selected due to high levels of economic activities in those markets.Sweetpotato fries were prepared and served to randomly selected consumers at the selected markets. In total, 332 consumers evaluated samples across the four regions. Samples were prepared and coded with three letters generated using XLSTAT software . Consumers were asked to evaluate fries and rate them for overall liking, using a 9\u2010point hedonic scale (1\u00a0=\u00a0Extremely dislike through 9\u00a0=\u00a0Extremely Like). Samples were served on white disposable plates with subjects handling samples with disposable white tissue papers. Consumers were asked to rinse their mouths with water between different samples.et al., Following the gendered mapping for fried sweetpotato product in Kano and Kwara States in Nigeria and Bawku in the Upper East Region of Ghana, consumer preference tests were conducted in the communities with 191 respondents , 101 females (F))  with means separation conducted using Tukey test at 5% significant level for each sensory attribute . Principal component (PCA) analysis using the correlation matrix of significantly different sample attributes was used to visualise how sweetpotato cultivars were differentiated across sensory attributes.Consumer liking scores in both surveys were subjected to one\u2010way ANOVA using JMP Pro 11 and mean separation performed by Tukey test. Cluster analysis was also carried out using Agglomerative Hierarchical Clustering (AHC) to group consumers into different segments based on shared characteristics using XLSTAT . One\u2010way ANOVA was then performed on the overall liking scores for each cluster using JMP Pro 11 and mean separation by Tukey test. An external preference mapping (PREFMAP) was created using a vector model by regressing consumer cluster groups onto the factor scores of the first two principal components from the DSA.et al., et al., et al., The appearance of fried sweetpotato was measured by uniform colour, surface browning and fibrousness Table\u00a0. Most ofet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Textural attributes Table\u00a0 are veryet al., et al., et al., et al., et al., Dioscorea rotundata), popularly called Pona, is the most widely consumed and preferred root and tuber variety  Table\u00a0 and Kuffet al., et al., et al., Due to the overlapping usage of flavour and taste attributes in sensory descriptions, taste attributes were described as perceived by only the tongue which included the four basic taste sensations  and umami while flavour attributes were described to include aroma through the nasal cavity as well as through the mouth. Sweetpotato is generally a sweet crop due to its ability to easily breakdown starch to maltose as a result of amylase activity and to the presence of other sugars  and Kuffour (Ghana) used for the community surveys Fig.\u00a0. Obare, et al., et al., et al.  across the locations), regardless of the different sensory attributes Table\u00a0. This is, et al. , where n, et al. . In addi et al., . The lea et al., , where y et al.,  since swet al., et al., et al., et al., et al., Consumers were generally grouped into three segments through agglomerative hierarchical clustering (AHC) of overall liking scores Table\u00a0 in GhanaP\u00a0=\u00a00.035) value indicates that age group distribution is dependent on type of cluster. Older people are more likely to prefer sweetpotatoes with characteristic attributes of this segment. The last group was driven by flavour attributes such as doughnut, ripe plantain and palm nutty flavours and uniform colour, which were all associated with orange\u2010fleshed cultivars. In terms of preference for orange\u2010fleshed cultivars, most consumers were in this group (47.8%). Younger consumers (ages below 25\u00a0years) were highest in this group. This was in line with the findings of Tomlins et al.  compared to the less sweet type (PGA14351\u20104) in Ghana. However, consumer segmentation showed that different cultivars were preferred by different consumer groups due to their unique attributes. Three consumer segments with varying attribute preferences were identified. One group preferred sweetpotatoes with sweet taste, crispy, crunchy and mealy textures, while another group was driven by dry texture and yam flavour. The third group was predominantly influenced by attractive colour, flavour and possibly softer textures. The test of independency showed that only age group was dependent on segment groupings. Community surveys in Ghana and Nigeria also indicated a similar trend. Though most currently available orange\u2010fleshed cultivars are generally perceived as poor candidates for fried products by processors due to higher oil consumption than other available cultivars, they command high consumer demand due to their attractive colour and unique flavour attributes. Sweetpotato cultivars of any colour, with dry, crispy, mealy texture and moderately sweet taste could be an ideal sweetpotato for many consumers. There is also a potential market for varieties with low sweetness with the above mentioned attributes. Clearly, these findings will contribute to the development of improved product profiles for sweetpotato breeders in West Africa. These findings could also aid industries to developed appropriate products to reach targeted consumers.Eric Kuuna Dery: Conceptualization ; Data curation (lead); Formal analysis (lead); Investigation (lead); Methodology (lead); Visualization (supporting); Writing\u2010original draft (lead); Writing\u2010review & editing (lead). Edward E. Carey: Conceptualization (supporting); Investigation ; Methodology (supporting); Supervision ; Writing\u2010original draft (supporting); Writing\u2010review & editing . Reuben Ssali: Investigation ; Supervision ; Writing\u2010original draft (supporting); Writing\u2010review & editing . Jan W. Low: Project administration (lead); Resources (lead); Supervision (supporting); Writing\u2010review & editing . Suzanne M Johanningsmeier: Methodology (supporting); Validation (supporting); Writing\u2010original draft ; Writing\u2010review & editing . IBOK NSA ODURO: Supervision (supporting); Writing\u2010original draft (supporting); Writing\u2010review & editing (supporting). Abena Boakye: Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Supervision (supporting); Validation (supporting); Writing\u2010original draft (supporting). Rachel M. Omodamiro: Investigation (supporting). Hauwa Ladi Yusuf: Investigation (supporting); Writing\u2010review & editing (supporting).The authors declare no conflict of interest in this work.Children were not used in the study. Respondents were informed about the study, they could stop the interview at any point, written consent from sensory panellists and from consumers participating in this study were obtained and the research respected the rules of voluntary participation and anonymity. Food samples were prepared according to good hygiene and local practices.A blindfold or red lightening system could have been used during the descriptive evaluation to mask the effect of colour on other attributes. Again, unlike the market survey and descriptive sensory analysis that used French fries sizes, the community survey employed chunk fries which were bigger.Table S1. Average scores and standard deviations of descriptive sensory characteristics for French fried sweetpotato.Click here for additional data file."}
+{"text": "Medical Genetics, Genomics and Bioinformatics\u201d, \u201cMedical Genetics, Genomics and Bioinformatics\u20132020\u201d and \u201cMedical Genetics, Genomics and Bioinformatics\u20132021\u201d [Medical Genetics, Genomics and Bioinformatics\u20142022\u201d  collected papers on medical genomics, human population genetics and computational biology applications in biomedicine, continuing the topic of medical genetics and genomics. Here, we focused on bioinformatics and systems biology approaches to medical genetics problems, molecular oncology and bioinformatics approaches for medical genomics.The analysis of molecular mechanisms of disease progression challenges the development of bioinformatics tools and omics data integration. We have presented an earlier series of journal special issues: \u201chttps://bgrssb.icgbio.ru/2022/, accessed on 12 May 2023). The current collection continues the series of post-conference journal special issues presenting the highlights from the set of meetings on genetics and systems biology highlighting recent trends in cancer genomics [The papers on bioinformatics applications were originally discussed at the \u201cBioinformatics of Genome Regulation and Structure/Systems Biology\u201d (BGRS/SB) multiconference 2022 and its biomedical symposia in Novosibirsk, Russia  and the new IJMS journal issue New Sights into Bioinformatics of Gene Regulations and Structure . The recent special issue on computational genomics in Life  and Genes journal also has works on medical bioinformatics [Molecular mechanisms of human disease progression ,2 are beMedical Genetics, Genomics and Bioinformatics\u20142022 presents recent studies on medical genomics. It contains eight research manuscripts and one review, each concerning a bioinformatics solution for the analysis of the molecular mechanisms underlying disease progression.This issue Jeong-An Gim  presenteAlmost all the research papers in this special issue deal with NGS data to study disease mechanisms and find candidate genes. Ionut-Florin Iancu  analyzedFrontiers in genetics special journal issue . Recent work by the same team on lymphatic dissemination in prostate cancer complemented this study [Elena Pudova et al.  analyzedis study . Overallis study  have shoYaron Trink and co-authors studied heterogeneity in Wilms\u2019 tumor pediatric malignancy related to faulty kidney development . Wilms\u2019 The topic of cell classification is continued by Olga Krasnova and colleagues  presentiIJMS special issue, Bioinformatics of Gene Regulations and Structure\u20132022  the same authors\u2019 group presented a new tool for scRNA-seq imputation via integration with single-cell ATAC-seq that increases the power of the analysis [Mark Melamud et al.  studied analysis .https://deafnessvariationdatabase.org/, accessed on 12 May 2023) for the selection of potential diagnostically important parts of this gene. Initial diagnostic testing for hearing loss was suggested. Studying genetic variants in populations is an important approach applied earlier for diabetes [Valeriia Danilchenko and colleagues  studied diabetes . Olga Sadiabetes  considerdiabetes  as a biodiabetes ,26.IJMS special issue New Sights into Bioinformatics of Gene Regulations and Structure topic at  to continue the paper selection on bioinformatics and genomics in human diseases, as well as the research topic at Frontiers in genetics .Overall, the current special issue on bioinformatics confirmed research interests in medical genomics and bioinformatics studies ,2. We no"}
+{"text": "The ongoing coronavirus disease COVID-19) pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is putting our public health services under enormous strain 9 pandemi, MERS-CoEffective disinfection, sterilization, and decontamination procedures are essential for reducing the environmental contamination of pathogens. A reduction of more than a few log units is required for effective treatments. Various innovative technologies for pathogen inactivation have recently been developed. However, some pathogens display intrinsic resistance to both chemical and physical inactivation.There are five generally recognized categories in the hierarchy of resistance as follows: (i) extremely resistant (prions), (ii) significantly resistant , (iii) resistant , (iv) susceptible , and (v) highly susceptible (enveloped viruses) ,17,18. TThis Special Issue comprises two original articles, one communication and one review describing various disinfection or sterilization procedures as well as discussing the underlying mechanisms of inactivation.The article by Takashi Yokoyama et al., titled \u201cVirucidal Effect of the Mesoscopic Structure of CAC-717 on Severe Acute Respiratory Syndrome Coronavirus-2\u201d , describMicroorganisms titled \u201cUniversal Virucidal Activity of Calcium Bicarbonate Mesoscopic Crystals That Provides an Effective and Biosafe Disinfectant\u201d [The inactivation effect of SARS-CoV-2 by CAC-717 revealed by Yokoyama et al. has recently been supported and further expanded by the results of a study by Kirisawa et al. published in an article in fectant\u201d . The stuStaphylococcus aureus and induces growth. Intriguingly, the supernatants of S. aureus cultures incubated with the DACC-coated dressing were found to downregulate inflammation associated with the cytokine overexpression of TNF-\u03b1 and TGF-\u03b21 as well as diminishing gelatinase activity in macrophage cultures and fibroblast/macrophage co-cultures. These findings should help stimulate the application of DACC-coated dressing-based tools in the management of acute or chronic wounds.The article by Silvestre Ortega-Pe\u00f1a et al., titled \u201cDialkyl Carbamoyl Chloride\u2013Coated Dressing Prevents Macrophage and Fibroblast Stimulation via Control of Bacterial Growth: An In Vitro Assay\u201d  reportedS. aureus and Enterococcus faecalis) and Gram-negative bacteria  were inhibited by treatment with CFEAS at concentrations of >95%. Furthermore, the anti-biofilm activity of CFEAS was effective at similar levels of 1.5% polyhexamethylene biguanide/betaine (PHMB). The study also found that CFEAS can be used as a safe antiseptic. Specifically, fibroblasts were shown to be less sensitive to CFEAS-induced cytotoxicity than macrophages. In addition, the authors showed that the treatment of subacute and chronically infected wounds with CFEAS significantly decreased the viable bacterial number of colony-forming units in the wound biopsies of patients with a venous leg ulcer. These findings indicate that CFEAS can effectively inhibit biofilm formation in a clinical setting. In conclusion, the use of CFEAS for antiseptic and antibiofilm treatment is a promising new approach for wound-healing.The article by Alejandro Cabrera-Wrooman et al., entitled \u201cAntiseptic Effects and Biosafety of a Controlled-Flow Electrolyzed Acid Solution Involve Electrochemical Properties, Rather than Free Radical Presence\u201d , investiA review by Pianpian Yan et al., titled \u201cNew Clinical Applications of Electrolyzed Water: A Review\u201d , summariMicroorganisms, which highlights the research of eminent scientists working on the topics of disinfection, sterilization, and decontamination. The Editor thanks all the authors of this Special Issue for sharing their invaluable experience and for their help in compiling the respective articles. The Editor also wishes to thank Meirong Duan and other members of the editorial staff at the Multidisciplinary Digital Publishing Institute (MDPI) for their unwavering commitment throughout the publication process. I hope that this Special Issue inspires readers and contributes to the development of the research field of the disinfection, sterilization, and decontamination of microorganisms. It has been an honor to organize this Special Issue for"}
+{"text": "Nature Plants, a new study  reveals how plants assemble translational condensates to balance tissue health and disease resistance.Biomolecular condensates assembled through phase transitions regulate diverse aspects of plant growth, development, and stress responses. How biomolecular condensates control plant immunity is poorly understood. In  Nature Plants, Zhou et al.  contributes to the formation of biomolecular condensates (Molliex et al. So, what can we learn from this study? First, it reinforces the emerging roles of biomolecular condensates in plant organismal defense (Zavaliev et al. In summary, Zhou and colleagues\u2019 discovery of a phase separation control mechanism of gene translation provides a major conceptual advance in understanding the complex plant immune system. Similar to a circuit rheostat, plants appear to fine-tune the intensity of immune signaling through HEM1 phase separation to balance cell survival and death. Future research using synthetic approaches to harness HEM1\u2019s phase behavior could have practical applications in both agriculture and human health."}
+{"text": "Insights in multiple sclerosis and neuroimmunology 2021.\u201d These cover a wide aspect of multiple sclerosis (MS)- related themes as well as themes in autoimmune encephalitis.A total of 19 articles are published in the Frontiers Research Topic \u201cMeca-Lallana et al. show in their article \u201cConsensus on early detection of disease progression in patients with multiple sclerosis\u201d that such consensus statements could help clinicians to find early in the disease course patients with secondary progressive MS (SPMS). Such an early identification is important to perform adequate therapeutic management. Standardized clinical assessments are meaningful in MS care. In the article \u201cMaking every step count: minute-by-minute characterization of step counts augments remote activity monitoring in people with multiple sclerosis,\u201d Block et al. used a model to predict disease progression over the longer term (>2 years) based on obtained measurements. These findings will be used to develop further descriptive metrics for activity. In their article \u201cCurrent status and future opportunities in modeling clinical characteristics of multiple sclerosis,\u201d Liu et al. suggest that there is a strong need to develop validated models of MS clinical outcomes by using cellular or/and molecular biomarkers. In the article titled \u201cModels of care in multiple sclerosis: a survey of Canadian health providers,\u201d Marrie, Donkers et al. claim that the ideal MS service is multidisciplinary in nature, ideally integrated, and with prompt access to care.There is a need for consensus criteria about the identification of certain types of MS. Coerver et al. show in the article \u201cThe association between blood MxA mRNA and long-term disease activity in early multiple sclerosis\u201d that MxA mRNA is expressed in inflammatory pathology in MS that is dependent on the endogenous type-1 interferon system and that this might be a prognostic biomarker for long-term inflammatory disease activity in MS. In the article \u201cGenetic risk variants for multiple sclerosis are linked to differences in alternative pre-mRNA splicing\u201d by Putscher et al., the authors show that genetic variants from MS risk loci affect pre-mRNA splicing. Amoriello et al. investigated soluble HLA-G (sHLA-G) levels in MS in the article \u201cInvestigating serum sHLA-G cooperation with MRI activity and disease-modifying treatment outcome in relapsing-remitting multiple sclerosis.\u201d They found that the HLA-G genotype strongly influences sHLA-G levels. Autoantibodies are of importance in various neuroimmunological disorders, and their role and mechanism of action are partly undefined. In the article \u201cPeptidylarginine deiminase 2 autoantibodies are linked to less severe disease in multiple sclerosis and post-treatment Lyme disease,\u201d Kim et al. make the case that anti-peptidylarginine deiminase 2 (PAD2) antibodies may attenuate inflammation. This effect is observable in tissues with high expression of PAD2. The role of hemolysis was analyzed in the article \u201cPeripheral hemolysis in relation to iron rim presence and brain volume in multiple sclerosis\u201d by Krajnc et al. The authors found an influence of hemolysis on the brain volume but not on the presence of iron rim lesions in progressive MS. Investigations about metabolomics in neuroimmunological disorders is of increasing interest. In their study \u201cMetabolomics of cerebrospinal fluid in multiple sclerosis compared with healthy controls: a pilot study,\u201d \u017did\u00f3 et al. investigated cerebrospinal fluid (CSF) from MS patients compared to controls regarding metabolomic profiles. They found differences in amino and fatty acids in the CSF of newly diagnosed patients with MS in comparison with controls. The most significant changes were seen in levels of arginine, histidine, and palmitic acid. They concluded that such a metabolomic profile may predict inflammatory disease activity in MS. In the article \u201cEffects of vascular comorbidity on cognition in multiple sclerosis are partially mediated by changes in brain structure,\u201d Marrie, Patel et al. showed that vascular comorbidity leads to changes in brain macrostructure and microstructure. In addition, this is associated with lower cognitive function in patients with MS.The myxovirus resistance protein A (MxA) has been long used as a marker for exogenous interferon-beta efficacy in MS treatment. Bridging therapies with injectable immunomodulatory drugs in the management of multiple sclerosis: a Delphi survey of an Italian expert panel of neurologists,\u201d Marfia et al. suggest that the value of bridging therapy with injectable immunomodulatory drugs in MS disease conditions is underscored. The article focuses on patients with MS who plan to become pregnant and patients with MS at risk for cancer recurrence. Ozanimod is a selective sphingosine-1-phosphate (S1P)-receptor 1 (S1P1) and S1P5 modulator used for the treatment of active forms of relapsing-remitting MS (RRMS). Ziemssen et al. present their real-world and long-term study \u201cOzEAN study to collect real-world evidence of persistent use, effectiveness, and safety of ozanimod over 5 years in patients with relapsing-remitting multiple sclerosis in Germany.\u201d The results of this study will add to the safety profile and efficacy profile of ozanimod in the treatment of RRMS. In the study \u201cSafety, adherence and persistence in a real-world cohort of German MS patients newly treated with ocrelizumab: first insights from the CONFIDENCE study,\u201d Weber et al. describe the safety profile of ocrelizumab in the CONFIDENCE real-world MS population study. The findings were consistent with the findings in pivotal clinical trials for the anti-CD20 B cell-depleting antibody ocrelizumab used for the treatment of patients with RRMS and patients with primary progressive MS (PPMS). Importantly, high treatment persistence and adherence were seen in this real-world MS population study. Fathi et al. suggested in their article, \u201cDynamic changes in kynurenine pathway metabolites in multiple sclerosis: a systematic review,\u201d that quinolinic acid is a possible player in the pathogenesis of MS. This conclusion is mainly based on the finding that quinolinic acid levels in CSF were higher in patients with MS than in healthy controls. The value of disease models induced in mice and rats on certain novel MS therapeutic approaches is outlined by Jayaraman and Jayaraman in their article \u201cImpact of histone modifier-induced protection against autoimmune encephalomyelitis on multiple sclerosis treatment\u201d about histone deacetylase (HDAC) inhibitors. HDAC inhibitors such as valproic acid and hydroxamates as well as others are possible candidates for future treatment of MS.In \u201cZhang et al. show in their article \u201cLong-term prognosis of patients with anti-N-methyl-D-aspartate receptor encephalitis who underwent teratoma removal: an observational study\u201d that early detection and removal of teratoma resulted in a favorable long-term prognosis in patients with anti-NMDAR encephalitis. Case studies can be of importance for defining potential new disease entities and for the description of rare disease variants. In the case study \u201cAcute cerebellitis associated with anti-homer 3 antibodies: a rare case report and literature review\u201d by Miao et al., the authors underscore the need for immune-mediated causes to be considered in acute cerebellitis. Importantly, immunotherapy can contribute to the improvement of cerebellar syndrome. Neuropsychological assessment is important in phenotyping and care of patients with neuroimmunological disorders and especially autoimmune encephalitis. In the article by Chan et al., \u201cCognitive and mood profiles among patients with stiff person syndrome spectrum disorders,\u201d it is clarified that neuropsychological testing in stiff person syndrome should include testing of verbal learning and recall, phonemic verbal fluency, attention, and processing speed.It has been shown that in paraneoplastic forms of autoimmune encephalitis, the removal of the associated cancer entity is of primary importance in long-term disease outcomes. For teratoma, Insights in multiple sclerosis and neuroimmunology 2021\u201d gives novel insight into current research themes on MS and autoimmune encephalitis.In conclusion, the Research Topic \u201cRW outlined and wrote the Editorial."}
+{"text": "Selenium in soil-plant-animal systems and its essential role for human health published original research reports and critical reviews representing different but interrelated research disciplines involving physiochemical and biological behaviors of Se within the larger foundation topics of agricultural soil, bioavailability, plant uptake, physiological responses, genetics, molecular biology, microbial communities, Se-biofortification strategies, and animal health.With approximate 1 billion people facing some degrees of selenium (Se) deficiency worldwide, it is imperative that the Se community work together and share the latest knowledge on various inter-related aspects of Se in supporting and protecting animal, human, and ecosystem health. In collaboration with Frontiers of Plant Science, Frontiers in Nutrition, and Frontiers in Veterinary Science, this Research Topic entitled Selenium is unevenly distributed in the soil, which has consequently resulted in soil Se deficiency issues and further low Se dietary intake in many parts of the world. To increase Se intake by consumption of Se-enriched plant- and animal-derived food products, we need to better understand and identify those effective strategies for Se delivery though agricultural production systems in different geographical regions. Enhancing bioavailable Se in soil will not only increase Se accumulation in crops but also result in the accumulation of specific bioactive Se compounds in food products. Importantly, the true value of successfully increasing Se concentrations in plant- and animal-based products could be highly determined by the fractionation and the speciation of Se, such as seleno amino acids or selenoproteins in Se-biofortified food products. The different Se compounds accumulated in plant tissues would further determine their bio-accessibility and the absorption of Se through human digestion systems. Similarly, animal health and reproduction are also very much dependent on the bioavailability and the absorption of Se from feeding materials. The adequate intake of Se from the feeding materials or using supplementary Se significantly affect animal\u2019s vital physiological functions that are related to reproduction or pregnancy health, and their auto-immune functions.In this Research Topic, 15 high-quality research papers that addressed various topics or faces of Se research, ranging from the biogeochemical cycling of Se to cellular and molecular processes that elucidate mechanistic functions of Se in human and animal health. Inorganic and organic Se transformations and physio-chemical properties of soils could all ultimately determine soil Se bioavailability for plant uptake and accumulation. Both the concentration and the speciation of Se in soil could affect the Se content and the Se status of crops, particularly in edible plant materials. Recent studies demonstrated that biofortification as an agronomic-based strategy can be utilized to mitigate a low transfer of Se and other nutrients from soil into the food chain and produce Se-enriched food products, which helps increasing dietary Se intake throughout Se-deficient susceptible regions of the world.Se biofortification of soybean genotypes in a tropical soil via Se-enriched phosphate fertilizers\u201d, Silva et\u00a0al. showed that the application of Se-amended phosphate fertilizers could be an effective method to deliver Se to the crop. Adding Se to the commonly used fertilizers could also be challenging due to the soil Se concentration baselines, soil types, redox protentional, pH, and soil microbial or invertebrate communities. Song et\u00a0al. indicated in \u201cSelenium effect threshold for soil nematodes under rice biofortification\u201d that, with the application of selenite for rice biofortification, higher concentrations of soil Se can negatively affect soil nematodes, suggesting that the presence of soil nematodes could be used as an effective bioindicator for the soil environmental changes related to Se content. In addition to the uptake of inorganic Se, plants can also absorb Se via organic Se application, as shown in \u201cUptake and translocation mechanisms of different forms of organic Se in rice\u201d by Wang, Q. et\u00a0al. This rice study provides important insights into the mechanisms underlying the uptake and translocation of organic Se, especially selenomethionine (SeMet), in plants. As an alternative to soil applied Se, foliar application has been used to apply Se to plants. Schiavon et\u00a0al. indicated that \u201cFoliar Se fertilization alters the content of dietary phytochemicals in two rocket species,\u201d while Wang, M. et\u00a0al. further outlined the differences between soil and foliar Se applications in a paper entitled \u201cSoil and foliar Se application: Impact on accumulation, speciation, and bio accessibility of Se in wheat\u201d. In addition to foliar Se application, Malka et\u00a0al. evaluated potential interactions between Se and Zn in foliar application, and indicated that \u201cSeparate foliar sodium selenate and zinc oxide application enhances Se but not Zn accumulation in pea seeds\u201d. Foliar application of Se may additionally influence plant metabolism, as well as increasing Se content in plant tissues, as shown by de Sousa et\u00a0al. in \u201cSelenium enhances chilling stress tolerance in coffee species by modulating nutrient, carbohydrates, and amino acids context\u201d, and demonstrated that foliar Se application improved coffee plants\u2019 ability to tolerate chilling stress.Agronomic Se biofortification has been commonly practiced by adding Se-amended fertilizers to the soil. In Brazil, soybean is a potential major crop for biofortification. In \u201cBanuelos et\u00a0al. in \u201cSalsola soda (agretti) as a Se biofortification crop grown under high saline and boron conditions.\u201d Under field conditions Se-biofortified Salsola soda was produced with poor quality waters containing high levels of Se. Careful attention must, however, be paid in regions where Se-biofortified crops are grown in naturally Se-rich soils or with poor quality waters because of the potential presence of toxic metals in the environment. In \u201cPrediction models for monitoring Se and its associated heavy-metal accumulation in four kinds of acro-foods in seleniferous area\u201d, Jiao et\u00a0al. demonstrated that models can be used to effectively predict toxic metal accumulation in Se-enriched foods in those concerned regions.To produce Se-enriched agricultural products, the biofortification strategy can also be practiced in regions where there are naturally high levels of Se in the soil and/or in irrigation waters, as demonstrated by Hu et\u00a0al. reviewed the importance of \u201cSeleno-amino acids in vegetables\u201d, a review of their forms and metabolism and thereby affect protein structures, functional properties and antioxidant capacity in newly-germinated Se-enriched soybeans. Relatedly, Huang et\u00a0al. also reported in \u201cSelenium biofortification of soybean sprouts: effects of Se enrichment on proteins, protein structure, and functional properties\u201d that Se-biofortified seeds also contain proteins whose quality has also been influenced by Se content. In addition, Li et\u00a0al. evaluated \u201cThe use of selenium for controlling plant fungal diseases and insect pests\u201d, indicating that Se improves the plant resistance to fungal diseases.Se-enriched food products can increase Se intake and promote human health with absorption of plant tissue containing different Se compounds including seleno-amino acids. Earlier studies have clearly demonstrated the important role of Se in plant and animal physiological processes and functions. Hall et\u00a0al. discussed Se biofortification through forages raised for livestock feed in \u201cImpact of selenium biofortification on production characteristics of forages grown following standard management practices in Oregon,\u201d demonstrating that foliar selenate treatment increased forage Se concentrations in a dose-dependent manner, and that coupling Se amendment with standard fertilization practices promoted forage growth and forage Se concentrations. In cases of low soil Se, providing sulfur fertilization could reduce forage Se and potentially alter Se supply to livestock consuming those forages.Excessive low or high Se in soil and consequently Se concentrations in animal feeds can pose health and reproduction risks for animals. Animal-based food products for human consumption are an excellent source of dietary Se intake for the human population. Thus, safely providing Se biofortified feed materials to animals would result in increased Se concentrations in animal-based food products for humans. Dahlen et\u00a0al. reviewed the role of Se in male and female reproductive process and the impacts of maternal dietary Se on offspring outcomes in ruminants in their paper \u201cSelenium supplementation and pregnancy outcomes.\u201d The scientific evidence indicates that Se plays a major role in both male and female reproductive processes and, therefore, as a micronutrient, Se is instrumental to ensure successful animal reproductive efficiency. Increasing the maternal supply of Se alters offspring outcomes in ways that are typical of developmental programming; thereby implying that Se supply to the mother can have significant effects into the next generation of livestock. In animals, mitochondrial function is essential to bioenergetics and consequently life functions. Clearly, the role of Se in antioxidants plays a role in normal cellular metabolism and consequently whole animal health, production, and wellbeing. In addition, Se appears to have a role in mitochondrial function besides through antioxidants. Wesolowski et\u00a0al. reviewed the non-antioxidant the roles of Se in mitochondrial function in \u201cBeyond antioxidants: Selenium and skeletal muscle mitochondria.\u201d The review paper demonstrates our emerging understanding of the role of Se in skeletal muscle mitochondrial function beyond the traditional constructs of antioxidants, and further highlights the importance of a greater understanding of Se in mitochondrial function and energetics.A major determinant of livestock production, health, and well-being is effective and efficient reproductive process that lead to healthy offspring. Selenium is one of the most influential natural-occurring micronutrient elements for living systems. Recognizing selenium\u2019s impact on a multitude of processes in nature requires multi-disciplinary research on Se absorption, chemical transformation, and biochemical and physiological metabolisms in soil-plant-animal systems that can help us develop and implement effective strategies to mitigate public health impacts or concerns of Se deficiencies in the world. In this Research Topic, with different contributions from original research to critical reviews, some of the most influential researchers have provided their latest research findings and demonstrated significant advances in the field concerned with Se in food chains and its effects on human and animal health.All authors  contributed to the article through writing, reviewing and editing and have approved the submitted version."}
+{"text": "Dear Editor, I agree that accurate representation of research is of great importance, and Iapologize for these mistakes.I am grateful to Dr Anne Witt and Dr Sheila Kredit for drawing attention to errors I havemade in Appendix 1 of \u2018Re-thinking Benign Inflammation of the Lactating Breast:Classification, Prevention, and Management\u2019.Dr Witt and Dr Kredit are correct to state that I have falsely represented: study andThe rates of follow-up in the Witt et al. systematic review.Analysis of Witt et al. in Anderson et al.\u2019sThe Witt et al. study is not a randomized controlled study (RCT), but a nested case-controlstudy. It is referred to as \u2018quasi-experimental\u2019 in the Anderson et al. systematic review, notas an RCT. In Appendix 1 of my article, I wrongly represent the numbers who responded tofollow-up emails in the Witt et al. study, wrongly attributing these inaccurate numbers toAnderson et al. The Witt et al. study demonstrated excellent follow-up in the cohort whoreceived Therapeutic Breast Massage in Lactation (TBML) and also in the control group.Although debate is welcomed, and accurate representation of research essential, Inevertheless contend that TBML should not be recommended to breastfeeding women asevidence-based management of breast inflammation on the basis of Witt et al.\u2019s study, for fourreasons:1.\u2003TBML was delivered as one element in a complex breastfeeding intervention. Itsefficacy was evaluated in small numbers for mastitis and plugged ducts, in the absenceof a control group.TBML was delivered in the context of full breastfeeding support provided by an InternationalBoard Certified Lactation Consultant/registered nurse and/or breastfeeding medicine physician,which included latch correction, feeding patterns, antibiotic prescription, milk removal oranalgesia as clinically indicated. The component of the study which investigates efficacy ofTBML for mastitis and plugged ducts is a small, pre- and post-TBML assessment , which lacks a comparison group. That is,pre- and post-intervention comparisons do not take into account the neurobiological effects ofpatient expectation (placebo effect), as Witt et al. acknowledge in their article.2.\u2003TBML did not show improvements in pain at 2-day and 12-week follow-up when theengorgement group was compared to the control group.Of the 15 participants with engorgement [in the TBML intervention group], measurementswere taken from each breast, giving a total of 30 separate pain scores .\u2004.\u2004. These scoreswere treated independently (n = 30) in the pre-post analysis and combined (n = 15) for thecomparison between the intervention and control groups, making interpretation quitedifficult.Anderson et al. state in their analysis of Witt et al.,In the component of Witt et al. which investigates efficacy of TBML for engorgement, theintervention group (n\u2009=\u200915) was compared to a control group (n\u2009=\u200973); 47% of the interventiongroup had severe engorgement compared to 7% of the control group. Comparison of theengorgement intervention and control groups showed no meaningful difference in pain at day 2nor in pain, exclusive breastfeeding or breastfeeding complications at week 12 in emailfollow-up.3.\u2003Pre- and post-TBML improvements can be explained by the ductal dilations (milkejection) and milk removal components of TBML alone.TBML in the Witt et al. study achieves milk removal by alternating hand expression of milkwith the massage technique, and by allowing direct breastfeeding of the infant during TBML(see Supplement Appendix A). The reduction in breast pain and also in size of plugged ductsobserved immediately after TBML can be explained by the milk removal components of TBML alone,which are associated with milk ejections and ductal dilations.4.\u2003There is no pathophysiological model which explains the proposed efficacy of thegentle areola-to-axilla massage component of TBML.Is increased lymphatic drainage the proposed pathophysiological mechanism of light massagefrom the areola to the axillae? If so, this proposed mechanism isn\u2019t supported by the latestresearch concerning the function of lymphatic vasculature. Interstitial fluid diffuses intothe initial lymphatic capillaries in response to rising pressure gradients between breaststroma and lymphatic capillaries, which mechanically opens these capillaries. Lymphaticcollection vessels contain valves, have smooth muscle in their walls, and are intrinsicallycontractile, actively pumping lymph towards the nodes. Although there is no convincingphysiological rationale to support the belief that application of external pressurefacilitates lymphatic removal of breast stroma interstitial fluid, there is reason to beconcerned that an external pressure application which moves towards the axilla risks increasedintra-alveolar milk pressures.Various breast massage techniques are offered to breastfeeding women around the world, as DrWitt and Dr Kredit note. Anderson et al. analyse the efficacy of a range of massage techniquesin three RCTs and three quasi-experimental studies, including Witt et al.\u2019s study of TBML.Although Anderson et al. conclude \u2018Overall, different types of breast massage were reported aseffective in reducing immediate pain for the participants\u2019, I contend that neither Witt etal.\u2019s data or Anderson et al.\u2019s data support Therapeutic Breast Massage as an evidence-basedintervention for presentations of lactation-related breast inflammation, despite its inclusionin Academy of Breastfeeding Medicine Clinical Protocol #36: The mastitis spectrum.Using the GRADE Working Group grades of evidence in their Summary of Findings, Anderson etal. report low certainty of outcomes for reduction in pain, increase in breast milk supply,and reduction or resolution of symptoms of breast inflammation, noting that \u2018the true effectmay be substantially different from the estimate of the effect\u2019. Anderson et al. observe thatthe ability to replicate or generalize results of the six studies are limited by:Significant heterogeneity of study methods, interventions and outcome measuresLack of detailed explanation of breast massage techniquesUse of invalidated toolsSmall sample sizes and Oketani massage techniques, or requirement for seven consecutive days of massage combined with preparation of freshtopical cactus and aloe leaf lotion and pre- and post-massage application of aloe and cactusflesh, may not be practical in many settings.Anderson et al. also note that requirement for extensive training for traditional Gua Sha breastfeeding women are commonly referred to multiple providers for unproveninterventions when problems emerge. Many popular treatments such as TBML lack both aconvincing evidence-base and a robust underlying pathophysiological model. Such treatments mayincrease the financial burden for families and health systems, and raise the spectre ofdiscriminatory breastfeeding support globally, with ease of access limited to affluentfamilies in advanced economies.Because clinical breastfeeding support remains a research frontier,Thank you for the opportunity to correct my mistaken representation of the Witt et al. andAnderson et al. studies in Appendix 1 of my article, for which I apologize. I welcomerespectful discussion and debate concerning interpretation of existing studies and also theopportunity to amend errors, knowing that as clinicians and researchers we share the samecommitment to improved outcomes for breastfeeding women and their babies.Pamela DouglasKind regards,"}
+{"text": "Thermal manipulation has garnered considerable attention for its potential applications in diverse areas, including microelectronics, thermal logic devices, and thermoelectrics. Manipulating heat transfer in nanostructured materials is particularly desirable, especially for structures with high thermal conductivity used in thermal dissipation. However, the demand for high-power micro/nano chips exceeds the capabilities of even cutting-edge thermal management technologies, which currently represent a bottleneck in further development. Conversely, structures with low thermal conductivity are of interest in various areas such as thermal barriers and thermoelectrics. Understanding heat transfer is thus a fundamental problem that requires comprehensive study. However, studying heat transfer in nanostructures presents significant challenges due to the dominance of interfaces, boundaries, and imperfections in its behavior, and the underlying physical mechanisms remain unclear .This Special Issue, entitled \u201cHeat Transfer in Nanostructured Materials\u201d, provides a platform for presenting original and review articles that showcase recent advances in heat transfer within low-dimensional materials and nanofluids. The issue will systematically introduce and discuss the design, construction, characterization, and potential applications of these structures.\u22121 K\u22121. Li et al. [2 nanowires that showed an increase in jump during metal-insulator transition temperature with increasing sample thickness. Phonons were identified as major carriers that dominate thermal transport in the nanowires. Jiang et al. [Low-dimensional structures have demonstrated significant potential for nanoscale dissipation as thermal interface materials (TIMs). Lv et al.  developei et al.  revealedg et al.  investigg et al.  examinedg et al.  presente3O4 nanoparticles as nanofluids. The connector enhanced the heat transfer coefficient within the second microchannel by increasing the randomness of molecules and particles, refreshing the fluid\u2019s memory before entering the second channel. The effects of Reynolds number and nanoparticles on the connector were also studied, revealing that introducing Fe3O4 nanoparticles increased overall thermal conductivity and the heat transfer coefficient. The connector effectively promoted the random motion of molecules and nanoparticles, with the enhancement being significant at low Reynolds numbers but becoming negligible with increasing Reynolds number. This paper also presented a brief review of current advancements in studying the effects of nanoparticles on fluid thermal conductivity, viscosity, and heat transfer coefficient. Arshad et al. [Heat transfer via nanofluids has emerged as an effective approach for thermal management in complex systems. Optimization of nano additives and microchannel designs can significantly improve heat transfer efficiency. Apmann et al.  investigd et al.  reportedThis Special Issue is expected to be of interest to readerships in both fields of science and engineering. Understanding heat transfer mechanisms in nanostructured materials is fundamental for further developments of nanoscale devices, yet it remains an extreme challenge. We anticipate more emerging works focusing on depicting the underlying physical pictures of heat transfer and developing strategies for thermal manipulation in nanostructures."}
+{"text": "Cancer is still one of the leading causes of death worldwide, despite that tremendous resources are being invested in drug discovery . Recent The majority of cancer medications consist of small molecule inhibitors. These inhibitors are engineered to enhance their efficacy by binding to specific cellular protein targets, which in turn initiate a series of downstream changes in cancer signaling and metabolic pathways . High-thin vivo patient-derived xenograft (PDX) samples  proliferation-associated phenotypes, or 2) intermediate phenotypes, such as transcriptomic alterations. Numerous well-established data portals, including The Cancer Genome Atlas (TCGA), DepMap Portal , and The samples . These i samples . These t samples . The selFunctional screening for cancer drug discovery: from experimental approaches to data integration\u201d is to highlight the recent advances in high-throughput functional genetic approaches, especially how results from such new technologies can be applied for future studies in cancer drug mechanisms of action. To achieve this goal, we carefully reviewed every submitted manuscript and screened for highly qualified reviewers. Eventually, we accepted and published nine articles including eight \u201cOriginal Research\u201d articles, and one systematical \u201cReview\u201d article on the mechanism and clinical trials of hepatocellular carcinoma immunotherapy  in the onset and progression of gastric cancer (GC). Ren et al. developed a necroptosis-related prognostic signature to reveal immune infiltration, which could predict drug sensitivity and inform personalized drug therapy for hepatocellular carcinoma (HCC) patients. Wang et al. reported a novel hub gene signature closely associated with ferroptosis, serving as a potentially effective biomarker for predicting the prognosis of HCC patients.The research articles presented in this Research Topic encompass efforts in cancer drug discovery from both experimental and computational perspectives. Liu et al. conducted a comprehensive analysis to elucidate the roles of cuproptosis-associated genes in tumor biology and cancer drug sensitivity across various cancers. Chen et al. discovered a novel diagnostic four-gene signature for hepatocellular carcinoma based on an artificial neural network, with applications in drug screening. Li et al. explored the functional effects of FDX1 in tumors, and further validated the inhibitory effect of FDX1 in copper-induced cell death, confirming FDX1\u2019s role as a cuproptosis biomarker. Ruan et al. leveraged pan-cancer analysis to identify DDX56 as a prognostic biomarker associated with immune infiltration and drug sensitivity. Zhang et al. uncovered an LncRNA signature related to cuproptosis, serving as a novel biomarker of prognosis in immunotherapy and drug screening for clear cell renal cell carcinoma.We believe that the articles featured in this Research Topic can offer valuable insights into the application of functional screening methods for cancer drug discovery. The findings presented in these studies are anticipated to enhance our understanding of the molecular mechanisms governing cancer progression and, ultimately, we hope they will positively impact drug and target discovery in the near future."}
+{"text": "This method has broad-range applicability to understanding microbial communities and their associations with biosignatures and soil carbon and mineralogic characteristics relevant to climate science and astrobiology.Permafrost is important from an exobiology and climate change perspective. It serves as an analog for extraplanetary exploration, and it threatens to emit globally significant amounts of greenhouse gases as it thaws due to climate change. Viable microbes survive in Earth's permafrost, slowly metabolizing and transforming organic matter through geologic time. Ancient permafrost microbial communities represent a crucial resource for gaining novel insights into survival strategies adopted by extremotolerant organisms in extraplanetary analogs. We present a proof-of-concept study on \u223c22 Kya permafrost to determine the potential for coupling Raman and fluorescence biosignature detection technology from the NASA Mars Perseverance rover with microbial community characterization in frozen soils, which could be expanded to other Earth and off-Earth locations. Besides the well-known utility for biosignature detection and identification, our results indicate that spectral mapping of permafrost could be used to rapidly characterize organic carbon characteristics. Coupled with microbial community analyses, this method has the potential to enhance our understanding of carbon degradation and emissions in thawing permafrost. Further, spectroscopy can be accomplished  It is located along the valley floor of Goldstream Creek in a region of discontinuous permafrost. Permafrost in this area is syngenetic ice-rich silt (loess) formed through sediment deposition, causing the permafrost layer to expand upward , a custom-built deep ultraviolet (DUV) Raman and fluorescence spectrometer designed by the NASA Jet Propulsion Laboratory. This same technology is employed on the Mars Perseverance rover. MOBIUS uses a 248.56\u2009nm NeCu pulsed laser  . The laser spot is annular in shape with an outer diameter of \u223c44\u2009mm and an effective illuminated area of 3540\u2009\u03bcm2  at a spectral resolution of 3.8\u2009cm\u22121/pixel. For fluorescence measurements, a grating of 300 lines/mm was used with a spectral range of 250\u2013410\u2009nm and a resolution of 0.16\u2009nm/pixel. Spectral positions were calibrated before sample measurements by validating the position of the zero-order reflection, the secondary laser line at 252.93\u2009nm . Local Raman maps covered 0.5\u2009\u00d7\u20090.5\u2009mm at 100 um spacing, resulting in 25 individual point spectra at 1200 laser pulses per point (30-second acquisitions).et al.,Raman scan locations were selected based on the fluorescence intensity distribution obtained during the initial survey to prioritize areas of intense fluorescence that may indicate the presence of concentrated organic/biological material. A Canon camera provided context imaging of the mapped sample with a \u223c20\u2009mm/pixel resolution. Data processing was performed using custom Python programs and visualization tools based on a Loupe software package to process and visualize hyperspectral Raman and fluorescence data sets Uckert, . Spectra2.3.We performed triplicate DNA extractions from each core section  directly from 0.5\u2009g of soil using the FastDNA Spin Kit for Soil . An additional cleanup to remove humic material and other inhibitors was performed using the Qiagen DNeasy PowerClean Pro Cleanup Kit . The 16S rRNA gene was amplified with the 515F/926R barcoded primer sets and conditions recommended by the Earth Microbiome Project. Libraries were sequenced on the Illumina MiSeq platform, generating 2\u2009\u00d7\u2009250\u2009bp paired-end reads.et al.,et al.,et al.,et al.,et al.,et al.,et al.,16S rRNA amplicon sequences were processed using the exact sequence variants (ESVs) pipeline in QIIME2, version 2022.2  16S ribosomal RNA sequences database (updated 2022/10/30) Madden,  and extr3.3.1.\u22121). The appearance of this Raman peak in a fluorescence spectrum is consistent with the prevalence of water ice in permafrost . The relative intensity of the water band to organic fluorescence varied significantly between and throughout each sample and provides a measure of relative changes in the organic/ice concentration ratio.The three permafrost samples exhibited consistent fluorescence signatures indicative of a similar continuum of organic matter present throughout each sample. This signature comprised broad fluorescence peaks at \u223c320 and \u223c410\u2009nm, typical of biological macromolecules such as nucleic acids and proteins, which are consistent with expectations based on the prevalence of biomass in permafrost , 2B Fri. The twormafrost , 2B. How2O stretching mode. However, when measured with higher spectral resolution and longer exposures, this was better resolved as an asymmetric peak with a narrow component at 3155\u2009cm\u22121 and a broader, weaker component at 3350\u2009cm\u22121   . Proteobacteria and Firmicutes were the most abundant phyla , followed by Acidobacteria (1.1%) and Chloroflexi (0.62%) . We did Clostridium sensu stricto 13, Bacillus, Pseudomonas, Massilia, and Ralstonia), which together account for 78% of all sequences, to known 16S rRNA gene sequences. Close relatives (>97% sequence identity) have been isolated from an assortment of environments and conditions and employ a diversity of life and metabolic strategies, indicating that multiple divergent mechanisms can be employed to survive in ancient cryoenvironments.To better understand the microbial inhabitants of late Pleistocene permafrost, we compared ESV sequences of the five most abundant genera . In contrast to Clostridium, close relatives of Bacillus ESVs are primarily mesophilic (plus a few psychrophiles) and are derived from various environments and conditions. Previous data suggest that Clostridium may persist as vegetative cells in permafrost, while Bacillus form endospores , which can then be subsampled for DNA sequencing. Since there is fine-scale variation in permafrost soils, sequencing the same imaged regions will likely reveal relationships between spectral signatures and community structure.Permafrost cross-sections showed a widespread distribution of partially degraded organic carbon, pockets of water ice, and known microbial constituents. While we found no definitive spectral signatures corresponding to microbial community structure, this may be due to subsectioning methods. Given the high prevalence of organic material in permafrost, signatures from individual microbes may be lost in the background continuum of signals from all other organic matter present when analyzed with spectroscopy alone. To ameliorate this in our first-order analysis, core sections were divided into two pieces: one for spectroscopy and the other for microbial analysis. In the future, fluorescence and Raman spectroscopy can be applied to the core samples et al.,Previous analyses from the tunnel demonstrated that replicate samples from directly adjacent cores had small variations in microbial community structure but highly significant differences when comparing permafrost of different radiocarbon ages located tens of meters apart  , and the action of microbial communities as they slowly metabolize and transform organic matter through geologic time  and slow  thaw. Together with carbon dating of sampled strata, microbial analyses, and greenhouse gas measurements, this has the potential to identify and predict the relationships among many complex factors  and reveal how these ultimately drive the contribution of permafrost thaw to the climate change equation.These methods provide a unique means of studying permafrost in a changing climate. The 1700 billion tons of ancient carbon stored in permafrost exists in varying forms, from labile to recalcitrant (Jorgenson 4.3.et al.,et al.,et al.,et al.,Characterizing Earth's ancient permafrost microbial diversity and survival strategies provides a baseline to guide the search for microbial life on other frozen desert worlds. Permafrost is found in the subsurface of Mars and is expected in the mixed crustal and ice silicates of icy planets and moons across the Solar System, including Ceres, Callisto, and possibly Ganymede and Titan Johnson, . Microbiet al.,The ability to rapidly and successfully characterize microbiologic and chemical conditions of ice and carbon-rich environments has important implications for extraplanetary exploration and studying permafrost on Earth. Recent breakthroughs in rapid DNA sequencing (Castro-Wallace et al.,et al.,et al.,et al.,et al.,et al.,et al.,in situ sampling methodologies with established microbial community interrogation techniques will save time in site exploration, retrieval methodology, and post-retrieval analysis while building a library to be used as a proxy for exoplanet biosignatures.Permafrost on Earth is dynamic in structure and formation, providing additional proxies for hypersaline environments such as brine lenses, legacy frozen substrate, and ice-rich sediment or ice wedges (Niederberger 5.et al.,in situ could greatly reduce transport and laboratory cost, shortening the timeline from sampling to results. Creating an index of microbial community characteristics and survival mechanisms for extraplanetary exploration will inform the search for extraterrestrial life. As the search for life continues, any information to constrain search locations saves money and shortens the time to discovery. Proxies for exobiology detection currently exist on Earth, and every effort should be made to systematically characterize their diversity before they are lost to climate change.Up to 40% of northern latitude permafrost may thaw by the end of the century (Chadburn"}
+{"text": "Drug reaction with eosinophilia and systemic symptoms (DRESS).Five articles are published in this Frontiers' Research Topic on Chen et al., offering an elegant review of DRESS. This comprehensive review delves into the pathogenesis of DRESS, potential biomarkers, and the relevant therapeutic rationales. With our current understanding of the genetic susceptibility, models of antigen presentation, and T-cell activation by drugs, DRESS along with other severe cutaneous adverse drug reactions can no longer be dismissed as unpredictable, at least for specific drugs. Prevention of DRESS associated with some medications is possible; the most successful example is that of HLA B1502 screening prior to carbamazepine use in the Han Chinese population . PLHIV experience a higher frequency of drug eruptions when compared with the non-HIV population . Immune Kuchinskaya et al.. This report underscores the challenges in recognizing and differentiating DRESS from other systemic inflammatory syndromes with similar presentations and laboratory findings. Lastly, Manieri et al. provided us a review of DRESS in childhood and highlighted that rapid-onset DRESS affects children more often than adults and is usually triggered by antibiotics or iodinated contrast media rather than by anticonvulsants.Furthermore, DRESS do occur in children, as highlighted in the case report by In conclusion, this Frontiers Research Topic provides valuable insights into the complex realm of DRESS, offering a deeper understanding of its mechanisms, treatment options, and challenges in various populations.Enjoy the wealth of knowledge shared in this Research Topic on DRESS!BJ: Writing \u2014 original draft, Writing \u2014 review & editing. YL: Writing \u2014 original draft, Writing \u2014 review & editing. SN: Writing \u2014 original draft, Writing \u2014 review & editing."}
+{"text": "Streptococcus pyogenes (Sp) Cas9 revealed through these techniques.Cas9 is an RNA-guided endonuclease from the type II CRISPR-Cas system that employs RNA\u2013DNA base pairing to target and cleave foreign DNA in bacteria. Due to its robust and programmable activity, Cas9 has been repurposed as a revolutionary technology for wide-ranging biological and medical applications. A comprehensive understanding of Cas9 mechanisms at the molecular level would aid in its better usage as a genome tool. Over the past few years, single-molecule techniques, such as fluorescence resonance energy transfer, DNA curtains, magnetic tweezers, and optical tweezers, have been extensively applied to characterize the detailed molecular mechanisms of Cas9 proteins. These techniques allow researchers to monitor molecular dynamics and conformational changes, probe essential DNA\u2013protein interactions, detect intermediate states, and distinguish heterogeneity along the reaction pathway, thus providing enriched functional and mechanistic perspectives. This review outlines the single-molecule techniques that have been utilized for the investigation of Cas9 proteins and discusses insights into the mechanisms of the widely used By measuring the resonance energy transfer efficiency   studies the surface structure and properties of samples by detecting the extremely weak interatomic interaction between the sample surface and a miniature force-sensitive sensor , whereas PAM-distal mismatches still allow for the stable binding of the complex to DNA targets. Specifically, 9\u201310 PAM-proximal matches are sufficient for ultrastable SpCas9\u2013gRNA binding. Moreover, as the dwell-time analysis shows two characteristic binding times, a two-step mechanism of Cas9\u2013RNA binding involving PAM surveillance and RNA-DNA heteroduplex formation (see the next section) was proposed . Fully unwound protospacer DNA coupled with full R-loop formation possibly drives the docking of the HNH domain, thus licensing cleavage-competent SpCas9 (see the following section \u201cDNA dissociation after cleavage\u201d). Modifications of gRNA or the engineering of SpCas9 could rebalance the unwinding-rewinding equilibrium and make it stricter to reach the cleavage-competent state, thus minimizing off-target effects. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al.SpCas9 is a multidomain DNA endonuclease. Structures of SpCas9 showed two distinct lobes, the alpha-helical recognition (REC) lobe and the nuclease lobe (NUS), as well as the more variable C-terminal domain (CTD) , the 3\u2019 flap generated by the cleaved NTS is possibly exposed and can be digested by exonucleases ( et al.One distinguished characteristic of SpCas9 is its stable binding to the on-target site after cleavage. Both ucleases  (Wang et  et al.. Therefo et al.in vitro, could facilitate the dissociation of DNA-cleaved SpCas9 from DNA. Zhang et al. used optical tweezers to examine the consequence of encountering a BLM helicase with a DNA-bound dSpCas9 from both sides ( et al. et al. et al. et al.The long lifetime of the SpCas9\u2013gRNA\u2013DNA complex limits the efficient usage of each SpCas9 protein and impairs the repair of DSBs (Clarketh sides . They prAs evident from this review, single-molecule studies provide not only a fundamental understanding of Cas9 mechanisms but also a framework for rational design aiming at improving Cas9 efficiency and minimizing off-target effects. Based on these studies, a detailed dynamic picture of DNA interrogation and cleavage of SpCas9 has been generated . Upon coQian Zhang, Ziting Chen and Bo Sun declare that they have no conflict of interest."}
+{"text": "IARC). Hepatocellular carcinoma is the most common type of liver cancer representing about 90% of all the cases of hepatic malignancy  mainly: METTL6, GSTZ1, ADH4, ADH1A, and LCMT1 can be utilized as a predictor of HCC patient\u2019s prognosis. Yang et al., have demonstrated the role of HIF2-alpha, a key metabolic regulator, along with VEGF in cellular proliferation and migration of HCC cells in response to insufficient radiofrequency ablation. Angiogenesis plays a very important role in the pathogenesis of several types of cancer including HCC. Tang et al., have shown that expression of angiogenesis-related genes (ARGs) exhibits predictive value in the prognosis of HCC patients. They identified about differential expression of 97 ARGs and further constructed 9 genes-based models to predict the prognosis of HCC. Tang et al., have demonstrated the importance of senescence-related genes in the prognosis of HCC patients. Their study demonstrates that cellular senescence-related genes can be utilized as a prognostic marker as well as a biomarker of therapeutic response. These studies altogether establish the importance of metabolic alterations related to gene expression and angiogenesis in the prognosis of HCC patients.Metabolic alterations are considered a hallmark of cancer . Tian etWang et al., have identified that genes related to N6-methyladenosine (m6A): B2M and SMOX can serve as prognostic signature and their expression may guide to design of novel therapeutic strategies for HCC patients. In a similar study, Huang et al., have demonstrated a 12 genes-based risk signature model in the prognosis of HCC patients. They have shown that SDC3, NCF2, BTN3A3, and WARS genes can serve as novel prognostic factors for HCC.Epigenetic modifications regulate several aspects of cellular physiology and different disease progression by regulating the gene expression machinery. The role of epigenetic alterations in the pathogenesis of different types of cancers including HCC is well-established but not completely understood. By utilizing the publicly available databases, Wang et al., have established a correlation between mitophagy-related genes and immune infiltration in a subset of HCC patients. They have shown that a subset of patients exhibiting higher mitophagy-related gene expression show poor prognosis and suppressed immune function. In another study, Qu et al., have shown that M2-like macrophage markers like PAM and LGALS3 expression positively correlate with the sensitivity of simvastatin and ARRY-162. Further, they have predicted ten anticancer drugs with higher sensitivity towards the high-mitophagy gene expression group. Further, Cao et al., have shown that March ligases expression regulates immune cell infiltration in HCC tumors. By utilizing the TCGA data set of liver cancer patients, Wang et al., have shown that genes related to copper metabolism correlate with immune infiltration in HCC. Their finding may be very useful in establishing the immunotherapy response biomarker. Liang et al., have shown that ferroptosis regulator membrane protein SLC7A11 exhibits the highest expression correlation with the immune checkpoint gene PD-L1. They have also established that SLC7A11 can serve as an independent prognostic signature itself for HCC patients. Furthermore, another study by Zhang et al., has shown that ferroptosis-related genes were significantly correlated with tumor immune infiltration and immune checkpoint genes expression. Long et al., have also explored the correlation of immune regulatory genes with HCC patients\u2019 survival. Their study has demonstrated that 5 immune regulatory genes expression has significant predictive importance in HCC patients\u2019 survival. In a review article Si et al., have discussed the importance of IL32 and IL34 expression in HCC pathogenesis and therapeutic targeting.Immune therapeutics are revolutionizing cancer treatment, so it\u2019s high time to identify the novel immune modulators of HCC pathogenesis and potential immune therapy targets. in silico analysis of publicly available databases, and very limited validation has been done in laboratory conditions. Most of the studies are correlative, so it will be premature to conclude their direct role of a predicted gene signature in HCC pathogenesis. More preclinical and clinical studies are needed to validate these findings.In general authors of these articles have done molecular characterization of HCC patient samples gene expression, and immune infiltration and studied their impact on the prognosis of HCC patients. Some studies have explored the correlation between gene signatures and therapeutic response along with their prognostic values. The role of metabolic alteration-related genes, angiogenesis-related genes, and genes involved in different types of cell death such as cuproptosis and ferroptosis have been shown to possess prognostic value and correlate well with the different immune phenotypes of HCC tumors. A key limitation of most of the studies is that results are based on purely"}
+{"text": "The potential benefits of Reporting and Data Systems (RADS) are well known: improve the communication between the radiologists and physicians; reduce the omission of relevant information in reports; reduce the variability and errors in image interpretation; facilitate the monitoring of results and provide a tool to ensure quality and research. Furthermore, the slightest error in the interpretation of the legend describing the results of an imaging study can modify both the medical decision to start or not a treatment, and to do it with a more or less invasive technique.In this sense, for example, the American College of Radiology (ACR) started the development of the Breast Imaging Reporting and Data System (BI-RADS) in 1993. In recent years, several systems have been developed to diagnose other malignancies based on BI-RADS. However, its utility has yet to be demonstrated which is why scoring systems are continually being revised to apply them to daily clinical practice. The RADS systems developed so far are specially designed for breast, colorectal, gynecological, liver, lung, prostate and thyroid cancers.Incorporation of Reporting and Data Systems into Cancer Radiology\u201d Research Topic. These manuscripts demonstrate how RADS benefit cancer patients, and how improvements to these systems can further benefit patients and optimize disease outcomes. For instance, in Wang et\u00a0al., the authors investigated the value of contrast-enhanced ultrasound in the differential diagnosis and risk stratification of ACR TI-RADS category 4 and 5 thyroid nodules with non-hypovascular, establishing a risk score with ability to improve both aspects.These aspects are clearly reflected in the research papers accepted in the \u201cSun et\u00a0al., it was evaluated the value of multiparametric magnetic resonance imaging (MIR) including synthetic MRI, diffusion-weighted imaging, dynamic contrast enhanced MRI, and clinical features in breast imaging\u2013reporting and data system (BI-RADS) 4 lesions, and develop an efficient method to help patients avoid unnecessary biopsy.In Zhou et\u00a0al., the authors established a predictive model incorporating clinical features and contrast enhanced ultrasound liver imaging- reporting and data system (CEUS LI-RADS) to improve the prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients.In Singh et\u00a0al., to minimize inter-radiologist variability, the diagnostic performance of an in-house developed semi-automated model using machine learning methods for prostate imaging-reporting and data system version 2.1 (PI-RADS v2.1) scoring was evaluated in prostate cancer patients. The authors in Meng et\u00a0al., assessed the value of using quantitative parameters from synthetic magnetic resonance imaging (SyMRI) and the Kaiser score (KS) to differentiate benign and malignant breast lesions in patients, identifying that the incorporation of T1 values improves the sensitivity and specificity of the KS protocol alone.In Yang et\u00a0al., a retrospective study was performed to create a predictive machine learning model based on liver imaging and reporting and data system (LI-RADS) features to identify microvascular invasion in hepatocellular carcinoma (HCC) patients, concluding that LI-RADS may help optimize the management of these patients.In Wu et\u00a0al., the authors conducted a retrospective Chinese population-based study of patients screened for lung cancer by computed tomography to assess the correlation between the probability of lung cancer and the number of lung nodules, concluding that this probability does not change with the number but does change with the size of the nodules.Finally, in All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Thus, migratory behaviour neither weakens nor strengthens bird\u2013haemosporidian cophylogenetic congruence, suggesting that other avian host traits are more influential in generating phylogenetic congruence in this host\u2013parasite system.Parasites display various degrees of host specificity, reflecting different coevolutionary histories with their hosts. Avian hosts follow multiple migration patterns representing short but also long distances. As parasites infecting migratory birds are subjected to multiple environmental and biotic changes through their flyways, migration may disrupt or strengthen cophylogenetic congruence between hosts and parasites. On the one hand, parasites might adapt to a single migratory host, evolving to cope with the specific challenges associated with the multiple habitats occupied by the host. On the other, as migrants can introduce parasites into new habitats, higher rates of host switching could also disrupt cophylogenetic patterns. We analysed whether migratory behaviour shapes avian haemosporidian parasite\u2013host cophylogenetic congruence by testing if contributions of host\u2013parasite links to overall congruence differ among resident and short-, variable- and long-distance migrants globally and within South America only. On both scales, we found significant overall cophylogenetic congruence by testing whether overall congruence differed between haemosporidian lineages and bird species. However, we found no difference in contribution towards congruence among links involving resident  Using a worldwide avian haemosporidian database  collected from 347 different host species and representing 430 localities around the globe , 101 host species and 113 localities.We extracted the dataset on haemosporidian lineages from the MalAvi database  each represented ~25% of our global dataset with most tropical species (~67%) sampled in South America. Haemosporidian parasites and their avian hosts showed phylogenetic congruence greater than expected by chance on both global and regional scales .In the Bayesian models evaluating the effect of host migratory distance category on the squared residual values of each individual link , we found that hosts contribute equally to parasite\u2013host cospeciation independently of whether or not they migrate, or their migration distance  and 2. Wet al., Parasite\u2013host cospeciation occurs when both clades speciate in tandem, creating congruent phylogenies, which can occur due to neutral processes such as host dispersal and isolation or due to host-driven selection such as host defence (Clayton et al., et al., et al., et al., et al., et al., et al., et al., et al. (Plasmodium juxtanucleare, a haemosporidian parasite previously observed only in Galliformes, infected wild passerines in Brazil. Such events can disrupt cophylogenetic congruence, leading to apparent incongruence between haemosporidians and their hosts (Ricklefs et al., Host defences may favour parasite cospeciation and lead to congruent phylogenies between parasites and their hosts, if they select for specific counter-adaptations that limit parasite success to the original host species (Clayton , et al.  recentlyet al., et al., et al., et al., et al., et al., et al., Furthermore, we demonstrated that host migratory behaviour does not affect haemosporidian cophylogenetic congruence, suggesting that other host features can be more important in determining haemosporidian infection of novel hosts, such as cell invasion ability or immunological defence. Similarly, even though migrants can disperse haemosporidians (de Angeli Dutra et al., et al., Culex quinquefasciatus in Hawaii and New Zealand enabled the infection of local endemic and na\u00efve fauna by Plasmodium species, especially the highly generalist Plasmodium relictum (Warner RE, et al., Vectors can also play a fundamental role in determining haemosporidian parasite transmission in nature (Yan et al. (Leucocytozoon, another related genus of avian haemosporidian parasites. As we also observed, host phylogeny influenced parasite\u2013host cophylogeny in all models, indicating that other phylogenetically conserved host traits may contribute towards parasite\u2013host cophylogeny. However, the narrower climatic niche and higher host specificity of Leucocytozoon spp. (Valki\u016bnas, et al., et al., et al., Leucocytozoon parasites, whereas migrants may be exposed to parasites from multiple regions and continents. This pattern could also lead to links involving associations between Leucocytozoon lineages and resident hosts contributing more towards cophylogenetic congruence compared to those involving migrant hosts. It is worth mentioning, however, that our relatively small number of migrants, especially for the South American analyses, might have hidden an association between migratory status and haemosporidian\u2013bird cospeciation.It is important to note, however, that Jenkins et al.  identifiPlasmodium and Haemoproteus separately. Nonetheless, we detected an effect of host phylogeny on host\u2013parasite cophylogenetic congruence, suggesting that congruence among parasites and their hosts may be linked to other host traits, and possibly also to vector specificity. It must be noted that, despite the fact haemosporidians and their avian hosts appear to have coevolved, these parasites are still capable of switching to phylogenetically distant hosts (Ferreira-Junior et al., Here, we demonstrate that haemosporidian parasites and their avian hosts generally share a common evolutionary history and show significantly congruent phylogenies. Furthermore, we also found that bird migration is not weakening or strengthening the congruence observed between parasites and their hosts, even when considering different spatial scales or the genera"}
+{"text": "Coxiella, Francisella, Rickettsia or Candidatus Midichloria mitochondrii endosymbionts, indicative of their importance to tick physiology. Genomic and experimental data suggest that endosymbionts promote tick development and reproductive success. Here, we review the limited information currently available on the potential roles endosymbionts play in enhancing tick metabolism and fitness. Future studies that expand on these findings are needed to better understand endosymbionts\u2019 contributions to tick biology. This knowledge could potentially be applied to design novel strategies that target endosymbiont function to control the spread of ticks and pathogens they vector.Ticks transmit pathogens and harbour non-pathogenic, vertically transmitted intracellular bacteria termed endosymbionts. Almost all ticks studied to date contain 1 or more of  There are 2 main tick families Ixodidae (hard ticks), which possesses a sclerotized hard shield called scutum, and Argasidae (soft ticks), which lacks scutum , Francisella endosymbionts (FEs), Rickettsia endosymbionts (REs) and Candidatus Midichloria mitochondrii (CMM)  and hard ticks   and the argasid tick O. amblus (CLEOA) revealed that they have complete pathways to produce thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), biotin (vitamin B7) and folate (vitamin B9)  and pyridoxine (vitamin B6)  and A. sculptum (CeAS-UFV) have complete pathways to synthesize riboflavin, biotin and folate and partial pathways for niacin, pantothenic acid and pyridoxine  has complete pathways for the synthesis of riboflavin, pyridoxine, biotin and folate and a partial pathway for the synthesis of thiamine , A. maculatum (FLE-Am) and F. persica, the endosymbiont of the soft tick Argas arboreus, showed that they possess complete pathways for the synthesis of riboflavin, biotin and folate  but F. persica seems to only possess a partial pathway for this process  and CLEAA, CLEOA and CERM possess complete pathways to produce lipoic acid , NADP+, pyridoxal 5\u2032-phosphate, S-adenosyl-L-methionine and thiamine diphosphate .Many cofactors and coenzymes that are critical to the functioning of essential enzymes are derived from B vitamins Douglas, . Severalin silico flux balance analyses of CRt and CE of R. sanguineus (CRs) identified excessive production of the amino acid proline, which is thought to play a significant role in arthropods due to its involvement in energy production and nitrogen metabolism  to O. moubata restored its reproductive fitness, indicating a role for FLE-Om in provisioning B vitamins required for normal tick development and reproduction , which in turn reduced the blood intake of the tick (Zhong et al., et al., H. longicornis, administration of antibiotics to R. sanguineus and R. microplus also reduced the density of CEs and tick blood intake, and transcriptomic analysis of CERM-free R. microplus metanymphs revealed that genes associated with tick blood-feeding capacity such as DAP-36, lipocalin, trypsin inhibitor-like family, Kunitz-type inhibitors, cystatin and evasins were significantly under-expressed (Guizzo et al., et al., et al., et al., Experiments also suggest that endosymbionts may contribute to the blood-feeding capacity of ticks . TreatmeI. ricinus and feeding females with tetracycline-containing bovine blood produced CMM-free ticks within 2 generations. Larvae that hatched from eggs laid by CMM-free females consistently performed poorly during blood feeding, suggesting that CMM is required for the emergence of larvae with intact blood-feeding ability (Guizzo et al., I. ricinus nymphs fed with gentamicin-treated blood had significantly lower engorgement weights, lower moulting proportions and lower weights of moulted unfed adult females in comparison to nymphs fed on antibiotic-free blood (Militzer et al., Francisella symbionts in H. doenitzi significantly increased in number during blood feeding, and Rickettsia sp. phylotype G021 and CMM multiplied massively in I. pacificus and I. ricinus, respectively, following blood meals (Sassera et al., et al., et al., CMM is the most common endosymbiont associated with D. variabilis and A. americanum larvae infected with Rickettsia symbionts displayed increased motility than uninfected larvae [42]. The locomotive ability of newly hatched larvae was determined on flat and inclined surfaces and Rickettsia-containing larvae displayed increased locomotive speed relative to uninfected larvae. Tick motility plays a role in host-questing success; thus, infection with Rickettsia symbionts may impact the disease risk posed by tick-borne pathogens.Finally, et al., et al., et al., et al., Coxiella, Francisella and Candidatus Midichloria branches (Epis et al., et al., et al., et al., In summary, a major function of tick endosymbionts seems to be the provisioning of B vitamins, especially riboflavin, biotin and folate . B vitamet al., et al., C. burnetii and F. tularensis are not vertically transmitted (Genchi et al., et al., Relatedly, another aspect of tick biology that we do not fully understand is how CEs and FEs evolved from pathogenic ancestors (Gerhart C. burnetii and F. tularensis (Zogaj and Klose, et al., In addition to vertical transmission, an essential factor that sustains endosymbiosis is the presumed dependence of ticks on nutrients provided by endosymbionts. Going forward, functional studies to identify specific metabolites that sustain tick\u2013endosymbiont relationships should be prioritized. Developing genetically tractable tick\u2013endosymbiont model systems would accelerate this area of research by facilitating the disruption of endosymbiont genes to assess their impact on tick physiology and fitness. Although methodologies to culture and genetically manipulate CEs or FEs have not yet been developed, genetic tools and culture media are available for related pathogens et al., et al., et al., Future functional studies should also device alternatives to the current practice of using antibiotics to generate endosymbiont-free ticks. This is because antibiotics may eliminate other members of the tick microbiota, thus making it difficult to determine whether any observed effect is solely due to the loss of the endosymbiont. Another key aspect to consider while investigating endosymbiont function is the potential contributions made by the rest of the tick microbiota towards tick physiology. For instance, gut microbiota may modify metabolites present in blood meal to make them amenable for use by tick or endosymbiont. Similarly, antibacterial peptides produced by the tick innate immune system in response to gut bacteria could impact the location and functions of tick endosymbionts (Narasimhan et al., Lastly, targeting keystone taxa among tick microbiota is an innovative approach to inhibit the spread of ticks. Recent studies showed that microbiota were disrupted in ticks fed on blood from mice vaccinated against keystone taxa (Mateos-Hern\u00e1ndez"}
+{"text": "Integrative neuroscience involves investigations into the sensory, motor, and cognitive systems. In contrast, translational neuroscience moves fundamental knowledge and interdisciplinary discoveries into clinical practice or applications to benefit human health. Bridging the gap between both fields could profoundly impact our comprehension of brain function and clinical applications . SpecifiFujiki et al., introduced the \u201cquadripulse theta burst transcranial magnetic stimulation\u201d (QTS), a new way to overcome failure rates in producing motor evoked potentials by transcranial magnetic stimulation. These authors employed a similar stimulation pattern as in previous studies (Szel\u00e9nyi et al., Chandrasekaran et al. introduced a novel, highly flexible spinal electrode array for cervical dorsal root stimulation employed in people with motor complete spinal cord injury. This targeted stimulation increased volitionally generated force and tactile sensations within a 6\u20138-week period, but only in particular muscles showing discernable force production during the pre-intervention assessment. These results are comparable to those found by other authors (Freyvert et al., The first two papers in this Research Topic have reported new methods to push the limits of precision in brain and spinal cord neurostimulation. They are relevant because non-invasive neurostimulation of the brain, peripheral nerves, and the spinal cord has unprecedented clinical interest. In this context, Soto et al. is a review covering the development of new active vestibular implantable devices to regain or modulate specific systemic functions. Like cochlear implants, pacemakers, or deep brain stimulators, the vestibular neuroprostheses are a strong example of how bridges between integrative and translational neuroscience are needed to achieve beneficial breakthroughs that will impact the lives of individuals. Vestibular dysfunction affects over 1.8 million people worldwide (Chow et al., The third paper by Ilic et al. deals with visual imagery in dreams of congenitally blind people. This theme is controversial (Andrade, Ilic et al. in this Research Topic analyses studies on the presence and nature of visuospatial imagery in dreams of blind people to elucidate how blind people \u201csee\u201d, whether they may recreate visuospatial imagery via sensory substitution, and whether they can dream in images. At the neurophysiological level, neuroimaging and sensory substitution studies suggest that the \u201cblind\u201d occipital cortex may be able to integrate non-visual sensory inputs, generating visuospatial impressions and enabling the development of a typical spatiotemporal organization of early visual areas even in the life-long absence of vision. This could explain the ability of some congenitally blind individuals to draw symbolic representations of various visual images in striking likeness to those drawn by normally sighted. Therefore, elucidating the mechanistic nature of visual impressions could open new translational possibilities for treating these neuro-disabilities.The fourth article by Andrade, . It has Mesmoudi et al. presented another interesting research covering the gap between integrative neuroscience and translational neuroscience in the context of the recent global health crisis of COVID-19, in which the discovery of ACE2 receptor mechanisms played a fundamental role in understanding this sickness. They employed data on mRNA expression levels of genes provided by the Allen Institute for Brain Science. Moreover, the localization of brain functions was provided by the LinkRbrain platform. These authors investigated which cognitive and sensorimotor functions are associated with the brain regions where ACE2/TMPRSS2 is overexpressed, hypothesizing that the infection might particularly affect them. The results show that central regions specific to ACE2 and MPRSS2 were localized in the brain stem, the subcortical, the orbitofrontal, and some occipital areas (see also Chen et al., Finally, In conclusion, these five papers, taken together, emphasize that we must bridge the gap between knowledge and practice, between theory and therapy. Thus, the synergy between integrative and translational neuroscience involving new neurotechnological developments could serve as the bridge that will lead us to a future where neurological conditions are better comprehended and more effectively treated. As we persist in exploring the frontiers of the brain, let us bear in mind that we could discover the key to unlocking the full potential of neuroscience for the benefit of humanity through the fusion of these two established disciplines.EM: Writing\u2014review and editing. GC: Writing\u2014review and editing. KS: Writing\u2014review and editing. AL: Writing\u2014review and editing."}
+{"text": "Wnt signaling in endocrine and metabolic disorders\u201d aims to emphasize the functional role of the Wnt signaling pathway in human endocrinology, focusing on metabolic disease. Endocrine and metabolic disorders encompass a wide range of conditions affecting various organ systems and physiological processes. The Wnt signaling pathway, originally recognized for its role in embryonic development and tissue homeostasis , used for more than 1,300 years in China as a treatment for lumbodynia, may exert its therapeutic effect on steroid-induced ischemic necrosis of the femoral head, is through targeting exosomal microRNAs (miRNAs) to regulate multiple signaling pathways, including Wnt, PI3K-Akt, and MAPK . In another original report investigating miRNAs and Wnt signaling, Tripathi et\u00a0al. demonstrate that miR-539-3p overexpression in osteoblasts downregulates several components of the Wnt signaling pathway and deteriorates trabecular microarchitecture, leading to decreased bone formation in ovariectomized mice. In the third original article in our Research Topic, a group of investigators led by Xiaolin Tu found that the small molecule C91 (CHIR99021) promotes osteogenic differentiation of bone marrow stromal cells via the activation of Wnt signaling .The first study in this Research Topic clarified that one of the mechanisms by which the \u201cVilaseca et\u00a0al. provide an interesting overview of the functional roles of estrogen deficiency in the processes involved in the development of Alzheimer\u2019s disease, including Wnt signaling and glucose transport in the brain, amyloid precursor protein processing to form senile plaques, and Tau phosphorylation forming neurofibrillary tangles.Franco et\u00a0al. elegantly explain the main differences between the physiological roles of canonical Wnt signaling  and its pathological involvement in the development of several human diseases, including cancer. Correctly interpreting the molecular bases of Wnt signaling and metabolism, ideally in a cell-type and tissue-specific manner (Franco et\u00a0al.; A very comprehensive review concludes our Research Topic: In conclusion, understanding the intricate interplay between Wnt signaling and endocrine/metabolic disorders holds great promise for the development of targeted therapies and improved patient outcomes.FC: Writing \u2013 review & editing. GS: Writing \u2013 original draft"}
+{"text": "However, in vivo validation is currently lacking. A previous metatranscriptomics study into the cause of idiopathic chronic diarrhoea in macaques reported the presence of an unidentified protozoan parasite related to Trichomonas vaginalis. In this work, we performed a reanalysis of the published data in order to identify the parasite species present in the macaque gut. We also leveraged the information-rich metatranscriptomics data to investigate the parasite behaviour in vivo. Our results indicated the presence of at least 3 genera of Trichomonad parasite; Tetratrichomonas, Pentatrichomonas and Trichomitus, 2 of which had not been previously reported in the macaque gut. In addition, we identified common in vivo expression profiles shared amongst the Trichomonads. In agreement with previous findings for other Trichomonads, our results highlighted a relationship between Trichomonads and mucosal bacterial diversity which could be influential in health and disease.Trichomonads, anaerobic microbial eukaryotes members of the phylum Parabasalia, are common obligate extracellular symbionts that can lead to pathological or asymptomatic colonization of various mucosal surfaces in a wide range of animal hosts. Results from previous  The vast majority of this work has focused on the human sexually transmitted parasite Trichomonas vaginalis. However, the importance of the proposed mechanisms during colonization of the complex mucosal environment in vivo is unclear. Validation of hypotheses in the natural setting is essential to avoid misinterpretation of results  microbiota  were used to examine Parabasalia gene expression. For transcript annotation, assembled parasite contigs were aligned to the T. vaginalis G3 annotated proteins  and Table S3 .A et al., de novo assembled contigs homologous to Parabasalia genes of interest, with E value, percentage identity and query coverage cut-off values of 1\u00a0\u00d7\u00a010\u221210, 88% and 90%, respectively. To broaden the taxonomic sampling for genes of interest, additional homologues were identified by consulting the literature and through the use of online BLAST . Summary statistics for the dataset and assembly are presented in Table S1. The de novo assembly is available in Data file S2.We aimed to investigate the identity of Trichomonad parasites reportedly present in this dataset (Westreich \u03b1) loci to identify the Parabasalia colonizing the macaque gut. Amongst all the samples, we assembled 58, 10 and 11 18S rRNA, actin and EF-1\u03b1 sequences, respectively, which shared greater than 88% sequence identity with reference Parabasalia sequences for at least 90% of their length (Table S2). We assessed the diversity of sequences present by maximum likelihood analysis and identified 10 well-supported clades for the 18S rRNA locus , 4 for the actin locus , and 1 for the EF-1\u03b1 locus . We generated phylogenies using representative sequences from each clade alongside a range of Parabasalia reference sequences in order to refine the identity of the parasite sequences. Analysis of a single representative sequence from each of the 18S rRNA sequence groups revealed at least 3 major lineages, related to Tetratrichomonas, Pentatrichomonas and Trichomitus spp., with strong bootstrap support only present for the latter  parabasalid genera which were identified , followed by Pentatrichomonas (mean abundance 0.025%) and Tetratrichomonas (mean abundance 0.020%). A substantial number of sequences (mean abundance 0.093%) were identified as parabasalid in origin but could not be assigned to a particular genus. Unidentified parabasalid reads appeared more abundant among animals in which Tetratrichomonas, Pentatrichomonas or Trichomitus classified reads were abundant, likely suggesting that they originated from 1 or more of these genera.To taxonomically assign the metatranscriptome reads, we included entified . AccordiTrichomonas (mean abundance 0.019%). This most likely reflects the greater representation of Trichomonas whole genome sequences available in the reference database, including T. vaginalis and T. gallinae, whereas the genera of interest were only represented by in vitro RNA-Seq data, which is likely to have an incomplete gene content. However, while it cannot be ruled out that Trichomonas spp. were present amongst the samples, we have focused our analysis on the most likely genera based on the phylogenetic results. Only 2 control macaques showed a total abundance of Parabasalia greater than 0.125%, limiting the statistical power for tests correlating variables with Parabasalia abundance amongst the control animals.In addition, a notable fraction of reads were classified as et al., We focused on the most abundant putative Parabasalia-derived contigs to explore the most biologically important functions, which are summarized in Trichomitus with strong support, and an additional contig NODE_1833 may have originated from Pentatrichomonas or Tetratrichomonas, although this was poorly supported. In addition, we identified a contig with high similarity to T. vaginalis coronin, an actin-binding protein implicated in phagocytosis . Results suggested that the lysozyme-like contig NODE_2008 originated from T. vaginalis genes previously implicated in pathobiology. Of particular interest for parasite adhesion to host or microbial cells . Cysteine peptidases are also implicated in Trichomonas pathobiology , a secreted cysteine peptidase demonstrated to induce host cell apoptosis  based on the microbial profile showed clear separation between the healthy and ICD groups. The macaques with ICD appeared to resolve into 3 subgroups, potentially indicating distinct microbial communities . An obvibundance . Of partP values derived from linear regression ranged from 0.21 to 0.27), although this is likely to have been influenced by the Parabasalia scarcity amongst the control animals , whereas Parabasalia abundance did not . Intriguingly, ICD macaques with greater Parabasalia abundance appeared to more closely resemble control macaques in terms of alpha diversity.Our results suggested a possible relationship between parasite abundance and microbiota diversity. Amongst the macaques with ICD, there was a significant positive relationship between Parabasalia abundance and microbial alpha diversity measures . There was also a significant negative relationship between Parabasalia abundance and Simpson evenness, indicating a more non-uniform distribution of abundance amongst microbial taxa in animals with greater abundance of Parabasalia . However animals . In addivs all correlation analysis at the genus level. We focused on the macaques with ICD and included only the most abundant taxa (greater than 0.005% in at least 1 sample). Amongst 358 taxa, with a total of 64\u00a0261 possible interactions, our results indicated 11\u00a0606 significant abundance correlations between genera. Of the 3 parabasalid genera of interest, Tetratrichomonas showed the greatest number of significant correlations with bacteria (110) followed by Pentatrichomonas (53), and Trichomitus, which showed far fewer significant correlations (17). Tetratrichomonas and Pentatrichomonas substantially overlapped in terms of bacterial genera showing significant positive and negative correlations, possibly indicating shared relationships with bacteria. In contrast, Trichomitus did not share common negative or positive relationships with any bacterial genera with either of the other parabasalid genera , with a moderate network clustering coefficient of 0.431, indicating a greatest potential interdependence with bacteria. Within network 3, the closeness centrality of Tetratrichomonas was 0.465, the 10th highest in the 41-node network, suggesting a relatively central hub-like position in comparison to most bacterial nodes. In contrast, Pentatrichomonas (network 7) and Trichomitus (network 23) inhabited smaller and more sparsely interconnected components, with 7 and 2 genera, respectively.To investigate specific interactions between Parabasalia and bacterial members of the microbiota, we performed an all d genera . Amongstmponents . Of the Tetratrichomonas and Pentatrichomonas were Gram negative, but this pattern did not extend to Trichomitus , 5 out of 53 for Pentatrichomonas  and 2 out of 17 for Trichomitus . This may indicate that the microbial community structure and interdependence was dramatically different between the ICD and control conditions.The majority of relationships identified amongst the macaques with ICD were not consistent amongst the control group. Only 1188 out of 11\u00a0606 total significant relationships for the macaques with ICD were homodirectionally concordant amongst the control animals, including 2 out of 110 relationships for Tetratrichomonas and Pentatrichomonas , but not Trichomitus, amongst the macaques with ICD compared with the healthy controls. The original authors ruled out several known common GI pathogens  as the cause of ICD by culture and microscopy-based methods. To complement this, we searched the dataset for potentially pathogenic viral lineage amongst the taxonomic profile. We focused on a selection of 29 potential primate-infecting eukaryotic viruses which we identified by the literature search .We performed a differential abundance analysis between the ICD and control groups in order to investigate any potential impact of the parabasalids on disease aetiology. Interestingly, differential abundance analysis suggested a moderate significantly higher abundance of Tetratrichomonas abundance . We identified a significant negative relationship between the abundances of 12 MetaCyc pathways and that of Tetratrichomonas amongst the macaques with ICD  and glycogen storage and processing (M\u00fcller, et al., T. vaginalis BspAs have been implicated in host adhesion in vitro (Handrich et al., T. vaginalis BspAs are differentially expressed in response to Mycoplasma symbionts, suggesting a potential role in parasite\u2013bacteria interactions in modulating parasite binding to host cells (Margarita et al., Our results suggested commonality in the expressed functional genes across the Trichomonads. We observed similar energy generation mechanisms for the macaque-infecting parabasalids as have been previously reported for et al., et al., et al., et al., et al., Trichomitus, our results suggested Tetratrichomonas had the greatest abundance correlation with differences in the microbiota. Tetratrichomonas participated in the greatest number of significant abundance correlations, and was a central node within a densely interconnected microbial positive correlation network. Correlation networks have been effectively utilized to identify keystone species within microbial communities with biological significance (Duran-Pinedo et al., Pentatrichomonas and Tetratrichomonas. In addition, of particular interest, a positive abundance correlation with Prevotella, which we observed for Tetratrichomonas in the macaque gut, has been described for T. vaginalis in the human UGT (Martin et al., et al., Tetratrichomonas and Pentatrichomonas were Gram negative. This is notable because other Trichomonads such as Dientamoeba fragilis (Chan et al., in vitro growth. Microbial interactions identified in this study varied hugely between the diseased and healthy conditions, similarly to previous results from the healthy and diseased human oral microbiota (Duran-Pinedo et al., et al., et al., Our results also indicated a potential influential interaction between Trichomonads and microbial diversity in the macaque gut, as has been reported for other hosts and mucosa (El Sayed Zaki et al., et al., et al., T. vaginalis (Pinheiro et al., Trichomitus, whereas Tetratrichomonas was the only Trichomonad genus correlated with bacterial functional expression. Negative correlation of Tetratrichomonas abundance with bacterial degradation pathways for monosaccharides such as GlcNAc and Sia5NAc, potentially derived from mucin glycoproteins (Yurewicz et al., et al., Previous studies have suggested the interaction between Trichomonads and the vaginal microbiota is bidirectional. The microbial profile can influence the ability of Trichomonads to colonize the mucosa (Rathod Campylobacter genus amongst the animals with ICD was originally reported (Westreich et al., Pentatrichomonas and Tetratrichomonas could indicate a causal role in disease. High P. hominis abundance in macaques with ICD was previously reported, but not causally liked to disease (Laing et al., et al., T. gallinae and Tritrichomonas musculis decreases GI microbial diversity (Ji et al., et al., et al., The absence of several known GI bacteria pathogens and microbial parasites was confirmed by culture and microscopy-based methods, and thus may be excluded as causative agents of ICD in the macaques. We performed an additional search for potentially pathogenic viruses amongst the datasets. However, we did not identify any clear differences for any putative host-infecting virus when comparing between diseased and control animals, suggesting viral infection may not be the primary cause of ICD. A greater abundance of reads classified as originating from the in vivo. Reference sequences from closely related parasite strains would also have greatly facilitated analysis (Breitwieser et al., in vivo metatranscriptome (Li et al., Our results revealed a relatively low parasite abundance in the macaque fecal samples, highlighting the need for greater sequencing depth or selective target enrichment (Gaudin and Desnues, in vivo insight into Trichomonad mucosal colonization, which validates numerous in vitro studies (M\u00fcller, et al., et al., et al., et al., et al., In summary, these metatranscriptomics analyses of Trichomonads in the macaque gut have provided the first"}
+{"text": "The unprecedented global climate change has severely impacted our environment and engendered severe threats to agricultural productivity . This haThe advancements in genomics and gene editing technologies have offered immense opportunities and potential solutions for the genetic improvement of crops . A plethThe deployment of these technologies has laid down the foundation of modern breeding for effectively channelizing the underutilized diversity hidden in the crop wild relatives into elite gene pools . The advDhakate et al., \u201cAdvances in crop breeding through precision genome editing\u201d by Nerkar et al. and \u201cIntegrating CRISPR-Cas and next-generation sequencing in plant virology\u201d by Mushtaq et al. that have very well built up the narrative of the Research Topic. The other crop-specific comprehensive reviews entitled \u201cCRISPR for accelerating genetic gains in under-utilized crops of the drylands: progress and prospects\u201d by Sharma et al., \u201cRecent advances in date palm genomics-a comprehensive review\u201d by Rahman et al., \u201cUnclasping potentials of genomics and gene editing in chickpea to fight climate change and global hunger threat\u201d by Singh et al., \u201cA CRISPR way for accelerated improvement of cereal crops\u201d by Basu et al., \u201cCRISPR/Cas genome editing system and its application in potato\u201d by Zhang et al., \u201cPhysiological and molecular basis of drought and heat stress tolerance to enhance productivity and nutritional quality of peanuts in harsh environments\u201d by Puppala et al., \u201cA perspective on selectable marker-free genome engineered rice: past, present and future scientific realm\u201d by Singh et al. and \u201cCRISPR/Cas genome editing in potato: current status and future\u201d by Tiwari et al. provide an up-to-date detailed compilation of the published research in date palm, dry-land crops, peanuts, chickpea, potato, and rice.In this Research Topic, we have collated a total of 19 articles, including original research and review articles, to get an essence of the spectrum of current efforts undertaken by applying modern tools for crop trait improvement. To develop a background on the theme, we have included three review articles entitled \u201cComprehending the evolution of gene-editing platforms for crop trait improvement\u201d by Dhakate et al., Tiwari et al. and Basu et al. have comprehensively reviewed the evolution of CRISPR/Cas systems into new-age methods of genome engineering across various plant species and the impact that they have had on tweaking plant genomes and associated outcomes on crop improvement initiatives. Hou et al. reviewed the four types of CRISPR/Cas structures and mechanisms available today and the application of CRISPR/Cas9 systems in overcoming the challenges of self-incompatibility and improving the quality and resistance of potato. The review describes how precise knocking or targeted mutagenesis of S-RNase and Sli genes using CRISPR/Cas9 has helped to create self-compatible and self-incompatible potatoes, respectively. Additionally, the suitability of CRISPR/Cas9 and CRISPR/Cas13a systems in knocking out more than 22 genes has been detailed. Kor et al. have described the role of RNA Pol III promoters in precisely targeting genetic variants in genome editing. Nerkar et al. has focused on the advancements in crop breeding through precision genome editing. This review has included an overview of different breeding approaches for agronomic traits such as disease resistance, abiotic stress tolerance, herbicide tolerance, yield, and quality improvement, reduction of anti-nutrients, improved shelf life; genome editing tools and approaches used for crop improvement and an update on the regulatory approval of the genome-edited crops. Sharma et al. has described the opportunities of implementing genome editing technologies in under-utilized crops to increase genetic gains.There has been continuous evolution in the development of gene editing-based technologies involving CRISPR/Cas platforms. Traditionally used CRISPR/Cas nucleases followed Sequence-Specific Nucleases (SSNs) such as Zinc-Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs), and led to domains such as epigenome editing, base editing, and prime editing. Zang et al. generated Nud mutants in wheat (TaNud) and barley (HvNud) using CRISPR/Cas9-based gene editing and investigated the heritability of the mutations in wheat. Nud gene is a transcription factor controlling the formation of the caryopsis, and loss-of-function mutation in the gene leads to the naked hull phenotype in barley. With the latest CRISPR/Cas9-based gene editing, combined with PCR-RE (polymerase chain reaction-restriction enzyme) approach, Zang et al. achieved a high editing efficiency (51.7%) of the three Nud alleles/homologs in wheat. This study has proven that with the improved vector system and CRISPR/Cas technology, it is not difficult to achieve precise genetic modification even in complex polyploid crops such as wheat which remained calcitrant to genetic modification technologies for a long time.Ravikiran et al. comprehensively investigated genetic variation in RSHT tolerance with the GWAS approach using the cutting-edge genotyping arrays available in rice. They utilized three GWAS models to identify significant marker-trait associations (MTAs) for spikelet fertility and grain yield. Most significantly, the authors reported a set of stable MTAs for both traits, showing an advantage of 6\u201310\u00a0g for yield and up to 28% for spikelet fertility. Additionally, they identified promising tolerant genotypes that carried favorable alleles of 29, 28, 25, or 24 putative MTAs, which could serve as new donors in nurseries.Heat and drought stresses cause substantial yield losses to crop production. According to the latest estimates, the heatwave episodes will particularly intensify in the Indo-Gangetic plains of India, which supports rice\u2013wheat cropping system . SimulatPuppala et al. focuses on the significant progress that has been made towards the characterization of germplasm for drought and heat stresses tolerance and identifying MTAs and QTLs associated with drought tolerance. Advances in phenomics and artificial intelligence to accelerate the timely and cost-effective collection of phenotyping data in large germplasm/breeding populations are also reviewed and discussed. A holistic breeding approach that considers drought and heat-tolerant traits to simultaneously address both stresses is introduced as a successful strategy to produce climate-resilient peanut genotypes with improved nutritional quality.Peanuts exposed to drought stress at the reproductive stage are prone to aflatoxin contamination, which imposes a restriction on the use of peanuts as health food and also adversely impacts the peanut trade . The revKumar et al. reported development of bread wheat variety HD3411 following marker-assisted backcross breeding for drought tolerance. They reportedly transferred four drought tolerance quantitative trait loci (QTLs) controlling traits, viz. canopy temperature, normalized difference vegetative index, chlorophyll content, and grain yield from the drought-tolerant donor line, C306 into a popular high-yielding, drought-sensitive variety HD2733. Marker-assisted selection coupled with stringent phenotypic screening was used to develop a promising genotype, HD3411. The line HD3411 has shown higher yield over selected cultivars and has been identified for varietal release and testing in the northeastern plain zone of the wheat-growing region in India.Mushtaq et al. have shown that the NGS coupled with CRISPR-based genome editing have enabled rapid engineering of resistance by directly targeting specific genomic sites of plant viruses and viroids. They also discussed the emerging developments in NGS technologies and CRISPR/Cas-based DNA or RNA tests for the characterization of plant viruses along with their potential advantages and limitations. Kaur et al. employed BSA-seq approach in a wild species of rice Oryza glaberrima and identified a novel locus on chromosome 6 for resistance to root-knot nematode (Meloidogyne graminicola). They reported 3 potential candidate genes within QTLs qNR6.1, qNR6.2 and qNR2.1. This research has expanded the breadth of genes available for resistance to root-knot nematode and the possibilities of deploying new genes in rice breeding.Besides abiotic stresses, plant disease outbreaks threaten global food security significantly. The crop pathogens are responsible for a substantial reduction in global crop yield and productivity. The global burden of viral, bacterial and fungal pathogens in farmers\u2019 fields ranges between 20% and 30% . It poseMontesinos-L\u00f3pez et al. in the article \u201cA general-purpose machine learning R library for sparse kernels methods (SKM) with an application for genome-based prediction\u201d demonstrated the usefulness of six machine learning models based on sparse kernel algorithm in two major crops, wheat and maize. Most importantly, this new package with six models allows user to use different formats of data, i.e., binary, categorical, count and continuous response variables. Recently, ML models are also being explored to resolve the off-target problems associated with CRISPR-Cas9. An article on \u2018Machine learning in the estimation of CRISPR-Cas9 cleavage sites for plant system\u2019 by Das et al. developed models on three ML-based techniques to estimate the cleavage sites of a given sgRNA. Out of the 11 trained models, the models based on the random forest technique, Artificial Neural Networks (ANN1-ReLU) and Support Vector Machine (SVM-Linear), performed better in the estimation of CRISPR-Cas9 cleavage sites showing an accuracy of 96.27%.Machine learning (ML) and artificial intelligence (AI) algorithms have been increasingly used nowadays to improvise genomic prediction models to predict the phenotypes of newly developed breeding lines. Punica granatum L.) breeding programs. The genetic architecture of seed-type trait has not been investigated much using modern approaches, and this has hampered the development of farmer-preferred and commercially viable pomegranate varieties. The recent advances in whole genome sequencing and transcriptome profiling in pomegranate have opened vistas for large-scale discovery of markers for trait discovery and improvement. A previous study in pomegranate had identified novel pre-miRNAs for seed-type trait in pomegranate . We believe that the articles compiled in this Research Topic will expand the existing knowledge on the strategies of crop improvement to mitigate climate change and ensure future food security.To summarize, a diverse collection of research and review articles included in this Research Topic has generated valuable information on the development of genetic and genomic resources in a variety of cereals , legumes (chickpea and peanut), fruit  and underutilized dryland crops. While, the review articles presented information on the evolution and refinement of new-age genomics, genome editing, and genome prediction models based on ML and AI algorithms for crop improvement, the research articles involved their application culminating into disease resistant, drought and heat resistant, high yielding crop varieties for instance line HD3411 in wheat ("}
+{"text": "Trianthema portulacastrum Linn. on dermal wounds via removal of oxidative stress and inflammation\u2019 by Ekta Yadav et al., RSC Adv., 2018, 8, 21621\u201321635, https://doi.org/10.1039/C8RA03500H.Correction and removal of expression of concern for \u2018Ameliorative effect of biofabricated ZnO nanoparticles of  The authors regret that there was an error in This correction supersedes the information provided in the Expression of Concern related to this article.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Objective of the present analysis is to represent the phenomenon of Heat\u2013mass transfer on MHD micro polar fluids caused by permeable and continuously stretching sheet along with slip impacts fostered in a porous medium. Consequently, the equation of energy includes the term of non-uniform heat source/sink. The equation regarding species concentration in cooperates the terms indicating order of chemical reaction to characterize the chemically reactive species. The application software MATLAB with governing syntax of bvp4c technique are employed to reduce equations of momentum, micro-rations, heat, and concentration into suitable required simplifications to derive necessary arithmetic manipulations of available non-linear equations. Various dimensionless parameters are portrayed in the available graphs with essential consequences. Analysis discovered that micro-polar fluid improves velocity and temperature profile while it suppresses micro-rations profile also magnetic parameter ( Investigations of micro polar fluids are of significant recognition because of numerous applications in various industries particularly suspension solutions, solidification of liquid crystals, animal bloods, and exotic lubricants. Bhargava and Takhar2 explored heat transfer of the micro-polar boundary layer (BL) near a stagnation point on a moving wall. Anika et al.3 analyzed consequences of thermal diffusion on the unsteady viscous MHD micro-polar fluid flow past an infinite plate together with hall and ion-slip current. Bhargava et al.4 performed numerical investigations for micro-polar transfer phenomena prompted by non-linear stretching sheet availing two distinct techniques of finite element and finite difference. Takhar et al.5 exercised mixed convection in MHD flow of micro-polar fluids across the stretchy sheet. Bhargava and Rana et al.6 examined nonlinear convective heat and mass transfer in a micro-polar fluid with continuously variable conductivity by employing the objectives of finite element technique.In recent past academic attainment of micro-polar fluid has drawn attracted attention among several engineering community and scientist community as a reason of its limited circumference associated with Newtonian fluids. These fluids are influentially determined by spin inertia and reinforces stress moments and body moments. The theory of microfluids is identified as complex theory against the case of constitutively linear theory and the corresponding underlying mathematical manipulations are not easily amenable to the solution of non-trivial problems in this field. A subclass of these fluids is defined as the micropolar fluids that exhibits micro-rotational effects and micro-rotational inertia. The classical framework of Navier\u2013Stokes model founds certain degree of limitation particularly listing as it cannot describes and elaborates the category of fluids pertaining microstructure characteristics, fluids possessing effective and influential applications. Therefore, analysis of micro polar fluids suggested by Eringen7 has fascinated many researchers to investigate alike problems on the boundary layer (B.L.) flow due to a stretching sheet, as it has numerous applications in industry like the extrusion of polymer sheet by a dye, crystal growing, continuous casting and drawing of plastic films. The pace of cooling and the stretching process are the only factors that directly affect the desired properties of the finished product. The stretching sheet may not be necessarily linear, as we can take in nonlinear fashion also, even though problem may not have noticeable technological relevance. In view of this, Vajravelu8 proposed the flow across a nonlinearly stretching sheet, while Cortell10 studied the flow and heat-transport caused by a stretching sheet for two unalike types of thermal boundary (TB) conditions on the sheet, viz., constant surface temperature (CST) and prescribed surface temperature (PST). Ganji et al.11 reported analytical solution for magneto hydrodynamic flow due to a stretching sheet in nonlinearly manner. Similar work has been studied by Ishak et al.12, Prasad et al.13, Van Gorder et al.14, Raftari et al.15, Abbas and Hayat16, Dadheech et al.17, Olkha et al.18 and Abel et al.19, among others.The flow of fluid across continuously stretching sheet under the influence of available magnetic field has significant emphasis on several domains of engineering particularly plasma investigations, geothermal energy extraction etc. Investigations pertaining to MHD effects on flow of fluid under consideration past a stretching sheet are indexed in an open literature. The first study by Crane20 examined chemically reactive species diffusion due to a plane elastic surface. Abo-Eldahab and Salem21 studied flow and heat transfer of non-Newtonian power law fluid flow with mass diffusion and chemical reaction on a moving cylinder under consideration of magnetic field effect. Chauhan and Jakhar22 reported 2D non-Newtonian flow and heat transport in a channel with suction at the top and a naturally permeable medium at the bottom. Chauhan and Ghiya23 suggested heat-transfer in second order fluid flow in between two stable permeable disks together with the consequences of magnetic field. Kumar24 investigated analysis of finite element combined with heat-mass transfer in hydromagnetic micro-polar flow past a stretching sheet. Emad et al.25 explored the investigations of flowing/suction impacts on the hydromagnetic heat-transfer by the application of mixed convection from continuously stretching surface together with internal heat generation/absorption. Tripathy et al.26 examined the numerical evaluations of hydromagnetic micropolar fluids past the stretching sheet embedded in a porous channel together with non-uniform heat sources and permissible chemical reactions. Chen and Taiwan27 inspected the theory of heat-mass transfer in MHD flow prompted by natural convection from permeable and suitably inclined stretching surface embedded with variable temperature of wall and concentration. Alam et al.28 examined numerical proposals of combined free-forced convection and mass transfer flow past the available vertical, porous plate in the porous channel together with heat generation and thermal diffusions. Aydin and Kaya29 investigated the MHD mixed convective heat transfer flow about the suitably inclined plate. Reddy and Reddy30 suggested investigations of mass transfer and heat generation consequences on MHD free convection flow across the inclined vertical surface in porous medium. Patil et al.31 proposed the influential consequences of Eyring\u2013Powell fluid across the stretching surface in the existence of magnetic field and chemical reactions.The consolidated impacts of heat mass diffusion together with chemical reaction has their dominant significance on several processes emerging in cooling of nuclear reactors, thermal insulation, geothermal reservoirs etc. Andersson et al.32 established melting impacts on the mechanism of heat transfer. Yacob et al.33 examined melting heat transfer in boundary layer stagnation point flow towards a stretching/shrinking sheet in a micropolar fluid. Hayat et al.34 examined Powell-Eyring stagnation point flow towards a surface stretching linearly with melting heat transfer. Melting heat and mass transport effects in non-Newtonian flow over a stretching surface with non-linear radiation and magnetic field effect was discussed by Khan et al.35. Gireesha et al.36 investigated melting heat transfer in MHD flow of dusty Casson fluid over a stretching surface.Fundamental phenomenon of melting heat transfer finds dominant significance in various technological and industrial exercises like comprehending melting of permafrost, magma solidification, metal purification, welding etc. Epstein and cho et al.37 investigated slip effects in viscoelastic fluid flow through porous medium due to a porous oscillatory stretched sheet. Govindarajan et al.38 discussed slip and mass transfer effects in a vertical channel under consideration of heat source and radiation. Olkha and Dadheech40 discussed entropy analysis for MHD flow for different non-Newtonian fluid caused by a stretching sheet with slip effect and heat source. Dadheech et al.41 investigated MHD flow for Casson fluid caused by a stretching sheet with slip effect. Dadheech et al.42 discussed entropy analysis for Williamson fluid caused by a vertical plate with Cattaneo-Christov heat flux and slip effect. The boundary layer flow for different fluids and geometrical configurations has been considered by59 in the presence of magnetic field.A fluid sometimes gets adhered to the solid boundary but in some circumstances, it does not get a hold like as in suspensions, melting of polymers, emulsion processes and several other non-Newtonian fluids often exhibits macroscopic wall slip. Fluids which manifest boundary slip finds applications in various domains such as polishing of heart valves, internal cavities and various other technological procedures. Ali et al.In perspective of given literature review we have observed that there are relatively few studies are performed on MHD Micro-Polar fluid prompted by melting stretching sheet. The main objective of current study is to determine flow behavior and heat transfer of Micro-Polar over a melting stretching sheet. The novelty of the presented work is increased by substantial validating slip effects with chemical reaction and non-uniform heat source/sink. The examinations furnished in the given article can be further utilized to make investigations in fuel industries, flow of crushed water problems, and in the extrusion of polymer sheets. The consequences of the investigations made are employed in various engineering designs, metallurgy industries also for improving the working efficiency of systems for flow of thermos fluids.26 with relevant boundary conditions are given as:In the momentum equation we take micropolar fluid, magnetic field and porous medium term. The magnetic field Bo is applied perpendicular to the stretching sheet and the effect of induced magnetic field is neglected since the magnetic Reynolds number is assumed to be small. We further assume that the impressed electric field is zero and Hall effect is neglected.The thermal contribution of non-uniform heat source and sink is introduced effectively in the energy equation.The mass transfer phenomenon due to diffusion of chemically reactive foreign species has been accounts for by considering the chemical reaction term of first order.Steady two-dimensional incompressible micro-polar fluid flows caused by a stretching sheet are examined. Corresponding velocity components mentclass2pt{minimContinuity equationMomentum equationAngular momentum equationEnergy equationSpecies equationhere 39) for flow, concentration and temperature is21)The appropriate boundary condition \u201352\u20135) reThe local \u201cskin friction coefficient\u201d The \u201ccouple stress\u201d at the surfaceThe \u201clocal surface heat flux 19. Later it has been determined that computed consequences had essential significant influences.The essential objective of given investigation is to demonstrate the influence of several physical parameters on velocity mentclasspt{minimaquations\u00a0 are evalmentclass2pt{minim, in micropolar fluids, the material parameter that can affect the velocity profile is known as the micropolar fluidity parameter (K). When the micropolar fluidity parameter (K) increases, it implies that the microstructure or internal degrees of freedom have a stronger effect on the fluid flow. This can lead to an increase in the complexity of the flow patterns and the velocity profile.Figure\u00a0Figure\u00a0Figure\u00a0Figure\u00a0Figure\u00a0Figure\u00a0Figure\u00a0Figure\u00a0Contours showing the impact of micro-rotation parameter, Moreover, the micro-rotation parameter affecting the velocity and temperature of a micropolar fluid more intensely near the surface slightly varies according to the boundary conditions (i.e. when The velocity The influence of The concentration profile Reduction in velocity In the present analysis, a numerical investigation of micro polar fluid flow due to melting stretchy surface in a porous medium has been carried out. The influence of abundant quantities on velocity, microrotation, temperature and concentration distribution are outlined as follows:"}
+{"text": "Similarly to the previous Special Issue entitled \u201cMolecular Mechanisms of Allergy and Asthma\u201d , this SpConsidering their pivotal role in allergies, T cell-related molecular and cellular mechanisms were the focus of four independent investigational works. Perveen et al.  showed tSeveral other papers focused on the molecular mechanisms related to mast cells (MCs), the pivotal effector cells behind allergic responses. Ashikari and coworkers  identifiFurthermore, while Nguyen and colleagues  focused Finally, Zhernov et al. exhaustively described the molecular mechanisms behind eosinophilic esophagitis  and scomIt is with great pleasure that I am presenting the articles included in this Special Issue to the asthma and allergy research community."}
+{"text": "The circular interactions between type 2 diabetes (TMD2) and major depressive disorder (MDD) are well documented but the understanding of their mechanisms has only recently gained more clarity. Latest research indicates, that the association between TMD2 and MDD is largely mediated by insulin resistance (IR).A metabolic subtype of MDD can be distinguished from other MDD subpopulations, that is characterized by predominantly atypical clinical presentation, IR and different responsiveness to antidepressant interventions. IR is a predictor of nonresponse to some antidepressants. The IR seems to be a state-marker of clinical or subclinical depression and the relationship between IR and MDD varies between sexes and ethnicities. Insulin has a direct impact on the monoaminergic systems known to underlie MDD symptoms: serotoninergic and dopaminergic, which are dysregulated in IR subjects. Several trials assessed the efficacy of insulin-sensitizing drugs in MDD with mixed results for metformin and more consistent evidence for pioglitazone and lifestyle intervention/physical activity.Recently published data suggest a significant role of IR in the clinical presentation, pathophysiology and treatment response in MDD. Further research of IR in MDD and integration of existing data into clinical practice are needed. Their work showed, that IR was elevated in atypical but not typical depression. Some researchers focused on specific symptoms and attempted to disentangle their links to metabolic markers. Chae et al.[\u25aa\u25aa] reported an analysis of German nationwide database which assessed data on the clinical presentation, metabolic syndrome components and inflammation variables in MDD patients. Regarding insulin levels, results showed significant associations between higher insulin and increased appetite, hypersomnia, insomnia and suicidal ideation. In sum their work unraveled several symptom-marker connections between: higher metabolic markers and increased appetite; lower metabolic markers and decreased appetite; lower metabolic markers and insomnia; higher insulin and increased appetite; higher insulin and lower albumin and insomnia. In line with the findings of the Netherlands Study of Depression and Anxiety [\u25aa\u25aa], their work reinforced the links between metabolic markers and atypical presentation of MDD and the observation, that those relationships are mainly noted for insomnia rather than hypersomnia. Similarly, in a cross-sectional analysis of primary care population Shell et al. reported that IR is only elevated during acute MDD episodes, while comparisons of patients with remitted MDD and general population indicated no significant differences. Another work comparing subjects with current MDD, remitted MDD and controls also concluded, that IR was significantly higher in acute MDD vs. controls [et al.[\u25aa\u25aa] noted that IR decreased in patients who experienced symptomatic improvement. They also noted that while baseline C-reactive protein (CRP) levels had a significant effect on the changes in depression severity it was fully mediated by IR. A study comparing IR in normal weight, nondiabetic adolescents included MDD and euthymic participants. It found associations between MDD and IR, which became insignificant after controlling for age, sex and BMI. However, the study sample was small (n\u200a=\u200a196) and less than a fourth of subjects presented IR (defined as HOMA >2.5), therefore the study was potentially underpowered to detect IR related differences [The above-mentioned meta-analysis by Fernandes et al.\u25aa\u25aa reportcontrols . Rashidis [et al.\u25aa\u25aa noted mall n\u200a=\u200a6 and lesferences .et al.[\u25aa\u25aa] published a cross-sectional study exploring the links between IR and depression status in obese individuals without diabetes, not medicated with antidiabetic drugs. They observed, that in female subjects IR (defined as 4th quartile vs. 1st\u20133rd quartiles HOMA that is >5.5) was significantly associated with mild, moderate or severe depression, with higher depression severity being related to higher risk of IR. To the contrary, no significant link between IR and depression was noted in male participants. \u0141api\u0144ska et al.[et al.[\u25aa\u25aa] performed a longitudinal assessment of links between baseline IR and depressive symptoms measured biennially for 8\u200ayears. The results indicated that high IR (4th vs. 1st quartile of studied population) was associated with progression of depressive symptoms. This relationship was significant in subgroups of men, overweight and elderly subjects but not in women, participants with normal BMI, those aged <65\u200ayears.He et al.\u25aa\u25aa publiska et al. studied l.. On the other hand, Gruber et al.[\u25aa\u25aa] summarized data coming from animal and human trials exploring the impact of insulin and IR on dopaminergic transmission. Based on the animal studies they have concluded that (a) insulin differently modulates dopamine release, increasing it if applied in the striatum and inhibiting it if applied in the ventral tegmental area (VTA), (b) insulin deficiency and resistance limits the synthesis and reuptake of dopamine as well as the excitatory stimulation and firing frequency of dopaminergic neurons in VTA, (c) restricted insulin signaling/IR in the nucleus accumbens reduces dopamine release and reuptake, (d) IR is linked to increased food intake, motivation to work for food, dampens reward sensitivity, impairs learning and preference formation as well as promotes behavioral despair resulting in anhedonic/anxious phenotype. Moreover, they summed human studies noting that (i) peripheral IR is a surrogate measure of central IR, (ii) intranasal insulin alters the activity and connectivity of dopaminergic circuitry and modulates reward behavior, (iii) the effects of intranasal insulin on reward processing differs with its dose, with low and high doses increasing the thresholds for reward the most, (iv) IR disrupts the reactivity to food cues, learning and motivation for reward (the last association is highly related to the state of satiety/hunger). While the relationship between high BMI and dysregulation of reward processing of food cues and intake is well established, a study exploring the effects of intranasal insulin on functional connectivity of the dopaminergic midbrain in humans reported, that the, these alterations are better predicted by IR rather than BMI [The alterations of serotonin, dopamine transmission are known to induce depressive symptoms. In an animal study, Martin the drug \u25aa\u25aa. On ther et al.\u25aa\u25aa summarthan BMI .et al.[et al.[\u25aa\u25aa,Surprisingly, IR seems to differently moderate treatment outcomes depending on its modality. In the earlier mentioned work by Brouwer et al., the trel.[et al.\u25aa\u25aa,26 obset al.\u25aa\u25aa,\u25aa. Also, et al.\u25aa\u25aa,. On the et al.\u25aa\u25aa,.et al.[et al.[et al.[et al.[Moulton et al. performel.[et al. publishel.[et al.. Lucianol.[et al.\u25aa reportel.[et al.\u25aa assesseIn sum, latest research suggests that a metabolic subtype of MDD can be distinguished from other MDD populations by the presence of particular pathophysiological mechanisms, symptomatology and responsiveness to treatment. IR seems to play an important role in this metabolic MDD subtype and it is positively linked to atypical depressive symptomatology. Insulin has a direct effect on the serotoninergic and dopaminergic neurotransmission which becomes disrupted by IR. The relationship between IR and MDD seems restricted to current depressive states of either clinical of subclinical severity and it differs between sexes, ethnicities normal/overweight subjects. Moreover, IR limits the efficacy of antidepressant drugs but light therapy might be more effective for subjects with IR than insulin sensitive ones. Insulin-sensitizing treatments might be beneficial for MDD patients, with most robust data supporting the addition of pioglitazone or interventions promoting healthy lifestyle and physical activity. Studies exploring the role of IR in MDD need replication in larger groups/patients of different ethnicities/in various metabolic states  and so do trials verifying the potential efficacy of insulin-sensitizing treatments in MDD. Existing data already allow for a step towards personalizing therapeutic approaches and may inform clinical decisions as well as future research for more individualized and efficacious MDD treatment.None.None.There are no conflicts of interest."}
+{"text": "Marek\u2019s disease virus (MDV), an Alphaherpesvirus belonging to the genus Mardivirus, causes T cell lymphomas in chickens and remains one of the greatest threats to poultry production worldwide. While losses caused by Marek\u2019s disease have been reduced through live-attenuated vaccines, field strains have increased in virulence over recent decades. MDV research has led to a profound understanding of virus-induced pathogenesis and tumor development ,2,3. OurA timely summary of the major methods of manipulating herpesvirus genomes was provided by Liao et al., with an emphasis on their applications in MDV research. The authors reviewed both the \u201ctraditional\u201d methods, such as site-directed mutagenesis and the use of cosmids, and more recent methods, like bacterial artificial chromosomes (BACs) and CRISPR/Cas9-mediated genome editing . The samYou et al. reported the characterization of a new splice variant of viral interleukin 8 (vIL-8), a chemotactic cytokine, showing that this new vIL-8 isoform is dispensable for MDV replication and pathogenesis .Two papers addressed pressing questions in MDV research using CRISPR/Cas9 approaches: the switch between lytic and latent MDV infections and the use of gene technology to generate MDV-resistant chickens. Roy et al. used CRISPR activation (CRISPRa) of viral genes to investigate the lytic\u2013latent switch. This switch seems to rely on the two MDV phosphoproteins pp24 and pp38 [In an attempt to improve MDV vaccines in the context of immunosuppression commonly caused by MDV and its widely used vaccines, Conrad et al. generated genetically modified vaccine candidates and assessed their vaccine-mediated protection and immunosuppressive effects .Ikaros cancer driver gene can contribute to MDV-induced tumorigenesis. Similar mutations also exist in some human cancers, suggesting that somatic mutations may explain the origin of MDV-induced lymphomas [Three contributions highlight the value of MDV infections in chickens as a model for human diseases. Erf et al. used a Mardivirus in vivo model to gain new insights into vitiligo, a chronic autoimmune disorder . A genomymphomas . Gennartymphomas .Finally, the methods paper on a cell culture system to study MDV integration by You and Vychodil et al. provided a method that allows the investigation of molecular mechanisms of MDV telomere integration, as well as the quantification of virus genome integration, without requiring laboratory animals .Although much progress has been made in MDV research and a growing body of knowledge about this DNA tumor virus exists, a number of challenges need to be overcome. Through this Special Issue, we hope to contribute to a better understanding of MDV as an important poultry pathogen, but also as a valuable animal model for herpesvirus research, virus\u2013host interactions, and virus-induced tumorigenesis."}
+{"text": "Glioblastoma (GBM) is the most lethal and prevalent primary brain tumor in adults with a five-year survival rate of only around 5 percent, afflicting about 3.19 people in every 100,000 . It is wEpigenetics and epitranscriptomics\u2014molecular changes of cellular DNA, chromatin, and RNA\u2014can alter the levels of gene transcripts and subsequently change the amount of proteins produced, including those responsible for tumor suppression, progression, or maintenance . Until nIn the early 2000\u2019s, Helen Blau et.al., introduced an evolving concept for adult stem cells suggesting that stem cells is rather a biological function instead of an entity . AccordiYu et\u00a0al., combined analysis of transcriptome and DNA methylation profiles of TCGA to derive a 6-gene model-based risk score. This approach allowed the authors to predict survival and the role of personalized treatment plans for GBM. Wang et\u00a0al., analyzed tumor associated fibroblasts infiltration by Estimating the Proportion of Immune and Cancer cells (EPIC) based on multiple glioma databases. They describe a novel transcript signature that predicts glioma prognosis. Shi et\u00a0al., showed that individual glioblastoma cell lines displayed increased expression of the short splice variant of YKL-40 after low serum treatment. In addition, unlike the full-length (FL) version, which was localized to all cell compartments, the short isoform could not be secreted and was localized only to the cytoplasm. Functionally, FL YKL-40 promoted cell proliferation and migration, whereas SV YKL-40 suppressed them. The authors described pathways that regulate the expression of the SV YKL-40 and discuss the significance for development of new therapies. Majc et\u00a0al., investigated the use of bioactive peptides from venoms as novel therapies targeting cancer specific pathways in glioblastoma. Finally, Basilico et\u00a0al., revealed that changing the rigidity of the mechanical environment tuned the response of glioblastoma cell lines through change in morphological features, epithelial-mesenchymal markers , EGFR and ROS expressions in an interrelated manner. Their work highlights the importance of microenvironment stiffness in the regulation of glioblastoma invasive properties.This Research Topic includes 5 original research papers. NT wrote the initial draft of the editorial. H-WL edited and both agreed on the final version."}
+{"text": "In the last decades, complex networks have been used extensively in neuroscience and other fields by employing networks to model interactions among system\u2019s components . MoreoveA common research theme in the study of complex networks is that of the determination of the role and impact of network topology on the emerging properties due to interactions and dynamics. How structural properties in brain regions affect neural dynamics or how do they differ in healthy and diseased subjects? How different types of plasticity affect the dynamics of neural activity in a network?This Research Topic contributes to better understand the impact of dynamics at different spatiotemporal scales, structure and plasticity on brain synchronous activity. To this end, it hosts interdisciplinary analytical and computational works from different fields, such as from complex systems, biophysics, systems biology, and computational neuroscience.Liu et al., aims to better understand the effect of the amyloid \u03b2 peptide (A\u03b2) which is hypothesized to be the major factor driving Alzheimer\u2019s disease (AD) pathogenesis. To this end, the authors derived and investigated a concise mathematical model for A\u03b2-mediated multi-pathway astrocytic intracellular Ca2+ dynamics. They investigated several interventions, such as ion channel blockers or receptor antagonists and demonstrated that a \u201ccombination therapy\u201d targeting multiple pathways simultaneously is more effective towards the treatment of AD.The first paper, by Cambell et al. investigated the fractal dynamics of blood oxygen level-dependent (BOLD) signals during naturalistic conditions. They implemented fractal analysis to quantify scaling behavior using the Hurst exponent (H) in data from the Human Connectome Project to compare H values across movie-watching and rest. Their results showed that movie-watching induces fractal signal dynamics and markedly different than dynamics observed during conventional tasks.van der Vlag et al. introduced a new computational tool called RateML that enables users to generate whole brain network models from a succinct declarative description, in which the mathematics of the model are described without specifying how their simulation should be implemented. With RateML, the end user describes the model\u2019s mathematics once and generates and runs code for different languages/platforms, targeting both CPUs for fast single simulations and GPUs for parallel ensemble simulations .Lei et al. introduced a new type of burst-oscillation mode (BOM), i.e. an alternating transition between two distinct phases . BOM was derived by extensively investigating the response dynamics of a one-dimensional (1D) paced excitable system with unidirectional coupling. These findings may facilitate a deeper understanding of bursts in nature and will have a useful impact in related fields.Shi et al. proposed a deep attributed network representation learning with community awareness (DANRL-CA) framework and two variants, i.e., DANRL-CA-AM and DANRL-CA-CSM, which incorporate the community information and attribute semantics into node neighbours with different methods. They designed a neighbourhood enhancement autoencoder module to capture the 2-step relations between node pairs. They conducted comparisons for node classification and link prediction and found that DANRL-CA-CSM can more flexibly coordinate the role of node attributes and community information in the process of network representation learning, and shows superiority in the networks with sparse topological structure and node attributes.Madadi Asl et al. employed a computational model to show that inhibitory spike-timing-dependent plasticity (iSTDP) at pallido-subthalamic synapses can account for pathological strengthening of pallido-subthalamic synapses in Parkinson\u2019s disease (PD) by further promoting correlated neuronal activity in the globus pallidus (GPe) - subthalamic nucleus (STN) network. Their results may shed light on how abnormal reshaping of GPe-STN connectivity by synaptic plasticity during parkinsonism is related to PD pathophysiology and contribute to the development of therapeutic brain stimulation techniques targeting plasticity-induced rewiring of network connectivity.Zheng et al. studied the emergence of spatiotemporal patterns in a general networked Hindmarsh-Rose (HR) model. Furthermore, they investigated stability properties, namely they obtained conditions leading to Turing instability in networks without delays and showed that there is a difference between the collected current and the outgoing current affecting the neuronal activity, which is relevant in the generation mechanism of short-term memory.Li et al. investigated the dynamics of networks of identical coupled oscillators in a setting where coherent oscillations coexist with incoherent ones, the so-called chimera state. They showed that stable and breathing chimera states in the original two coupled networks typically have very small basins of attraction. Then, they studied the emergence of chimera states by stimulating brain regions and quantified it using the order parameter and chimera index. These two indices were found to be weakly and negatively correlated."}
+{"text": "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by defective cardiac ryanodine receptor (RyR2) calcium release during times of adrenergic stimulation, resulting in bidirectional or polymorphic ventricular tachycardia. Flecainide is a class 1c anti-arrhythmic drug that has demonstrated therapeutic efficacy in treating CPVT. However, its mechanism of action remains disputed. One group proposes a direct effect of flecainide on RyR2-mediated calcium release, while another proposes an indirect effect via sodium channel blockade and modulation of intracellular calcium dynamics. In light of recent studies, this commentary aims to explore and discuss the evidence base for these potential mechanisms. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia, leading to syncope and sudden cardiac death. The most common genetic mutations resulting in CPVT are found within genes responsible for coding the cardiac ryanodine receptor (RyR2). These are usually inherited in an autosomal dominant manner and are termed CPVT1. A recessive form (CPVT2) is caused by gene mutations for cardiac calsequestrin. CPVT is linked to seven genes with autosomal dominant  or autosomal recessive  inheritance [This results in a transient inward current, perpetuating the onset of malignant arrhythmias via delayed afterdepolarizations (DAD) and triggered activity. The first-line drug therapy for CPVT is \u03b2-adrenergic receptor blockers. However, some patients are refractory and experience persistent tachyarrhythmias. The class 1c antiarrhythmic drug flecainide, a known inhibitor of the sodium current (INa), has demonstrated effectiveness in treating CPVT; however, the mechanism responsible for the therapeutic efficacy of flecainide in CPVT remains disputed.Gaining a comprehensive mechanistic understanding of the clinical efficacy of flecainide in CPVT is critical for cases of arrhythmias that may share similar clinical presentation but differ significantly in their underlying mechanisms. Furthermore, abnormalities in calcium handling, including defective RyR2 functioning, are implicated in several other diseases of significant global burden, including muscular dystrophy, malignant hyperthermia, and Alzheimer\u2019s disease. Consequently, RyR2 is a major therapeutic target, and the development of new drugs targeting RyR2 carries significant clinical potential for treating CPVT and other diseases.et al. [Hilliard et al.  comparedet al. [In a recent study, Kryshtal et al.  investiget al. [Other studies proposed contrasting mechanisms explaining wave suppression. Liu et al.  examinedet al. [In adult rat cardiomyocytes, Sikkel et al.  conducteet al. [Bannister et al.  investiget al. [et al. [Several factors should be considered to account for the varying results of flecainide on SR Ca2+ release via RyR2, which suggest a direct effect in some studies  and no eet al.  demonstr [et al.  only appet al. [et al. [Yang et al.  used in  [et al. . As estaThe debate regarding the primary mechanism responsible for the therapeutic efficacy of flecainide in CPVT remains highly disputed and unresolved. Numerous studies propose INa-mediated modulation of intracellular calcium dynamics, while several others propose direct RyR2 inhibition as the primary mechanism. Moving forward, the mechanisms of flecainide in CPVT will increase our knowledge of Ca2+ dysregulation in cardiac myocytes and aid in the development of a more specialized therapeutic approach for CPVT."}
+{"text": "Exercise and lifestyle modifications have established themselves as the pillars of primary care, proving to be potent weapons in the war against non-communicable diseases. With the World Health Organization (WHO) naming physical inactivity as a leading risk factor for global mortality , it is cThere is extensive research highlighting the wide-ranging benefits of physical activity, spanning from mitigating the risks of cardiovascular diseases, diabetes, and stroke, as well as mental health conditions  includinConsidering this, primary care professionals across the world are progressively incorporating exercise-based lifestyle modifications,  particulAddressing the evaluation of physical activity within the context of primary care practice presents a noteworthy challenge . The impIn addition, adherence rates continue to fall below satisfactory levels, underscoring the imperative need for the development of strategies aimed at bolstering acceptance and participation . CentralZhang et al.; Hu et al.; Liu Y. et al.; Cheng et al.; Mainous et al.; Lin et al.; Wattanapisit et al.; Liu Z. et al.; Feng et al.; Felemovicius et al.; Heyn et al.).Furthermore, illustrating instances of successful integration of exercise recommendations within real-world settings can serve as practical models for future endeavors . CollaboZhang et al. in their paper \u201cExercise for Neuropathic Pain: A Systematic Review and Expert Consensus\u201d emphasize that a proper exercise program can serve as an effective alternative treatment or complementary therapy for most patients with neuropathic pain (NP). This consensus provides actionable recommendations for clinicians and policymakers alike in formulating exercise prescriptions to treat NP.Hu et al. evaluated all-cause mortality and cardiovascular mortality in the Guangzhou Heart Study (GZHS), an ongoing prospective population-based cohort study in South China. Specifically, they investigated the effect of the Healthy Lifestyle Index and lifestyle patterns on the risk of mortality in a large Chinese population. Their study results suggest that accumulative dimensions of a healthy lifestyle can lower the risk of death, and adherence to the healthy lifestyle pattern was associated with non-smoking and low-level alcohol consumption which reduces the risk of all-cause mortality. These findings highlight the need to consider multi-dimensional lifestyle approaches when developing health promotion strategies.A population-based study by Efficacy of electro-acupuncture in postpartum women with diastasis recti abdominis: A randomized controlled clinical trial\u201d by Liu Y. et al. evaluated the long-term efficacy and safety of electro-acupuncture (EA) in treating diastasis rectus abdominis (DRA) during postpartum. The study results showed that AE treatment improved multiple health parameters and symptoms related to Diastasis Recti Abdominis (DRA), displaying lasting effects up to 26 weeks postpartum.The clinical trial \u201cCheng et al. investigated the effectiveness and response of a multidisciplinary Workplace health promotion (WHP). They used a retrospective cohort sample of healthcare workers participating in a multidisciplinary WHP program in five healthcare facilities. The 20-week intervention included exercise classes, nutrition consultation, and behavioral education followed by anthropometrics, body composition, and physical fitness (PF) measures. Their study results demonstrated that a multidisciplinary WHP could enhance anthropometric and physical fitness profiles among healthcare workers.Furthermore, Mainous et al. evaluated the relationship between depression-high depressive symptomatology and adherence to lifestyle interventions among patients with prediabetes. They analyzed the 2017-20 20 National Health and Nutrition Examination Survey (NHANES), a nationally representative population of U.S. adults. Their findings showed that depression-high depressive symptomatology decreases the likelihood of adherence to exercise-based lifestyle recommendations among patients with a confirmed diagnosis of prediabetes underscoring the interplay between mental health and lifestyle changes.Lin et al. conducted a randomized controlled trial with 66 full-term infants with eczema randomly assigned to an eczema control (EC) group and an eczema with MPIM (EM) group as compared to a healthy control (HC) group. The mothers in the EC group received the instruction of routine care, while the mothers in the EM group applied massage on the infants plus receiving the same instruction of the routine care. HC group received no specific intervention. Compared with the EC group, the EM group showed significantly lower scores on eczema outcomes supporting the reduction of infantile eczema, along with relieving maternal anxiety and depression.A randomized trial by Wattanapisit et al. highlights the importance of training, integrating, and applying knowledge and skills pertaining to PA promotion in clinical settings with the goal of covering several aspects of sport and exercise science. They remind us that PCPs are usually not specialists in these subject areas, and it is essential to supplement and provide knowledge for proper clinical practices. They include the collective perspective of experts in the field.An intriguing opinion paper by Liu Z. et al. conducted a systematic review and meta-analysis to evaluate the effects of a traditional Chinese Qigong therapy called Baduanjin which is characterized by symmetrical body posture and actions, breathing control, meditative state, and concentration. They reviewed randomized controlled trials evaluating Baduanjin therapy's effects on neck pain and functional movement in older individuals. Although the results of the synthesis methods support Baduanjin therapy as a safe and positive treatment for neck pain in older individuals, they called for caution as more studies are needed to validate and support its benefit.Feng et al. through a population-based study in Taiwan, investigated whether physical activity (PA) is associated with a reduced risk of hemorrhagic stroke (HS). Their study supports the beneficial effect of PA on reducing HS risk. However, high-PA did not appear to have a greater protective effect than low-PA in diabetes and hypertension outcomes. Thus, their conclusions support that even <90 min of PA per week might be beneficial in reducing HS risk. They also note that recommendations based on low PA levels are more likely achievable and sustainable across the general population. Additionally, personalized recommendations, based on pre-existing comorbidities, may help optimize the beneficial effects of PA on HS prevention.Felemovicius et al. evaluated a novel composite topical Lidocaine agent treatment for Pruritus ani, or rectal or anal itch, which is a common perianal disorder that affects approximately five percent of the population of the developed world. The SOOTHER Trial showed efficacy in providing rapid and effective relief of pruritus ani in an ambulatory population.The SOOTHER Trail by Heyn et al.) from the University of Colorado School of Medicine and Colorado Children's Hospital underscores the importance of lifelong monitoring of children with disabilities to identify and modify disease-induced risk factors through lifestyle interventions. Their study, \u201cThe association between isometric strength and cognitive function in adults with cerebral palsy,\u201d supports using simple tests like hand grip strength to evaluate early signs of frailty and neurocognitive decline in adults with Cerebral Palsy.Finally, a study by a research team , it becomes evident that they underscore the pivotal significance of exercise and lifestyle modifications within primary care. Through their findings, they shed light on the multifaceted roles of these interventions across various health contexts. As we continue to navigate the intricacies involved in implementing efficacious exercise prescriptions and clinical physical activity recommendations in primary care settings, these studies serve as valuable resources that enrich our comprehension and improve our ability to promote healthier lifestyles effectively for diverse patients within the realm of primary care.In summary, when considering the results of the studies from this Research Topic collectively (PH: Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "HormoneWang et. al.), but its regulatory network in many non-model fruits is not yet fully understood. Li et\u00a0al. investigated the regulation of ethylene in mango fruit ripening, using ethylene and 1-methylcyclopropene (1-MCP), the action inhibitor of ethylene.They found that MiERF2 and MiERF8 may play critical roles in regulating mango fruit softening. Wang et\u00a0al. reported that blueberry had an atypical climacteric ripening process, where a respiratory climacteric character was developmentally regulated by ethylene, but with non-autocatalytic ethylene production during fruit ripening. Except for ethylene, increasing evidence show that other hormones such as auxin, abscisic acid (ABA), brassinosteroids (BRs), gibberellins (GAs), melatonin (MT) and cytokinins (CKs) control fruit ripening . It is generally considered that ethylene is the key actor of climacteric fruit ripening and ABA is the core player of non-climacteric fruit . However, increasing evidences have shown that fruit ripening is regulated by a balance of multiple hormones rather than by a single one, and the crosstalk between ethylene and ABA signaling plays a leading role in regulating fruit ripening. In climacteric fruits, ABA usually accumulates before the initiation of climacteric period that can promote ethylene biosynthesis via upregulating ethylene biosynthesis related genes and accelerating ethylene-triggered ripening  plays a negative role in fruit ripening process (Liu et\u00a0al. also found that CK suppressed the loss of total sugar and sucrose and the accumulation of acetic acid and ethanol in the fruit aril, reduced the malondialdehyde accumulation in the pericarp of the overripe litchi fruit. Cytokinin treatment repressed the litchi fruit ripening process and maintained fruit quality in the on-tree overripe fruit. However, more information is needed about the interaction of CKs with other hormones.GA works as a negative regulator of fruit ripening, which inhibits the ethylene biosynthesis and perception during fruit ripening of tomato . SA regu process . The app process . Liu et\u00a0In conclusion, the exciting new findings presented in the present topic collection and other works provide a broad and in-depth understanding of hormone signal interactions in regulating fruit ripening. It is believed that increasing new knowledge will emerge in this exciting and evolving field.XZ and QZ wrote the manuscript, HZ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Skeletal muscles are an indispensable actor for daily activities, playing an essential role in locomotion through both the control of posture and position and by joint stabilization. In addition, they are involved in body temperature maintenance and constitute nutrient reserves. Skeletal muscle represents approximately 40% of human body weight, but this percentage physiologically decreases when tissue undergoes atrophy. During aging, a decline in muscle strength and mass can be observed and muscle mass decreases by approximately 3\u20138% per decade after 30 years of age and this reduction appears significant after 60 years . Muscle With regard to sarcopenia, Shin et al. (2023)  discusseIn their paper, Jeun and Choung (2023)  describeAnother high-quality protein that contributes to the maintenance of skeletal muscle mass is egg white protein (EGG), an arginine-rich protein source with a lower amount of leucine. Koshinaka et al. (2023) demonstrated that EGG supplementation in rats had a higher efficiency in muscle gain compared to other common animal-based proteins .Continuing the discussion of dietary protein as an important strategy to manage and prevent sarcopenia, Lees et al. (2023) , in theiThis Special Issue also includes a paper evaluating rosemary leaf extract activity in primary skeletal muscle cells . RosemarAmong the original articles published in this Special Issue, Salucci et al. (2023)  describeFinally, this Special Issue contains two reviews that recognize nutritional interventions as an important strategy to manage and prevent skeletal muscle loss. In this regard, Massini and colleagues (2023)  discusseNutrients, titled \u201cNutrition and Regulation of Muscle Protein Synthesis\u201d, highlights the strategic role of nutritional approaches, based on supplementation with vitamin (B6), herbal extract (GBE), phenolic compounds , and high-quality dietary proteins , in the prevention of muscle mass loss associated with diseases or aging.In conclusion, this Special Issue in The Guest Editor warmly thanks all of the authors for their contributions to this Special Issue."}
+{"text": "Klebsiella variicola strain during a laboratory evolution study, resembling genetic changes observed in clinical isolates.The appearance of colony morphotypes is a signature of genetic diversification in evolving bacterial populations. Colony structure highly depends on the cell\u2013cell interactions and polymer production that are adjusted during evolution in an environment that allows the development of spatial structures. Nucci and colleagues describe the emergence of a rough and dry morphotype of a noncapsulated  Klebsiella variicola.Commentary on the paper by Nucci et al that explains the genetic basis and fitness effects of specific mutations leading to rdar-like colony morphotypes in noncapsulated IS elements drive rapid loss of K. pneumoniae capsule production in experimentally evolved population (Nucci et al. Bacillus thuringiensis, where an IS4-like element disrupts a gene encoding a guanylyltransferase, causing increased hydrophobicity and aggregation (Lin et al. B. thuringiensis fuzzy morphotypes, K. variicola rdar-like derivatives display diminished aggregation (Nucci et al. In their recent ria Fig.\u00a0. While tK. variicola display increased growth rate and fitness advantage compared with the ancestor (Nucci et al. The rdar-like clones of K. variicola background was used, while colonies with distinct morphology were less apparent in capsulated strains that followed a different evolutionary path (Nucci et al. mrkH or nac alleles demonstrated that these mutations convey lower influence on cell\u2013to\u2013cell aggregation in the capsulated background and the fitness effects were only marginally larger in capsulated strains compared to noncapsulated strains. Historical contingency, where the existing mutations influence the subsequent adaptation path might explain the larger rdar-like morphotype frequency in noncapsulated K. variicola. This highlights the opportunity to discover novel evolutionary paths in strains lacking the most frequently mutated targets. Deleting the three most frequently mutated pathways in Pseudomonas fluorescens and subsequent experimental evolution in a static microcosm revealed 13 new mutational pathways that all result in wrinkly spreader colony morphotype (Lind et al. B. subtilis permits the evolution of clones with enhanced biofilm formation, explained by the production of novel, cysteine containing amyloid fibre variants (Drago\u0161 et al. P. fluorescens example, the reconstituted B. subtilis strains with cysteine-encompassing amyloid fibres convey a disadvantage in the presence of the exopolysaccharide (Drago\u0161 et al. The rdar-like morphotype was detected after plating by Nucci and colleagues  when a nK. pneumoniae genomes revealed comparable IS element insertion in the mrkH gene of numerous clinical isolates. Isolates with interrupted mrkH genes were mostly originated from human host samples, including urine and blood as the main source (Nucci et al. Klebsiella isolates, potentially explained by the negative frequency selection of these mutations. The detection of specific mutations or gene disruptions in natural populations further validate the relevance of experimental evolution studies in the laboratory settings as previously reported in Klebsiella (Nucci et al. Finally, the work by Nucci et al. highlights the relevance of laboratory evolution for real-life scenarios. Detailed analysis of The study of Nucci et al.  highligh"}
+{"text": "Ralstonia solanacearum is one of the most devastating agents affecting different plants in 45 families. Several management practices have been used effectively for the management of this bacterium in different plants, including the use of biological control agents . However, because of difficulties in handling, culturing, and maintaining biocontrol agents or the issues related to their practical efficacy in soil, the use of their antimicrobial compounds is considered a good alternative. Ye et\u00a0al. investigated an antibacterial furoic acid compound, 5-(hydroxymethyl)-2-furoic acid, produced by the fungus Aspergillus niger. The soil application of this compound effectively controlled the R. solanacearum population in soil by direct killing effect as well as enhancing host resistance in tomato plants. Wang et\u00a0al. reviewed other studies for the management of this bacterium, including biological, organic, breeding, genetic engineering, physical, cultural, chemical and nano-technological approaches.Soil-borne plant pathogens pose a significant threat to plants, and their management is comparatively more difficult than other plant pathogens because of their nature of the hidden enemy, long persistency in soil, vast genetic diversity and host range . HoweverDutta et\u00a0al., in their review, focused on several aspects of the use of nanotechnology in the management of soil-borne plant pathogens highlighting the role of nanoparticles as protectants and inducers of plant defense against soil-borne plant pathogens. Uncovering the mechanism of host resistance and discoveries of host genes/proteins that regulate host resistance against soil-borne plant pathogens will help plant genetic engineers develop plants that can better fight against soil-borne plant pathogens. Tian et\u00a0al. reported that small G-protein StRab5b positively regulates potato resistance against the soil-borne fungus Phytophthora infestans. Pazarlar et\u00a0al. found that Bacillus cereus EC9 protects tomatoes against Fusarium wilt through JA/ET-activated immunity. In another study by Ling et\u00a0al., it was shown that WRKY genes confer resistance to Cucumis metuliferus against root-knot nematodes (RKN). The RKN-resistant variety of C. metuliferus (cm3) was found to specifically recruit beneficial bacterial communities in soil upon infestation with RKN, as reported by Song et\u00a0al. Similarly, Sikandar et\u00a0al. reviewed overall management strategies, including several recent efforts to improve host resistance against Meloidogyne enterolobii.Nanotechnology emerged as one of the most rapidly advancing sciences of the twenty-first century, and plant scientists revealed the effective application of nanotechnology for the management of plant pathogens. Dutta et\u00a0al. unveil the molecular mechanism by which Trichoderma fungus, one of the most used and studied biocontrol fungus, induce host resistance against pathogens including the role of exogenous elicitors in the induction of host resistance. Zhou et\u00a0al. proved that exogenous application of elicitor isotianil could significantly alleviate the symptoms of Fusarium wilt on the banana. They further confirmed that isotianil application might contribute to disease control by inducing host plant defense against Fusarium infection. Investigation into how the pathogens achieve virulence at the molecular level is also essential for understanding the action mechanism of the pathogen. Xu et\u00a0al. revealed the role of cAMP phosphodiesterase in the formation of sclerotia and achieving virulence in Sclerotinia sclerotiorum, an important phytopathogenic fungus that causes stem rot and white mold disease.Enhancing host resistance is also a prominent action mechanism of many biocontrol agents. In their review, Most investigations conducted for the management of soil-borne pathogens are based on greenhouse or controlled laboratory conditions. Although the outcomes of these studies provide useful insights into the action mechanism and control efficacy, field investigations are vital for assessing the practical applications of these strategies. Field assessments consider the complex interplay between plants, pathogens and soil, and environmental factors that can affect disease management and development. This more accurately illustrates how these strategies perform in real agricultural scenarios. Moreover, field assessment can give an actual clue of management strategy on economic feasibility.RK: Writing \u2013 original draft, Writing \u2013 review & editing, Conceptualization."}
+{"text": "The 38th issue of Financial Innovation (FIN), Volume 9, No. 2 (2023) presents 23 papers contributed by authors and co-authors from nineteen countries and areas: Canada, Chile, China, France, Germany, Italy, Netherlands, New Zealand, Oman, Portugal, Romania, Russia, Spain, South Africa, Taiwan, T\u00fcrkiye, UK, USA and Vietnam. These papers can mainly be categorized into three sub themes. \u2022 Financial risk management and analysisG\u00f3mez-\u00c1guila et al. (2022) introduce a new procedure to improve the estimation of the Hurst exponent in financial time series and prove that pure price series are not necessarily self-similar. Yeh and Liu (2023) use visualization techniques to help explore the Growth Value Model (GVM) intuitively. De Blasis (2023) addresses the calibration issues of the weighted-indexed semi-Markov chain (WISMC) model applied to high-frequency financial data. Ivanyuk (2023) presents an optimization approach\u2014residual-based bootstrap averaging (RBBA) and shows why and how it works. Monteiro et al. (2023) examine the linear interdependencies between international industries, with a focus on the relationships between the US and other six countries, focusing mainly on international stock indexes or firm-level returns. Mo et al. (2023) present an adaptive measurement model of spatiotemporal correlation coefficients based on the clustering theory and conduct an empirical analysis based on the model. Loughran and McDonald (2023) find a slight positive correlation between industry performance and the use of pandemic-related words, as opposed to the expected negative correlation. Gupta and Pierdzioch (2023) prove that aggregate and state-level economic conditions can predict the subsequent realized volatility of oil price returns.\u2022 Behavior financeCheng et al. (2023) find that rumor propagation outperforms management shocks and other variables in predicting abnormal trading behavior. Wang and Lee (2023) chose three life insurance stock futures in India and one in Taiwan as samples and examine that insurance futures are a safe haven for COVID-19 pandemic risks. Dur\u00e9ndez et al. (2023) find that Management control systems (MCS) and managers\u2019 risk attitudes fully mediate the relationship between financial literacy (FL) and innovation. Alp et al. (2023).examine the presence of investor overconfidence by employing an artificial intelligence technique and a nonlinear approach to impulse responses to analyze the impact of different return regimes on the overconfidence attitude. Madeira (2023) demonstrates how households\u2019 characteristics affect their choice of lenders, consumer debt amounts and default behavior. Cruz et al. (2023) propose an approach to the profile of microcredit holders from the Hispanic minority in the US to identify the factors that explain the punctuality of their microcredit repayments. Zhou et al. (2023) develop a behavioral heterogeneous agent model (HAM) comprising fundamentalists, chartists, and stabilizers to investigate investors\u2019 dynamic switching mechanisms under government intervention.\u2022 Stock marketHtun et al. (2023) find that correlation criteria, random forest, principal component analysis, and autoencoder are the most widely used feature selection and extraction techniques with the best prediction accuracy for various stock market applications. Zhang et al. (2023) propose three novel strategies to address common issues in predicting high-frequency stock prices using machine learning methods. Cepoi et al. (2023) explore the impact of the COVID-19 pandemic on information asymmetry for the case of the Romanian capital market. Meng et al. (2023) examine the effect of stock market liberalization on market efficiency by using a recent stock market liberalization reform policy in China\u2014the Stock Connect\u2014as a quasi-natural experiment. Mensi et al. (2023) provide strong evidence of quantile dependence between gold and stock returns. Li and Chen (2023) conduct a theoretical analysis of low-price collusion in SBIC from the perspective of strategic interaction between institutional investors and the regulator. Mestre (2023) proposes a wavelets approach to estimating time\u2013frequency-varying betas in the capital asset pricing model (CAPM) framework. Carrillo-Hidalgo et al. (2023) develop a dynamic regression model to predict the behavior of shares in the Spanish tourism sector according to the evolution of the COVID-19 pandemic in the medium term. It is confirmed that both the number of deaths and cases are good predictors of abnormal stock prices in the tourism sector."}
+{"text": "Neurological disorders are a large and heterogeneous field of research that can be tackled through a variety of approaches, ranging from epidemiology to molecular biology, through clinical, biostatistical, and laboratory experiments. The objective of this article collection was to gather the most recent evidence on signaling and genetic regulation of major neurological disorders . The articles included in the collection offer interesting insights into a range of biological processes involved in neurodegeneration. In addition, one contribution described an in silico approach to develop drugs for Parkinson\u2019s disease (PD). Barrera-Vaquez et al., 2023  sought tAlzheimer\u2019s disease (AD) is certainly the best known neurodegenerative disorder. It is characterized by deficits in multiple cognitive domains always including the memory domain and always involving neurodegeneration in the hippocampus. Several hypotheses have been proposed to explain the complex pathophysiology of AD, including altered neurogenesis and neuroinflammation. Olabiyi et al., 2021 [1\u221242, caspase 3, caspase 9, and cytosolic phospholipase A2. To further test their findings, the authors performed an in vitro experiment by exposing HT22 cells to a 12/15-LOX shRNA and a p38 MAPK inhibitor in high-glucose medium. The finding that the 12/15-LOX pathway plays a role in diabetic brain damage by activating p38 MAPK to promote inflammation and neuronal apoptosis, and that this mechanism could be inactivated by 12/15-LOX inhibitors is worth future research, perhaps not only limited to diabetic cognitive impairment.The role of lipid-mediated inflammation in neurodegeneration was evaluated by Chen et al., 2022 . The autIn their contribution, Zhang et al., 2022  studied Jang et al., 2022  studied Neurodegeneration does not necessarily result in neuronal death. Indeed, brain cancer development can be a consequence of a neurodegenerative process that leads to loss of function, immortalization of cancer cells, and eventually, death of the individual. Oncogenesis shares pathways with neurodegeneration. For example, Chuang et al., 2021  found thNeurodegeneration is highly influenced by lifestyle habits, including alcohol (ab)use. A deeper understanding of the genetic basis of the risk of alcohol use and tendency to abuse is highly sought after. Al-Sabagh et al., 2022  tested tWhich aspect of neurodegeneration should be addressed first?"}
+{"text": "Xie et.al identify a homozygous missense variant in DND1 that causes non-obstructive azoospermia in humans . Aprea et.al. identify the pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 that cause defects of sperm flagella composition and male infertility. They find that immunofluorescence microscopy in sperm cells is a valuable tool to identify flagellar defects related to the axonemal ruler, radial spoke head, and the central pair apparatus . Yuan et al. finds a Gly684Ala substitution in the androgen receptor that causes azoospermia  and Fang et al. reports the phenotypic findings and genetic considerations of congenital absence of the vas deferens with hypospadias or without hypospadias: , which might advance the genetic diagnosis and clinical genetic counseling for male infertility. Zhu et al. also verifies that FISH could analyze numerical chromosomal abnormalities in the sperm of Robertsonian translocation der   carriers . Moreover, Wang et.al review various phenotypes resulting from different pathogenic genes, including sperm ultrastructure and encoding proteins with their location and functions as well as assisted reproductive technology outcomes, providing additional clinical views and broadening the understanding of this disease . Finally, Xu et al. reports a case of the birth of a boy after intracytoplasmic sperm injection using ejaculated spermatozoa from a non-mosaic KS man with normal sperm motility, which increases our knowledge of non-mosaic KS . The findings in these studies broaden our understanding of genetic factors in male infertility and were also included in our Research Topic scope.Our Research Topic is \u201cGenetic Factors in Male Infertility\u201d and the goal of this Research Topic is to collect more papers on the aspect of identifying different gene variants and various types of RNAs mainly focused on male infertility including azoospermia, oligozoospermia, teratozoospermia, and asthenozoospermia. In order to achieve this goal, we carefully reviewed every submitted manuscript and screened for highly qualified reviewers. Eventually, we accepted and published seven articles including four \u201cOriginal Research\u201d articles, one \u201cBrief Research Report\u201d article, one \u201cCase Report\u201d article, and one \u201cReview\u201d. These articles covered the genetic factors of non-obstructive azoospermia and teratozoospermia and the clinical outcomes of men with non-mosaic Klinefelter syndrome (KS)."}
+{"text": "Despite increasing awareness of the ubiquity of microplastics (MPs) in our environments, little is known about their risk of developmental toxicity. Even less is known about the environmental distribution and associated toxicity of nanoplastics (NPs). Here, we review the current literature on the capacity for MPs and NPs to be transported across the placental barrier and the potential to exert toxicity on the developing fetus.This review includes 11 research articles covering in vitro, in vivo, and ex vivo models, and observational studies. The current literature confirms the placental translocation of MPs and NPs, depending on physicochemical properties such as size, charge, and chemical modification as well as protein corona formation. Specific transport mechanisms for translocation remain unclear. There is emerging evidence of placental and fetal toxicity due to plastic particles based on animal and in vitro studies.Nine out of eleven studies examined in this review found that plastic particles were capable of placental translocation. In the future, more studies are needed to confirm and quantify the existence of MPs and NPs in human placentas. Additionally, translocation of different plastic particle types and heterogenous mixtures across the placenta, exposure at different periods of gestation, and associations with adverse birth and other developmental outcomes should also be investigated.The online version contains supplementary material available at 10.1007/s40572-023-00391-x. Since the production of plastics accelerated after the early 1950s, approximately 6300 million metric tons of plastic waste have been generated worldwide, over three-quarters of which have been discarded in various environments .The most commonly used plastic polymers are high- and low-density polyethylene, polyvinyl chloride, polyethylene terephthalate, polypropylene, and polystyrene . PrimarySince MPs and NPs are known to be widely present in food, water, and air, humans are most commonly exposed through ingestion and inhalation routes . A commoThe toxicity of micro- and nanosized plastic particles likely depends on their physicochemical properties including size, shape, molecular structure, functionalization, surface charge, and material type . There iThe potential for wide-ranging health risks associated with MP and NP exposure combined with the heightened susceptibility to environmental agents during fetal development underscores the importance of investigating the maternal-to-fetal transfer of such particles across the placenta. The role of the placenta is to facilitate essential nutrient, gas, and waste exchange for the fetus, but it is not impervious to environmental toxicants. The placental barrier consists of the syncytiotrophoblast layer, cytotrophoblast cells, and the endothelial cell layer of the fetal capillaries see Fig.\u00a0 21\u2022]. T\u2022. T21\u2022].Existing reviews cover the health risks posed by MPs, NPs, and other nanomaterials including placental transport, but none focus solely on the transport of plastic particles across the placenta , 27,\u00a028.Articles were identified for review through a comprehensive literature search using PubMed and Web of Science databases. The search strategy utilized terms such as \u201cplacenta,\u201d \u201ctransport,\u201d \u201cparticle,\u201d and \u201cplastic\u201d with Boolean operators  and Web of Science\u2019s Core Collection (N\u2009=\u2009435). A total of 146 duplicate articles were identified and removed using Endnote. Nineteen additional articles were retrieved from the reference lists of included reviews and other studies. Titles of all papers were screened, abstracts of 51 papers were screened, and 36 full-text papers were assessed for eligibility. Articles were excluded if they did not assess the transport of particles made of plastic across the placental barrier , if they did not explicitly investigate transport across the placental barrier, or if they were not primary research studies . The final selection of 11 primary research articles included 4 studies using in vitro human cell models, 2 in vivo animal studies, 1 study with both in vitro human cells and an in vivo animal model, 3 studies using ex vivo human placental perfusion models, and 1 observational study in humans. The study selection process is outlined in Fig.\u00a0The literature search was conducted in July 2021 and updated in February 2022. A total of 752 articles were identified using PubMed  are provided for the translocation studies specifically. The reported \u201cmajor findings\u201d include results from toxicological investigations as well Table .Using an ex vivo human placental perfusion model, Wick et al. (2010) observed size-dependent maternal-to-fetal placental translocation of fluorescent polystyrene particles. After 180\u00a0min of perfusion, fluorescence measurements and transmission electron microscopy micrographs showed that beads sized 50, 80, and 240\u00a0nm were able to cross the placenta to the fetal compartment, while 500-nm beads did not \u2022. LeveraUsing BeWo b30 cells, Kloet et al. (2015) observed that translocation of 50-nm polystyrene nanoparticles was not dependent on the surface charge of the particles. Translocation of three types of 50-nm polystyrene NPs, one positively charged and two negatively charged, was assessed [protein corona. Using the ex vivo human placental perfusion model, Gruber et al. (2020) found that dynamic protein coronas influenced the translocation of plain 80-nm polystyrene nanoparticles across the placental barrier. First, the group showed the addition of plasma to the perfusion medium increased the maternal-to-fetal transfer of NPs [It is plausible that the interaction of plastic particle surfaces with various endogenous biomolecules affects particle transport. In biological fluids, proteins can rapidly cover the surface of nanomaterials forming a r of NPs \u2022. The cor of NPs \u2022. For exr of NPs \u2022. Using r of NPs \u2022. Media r of NPs \u2022. In allKloet et al. (2015) also investigated the role of specific transport mechanisms by assessing whether the distribution of NPs in the compartments changed in the presence of inhibitors of endocytosis and specific ATP-binding cassette transporters. They found that inhibitors of P-glycoprotein and breast cancer resistance protein had no effect on translocation of either NP and that an inhibitor of multidrug resistance protein 1 increased basolateral translocation of the positively charged NP and had no effect on the translocation of the negatively charged NP \u2022. OveralIn contrast, Grafmueller et al. (2015) posit that the translocation of polystyrene particles across the placenta mainly involves an active, energy-dependent transport pathway. The investigators used the ex vivo human placental perfusion model to assess the bidirectional transfer of both plain and carboxylate modified polystyrene particles with fluorescent labels 50\u2013300\u00a0nm in diameter \u2022. After Since there is accumulating evidence that plastic particles can cross the placental barrier, it is important to investigate the toxic potential of these particles. In the studies using ex vivo placental models by Grafmueller et al. (2015) and Wick et al. (2010), general measures of placental viability, functionality, and transfer were observed not to be affected by perfusion of plastic particles \u2022, 35\u2022. HIn different in vitro models, the human 3A-Sub-E trophoblast cell line and villous cytotrophoblasts derived from term placentas of normal pregnancies, Huang et al. (2015) did observe cytotoxicity of carboxylate-modified NPs. Following exposure to 20- and 40-nm particles in both trophoblast models, they observed elevated cleaved caspase 3, a marker of apoptosis induction, based on Western blot analysis \u2022. They aInterestingly, Hesler et al. did not observe transport across a placental BeWo b30/HPEC-A2 co-culture model at either concentration tested (10 and 100\u00a0\u00b5g/mL) after 24\u00a0h of exposure. The researchers used a different detection system than previous studies, asymmetrical flow field-flow fractionation (AF4), and noted the possibility of translocated particles being present below the limit of detection \u2022. Using Given some evidence of the toxicity of plastic particles on trophoblast and embryonic cell lines, the distribution of plastic particles in fetal organs after transport across the placenta warrants consideration. Kenesei et al. (2016) used an in vivo model to investigate the distribution of surface-modified fluorescent polystyrene nanoparticles after intravenous injection of pregnant mice. Using spectral imaging fluorescence microscopy, they found carboxylated NPs in the lacunas of the placenta 5\u00a0min after particle administration \u2022. ParticIn a pilot observational study, Ragusa et al. (2021) were the first to report MPs found in human placenta samples, confirming the placental translocation of plastic particles observed in ex vivo and in vitro models. The researchers obtained placentas from 6 patients in Italy with uneventful pregnancies \u2022\u2022. SamplEleven studies investigating the capacity for MPs and NPs to cross the placental barrier were reviewed. Placental translocation of plastic particles was observed in multiple experimental models including in vitro cell cultures, in vivo animal models, and ex vivo human placental perfusion systems as well as in an observational study of MPs in human placentas after delivery. One study conducted in an in vitro co-culture context and one study conducted in mice did not observe placental translocation of the plastic particles tested. Given the wide variety of systems used, it is important to weigh the strengths and limitations of the different models when comparing study results.While in vitro models are easier to obtain and utilize for high-throughput studies, they can be over-simplified compared to an in vivo environment. Promisingly, translocation of compounds across in vitro models has been shown to correlate well with the ex vivo human placental perfusion model \u2022, 39, 40In vivo studies of placental translocation of plastic particles in a whole-body system are valuable for understanding more realistic and comprehensive exposure conditions. As such, the study Fournier et al. (2020) conducted in rats provides insight into fetal deposition of NPs after maternal inhalation. Additionally, Kenesei et al. (2016) and Huang et al. (2015) investigated placental translocation of NPs in mice. However, extrapolation of findings from animal studies to humans is difficult due to significant interspecies differences in the placenta; rats show differences in placental morphology, yolk sac function, and steroid hormone biosynthesis, for example , 43.The ex vivo human placenta model used by Wick et al. (2010), Grafmeuller et al. (2015), and Gruber et al. (2020) provides advantages over animal models by more accurately representing the structure of the human placental barrier and over cell culture models by allowing for dynamic flow during exposure. The process of tissue degradation, however, limits experiments with these ex vivo models to a few hours \u2022. BecausThe current literature suggests that the placental translocation and toxicity of MPs and NPs depend on physicochemical properties such as size, charge, and chemical modification. Wick et al. (2010), Cartwright et al. (2012), and Aengenheister et al. (2018) showed size-dependent transport of polystyrene particles across the placenta, while Kloet et al. (2015) found that polystyrene particles of the same size had different translocation properties likely dependent on functional groups. Kloet et al. (2015) also showed that functional groups and charge affect the cytotoxicity of polystyrene particles on placental trophoblast cells. This has implications for the risk assessment of the developmental toxicity of MPs and NPs\u2014more characteristics modulating the translocation and toxicity of plastic particles justify the assessment of more variations and types. Furthermore, Gruber et al. (2020) showed dynamic protein coronas affect placental translocation of NPs, posing another variable in experimental risk assessment.Nine out of eleven studies examined in this review found that plastic particles were capable of placental translocation; observations of MPs in human placentas by Ragusa et al. (2021) make this consensus even more convincing. The mechanism that plastic particles use to cross the placenta remains unclear: Kloet et al. (2015) suggested it was passive diffusion and Grafmueller et al. (2015) suggested it was active transport. It is possible that these mechanisms are not mutually exclusive and the process depends on some combination of both.All of the experimental studies utilized mostly uniform, spherical, polystyrene particles. Polystyrene is widely used to package foods and has been found to be one of the most frequently detected plastic polymers in human blood \u2022. MPs anGiven the evidence that MPs and NPs can not only translocate across the placenta but also subsequently deposit in fetal tissues and exert toxicity \u2022, 34\u2022\u2022, Supplementary file1 (DOCX 17 KB)Below is the link to the electronic supplementary material."}
+{"text": "Over the last few decades, great efforts have been dedicated to the discovery of various nanomaterials. Due to their unique optical, magnetic, and electrical properties (among others), they have found applications in medicine (drug delivery), agriculture, electronics, catalysis, etc. Thus, due to the increasing possibilities, the need to design and fabricate novel nanoparticles is rapidly increasing. In this Special Issue \u201cAdvanced Nanomaterials in Biomedical Application\u201d, a total of seventeen articles\u2014including five reviews\u2014have been published, addressing the most recent advances in nanomaterials in terms of both synthesis and characterization as well as technological applications. In the following, we provide a brief overview of the key findings presented in this Special Issue.50 values were more than 1000 times lower compared to cisplatin. Furthermore, the derivative with the highest activity cisplatin\u2013diacetyl caffeate conjugate and its MSNs induced apoptotic cell death by causing potent caspase activation. Moreover, in vivo studies conducted using BALB/c mouse models with breast tumors showed that the same compound and its MSNs exhibit tumor growth inhibition with a reduced necrotic area and lowered mitotic rate. The review paper by Spoial\u0103  and containing 72 Mo(VI) and 60 Mo(V), to the existing states of the human papillomavirus (HPV) major capsid protein, L1-pentamer (L1-p), and virus-like particles (VLPs). The color responses result from the different binding modes between [Mo132] and the capsid protein. This straightforward colorimetry approach is of importance to estimating the existing states of the HPV capsid protein and could be used in the future to analyze the quality of the HPV vaccine and the existing states of other viruses.The studies conducted by Xue et al.  have shoMany studies have shown that CSC chemokine receptor 4 (CXCR4) is a promising target for cancer therapies, and intracellular siRNA delivery to suppress CXCR4 expression in cancer cells is an effective therapeutic strategy. Thus, Cao et al.  synthesiMin and co-authors  presenteThe work of Tyubaeva et al.  exploresRen and coauthors  summarizDing et al.  designedIn their review article addressing SARS-CoV-2, a hot topic lately, Kianpout et al.  gave an A new nano-emulsion adjuvant based on squalane  containing CpG was prepared, and its in vivo properties were examined . The SNAS35A  with poly acid (PLGA) nanoparticles, the selective delivery of cytotoxin to macrophages, in comparison to epithelial cells, was suggested. This drug delivery system presents anti-inflammatory effects.Harada et al., reported a useful technique for protein delivery to macrophages . By applIn the study by Wen et al. , osteoim"}
+{"text": "They confirmed that [NiFe] large subunits dimerize in the absence of their small subunit (Hartmann et al., Kisgeropoulos et al. investigated the effect of amino acid exchanges of the primary proteinaceous proton acceptor in [FeFe]-hydrogenase. The data expand previous work (Cornish et al., Ka of the proton acceptor is one factor controlling the catalytic bias of the enzyme. Three further articles dealt with functional aspects of hydrogenases. Morra reviewed the identification and characterization of novel [FeFe]-hydrogenases, described their functional roles, and recent findings regarding their O2 tolerance. Kpebe et al. reported on the essential role of a bifurcating [FeFe]-hydrogenase in the sulfate reducer Solidesulfovibrio fructosivorans, showing that during ethanol oxidation, the hydrogenase confurcates electrons from NADH and reduced ferredoxin to produce H2, which is later on used for energy conservation using sulfate as electron acceptor. The function of a bidirectional [NiFe]-hydrogenase in Synechocystis sp. PCC 6803 was investigated by Burgstaller et al.. They showed that this hydrogenase is essential for growth on arginine and glucose in the presence of light and O2, and interestingly this function seems to be unrelated to H2 catalysis. Instead, an H2-independent role for the transfer of electrons into the photosynthetic electron transfer chain is proposed, which is an important hypothesis that may also be relevant for certain multisubunit hydrogenases in other species.This Research Topic comprises 11 articles that aimed to bring together recent advances in hydrogenase research, including structure, function, maturation, and application. In terms of structural investigation, Haase and Sawers investigated residues that contribute to [NiFe]-hydrogenase maturation. They found a histidine residue in a HypC-type chaperone that is important for efficient binding to its maturation partner HypD (Blokesch and B\u00f6ck, Fan et al. significantly improved the [NiFe]-cofactor incorporation in the course of heterologous production of a [NiFe]-hydrogenase from Cupriavidus necator in Escherichia coli. Previously, cofactor insertion was not functional, resulting in production of inactive hydrogenases (Fan et al., On the subtopic of hydrogenase maturation, Hogendoorn et al. isolated the novel strain \u201cCandidatus Hydrogenisulfobacillus filiaventi\u201d R50 gen. nov., sp., nov. which was characterized as a chemolithoautotrophic thermoacidophilic aerobic H2-oxidizing bacterium. This strain excretes about half of the fixed CO2 in the form of amino acids, which makes it a promising candidate for the industrial production of organic compounds from CO2, using H2 as energy source. H2 oxidation in this strain is facilitated by two [NiFe]-hydrogenases from the groups 1b and 1h, with the latter conferring high affinity toward H2 (S\u00f8ndergaard et al., Kobayashi et al. engineered the acetogenic bacterium Moorella thermoacetica for enhanced acetate, ethanol and acetone production. They found that H2 supplementation under mixotrophic conditions increases NADH levels but can inhibit growth due to an unbalanced redox status. This study emphasized the role of a reversible electron-bifurcating group A3 [FeFe]-hydrogenase for balancing the cellular redox state. These observations may also be exploited for biohydrogen production by that strain. Another way to produce H2 was analyzed by Barahona et al.. In order to enhance nitrogenase-driven H2 production in Rhodobacter capsulatus, they used a sensory hydrogenase coupled to the production of a fluorescence signal. By inducing genome-wide mutations and using high-throughput fluorescence-activated cell sorting, they were able to generate mutants with elevated H2 evolution capabilities. Finally, Schumann et al. reviewed current state-of-the-art and future perspectives for efficient light-driven H2 production using phototrophic microorganisms. This technology potentially enables conversion of solar energy into a chemical compound that enables storage and transport. However, as discussed by the authors, extensive engineering is required for this technology to be efficient and scalable.Another four articles explore the application of hydrogenases. 2-based biologically green technologies.Taken together, the Research Topic advances our knowledge especially on the function and application of hydrogenases and provides important perspectives for future HSF: Writing\u2014original draft, Writing\u2014review and editing. CP: Writing\u2014review and editing. FV: Writing\u2014review and editing. CG: Writing\u2014review and editing."}
+{"text": "Metastasis and resistance to cancer therapeutics are critical barriers to curing cancer. This special issue entitled \u201cCancer Metastasis and Therapeutic Resistance\u201d contains nine original contributions. The articles span a variety of human cancers, including breast, lung, brain, prostate, and skin and touch upon significant areas of interest such as cancer stem cell function, cancer immunology, and glycosylation. This special issue contains one review article by Kilmister et al., which touches on the important topic of cancer stem cells (CSC) . These sSriratanasak et al. also tackle important aspects of CSC regulation in a research article that examines the impact of cisplatin-induced senescence on lung cancer cells . TypicalThis issue had a significant set of original research, tackling different aspects of breast cancer. The article by Barutello et al. examines a combination of methods to target the cystine-glutamate antiporter xCT and p53 using the drug APR-246, which restores the wild-type function of p53 in mutant p53 tumors . FindingThe research article by Cheng et al. looks more distinctly at guanylate binding protein 5 (GBP5) and its expression in triple-negative breast cancer (TNBC) . This stPrior studies have shown that fucosylation, a type of glycosylation, promotes metastatic phenotypes and signaling in breast cancer cells ,10. DoudRhosin is a RhoGTPase RhoA/C-yes associated protein (YAP) pathway inhibitor . TsubakiPenas-Mart\u00ednez et al. provided an interesting brief study about the effect of antithrombin (AT) on glioblastoma . RecentlSpine magnetic resonance imaging (MRI) can be typically used to guide treatment for vertebral metastasis. Pichon et al. aimed to improve imaging techniques for metastatic breast and medullary thyroid cancers with metastasis of the spine . The stuIuliani et al. contributed a brief report investigating the effect of an agent abiraterone (ABI), which is a selective inhibitor of androgen biosynthesis, on the osteoblast secretome . These sArticles in this special issue span many topics, all aimed to increase knowledge in the area of metastasis and therapeutic resistance. Common themes include areas of significance in understanding the CSC function as well as breast cancer biology. The overall aim of this issue is to provide a broad representation of research areas that examine mechanisms and approaches for confronting metastasis and the failure of cancer treatments."}
+{"text": "Perrier et al. conducted NGS in six patients with leukodystrophy and described a range of pathogenic variants  of leukodystrophies. Ek et al. emphasized that a genome-wide analysis, with variant calling strategies extended to structural variants (SV) and short tandem repeat expansions (STRs) in addition to single nucleotide variants and small insertions/deletions (SNVs/INDELs), was critical to enhance diagnostic yield for neuromuscular disorders (NMDs). Corroborating literature review and genomic sequencing, Bar et al. identified 22 candidate genes for cyclic vomiting syndromes (CVS), which further suggests a cellular model of the disease mechanism.Next-generation sequencing (NGS) has propelled the diagnosis of neurological disorders, the discovery of new candidate disease loci, and precision therapy. He et al. performed whole-exome sequencing and Sanger sequencing in three patients with adrenomyeloneuropathy (AMN) and identified one known mutation (c.1415_1416delAG) and two novel ABCD1 variants (c.217C>T and c.160_170delACGCAGGAGGC) in the Chinese population, indicating the importance of ABCD1 gene analysis in the diagnosis of patients with spastic paraplegia. Zambrano et al. used NGS to describe two Ecuadorian siblings with muscular dystrophy and deafness who carried EMD and EYA4 mutations associated with phenotypes. Genotypes are also linked to clinical manifestations and laboratory tests. Yang et al. identified differences in serum ceruloplasmin levels correlated to the age of symptom onset and genotypes (ATP7B variant); the authors established the cutoff value (0.13 g/L) of serum ceruloplasmin levels for the diagnosis of Wilson disease (WD) in a Chinese cohort with high sensitivity and specificity. It is hoped that diagnosing and treating neurogenetic illnesses will become easier with the advancement of diagnostic methods.In studying several rare diseases of the nervous system, SM and CL prepared the original draft. BY, LY, and HS critically review and edit the manuscript. All authors have reviewed and approved of the final manuscript."}
+{"text": "Jin  Despite the implementation of numerous weight loss initiatives by various governments, the global prevalence of obesity continues to rise . This noet al [et al [Since its rediscovery in adult humans, research into thermogenic fat has increased tremendously . This iset al  and Yadal [et al  now provet al [In the first study by Jin et al  VSG and et al . When thet al , again ret al [Firmicutes and decreased the fecal abundance of Bacteriodetes, associated with stabilization of the intestinal epithelial barrier. Mass spectrometry analysis then revealed that 3 metabolites were increased in the feces of VSG-operated mice: licoricidin, muramic acid, and 3-hydroxybutyryl carnitine. Moreover, fecal licoricidin not only negatively correlated with various gut microbiota known to promote metabolic disease, but circulating licoricidin levels were doubled in VSG-operated mice suggesting that it could communicate directly with subcutaneous white fat. To formally test if gut microbiota-derived products contribute to thermogenesis in subcutaneous white fat after VSG, mice were treated with a broad spectrum antibiotic cocktail via their drinking water for 2 weeks. Strikingly, this not only prevented the weight loss and metabolic benefits associated with VSG similar to a previous study in diet-induced obese mice [per se contributes to the activation of thermogenesis in subcutaneous white fat after VSG.Jin et al  then reaese mice , but it et al [Next, Jin et al  determinet al , 21 and et al , respectet al , are neeet al [et al [et al [et al [18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging experiments to determine if brown fat contributes to increased energy expenditure in mice receiving post-RYGB fecal microbiota. This revealed that brown fat 18F-FDG uptake in response to overnight cold exposure, the natural stimulus for brown fat, almost doubles in mice receiving post-RYGB feces compared with mice receiving pre-RYGB feces. Accordingly, brown fat UCP1 protein expression was also markedly enhanced.In the other study by Yadav et al  stool sal [et al  apart frl [et al  is that l [et al  found th18F-FDG uptake. This could have provided evidence that post-RYGB microbiota enhance blood glucose clearance in response to insulin treatment through using brown fat as a glucose sink. It would have also been interesting to determine if the patients themselves showed increased oxygen consumption and brown fat 18F-FDG uptake after RYGB, which would have provided the key evidence that this beneficial metabolic change in the host is potentially gut microbiota-mediated and is transmissable to germ-free mice.Considering that the post-RYGB feces-treated mice showed enhanced insulin sensitivity in the absence of any differences in body weight, it would have been interesting to determine if insulin increases brown fat et al performed metabolomic analyses of their feces. This revealed that thermogenic molecules like the short chain fatty acid butyrate [et al [Finally, after showing that differences in patient fecal microbiota after RYGB can be transferred to germ-free mice, such as an increase in Akkermansia municiphila, Yadav butyrate , 25 and butyrate  were incbutyrate  were redbutyrate . Considee [et al . It woulet al [et al [Figure 1). Notably, changes in bile acid metabolism by gut microbiota after VSG leads to the generation of cholic acid-7-sulfate in the liver and its accumulation in the gut [While we are witnessing the dawn of a new era for obesity pharmacotherapy with gut hormone preperations causing unprecendented levels of weight loss, bariatric surgery remains the most effective . The higet al  and Yadal [et al  are grou the gut , which h the gut . Thus, uet al [et al [The findings of Jin et al  and Yadal [et al  demonstrl [et al , and actl [et al ."}
+{"text": "This is a Research Topic on thoracic oncology. Thoracic malignancy is a term used to describe any cancer presented in organs, glands, or structures within the thoracic cavity. Lung cancer is the second most frequent malignancy after breast cancer, accounting for 2.21 million cases annually, and the leading cause of cancer mortality worldwide (1.8 million deaths) for women and men combined  inhibitor and is administered as first-line treatment to ALK-positive metastatic non-small cell lung adenocarcinoma patients. Xing et\u00a0al., systematically reviewed the efficacy and safety of Brigatinib. Tyrosine kinase inhibitors is another type of lung cancer targeted treatment. Currently, mutation status is determined by examining lung tumor tissue biopsies. Hu et\u00a0al., discuss the advances of PET/CT in establishing EGFR mutation status in lung cancer and their clinical significance.Better understanding of the disease has advanced and improved lung cancer treatment and clinical management. Patients may receive chemotherapy, radiotherapy, targeted therapy, immunotherapy, and surgery. Mizuno et\u00a0al., discuss the current status and future perspectives of PD-1/PD-L1 immune checkpoint blockade in lung cancer. ICIs may cause immune-related adverse events. Hao et\u00a0al., present the pathogenesis, risk factors, and clinical presentation of immune checkpoint inhibitor-related pneumonitis. Non-small cell lung cancer patients with mutations on the MET pathway present poor clinical outcomes. The development of targeted tyrosine kinase inhibitors and bispecific antibodies for MET genetic alterations have benefited this cohort of patients. Michaels and Bestvina discuss the evolution and current state of MET selective therapy. Surgery remains the first-line treatment for early stage lung cancer patients with resectable tumors. The surgical methods have developed resulting to smaller surgical traumas, fewer complications, and quicker post-operational recovery periods. Fuzhi et\u00a0al., outline the importance of evaluating pulmonary function in individuals who have undergone surgery for lung cancer, as well as the alterations in pulmonary function that occur after surgery. Additionally, they discuss strategies for effective rehabilitation of pulmonary function and factors that may affect the success of such rehabilitation.The introduction of immune checkpoint inhibitors (ICI) revolutionized cancer treatment and extended survival. However, not all patients respond to ICI therapy and benefit in terms of survival. It is still not clear which is the cohort of patients that would benefit the most. Addala et\u00a0al., 2022; Zhao et\u00a0al., 2022). Parotid and gastric metastases for patients with lung cancer are rare and thus not very well studied. Wang et\u00a0al., and Tang et\u00a0al., present two reviews on primary lung cancer with parotid and gastric metastases.Metastasis is a major factor that leads to mortality, and approximately 90% of cancer deaths are attributed to metastases. Malignant pleural effusion (MPE) is a common clinical problem for patients with lung cancer. The conduction of large-scale randomized clinical trials advanced diagnosis and clinical management. However, treatment focuses on symptom relief and control of fluid accumulation (Boulanger et\u00a0al., reviewed the connection between financial toxicity, quality of life, and survival in high value care.Financial toxicity refers to the adverse impact of cancer treatment expenses on a patient\u2019s quality of life. Lung cancer survivors often experience a rise in unemployment, psychological stress and a decrease in wages, indicating the persistent impact of financial toxicity. Carcinogen derived thoracic cancers including lung and oesophageal are amongst the most frequently diagnosed malignancies worldwide. Despite advances like the introduction of ICIs the clinical management of these patients remains challenging. Endotyping of lung cancer patients in combination with targeted treatments has improved survival. Metastases are common and more studies are necessary to understand the underlying biology. Finally, the effect of cancer on the financial sustainability and stability of patients is an important factor we need to investigate and gather more data.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Wu H. et al., Wu H.-N. et al., Li et al.).Multidrug-resistant (MDR) microbes infection for critically ill patients is a big challenge in clinical practice and is associated with greatly increased mortality . This ReWu H.-N. et al. retrospectively analyzed the distribution and antibiotic resistance of pathogens based on the clinical data of intensive care patients with bloodstream infections presented to a Chinese tertiary hospital and explored the value of procalcitonin (PCT) for the differentiated diagnosis of bloodstream infections caused by various pathogens. Gram-negative bacteria were the most frequently isolated microorganisms and were associated with a higher percentage of complications such as brain dysfunction, acute kidney injury, and thrombocytopenia. It was observed that PCT was a not good biomarker to distinguish bloodstream infections caused by various pathogens or fungi. Given that the mortality for patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infection is reported to be as high as 30%\u221270%, Wu H. et al. used a logistic analysis to assess the association between the neutrophil-to-lymphocyte ratio (NLR) on 4th-day and 28th-day mortality. After balancing the confounders, NLR on the 4th day was associated with the 28th-day mortality, whereas the appropriate initial therapy was an independent protective factor. Moreover, the authors suggested that the trend of the NLR during therapy may help to evaluate the efficacy of different anti-infection therapy strategies at an early stage. In another article, Li et al. described their experience in the management of post-neurosurgical central nervous system infection caused by MDR Gram-negative bacteria with combined intraventricular and intravenous polymyxin B administration. After a mean duration of 14 days of treatment, all six cases caused by CRKP or carbapenem-resistant Acinetobacter baumannii (CRAB) were cured and no obvious kidney injury occurred.Karlsson et al., Yoon et al., Casarotta et al.). Yoon et al. demonstrated that bacterial superinfections were common in a tertiary Korean academic hospital and that more than one-third of the bacterial superinfection cases were caused by multidrug-resistant pathogens. Moreover, bacterial superinfection was associated with significantly fewer ventilator-free days, longer ICU and hospital stays. As many studies reported that a CRAB-associated bloodstream infection was the crucial risk factor for death in patients with COVID-19 . In a prospective longitudinal study in Sweden conducted by Karlsson et al., the authors evaluated the complicated bacteriuria and antibiotic resistance for ICU-admitted COVID-19 patients. They found that the vast majority of patients received antibiotics on ICU admission. Longer stays in ICUs linearly correlated with bacteriuria, and the authors proposed that biofilms in urinary catheters act as a reservoir of pathogenic bacteria with the potential to develop and disseminate antibiotic resistance.This Research Topic also includes three articles on the superinfection of patients with SARS-CoV-2 infection who were admitted to the ICU  study, given that CPR scenarios are at high risk for healthcare-associated infections. By studying Advanced Cardiovascular Life Support (ACLS) courses in a manikin simulation, they found more than half of hand-cleaning indications could have been accomplished without delaying patient resuscitation and they concluded that hand disinfection can be implemented without compromising quality in acute care. In patients with severe acute pancreatitis (SAP), secondary MDR pathogen infection plays a vital role in increased mortality and prolonged hospital and ICU stays  to enhance the resolution of late-phase organizing pneumonia caused by CRKP. Organizing pneumonia is a pattern of lung-tissue repair after injury and it can be cryptogenic or a response to a specific lung injury in many diverse clinical contexts. Given the therapy for organizing pneumonia is empirical and few therapies have been confirmed besides systemic glucocorticoid therapy (This Research Topic also includes an original study by  therapy , they deQL: Writing\u2014original draft. S-JZ: Writing\u2014review and editing. J-CZ: Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "Methodological advancements have played a pivotal role in driving progress within the field of biomedicine. A striking illustration of this trend is the groundbreaking discovery of the CRISPR/Cas9 technology by Emmanuelle Charpentier and Jennifer A. Doudna in 2012, a feat that earned them the Nobel Prize in Chemistry in 2020. This innovation, which facilitates precise gene editing, has revolutionized the capability to incorporate gene sequences into genomes with an unprecedented level of accuracy and efficiency (Jinek et al., Streptococcus pyogenes. Within this context, Charpentier uncovered an entirely novel molecule, tracrRNA, which constitutes a crucial component of the bacterium's innate defense mechanism aimed at neutralizing viruses by cleaving their DNA strands (Deltcheva et al., The genesis of the CRISPR/Cas9 technology emerged unexpectedly from investigations into Consequently, the CRISPR/Cas9 technology has emerged as a cornerstone of modern biotechnology over the past decade. Its global utilization across bioscience domains underscores its impact and significance, and it applications have extended far into the field of clinical neurosciences. So far, CRISPR/Cas9 has inseminated Cellular Neuropathology in the following ways:Treating Genetic Disorders: CRISPR/Cas9 technology holds promise for treating genetic disorders in the nervous system. Researchers have been exploring its potential for correcting mutations associated with neurodegenerative diseases such as Huntington's disease (Morelli et al., Modeling Neurological Disorders: CRISPR/Cas9 has been used to generate cellular and animal models of various neurological disorders. This allows scientists to study disease mechanisms more accurately, potentially leading to insights into the underlying causes of disorders like Alzheimer's disease (Schrauben et al., Understanding Neurodevelopment: By precisely manipulating genes in developing organisms, researchers have been able to uncover the roles of specific genes in brain development (Zhang et al., Functional Genomics: CRISPR/Cas9 technology has enabled scientists to perform large-scale functional genomics studies in neural cells (Sandberg et al., Pain Management: Researchers have explored the use of CRISPR/Cas9 technology to modulate pain perception by targeting specific genes involved in pain pathways (Reese et al., Gene Therapies for Neurological Disorders: CRISPR/Cas9-based gene therapies have shown promise in preclinical studies for various neurological disorders (Ou et al., Regenerative Medicine: CRISPR/Cas9 technology has been investigated for promoting neuronal regeneration after CNS injuries (Keatinge et al., It is important to note that while CRISPR/Cas9 technology holds immense potential, there are also challenges to overcome, including off-target effects, delivery methods, and the need for rigorous safety assessments before any clinical applications can be more widely adopted. The use of CRISPR/Cas9 in clinical neuroscience has also brought about important ethical discussions. Ensuring the safety and specificity of gene editing techniques in the complex and delicate nervous system is a critical consideration.in vitro and in vivo. With this Research Topic, we would like to expand current knowledge in the field functional genomics and gain further insight into neurodevelopmental disorders. This Research Topic is open for all disease areas. Papers outlining limitations and challenges of CRISPR/Cas9 technologies are particularly invited. In this search for the best ideas and concepts, Original research, Reviews, Perspectives and Opinions are envisaged. Papers will be reviewed based on excellence, originality and innovation potential. Outstanding papers will be featured in an editorial. We are looking forward to your contributions to this new Research Topic.In an effort to identify the most promising concepts in translational neurosciences, the Cellular Neuropathology section of Frontiers in Cellular Neurosciences recently launched a platform, the Hot Topics hub Hermann, . Within DH: Conceptualization, Investigation, Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "MWCNTs. The hybrid nanofluid is under the influence of magnetohydrodynamic effects and chemical reaction with activation energy. The governing partial differential equations (PDEs) are transformed into ordinary differential equations (ODEs) using suitable similarity transform. Homotopy analysis method is used to solve the non-linear system of ODEs and MWCNTs while the mass transfer rate depicts contrasting behavior.Hybrid nanofluids are extensively analyzed in recent studies due to their better performance in numerous areas such as heat and mass transfer enhancement, biological fluid movement, medical equipment, heat exchangers, electronic cooling and automotive industry. In current study the nanoparticle concentration utilized is much important in biomedical industry. Major applications include drug delivery, radio-pharmaceuticals, centrifuging blood to obtain red blood cells and plasma, medical implants, onco therapeutics and photo thermal cancer therapy. In this regard, the primary focus of this study is to simulate a blood based unsteady hybrid nanofluid flow between two rotating, stretching disks and convective boundaries. The two nanoparticles in this study are uranium dioxide  Jabbaripour et al.2 examined a water based three dimensional hybrid nanofluid flow with aluminum and copper nanoparticles at slip boundary conditions. Subhani and Nadeem3 analyzed water based micro-polar hybrid nanofluid flow with copper and titanium oxide nanoparticles over a stretching surface. Khan et al.4 studied the convective flow of Casson-nanofluid with gold nanoparticles through a rotating disk under impact of non-linear thermal radiation. Izaday et al.5 numerically scrutinized a Ag nanoparticles passing through an artery is analyzed by Chahregh and Dianrvand6 to better understand the blood circulation through the respiratory system. Ghasemian et al.7 presented their work on three-dimensional unsteady Maxwell nanofluid. Alghamdi et al.8 examined the flow of a 9 conducted a study on flow of 10 considered MFD viscosity effects on flow of a magnetic nanofluid. Waqas et al.11 simulated the free convective flow of a water based nanofluid. 12 simulated a stagnation point flow of a hybrid nanofluid with respect to the masses of two types of nanoparticles i.e., magnesium oxide and silver. Mansourian et al.13 analyzed the flow of a ferro-hybrid nanofluid passing over a stretching sheet.The nanofluids are formed by adding particles of nano-meter size into base fluid either by directly mixing (one-step method) or synthesizing nanoparticles first and then mixing (two-step method). The nanofluids consist of two-phases, fluid phase (base-fluid) and solid-phase (nanoparticles). Base fluids usually are water, ethylene glycol, blood and engine oil etc. while nanoparticles are mostly metal oxides, carbides or carbon nanotubes CNTs. When two types of nanoparticles are mixed into the base fluid then hybrid nanofluid is formed. Hybrid nanofluids enhance the efficiency of base fluids in terms of effective thermal conductivity, diffusivity, viscosity and heat transfer rates. These fluids are potentially useful in microelectronics, hybrid-powered engines, solar energy collectors, heat exchangers, drug transport and many medical equipment. Due to vast applicability, many researchers have attempted to analyze and simulate various hybrid nanofluid models in most recent studies. Rashidi et al.14. He developed a differential setup to analyze the hydrodynamical flow over an infinite rotating disk. His work was further extended by Griffiths15 where he analyzed generalized Newtonian fluids which provided a comprehensive description to non-Newtonian boundary layer flows. Rashidi et al.16 investigated the slip flow of a nanofluid on a rotating porous disk. Khan et al.17 numerically analyzed Oldroyd-B nanofluid flowing over an exponentially stretched surface with radiative effects. Hayat et al.18 studied a third grade nanofluid flow over a single rotating and stretching disk with thermophoresis and Brownian motion. Shah et al.19 investigated a nanofluid flow between two rotating and stretching disks with silver based CNTs under MHD effects. Usman et al.20 presented work on enhancement of heat transfer in a blood based nanofluid with power-law model and heat source/sink stimulated by two rotating stretchable disks. Convective flow of a Newtonian fluid between co-rotating stretching disks with Soret and Dufour effects is examined by Sharma et al.21. Rauf et al.22 explored the rate of heat transfer in a hybrid ferrofluid boundary layer flow passing over a rotating and non-linearly stretching disk in presence of an alternating magnetic field. Usman et al.23 presented steady flow model of a power law fluid co-axially rotating between two stretchable disks with heat source/sink.Flow originated by rotating stretching disks have gathered researchers\u2019 interest due to their applications in food processing, medical equipment, industrial and engineering sectors. Fruitful outcomes have been drawn through several researches but the pioneering work on rotating disk was presented by Karman24, Salahuddin et al.25, McCash et al.26, Raza et al.27 and Nisar et al.28 explored effects of chemical reaction with activation energy on various non-Newtonian and nanofluid models. Saleem et al.29 studied the effects of chemical reaction on flow of a second-order viscoelastic fluid with heat generation effect. Gowda et al.30 recently analyzed the heat and mass transfer rate in a non-Newtonian second grade nanofluid model undergoing chemical reaction with activation energy. Zaib et al.31 applied binary chemical reaction with MHD effects on Casson nanofluid flowing over a wedge. Khan et al.32 analyzed a chemically reactive nanofluid flow over a moving needle with viscous dissipation. Flow of cross nanofluid with immersed gyrotatic microorganisms is presented by Azam et al.33 under effects of non-linear thermal radiation.Addition of surfactants, stabilizers and various nanoparticles in blood causes major chemical reactions. Activation energy is the minimum amount of energy required to start off that chemical reaction. Arrhenius equation is utilized to describe the change of rate constant with changing temperature in a chemical reaction. These reactions take place mostly in chemical reactors which are most of the time limited through the rate of mass transfer. In this context, it becomes much important to incorporate chemical reaction effects in order to analyze the flow problem in this study. Other researchers including Hamid et al.34 in 2009 pioneered working with convective boundary conditions while investigating the Blasius flow. Afterwards, various authors analyzed different fluid models in this regard. Yao et al.35 analyzed the heat transfer in viscous fluid flow past a stretching/shrinking wall with a convective boundary condition. Hayat et al.36 investigated the stagnation point flow of a Casson fluid with mixed convection over a linearly stretching surface with thermally convective boundary. Wang et al.37 studied the bio-convective flow of a Maxwell nanofluid with slip effects and passing over an exponentially stretched surface. Haq et al.38 investigated the flow behavior of a Casson nanofluid with convective boundaries. Zaib et al.39 simulated flow of a nanofluid with convective boundaries in a Darcy-Brinkman porous medium. Boundary layer flow of a Casson fluid is examined by Hussain et al.40 with convective boundary conditions and flow over a stretching wedge. Furthermore, recent researchers on convective boundaries are presented by various authors including Akhtar et al.41, Anuar et al.42, Mabood et al.43, Becerro et al.44 and Rasheed et al.45.Convective conditions are characterized by interaction between boundaries of the machinery and the surrounding environment. Heat exchange by convection is the main cause of thermal response in the machine tools which is important in describing the fluctuations due to environmental changes or addition of cooling liquid. The heat transfer coefficients (HTCs) in these conditions are the proportionality constants when convective heat flux and temperature difference (between fluid and structure) are related. AzizMWCNTs. The governing unsteady non-linear PDEs are converted into ODEs by applying suitable similarity transformations. The obtained system of ODEs is then solved by using homotopy analysis method (HAM)46. To provide convergence of the solution In light of the literature review stated above, it is observed that an unsteady flow of a blood base hybrid nanofluid between two rotating and stretching disks with chemical reaction and activation energy along with convective boundaries has not been investigated. Moreover, uniqueness and need of present work is discussed in comparison with existing recent literature on unsteady hybrid nanofluid flow in Table We consider an unsteady blood hybrid nanofluid flow between two rotating and stretching disks in cylindrical coordinate system mentclass2pt{minimu, v and w are radial, tangential and axial velocities in r, z directions, respectively. T represents hybrid nanofluid temperature and C is the concentration. Chemical reaction rate is denoted by s is a constant power. Also, b is a positive constant with dimension of k is thermal conductivity and D is the thermal diffusivity. MWCNTs are presented in Table entclass1pt{minima57Pr is the Prandtl number, M is the magnetic interaction parameter.In order to non-dimensionalize the problem and to convert the system of partial differential equations into ordinary ones , the following similarity transforms are introducedmentclass2pt{minim use Eq.  and obtamentclasspt{minimaSkin friction sing Eq.  we obtaiIn order to solve system of highly non-linear ordinary differential equations in Eqs. \u201311) we  we 11) w The final form of series solution obtained as a result is as followsough Eq.  and geneAfter computing the series form solution through homotopic approach the convergence of results is optimized through entclass1pt{minimaThe flow problem is simulated in the fluid domain to depict the behavior of hybrid nanofluid under various effect and physical parameters. In this regard, each fluid phenomena is discussed in detail for hybrid nanofluid in following sections for velocity, temperature and concentration profile.M. In Fig. M. As M increases, the viscous forces in fluid layers decreases causing increase in velocity in all directions. This increase in velocity results in increased temperature of hybrid nanofluid. The temperature profile is analyzed for both fully convective and non-convective boundaries. It is observed that temperature in fully convective boundaries is higher when compared with thermally non-convective (The ratio of electromagnetic force to the viscous forces in a fluid flow is characterized by magnetic interaction parameter, Unsteadiness parameter, The parameters MWCNTs in blood increases the velocity of the hybrid nanofluid in radial, tangential and axial direction. Temperature of the hybrid nanofluid decreases with increased volume fraction of MWCNTs. It is also observed that fully convective boundaries offer higher temperature than non-convective boundaries in case of increasing volume fraction of carbon nanotubes.In Fig. Pr decrease fluid temperature due to reduced thermal conductivity inside the fluid. Fully convective boundaries offer higher temperature as compared to non-convective disks when Pr is increased. Increase in activation energy parameter Convective and non-convective boundary cases for temperature and concentration are shown in Fig. M increases the skin friction due to enhanced Lorentz forces between fluid particles. Increasing volume fraction of CNTs increases the skin friction as nore solid nanoparticles move through the fluid. Unsteady parameter U and stretching parameter Figure Pr, CNTs increases the heat transfer in Fig. Pr, Rate of heat transfer is the ratio of convective heat transfer and conductive heat transfer during a fluid flow. Figure CNTs volume fraction The ratio of mass transfer by convection and diffusion is the Sherwood number which is the mass transfer rate in the fluid. Figure M and Radial, tangential and axial velocity of the hybrid nanofluid increases with increase in Increase in M and Pr.Temperature of the hybrid nanofluid boosts with higher values of Convective boundary conditions result in higher temperature of hybrid nanofluid when compared with non-convective boundary condition case.Increase in Skin friction increases with increase in both volume fractions The rate of heat transfer decreases with increasing volume fraction CNTs decreases the rate of mass transfer in the hybrid nanofluid.Increase in volume fractions of both nanoparticles Current investigation focuses on simulating an unsteady and convective flow of blood based hybrid nanofluid undergoing chemical reaction with activation energy. A novel semi-analytical approach that is homotopy analysis method is utilized to solve the modeled system of non-linear ODEs. Convergence control parameters"}
+{"text": "Pharmacoepidemiology, the study of the use and effects of medicines in large human populations, is a bridging science between clinical pharmacology and epidemiology. Pharmacovigilance is \u201cthe science and activities related to the detection, evaluation, understanding, and prevention of adverse effects or other problems associated with medicines.\"This Research Topic contains six manuscripts using pharmacoepidemiological methods, five original research papers, and one perspective paper, including one paper using electronic health records as an information source, two papers using spontaneous reporting systems, and three papers using nationwide medical information based on claims data.Alsowaida et al.). The global epidemic of COVID-19 has made the development of effective drugs for the treatment and prevention of COVID-19 a global priority. Several post-marketing studies have reported significant bradycardia with remdesivir administration, and this article provides validation in an evidence-based source.First, a retrospective cohort study using electronic medical records was reported by  to methotrexate (MTX)-based therapy could help reduce the dose-dependent adverse events of MTX, providing clinical evidence to support the beneficial effect of FA.Lin et al. hypothesize that statins inhibit MSU-induced gout flares through their anti-inflammatory properties, and a cohort study using the 2000 Longitudinal Generation Tracking Database (LGTD 2000), a randomly selected dataset of 2 million NHI recipients, found that statins have chemopreventive potential against MSU.Taiwan\u2019s National Health Insurance (NHI) program covered more than 99.9% of the 14 Taiwanese population by 2014 . The NHIYen et al. recruited participants with type 2 diabetes mellitus (T2DM) and cirrhosis from the NHIRD between 1 January 2000 and 31 December 2017 and followed them until 31 December 2018. This report found that using alpha-glucosidase inhibitors was associated with a reduced risk of mortality, hepatocellular carcinoma, compensated cirrhosis, and liver failure in patients with diabetes and compensated cirrhosis.Shida et al. carefully explained the details of these studies.This type of study has not been conducted exclusively in Taiwan. The Pharmaceuticals and Medical Devices Agency (PMDA), the Japanese regulatory authority, conducts various pharmacoepidemiological studies based on actual data from its medical information database for post-marketing drug safety evaluation. Since various medical information is a source of pharmacoepidemiological studies, researchers should properly characterize the sources and consider the study design.The inverse signals detected by pharmacoepidemiological studies are known to be helpful in the search for drug candidates , and man"}
+{"text": "Alternative splicing is a major mechanism to increase the number of proteins that can be made from the limited number of genes present in the human genome. During transcription of genes into precursor messenger RNA (pre-mRNA), non-coding introns are spliced out to make a messenger RNA (mRNA) that encodes the functional protein. During the splicing process some exons can be included or excluded and this process is termed alternative splicing. This is a highly regulated process that produces diverse mature mRNA transcripts from a single gene. Alternative splicing is present in almost every gene and is widespread in eukaryotic evolution. Moreover, the majority of genes expressed in the mammalian central nervous system undergo extensive alternative splicing, with some genes capable of contributing to over a thousand isoforms. This results in a variety of proteoforms exhibiting differences in function, binding preferences, catalytic activity, and localization. Disruptions in alternative splicing have been associated with numerous neurological disorders. A comprehensive understanding of its role in healthy and pathological nervous system function is still emerging. It is timely to gather current knowledge, advancement and challenges in this field. With this objective, we brought together several articles that discuss involvement of splicing and associated genetic perturbations in the central nervous system across the evolutionary scale\u2014from fly to human.Feng et al. focuses on the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a key RBP associated with neurodegeneration and cancer. The authors discuss hnRNPA1's role in gene transcription, mRNA translation, and stability, highlighting its importance and potential as a therapeutic target. Another study by Titus et al. reveals the functional role of the RBP Caper in Drosophila, emphasizing its significance in sensory and motor neurons development and its regulatory role in Drosophila gravitaxis behavior.Many RNA binding proteins (RBPs) play a crucial role in splicing regulation. The review by Lu Y. Q. et al. reveal the causative role of TANK-binding kinase (TBK1) in Amyotrophic Lateral Sclerosis (ALS) through mutational analysis, emphasizing the importance of intronic sequencing and pre-mRNA splicing analysis in understanding the complex mutational spectrum and pathogenesis of ALS. Reis et al. uncover a severe early onset dementia syndrome caused by an intronic splice donor variant in expanding our understanding of early onset dementia syndromes with a digenic background. Chen et al. identify a de novo splicing variant of the FOXP1 (Forkhead Box P1) gene in a patient with FOXP1 syndrome , providing insights into the genetic basis of global developmental delay, intellectual disability, and language delay. Fan et al. identify a disease-causing and aberrant splicing-inducing variant of TSC complex subunit 2 gene (TSC2) in a Han-Chinese family with Tuberous Sclerosis Complex (TSC), expanding the phenotypic and genetic spectrum of TSC and potentially contributing to its diagnosis and treatment. Wang et al. report a novel heterozygous STXBP1 (Syntaxin Binding Protein 1) splice variant with abnormal intron retention in a patient with Ohtahara syndrome (a rare form of epilepsy), highlighting the significance of splicing defect analysis in understanding the pathophysiology of neurodevelopmental disorders. Levchenko et al. reveal a deep intronic variant in the SNX14 (Sorting Nexin 14) gene in patients with spinocerebellar ataxia type 20, providing insights into the molecular pathogenic mechanism underlying the formation of a novel donor splicing site and potential therapeutic implications.Several studies identify splicing mutations associated with various neurological conditions. Xia et al. assess multiple mutations in three repeat (3R) tau for microtubule binding properties and prion-like aggregation propensity, contributing to the understanding of diverse presentations of tauopathies. Using bioinformatics pipelines, Farhadieh and Ghaedi reveal alternative splicing events (ASEs) in postmortem brain tissue with a cell-specific perspective, providing insights into AD pathology at the cell level. Lu Y. et al. identify several significant AS events in an AD mouse model, offering novel pathological mechanisms mediated by splice changes. Alalwany et al. investigate the neuroprotective effects of VEGF splice isoforms against AD-related neurotoxicity, suggesting potential therapeutic avenues.Tauopathies, including frontotemporal dementia and Alzheimer's disease (AD), are neurodegenerative diseases caused by tau brain aggregates. Tau protein, a microtubule-associated protein, can be disrupted in disease states due to the balance of tau splice isoforms. Winsky-Sommerer et al. analyze the transcriptome and translatome in the female mouse hippocampus at different ages, revealing age-associated splicing changes and their potential role in age-related deficits in hippocampal-dependent behavior. The study provides a comprehensive resource for understanding age-associated splicing changes with implications for neurological diseases.Aging is a major risk factor for neurological disorders including dementia. Baxter et al. explore the correlation between high K+ exposure, delayed-onset NMDA receptor-dependent neuronal death, and exon inclusion levels in neurons and astrocytes in vitro. The study highlights the neurotoxic nature of certain stimulation paradigms and emphasizes the importance of NMDA receptor blockade.Differential splicing of exons in neurons can alter protein properties, including ion channels, neurotransmitter receptors, and synaptic cell adhesion molecules. The Research Topic brings together up-to-date research focused on the biology of splicing and its regulators and associated mutations in neurological diseases. It provides new insights into the pathophysiological role of splicing modulations and offers possible strategies for therapeutic targets.KL-A: Conceptualization, Writing \u2013 original draft, Writing \u2013 review & editing. MS: Conceptualization, Writing \u2013 original draft, Writing \u2013 review & editing."}
+{"text": "Epidemiological studies indicate an alarming narrowing in the gender gap of alcohol and tobacco use especially in adolescents, which may reflect changes in sociocultural patterns in women. Moreover, women use more often alcohol to cope with stress and negative feelings. Pharmacokinetics and pharmacodynamics differences, reward process specificities, and female hormones play a major role in gender differences. Women\u2019s consumption of alcohol may be associated with serious birth and developmental consequences in newborns.Thibaut F et al. WFSBP and IAWMH Guidelines for the treatment of alcohol use disorders in pregnant women. The World Journal of Biological Psychiatry 2019 20(1):17-50None Declared"}
+{"text": "Vibrio campbellii is described in the paper by Zhou et al. .A new chitin-active AA10 lytic polysaccharide monooxygenase from the marine bacterium  The longest linker, connecting the CBM73 to the other three domains, has typical features of an extended linker, with low sequence complexity and abundance of proline (four) and glutamate (four). Indeed, based on various observations, including lacking electron density for the CBM73 in one of the et al. have gone a long way in the further characterization of their LPMO domain, thus providing important information for the LPMO field. In particular, their data on binding of various metal ions are unique and shed light on the binding potential of the unique copper binding histidine motif in LPMOs. As a point of warning, the pH and temperature optima for \u2018LPMO activity\u2019 described in the paper are based on measuring H2O2 production resulting from an off-pathway oxidase reaction of the LPMO with molecular oxygen  have a role in the pathogenicity-related physiology of Vibrio species. The novel, complete crystal structure of VhLPMO10A and the adjacent functional data provide an excellent starting point for digging deeper into the true biological role of these enzymes. Importantly, GbpA, VhLPMO10A and several other LPMOs with putative roles beyond biomass processing (e.g. Askarian et al., 2021et al., 2022i.e. a polymer of a sugar, N-acetyl\u00adglucosamine, that is abundant in carbohydrate-containing microbial structures, such as cell walls. It needs to be questioned whether chitin is the true substrate of these LPMOs. In this respect, it is worth noting that the topology of the substrate-binding surfaces of the LPMO domains of GbpA and VhLPMO10A is somewhat different from those of LPMOs known to play a key role in chitin degradation, such as SmLPMO10A (also known as CBP21; see arrows in Fig. 3 in Zhou et al., 2023Zhou et al., the biological function of proteins such as VhLPMO10A and GbpA remains largely enigmatic. From work on GbpA, it seems certain that these proteins are important mediators of the interaction between Vibrio and relevant host surfaces (Kirn et al., 2005et al., 2012Vibrio cells. Interestingly, the GbpA ortholog of the non-pathogenic bacterium Aeromonas veronii Hm21 stimulates epithelial cell proliferation in Zebrafish (Banse et al., 2023VhLPMO10A may have substrates that are yet to be discovered.Despite the structural and functional insights provided by Zhou"}
+{"text": "The detrimental effects of APOE4, the strongest genetic risk factor for AD, have been characterized in different brain cell types, including oligodendrocytes  isoform encoded by the \u201cC\u201d allele of the rs11136000 polymorphism impairs oligodendrocyte progenitor cell (OPC) proliferation and myelination through paracrine signaling from astrocytes   and microtubule-associated protein tau (MAPT) genes , is expressed in microglia and mediates extracellular lipid sensing (Deczkowska et al., TREM2 and other genetic risk variants specific to microglia, neuroimmune myelinoids can be generated by seeding iPSC-derived microglia onto the myelinoid to allow microglia infiltration and interaction with other cell types in the organoid (The roles of genetic risk factors for AD in myelin homeostasis can be defined by deriving genetically engineered myelinoids that express genetic risk variants, such as APOE4 . As a tres APOE4  (Huang ees APOE4 . Anotherorganoid  (Cerneckorganoid . Given torganoid .+ T cells in the aging mouse brain, leading to oligodendrocyte activation and death (Kaya et al., Peripheral effectors, such as immune cells and serum proteins have been recently implicated in AD pathogenesis as well (Gate et al., in vivo to promote advanced myelinoid maturation and vascularization (in vitro (Mansour et al., Finally, various myelinoids discussed earlier can be transplanted rization . Indeed,It is also important to consider various limitations of the brain organoid technology for modeling AD, so that appropriate experimental controls can be utilized (Cerneckis et al., Although AD has historically been considered a gray matter disease, emerging evidence indicates concurrent white matter dysfunction during AD progression. The versatile myelinoid platform offers unprecedented access to human brain myelination models that can be tailored to address specific hypotheses pertaining to myelin dysfunction in AD. For example, microglia can be incorporated into myelinoids described in JC: Writing\u2014original draft, Writing\u2014review and editing. YS: Writing\u2014review and editing."}
+{"text": "The rapid advancement of biomedical sensor technology has revolutionized the field of functional mapping in medicine, offering novel and powerful tools for diagnosis, clinical assessment, and rehabilitation. The ability to collect and analyze various physiological signals, even in real-time, has provided unprecedented insights into the \u201chidden\u201d functioning of the human body. Biomedical sensors have not only enhanced our understanding of human physiology but have also significantly impacted clinical decision-making, patient management, and the development of personalized medical interventions.This Special Issue presents a collection of 14 papers that showcase the diverse applications of biomedical sensors in the context of functional mapping. The papers can be grouped into three sections, highlighting their contributions to (i) medical diagnosis, detection and prediction; (ii) neurological and rehabilitation assessment; and (iii) medical applications and monitoring. Together, these papers shed light on the transformative role of biomedical sensors in understanding physiological mechanisms and enhancing healthcare practices.This section focuses on the application of biomedical sensors for medical diagnosis, detection and prediction. The papers included in this section have a specific focus on the detection of conditions such as COVID-19 and hand osteoarthritis and the prediction of emotions by biosignals. Furthermore, novel approaches based on artificial intelligence and cutting-edge technologies are described.The paper \u201cCOVID-19 Detection Using Photoplethysmography and Neural Networks\u201d [In the paper \u201cToward Early and Objective Hand Osteoarthritis Detection by Using EMG during Grasps\u201d , researcThe third paper \u201cApplications of Laser-Induced Fluorescence in Medicine\u201d  exploresAdditionally, the paper \u201cPredicting Emotion with Biosignals: A Comparison of Classification and Regression Models for Estimating Valence and Arousal Level Using Wearable Sensors\u201d  delves iThis section explores the applications of biomedical sensors in neurological assessment and rehabilitation. The papers collected in this section describe interesting advancements in the analysis of electroencephalography (EEG), EMG and Near-Infrared Spectroscopy (NIRS) signals for the extraction of biomarkers to characterize individual status in neuromuscular applications that can have a potential impact, for example, on the assessment of rehabilitation effectiveness.The paper \u201cReliability of Mental Workload Index Assessed by EEG with Different Electrode Configurations and Signal Pre-Processing Pipelines\u201d  evaluateIn the paper \u201cA Novel Approach for Segment-Length Selection Based on Stationarity to Perform Effective Connectivity Analysis Applied to Resting-State EEG Signals\u201d , researcThe paper \u201cReliable Fast (20 Hz) Acquisition Rate by a TD fNIRS Device: Brain Resting-State Oscillation Studies\u201d  introducThe paper \u201cCombined Use of EMG and EEG Techniques for Neuromotor Assessment in Rehabilitative Applications: A Systematic Review\u201d  presentsNext, the paper \u201cWhole-Body Adaptive Functional Electrical Stimulation Kinesitherapy Can Promote the Restoring of Physiological Muscle Synergies for Neurological Patients\u201d  introducFinally, the paper, \u201cTechnology Acceptance Model for Exoskeletons for Rehabilitation of the Upper Limbs from Therapists\u2019 Perspectives\u201d  addresseThis last section emphasizes the role of biomedical sensors in medical applications and monitoring, describing novel technologies and tools to improve health monitoring in different medical scenarios.The paper \u201cTowards a Practical Implementation of a Single-Beam All-Optical Non-Zero-Field Magnetic Sensor for Magnetoencephalographic Complexes\u201d  introducThe paper \u201cExperimental Assessment of Cuff Pressures on the Walls of a Trachea-Like Model Using Force Sensing Resistors: Insights for Patient Management in Intensive Care Unit Settings\u201d  investigContinuing in the realm of prosthetic control, the paper \u201cQuestioning Domain Adaptation in Myoelectric Hand Prostheses Control: An Inter- and Intra-Subject Study\u201d  delves iThe last paper in this section, \u201cMulti-Scale Evaluation of Sleep Quality Based on Motion Signal from Unobtrusive Device\u201d , introdu\u201cBiomedical Sensors for Functional Mapping: Techniques, Methods, Experimental and Medical Applications\u201d presents a comprehensive collection of cutting-edge research in the field of biomedical sensors. The papers cover a wide range of applications, including medical diagnosis and detection, neurological assessment and rehabilitation, and medical monitoring. These advancements pave the way for improved healthcare practices, patient outcomes, and personalized medicine. As biomedical sensor technology continues to evolve, the findings from these research studies hold significant promise in revolutionizing medical practices and addressing complex health challenges, ultimately leading to better human health and well-being.The Special Issue"}
+{"text": "Ocular neurodegeneration including high myopia, glaucoma, macular degeneration, optic nerve atrophy, and retinopathy can lead to blindness without timely and appropriate treatment. As the retina is actually an extension of the brain, studies on the molecular mechanisms by which these eye diseases develop are currently one of the hottest research areas in neuroscience.Novel mechanisms, diagnostic and therapeutic strategies for ocular neurodegeneration\u201d is to extend our knowledge related to retina and vision disorders by bringing together work in ophthalmology, optometry, psychology, neuroscience, and vision science.Investigations on neuronal correction of visual deficits have enriched our knowledge of functional eye diseases including ocular neurodegeneration. Nevertheless, it is urgently needed to further our understanding of how these eye diseases develop. Notably, novel therapies with superstar pharmacological intervention or new methods such as gene therapy or stem cell therapy have been attracted into this research area. The aim of this Research Topic \u201cMolcak et al. have summarized the expression, distribution, functions, and interactions of purinergic receptors in the retina and included potential crosstalk with other systems. Dissection of how these processes are affected will improve our understanding of the mechanisms that drive age-related macular degeneration (AMD).Avrutsky et al. have shown their original research data that caspase-9 inhibition has significant retinal protection from retinal vein occlusion (RVO). To be more specific, they have compared the therapeutic effect of caspase-9 inhibition with VEGF neutralization in an established mouse model of RVO, and they have conducted a series of examinations, including fundus angiography, optical coherence tomography (OCT), and electroretinography (ERG), for analyzing pathological changes.Ye et al. have investigated the long-term safety, efficacy, and binocular balance of monovision surgery using Implantable Collamer Lens (ICL) V4c implantation and Femtosecond Laser-Assisted in situ Keratomileusis (FS-LASIK) for the treatment of myopic patients with presbyopia. The results show that CL V4c implantation and FS-LASIK monovision treatment have long-term safety and binocular visual acuity at various distances.Lan et al. have demonstrated the control ability and characteristics of fixational displacement among healthy adults in a convenient method by using eye-tracking technology. A total of 100 healthy people were recruited for this study, providing an objective view that the fixation stability decreased significantly in the group aged over 50 years old.Chen et al. have reported a non-invasive diagnosis tool to assess blood flow perfusion in a visual pathway for ocular ischemic syndrome (OIS), which is attributable to chronic hypoperfusion caused by marked carotid stenosis. They have detected blood flow perfusion in a visual pathway by 3D pseudocontinuous ASL (3D-pCASL) using 3.0T MRI (magnetic resonance imaging). The results indicate that that there is a lower blood flow perfusion value in the visual pathway in patients with OIS.Velmurugan et al. have summarized different gene therapy methods in Leber hereditary optic neuropathy (LHON), suggesting that a mitochondrially targeted AAV (adeno-associated virus) gene therapy is more efficient than an allotopic AAV gene therapy for rescuing the LHON phenotype.Zheng et al. have presented a surprising treatment for restoring vision in adult amblyopia rats. By using molecular and histological approaches, they have revealed that low-frequency repetitive transcranial magnetic stimulation (rTMS) reinstates the amplitude of visual evoked potentials without influencing the impaired depth perception of amblyopic rats. They conclude that rTMS enhances functional recovery and visual plasticity in an adult amblyopic animal model.Zhang et al. have given a bibliometric analysis of apoptosis in glaucoma. This research will broaden our comprehension about the role of apoptosis in the process of glaucoma and provide guidelines for us in basic research and disease treatment.Zhen et al. have summarized rhodopsin-associated retinal dystrophy and its disease mechanisms and therapeutic strategies. In particular, they emphasize that innovative therapy strategies, such as gene therapy  and stem cell therapy, are promising methods for the future treatment of retina pigmentosa. Nevertheless, greater efforts are needed from basic researchers and clinicians to facilitate the translation of recent research findings from the laboratory into clinical practice.Xiang et al. have interrogated the question of whether children with monocular myopia need to wear glasses. They consider the facts that (1) monocular myopia could lead to the accommodative dysfunction and unbalanced input of binocular visual signals, resulting in myopia progression; (2) monocular myopia may also be accompanied by stereopsis dysfunction, and long-term uncorrected monocular myopia may worsen stereopsis acuity in adulthood; (3) patients with monocular myopia could exhibit stereopsis dysfunction at an early stage; thus, they come to a conclusion that children with monocular myopia must wear glasses to restore binocular balance and visual functions, thereby delaying myopia progression.Boal et al. have presented a study showing that retinal ganglion cells adapt to ionic stress in experimental glaucoma. Their data indicate that in response to prolonged IOP (intraocular pressure) elevation, RGCs  undergo an adaptive process that reduces sensitivity to changes in K+ while diminishing excitability. These experiments give insight into the RGC response to IOP stress and lay the groundwork for mechanistic investigation into targets for neuroprotective therapy.Li et al. have systemically analyzed independent risk factors for the progression of different degrees of diabetic retinopathy and non-diabetic retinopathy among type 2 diabetic patients. They conclude that young age, short axial length, and higher levels of FBG (fasting blood glucose) and urinary albumin creatinine ratio (UACR) were the independent risk factors for the progression of diabetic retinopathy in type 2 diabetes.Wareham et al. have presented data on collagen mimetic peptide repair of the corneal nerve bed in a mouse model of dry eye disease. Their data suggest that repair of underlying collagen in conditions that damage the ocular surface could represent a novel therapeutic avenue in treating a broad spectrum of diseases or injury.Wang and Wang have shown a preliminary study of spectral-domain optical coherence tomography (OCT) combined with ERG in the assessment of conbercept for neovascular age-related macular degeneration (nAMD). Their data suggest that (1) conbercept is useful for the short-term treatment of nAMD; (2) it can safely improve the visual acuity of affected eyes; and (3) it can restore the structure and function of the retina.Zhou et al. have shown that increased intraocular inflammation in retinal vein occlusion is independent of circulating immune mediators and is involved in retinal oedema. Their results suggest that (1) intraocular inflammation in RVO is driven primarily by local factors but not circulating immune mediators; (2) intraocular inflammation may promote macular oedema through the PI3K-Akt, Ras, MAPK, and Jak/STAT signaling pathways in RVO; and (3) systemic factors, including cytokines and lipid levels, may be involved in retinal microvascular remodeling.Wang et al. have assessed the precision and reliability of a novel computerized heterophoria test (CHT). Their data suggest that (1) the CHT can be used to demonstrate excellent inter- and intra-examiner repeatability and good correlation with the POCT ; (2) the differences between the CHT and POCT are within the permissible range of error; and (3) the CHT could provide a precise and reliable measurement for clinical applications.Altogether, this Research Topic of articles emphasizes novel diagnostic and therapeutic approaches for a variety of ocular neurodegeneration diseases, which are necessary to further explore.WW: Funding acquisition, Writing\u2014original draft. WT: Writing\u2014review and editing. YL: Writing\u2014review and editing. TH: Funding acquisition, Writing\u2014review and editing. DW: Writing\u2014review and editing. HL: Conceptualization, Funding acquisition, Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "Worldwide, one new case of dementia is detected every 3 s , Ramer et al. examined whether childhood 24HAC behaviors were associated with executive function or academic performance in adolescence. Self-reported sleep quality, recreational screen time, and actigraphy-assessed physical activity were collected during grade 5 when the children were ~11 years; executive function and academic performance were collected during grade 9 at age ~15 years. Using structural equation modeling, the authors found: (1) adolescent executive functions were negatively affected by greater childhood recreational screen time and positively affected by better sleep quality; and (2) the negative association between childhood recreational screen time and adolescent executive functions were attenuated by greater childhood physical activity. Interestingly, childhood physical activity was negatively associated with adolescent executive functions; however, this relationship was mitigated by greater sleep.In a longitudinal analysis from the United States of data from the National Institute of Child Health and Human Development (NICHD) Longitudinal Study of Early Child Care and Youth Development  to data from the Adult Changes in Thought study  and examined the interactive relationships of 24HAC behaviors with global cognitive function. Physical activity and sedentary behavior were assessed by actigraphy, while sleep was estimated as self-reported time in bed. No significant associations were found across all three analytic methods in this cross-sectional study.Mellow et al. cross-sectionally examined the associations between 24HAC composition and cognitive function among 384 Australian healthy adults, aged 60\u201370 years. The 24HAC was assessed by actigraphy and by questionnaires. Cognitive measures included global cognition, memory, executive functions, and processing speed. Using compositional data analysis, no association between 24HAC composition and cognitive function was found.Hicks et al. cross-sectionally explored how chronotype\u2014an individuals' preferred activity and sleep pattern\u2014and physical activity were associated with cognitive performance  in 153 American adults aged > 60 years, with and without self-reported sleep disorders. Wrist-worn actigraphy assessed physical activity and chronotype. Using multivariate analysis of covariance, no differences in physical activity or cognitive performance between different chronotypes were found.The results indicate that there is still much we do not understand about the 24HAC and cognitive health relationship. It is difficult to broadly characterize the 24HAC and cognitive health relationship at this time given that: (1) most of the evidence is cross-sectional; and (2) there are few studies on the 24HAC and cognitive health relationship in children, adolescents, younger, or middle-aged adults.Wu et al., Mellow et al., and Hicks et al. all found no association between 24HAC composition and cognitive function in healthy older adults; only Hyodo et al. found an association between 24HAC composition and cognitive function. It is possible that time-use composition fails to capture aspects of the 24HAC  that may be more important for cognitive health.Nevertheless, there are several conclusions we can draw from these studies. Notably, time-use composition of the 24HAC does not appear to be strongly associated with cognitive function in healthy older adults. Ramer et al. used a longitudinal design. We strongly urge that future studies use longer follow-up periods and include wider age-ranges in study samples.There is an obvious lack of longitudinal studies in this emerging field of research. Only Our article collection mainly includes studies in older adults, but does not include any research among clinical populations at risk for, or living with, cognitive decline or dementia . People living with clinical conditions which are associated with cognitive decline are often less active, more sedentary, and have poorer sleep (Falck et al., Finally, it is unclear what modifiable and non-modifiable moderators and mediators can impact the 24HAC and cognitive health relationship. None of the studies in this Research Topic explored sex differences. Females have twice the risk of dementia (Ferretti et al., Preserving cognitive abilities across the lifespan is critical for qualify of life and wellbeing. The 24HAC holds promise as a means of maintaining cognitive health from childhood into older adulthood. Future work is needed to identify the temporal 24HAC and cognitive health relationship, as well as understand how different populations, mediators, and moderators such as sex, may impact this relationship across the lifespan.RF wrote the first draft of the manuscript. TL-A, JV, HM, DM, PG, and HS each provided critical edits and wrote portions of the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Viruses are medically important obligatory parasites that can impact the health and quality of life of infected patients. Historically, prophylaxis against viral diseases like poliomyelitis and measles became possible by the successful development and roll out of vaccines in the 1950s and 1960s [Virus Microscopy, Coomer and Padilla-Parra discuss the imaging of HIV-1 virus entry and transmission in organoids of the female genital tract and colorectal tract, using techniques such as two-photon confocal microscopy and light sheet microscopy. Hu and Noda describe the structural analyses of Ebola and Marburg virus (Filoviridae) nucleocapsid structures as dissected by single particle analysis using cryo-electron microscopy. Menke et\u00a0al. elaborate on techniques such as super-resolution microscopy and quantitative image analysis for investigating the cell entry and infection biology of Orthohantaviruses. Finally, Petkidis et\u00a0al. highlight the power of label-free microscopy including quantitative phase imaging and atomic force microscopy to investigate virus entry and infection.In this Microscopy special issue"}
+{"text": "Primary breast neuroendocrine neoplasms (BNENs) are a rare form of breast cancer, accounting for less than 0.1% of all breast malignancies. These neoplasms have a similar clinical presentation as conventional breast carcinomas, differing mainly in their histopathology and expression of neuroendocrine (NE) markers, chromogranin and synaptophysin. Owing to their rarity, current knowledge of these tumours comes mainly from corroborative case reports or retrospective case series. There is hence a lack of randomised data on the treatment of these entities and current protocol suggests similar treatment as that of conventional breast carcinomas. We report the case of a 48-year-old with a breast mass, which on further work-up was diagnosed as locally advanced carcinoma breast, that required a mastectomy and axillary node dissection on the same side and revealed NE differentiation on histopathological examination. Hence, immunohistochemical staining was indicated which confirmed NE differentiation. We discuss the current knowledge on incidence, demographics, diagnosis, histopathological and staining characteristics, prognostic factors and treatment modalities of BNENs. Primary breast neuroendocrine neoplasms (BNENs) constitute an under-recognised subtype of breast malignancies. This entity accounts for less than 0.1% of all cases of carcinoma breast and under 1% of primary neuroendocrine neoplasms (NENs) .The updated WHO Classification of Tumours of the Breast, in 2019, defined BNEN as a tumour with greater than 90% of cells showing NE differentiation, that is, expressing NE markers \u2014 chromogranin and synaptophysin (SYN) . First dThe present case report outlines a unique case of a primary BNENs.A 48-year-old nulliparous lady without comorbidities presented with a 3-month history of a lump in the lower outer quadrant of her left breast. On examination, a 2 \u00d7 2 cm, irregular, hard lump fixed to the surrounding breast tissue was palpated. Multiple, non-tender enlarged level 1 lymph nodes were also felt in the left axilla.Mammography showed an irregular, infiltrating, Breast Imaging-Reporting and Data System (BIRADS) -V lesion in the posterior aspect of the lower outer quadrant measuring 2 \u00d7 2 \u00d7 1 cm. Significant left axillary lymphadenopathy was also noted.Fine needle aspiration cytology of a level 1 axillary lymph node revealed metastatic breast cancer. Ultrasound-guided tru-cut biopsy of the breast lump yielded nests of cells with nuclear moulding and coarse chromatin. A provisional diagnosis of carcinoma with NE differentiation was made.A chest X-ray showed normal findings and an ultrasound study of the abdomen and pelvis revealed post-hysterectomy status with no other sonological abnormalities.She underwent a left modified radical mastectomy with axillary node clearance, following the workup.On gross examination, a 3 \u00d7 2.5 \u00d7 1 cm, grey-white, well-circumscribed, unifocal, firm mass was noted. Histologically, the tumour was composed of densely cellular nests and trabeculae. The cells were arranged as solid sheets with rounded margins with delicate fibrovascular stroma separating them. Neoplastic cells were larger and polygonal, with eosinophilic, granular cytoplasm and coarse and fine nuclear chromatin .in situ (DCIS) was found. Electron microscopy revealed dense core secretory granules. On Immunohistochemistry (IHC), the tumour was hormone receptor- oestrogen and progesterone  positive and negative for HER2/neu (a non-hormone IHC marker for breast cancer that guides treatement options). More than 90% of the cells were strongly positive for neuron-specific enolase (NSE) and SYN  and Cyclophosphamide (600 mg/m2) followed by four cycles of single-agent docetaxel (75 mg/m2). The chemotherapy was followed by adjuvant radiation. 50 Gy of three-dimensional conformational radiation therapy with radical intent was given in 25 fractions without concurrent chemotherapy.She received standard-of-care therapy with four cycles of Adriamycin  show similar round or spindle-shaped cells with palisading of the nucleus, abundant eosinophilic and fine granular cytoplasm, and nuclei with \u2018salt and pepper chromatin\u2019. Tumour cells form islands, nests and trabeculae which are surrounded by a delicate fibrovascular stroma. According to the WHO classification of tumours 2019, essential criteria for BNENs include histological and immunohistochemical features of NE differentiation and co-existing DCIS is described as a desirable criterion . In the et al [et al [WHO describes BNENs as tumours with >90% of cells showing histological and IHC features of NE differentiation, mainly the expression of NE markers such as SYN and chromogranin A (CGA). CD56 and NSE may also be positive but are not as specific . In addiet al  found thet al . Previouet al . In our l [et al  noted thAs clinical characteristics and imaging features of BNEN are non-specific, histological features and immunohistochemical staining of tissues remain the cornerstone of diagnosis.As per 2019 WHO classification, well-differentiated BNENs were described as NETs which are considered low to intermediate-grade tumours in the current classification. Poorly differentiated BNENs, earlier described as NECs (neuroendocrine carcinoma) are considered high-grade tumours which include small-cell NEC and large-cell NEC . BNEN paThe differential diagnosis for these primary carcinomas is essentially metastasis from NECs at other sites. Presence of DCIS and the absence of tumours in other organs in radiology help in clinching the diagnosis of primary NEC of the breast . In the In terms of the prognosis of BNENs, the current literature is rather ambiguous with different investigators presenting conflicting reports. This ambiguity can also be attributed to the comparative smaller incidence of these tumours and the lack of larger studies on them.et al [et al [et al [et al [Previously, based on small studies, BNENs were thought to have a prognosis similar  or even et al  and Yangl [et al  suggest l [et al . Cloyd el [et al  have shol [et al  where thl [et al . In the l [et al .Presently, there is limited information to recommend a specific treatment protocol for invasive breast carcinomas with NE differentiation and current guidelines suggest treatment same as that of conventional breast cancer (IDC-NOS).et al [et al [Surgery remains the mainstay of treatment for early-stage BNEN. The type of surgery is decided upon by criteria similar to that of IDC-NOS. Of these, the location of the tumour and its size determines the surgical method. There is no sufficient evidence to date showing the most efficient chemotherapy regimen for these cancers. Generally, chemotherapy used in patients depends on the histological features of the patient\u2019s tumour. Regimens containing platinum-etoposide, usually indicated for small-cell lung cancer, can be used in poorly differentiated small-cell BNENs , while aet al  in 2015 et al . Adjuvanet al . Somatoset al . Studiesl [et al  stated tl [et al .Our patient was surgically treated with a modified radical mastectomy of the affected breast with standard adjuvant chemotherapy indicated for Her2/neu negative breast carcinomas. Afterwards, she was started on adjuvant endocrine therapy and has since been in clinical remission. Treatment given was independent of NE features and according to principles of treatment for IDC-NOS, as indicated in the existing literature.There is an unmet need for further studies into these rare tumours for further understanding of these unusual clinical entities and for developing new treatment interventions. This case strengthens the importance of histopathology and early identification of NE features in patients with invasive breast cancer, which will help in early treatment and improved outcomes.The authors have no conflicts of interest to declare.There was no funding received for publishing this case report."}
+{"text": "Autophagy in Inflammation Related Diseases, Volume II\u201d to collect related studies for the discussion of such issue.Autophagy is a vital catabolic mechanism to degrade and recycle long-lived proteins and useless organelles relying on lysosomes . Since iWang et al. revealed that aspirin-triggered Resolvin D1 (AT-RvD1) produced an alleviative effect on neuropathic pain through the induction of autophagy-mediated suppression of the NLRP3 inflammasome. In addition, Pei et al. demonstrated that alantolactone attenuated interleukin (IL)-1\u03b2-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of signal transducer and activator of transcription 3 (STAT3) and nuclear factor (NF)-\u03baB signaling pathways in osteoarthritis. In a review paper, Feng et al. reported that autophagy was involved in the regulation of heparinase-mediated promotion of coagulation disorder and pulmonary fibrosis in acute respiratory distress syndrome (ARDS). In other two review papers, the role of autophagy in the regulation of fibrosis and immunopathogenesis of inflammatory bowel disease was discussed in detail . In addition, Huang et al. demonstrated the hepato-protective role of autophagy in non-alcoholic fatty liver disease (NAFLD).In our Research Topic, six brilliant studies have been collected and officially published in Frontiers in pharmacology. Among them, Autophagy in Inflammation Related Diseases,\u201d has collected several latest original studies for the exploration of potential targets taking advantage of autophagy in the treatment of several kinds of inflammation-related diseases. Furthermore, several brilliant review papers have discussed the role of autophagy in several inflammation-related disorders through reviewing and summarizing the previous studies. We believe that our Research Topic would bring new insights in the investigation of autophagy in inflammation-related diseases.All in all, our current Research Topic, together with the former one entitled \u201c"}
+{"text": "Biosensors, \u201cElectrical/Optical Biosensing and Regulating Technology\u201d, presents a collection of papers that describe the latest advances in electrical/optical biosensors and systems. These papers report on the development and application of electrical/optical biosensing and regulating technologies that are expected to significantly enhance biomedical research. By bringing together these cutting-edge technologies and research findings, this Special Issue facilitates the advancement of biosensing and regulatory technology and its impact on the field of biomedical research.Biosensing has emerged as a powerful tool for exploring biomedical mechanisms. Utilizing highly sensitive electrical and optical sensing technologies, biosensors can detect weak signals and trace biomarkers in a dynamic, real-time, and label-free manner. The current Special Issue of Sun and colleagues have extensively reviewed the application of optical and electrical sensors in flexible wearable wound detection . They emZhan et al. conduct a review of electrochemical sensors and their applications in detecting glycated hemoglobin (HbA1c) . This stMicrofluidic paper-based analytical devices (\u03bcPADs) have greatly promoted the development of in vitro diagnostics due to their low cost, high efficiency, and ease of use. In their review, Zhang et al. provide an overview of the origin, fabrication methods, detection techniques, and innovative applications of \u03bcPADs in in vitro diagnostics . They al2+ is an innovative approach. The detection system has good sensitivity, with a detection limit (LOD) of 1.8 \u03bcM in bovine serum samples, and good selectivity, with a recovery rate of 92.8~110.1% and a relative standard deviation (RSD) of 1.72~4.89%. The platform\u2019s advantages of low cost, easy portability, strong operability, high throughput, and good repeatability make it a promising tool for point-of-care testing (POCT) applications.The smartphone-based ratio fluorescence probe (SRFP) platform developed by Wu et al. is promising for the detection and quantification of calcium ions in serum . The useYang et al. have developed an innovative platform for high-throughput biochemical analysis that integrates a spectrophotometer with a high-precision ball screw-driven two-dimensional motion slider . The steFunctional near-infrared spectroscopy (fNIRS) is a non-invasive method that can be utilized to detect cerebral hemodynamic responses and reflect the pattern of brain activity under different levels of stress. This technique can be used to assess individual cognitive abilities and psychological/physical health. Bak et al. conducted a study that focused on utilizing the laterality index (LIS) values calculated by fNIRS to differentiate between different types of stress . The autLiang et al. have proposed a novel method for quantitatively analyzing global DNA methylation using methylation-specific antibodies (5mC) modified magnetic beads (MB) for immune recognition and affinity enrichment . The metTerahertz radiation is a relatively new and unique radiation source that has been widely applied in various fields. In a recent study by Qi et al., the effects of 0.14 THz terahertz radiation on mouse behavior were investigated . The stuElectrical/optical biosensing and regulating technology can provide accurate and real-time measurements of various biological and environmental parameters, which can help researchers and scientists better understand complex biological systems and environmental processes. This Special Issue showcases the progress and potential applications of different sensor technologies in various fields, opening up new avenues for the future development of biosensing."}
+{"text": "Mitochondrial bioenergetics and its function in tissue homeostasis are vital for regulating energy processes. As cells age, mitochondrial functions are often disrupted by both intrinsic and extrinsic threats including oxidative stress . AlthougGr\u00fcn et al.; Zhang et al.) and one on human non-small cell lung cancer  along with a review article by Jagtap et al., collects new knowledge on mitochondrial function and shed light on the role of oxidative stress in altered mitochondrial bioenergetics and its relevance with aging-related pathologies. The aging-related decline in proteomic turnover, protein processing/folding, and quality control processes exaggerates the risk of oxidative stress to mitochondrial energetics  and reduced GO (rGO) that was found to be mediated by oxidative stress, lipid peroxidation, and mitochondrial dysfunction  and altered activities of several enzymes/indicators associated with myocardial activity and lipid peroxidation, respectively. These data revealed evidence of GO and rGO cardiotoxicity to myocardial cells that was mediated by oxidative stress, lipid peroxidation, and mitochondrial dysfunction.function ; 2. UsinLi et al. provided evidence of the anticancer function of ROS, which was essentially promoted by NRF2 inhibition , Li et al. analyzed ethanol fractions of Helicteres angustifolia L.  root and showed that 40% ethanol fraction  produced selective toxicity to NSCLC cells. Mechanistically, this bioactivity of EF40 was found to be linked with reduced expression of NRF2 that abundantly expresses across several cancers. Of note, EF40-led suppression of NRF2-dependent cellular defense response promoted the intracellular accumulation of ROS in the NSCLC cells. The biochemical analyses further explained the activity of EF40 in cell cycle arrest and apoptosis, promoted through the ROS-led DNA damage response. An evident decrease in matrix metalloproteinases (MMPs) and hnRNP-K expression levels in EF40-treated NSCLC cells further suggested its anti-migratory activity, which was corroborated by significantly reduced tumor growth and lung metastasis in an in vivo xenograft mice model. Conclusively, Li et al. provided direct evidence of the utility of ROS function in promoting anticancer activity that also reaffirmed the significance of NRF2-regulated defensive antioxidant response in cell survival.Although the oxidative stress produced by high ROS levels is central to the cardiotoxicity of myocardial cells, its lethality can be seen in cancer cells. In line with this, an original study by hibition ; 3. UsinJagtap et al. in a review report comprehensively discussed the new knowledge and developments in the stream (Protein synthesis, protein processing and folding, and quality control mechanisms are critical cellular processes that are directly linked with mitochondrial homeostatic function, which progressively decline with aging. Although the role of protein homeostasis or \u2018proteostasis\u2019 in cellular function is understood, its significance in mitochondrial physiology under neurodegenerative conditions needs to be resolved. To this end, e stream ; 4. The Conclusively, the original research and review articles published under the present Research Topic shed light on the role of oxidative stress in altered mitochondrial bioenergetics and its outcome. It also discusses new knowledge on impaired mitochondrial bioenergetics and its relevance with age-related pathologies."}
+{"text": "Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative therapeutic approaches including diets are, therefore, under investigation. Ketogenic diet (KD) is effective for treatment-resistant epilepsy and metabolic diseases, however, only a few clinical studies suggest its beneficial effect also for mental disorders. Animal models are a useful tool to uncover the underlying mechanisms of therapeutic effects. Women have a twice-higher prevalence of mood disorders but very little is known about sex differences in nutritional psychiatry. In this review, we aim to summarize current knowledge of the sex-specific effects of KD in mood disorders. Ketone bodies improve mitochondrial functions and suppress oxidative stress, inducing neuroprotective and anti-inflammatory effects which are both beneficial for mental health. Limited data also suggest KD-induced improvement of monoaminergic circuits and hypothalamus\u2013pituitary\u2013adrenal axis\u2014the key pathophysiological pathways of mood disorders. Gut microbiome is an important mediator of the beneficial and detrimental effects of diet on brain functioning and mental health. Gut microbiota composition is affected in mood disorders but its role in the therapeutic effects of different diets, including KD, remains poorly understood. Still little is known about sex differences in the effects of KD on mental health as well as on metabolism and body weight. Some animal studies used both sexes but did not find differences in behavior, body weight loss or gut microbiota composition. More studies, both on a preclinical and clinical level, are needed to better understand sex-specific effects of KD on mental health. High-fat low-carbohydrate ketogenic diet (KD) was originally introduced into clinical practice for the management of drug-resistant epilepsy nearly 100\u00a0years ago Peterman  and is sBesides epilepsy, metabolic and cardiovascular diseases growing amount of data suggest a beneficial effect of KD also in neurodegenerative diseases  is a leading mental disorder affecting up to 300 million people worldwide, producing a huge burden on society\u2019s wellbeing and the world economy , medium-chain FA (MCFA) and long-chain FA (LCFA) , BD, psychotic disorders and schizophrenia , but have not reported their results yet. No RCTs of KD have been performed or started for MDD, while animal studies, case reports and a few small clinical trials suggest its beneficial effect on the mood. A recent small trial found improved depressive symptoms in 6 MDD patients and 12 BD patients after 3\u00a0weeks on KD  have been performed for KD in any mental disorder up to date. Few studies are registered on Disturbed monoamine neurotransmission is a key mechanism of depression, schizophrenia, ADHD, ASD and other mental disorders  axis dysregulation is a core symptom of mood and anxiety disorders with elevated cortisol level and disturbed feedback inhibition  and Firmicutes   metabolism in the motor and somatosensory cortex, but not in the midbrain and basal ganglia. However, the total level of dopamine, serotonin and noradrenaline remained unchanged in all brain regions explored in this study  and Firmicutes   better in men compared to pre-menopausal, but not post-menopausal women  gene expression (Salberg et al. Rats fed with a high-fat high-sugar diet for 12\u00a0weeks showed opposite changes in HPA axis activity with decreased corticosterone level in males but increased level in females (Sahagun et al. Sex-specific effects of KD on mental health were evaluated almost only in animal studies, although one study with obese volunteers did not find any sex differences in KD-induced changes in mood and cognitive function (Halyburton et al. Still very little is known about sex differences in gut microbiota in general (Reviewed in (Jaggar et al. Sex differences in diet-induced changes in gut microbiota were reported only in a few studies with polyphenol (Most et al. Data from experimental animal models and small clinical studies suggest that the ketogenic diet may have beneficial effects both in MDD patients and in the healthy population. Its repeatedly proven neuroprotective and anti-inflammatory effect is thought to be a key mechanism of its potential antidepressant effect. Moreover, key pathways of MDD pathogenesis, such as HPA axis hyperactivity and brain monoamine circuit disturbances have also been shown to be improved by KD in animal stress models. Recent animal studies using depression models showed synergistic effects of antidepressants combined with omega-3-rich fish oil (Paula Farias Waltrick et al."}
+{"text": "NAFLD-MAFLD Conundrum\u201d, is to discuss the current debate on renaming nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and the implications of changing terminology, summarizing the current state of knowledge regarding MAFLD and anticipating the necessity for a new nomenclature which is metabolic dysfunction-associated steatotic liver disease (MASLD)   given inOverall, four original articles, a systematic review and two narrative reviews have been published in this Research Topic.Wen et\u00a0al. which included 10 cohort studies and showed that patients diagnosed with MAFLD alone had higher cardiovascular mortality than those diagnosed with NAFLD alone.The importance of a new definition is well established in the systematic review by Liao et\u00a0al., where they observed that the number of publications on MAFLD increased dramatically, especially in the last three years. In particular, gut microbiota became an important research direction for etiological and therapeutic investigations into MAFLD, as well as, insulin resistance, a key factor in studying the development of MAFLD. They concluded that liver fibrosis was an important focus of disease development.Our Research Topic aimed to identify the hot topics and new trends in the gut-liver axis in NAFLD/MAFLD research starting from the bibliometric analysis conducted by Yang et\u00a0al. confirmed the previous analysis revealing that gut microbiota, inflammation, insulin resistance, short-chain fatty acids, and randomized controlled trials will be the new focus of research in the field.Another bibliometric analysis by Li et\u00a0al. in a cross-sectional study among 4,195 participants aimed to evaluate the diagnostic efficacy of different anthropometric indices, including body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), cardiometabolic index (CMI), triglyceride-glucose (TyG) index, hepatic steatosis index (HSI), lipid accumulation product (LAP), body roundness index (BRI), visceral fat index (VAI), abdominal volume index (AVI), cone index (CI), and body fat index (BAI), in adults with MAFLD to identify the best cut-off point for diagnosis of MAFLD in United States adults. In particular, the authors concluded that LAP may be a sensitive marker for diagnosing MAFLD in United States adults.Xiao et\u00a0al. is the skeletal muscle mass (SMM). In the same cohort of Li et\u00a0al., the authors demonstrated that the distribution of SMM differently affected MAFLD and significant fibrosis in the sex groups. Higher appendicular SMM was associated with a lower risk of MAFLD, while the risk of significant fibrosis in females was increased with the trunk SMM. Concluding the two published reviews focused the attention on molecular characterization of NAFLD/MAFLD  and on the latest treatments .Another important parameter taken into account by We hope that this Research Topic will help to produce new evidence about NAFLD/MAFLD and contribute to better understand the new definition of MASLD, in order to clear the complexity of this disease.AD: Conceptualization, Writing \u2013 original draft. RK: Writing \u2013 review & editing. SA: Validation, Writing \u2013 review & editing."}
+{"text": "Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurrent unwanted thoughts (obsessions) and associated repetitive behaviors (compulsions), affecting around 1.1\u20131.3% of the global population ; it has been shown to play a key role in neurogenesis and neural development, and possibly in synaptic vesicle transport. In SPRED2-deficient mice, alterations in neural transmission were observed in thalamo-amygdala circuits. Subsequently, it was found that these mice, like those in which SAPAP3 had been deleted, also showed altered ultrasonic vocalizations. These changes were observed in both young and older mice, and appeared to increase with age  of SAPAP3 has been specifically associated with the Contamination/Washing dimension of OCD, as well as with a poor response to serotonin reuptake inhibitors , coding for a protein related to SAPAP3 which is also involved in synaptic connectivity, were significantly associated with clinical OCD  have also been associated with childhood OCD (Gazzellone et al., SAPAP1 has been knocked out exhibit impaired scaffolding at glutamatergic synapses and altered social behavior (Coba et al., BDNF and NTRK2 genes, which are proximal components of the same cellular cascade as SPRED2, may exert a protective effect against OCD; these effects may be mediated by beneficial effects on this particular signaling pathway (Alonso et al., Copy number variants in Taken together, these findings suggest that genes involved in neurodevelopment and synaptic connectivity, when disrupted, induce not just OCD-like behavior but alterations in brain development, sensory processing, cognitive functioning and social behavior in animals. At least one of these genes is also associated with certain facets of OCD in humans. There is evidence from animal research that alterations in these genes are associated with functional changes involving prefrontal, striatal and limbic brain regions. The consistency of these findings across rodents and humans suggests that at least some of the genetic mechanisms underlying OCD could be evolutionarily conserved. The fundamental phenotype involved in this process may represent lower-order deficits arising from alterations in neural development, which could influence higher-order cognitive processes in a \u201cbottom-up\u201d manner (Benzina et al., The argument presented above would gain support if it were possible to demonstrate neurodevelopmental antecedents of OCD in humans. In this case, too, the available evidence suggests that at least some types of OCD have developmental antecedents. The evidence for these developmental alterations has been summarized in recent reviews (Poletti et al., SAPAP3 or SPRED2 knock-out mice.Specific phenotypes have also been linked to these developmental alterations. For example, patients with OCD show evidence of impaired olfaction, which is a marker of brain dysfunction of developmental origin (Crow et al., An endophenotype is a heritable trait that can be measured in an objective manner, and which is present in individuals with a given psychiatric disorder, as well as their unaffected first-degree relatives, at rates significantly higher than in healthy controls or in the general population (Gottesman and Gould, A tentative integration of the findings described above is presented in During the course of cognitive development in early life, alterations in these processes affects \u201chigher-order\u201d cognitive processes such as flexibility and decision-making capacities (Abramovitch et al., The model outlined above represents a tentative yet coherent approach to understanding the mechanisms through which evolutionarily conserved cellular and neurobiological processes could contribute to the development of OCD in humans. Much remains to be learned about the specific association of each process with OCD, their relationship to the different dimensions of OCD, and the opportunities they offer for early intervention, improved treatment, and the identification of specific endophenotypes such as sensory over-sensitivity (Fontenelle et al., The sole author of this work was responsible for the conceptual framework, literature review, writing, editing, and proofreading of this paper."}
+{"text": "Neurodegenerative and neurodevelopmental diseases represent neurological disorders that variably affect individuals and produce negative consequences, such as altered social interaction, restricted/repetitive behavior, and other medical and mental health conditions that result in lifelong functional and social impairments with high economic and social costs  and presents a compelling argument in support of salivary biomarkers to diagnose this complex disorder, which currently relies solely on behavioral assessments .The mini review entitled, \u201cSalivary MicroRNA Profiling Dysregulation in Autism Spectrum Disorder: A Pilot Study\u201d, demonstrates how saliva can help clinicians support the ASD diagnostic process through the standardization of conditions used to isolate biomarkers that can robustly detect disease in a more simple way . The second, entitled \u201cSalivary Inflammatory Biomarkers are Predictive of Mild Cognitive Impairment and Alzheimer's Disease in a Feasibility Study,\u201d provides evidence for the feasibility of saliva as a valuable source of biomarkers for the early detection of cognitive impairment in individuals on the AD continuum and potentially other neurodegenerative diseases.This mini review is followed by two original research articles. The first, entitled \u201cNon-Invasive Diagnosis and Monitoring Tool of Children's Mental Health: A Point-of-Care Immunosensor for IL-6 Quantification in Saliva Samples\u201d  and \u201cMultisite Dopamine Sensing with Femtomolar Resolution Using a CMOS Enabled Aptasensor Chip\u201d  provide examples of how point-of-care (POC) biosensors can help societies fast track patient needs in the early diagnostic process. For instance, preliminary analysis of retrospective PoliBiobank data  demonstrates that miRNA and inflammatory molecule biomarkers in saliva samples collected from healthy individuals and those diagnosed with neurodegenerative and neurodevelopmental diseases, using traditional techniques, can be detected via real-time PCR and the MSD platform, respectively (unpublished data).The two remaining studies, \u201cFinally, as we highlighted in Goldoni et al. , our hopAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Neurological disorders (ND) are now globally recognized as the primary cause of death and disability. The prevalence, incidence, deaths, and disability-adjusted life years (DALY\u2019s) were estimated from 1990 to 2016 in 195 countries for nearly 15 common neurological disorders . Based oThe rapid development of India resulted in an increased burden of neurological disorders, which form a significant proportion of non-communicable diseases. A survey on the burden of neurological disorders in India revealed that non-communicable neurological disorders doubled, whereas communicable neurological disorders reduced to about one-fourth from 1990 to 2019 . The preIn the present era, a significant increase in neurological disorders has been observed throughout the globe due to the COVID-19 pandemic or as co-morbidities of post COVID-19 complications. The partial or complete lockdown situations in the last 2\u00a0years have confined everyone in their respective territories, leading to changes in neurological complications like anxiety, depression, stress, and psychological disturbances in the general public, especially in children. It has been reported that isolation and post-traumatic stress was the leading cause of depression and altered mood in post COVID-19 patients . A studyIt is the hour of need to deal with the increasing number of neurological disorders in developing and developed countries with safer and therapeutically efficacious medicines. We can achieve this goal with advanced clinical and translational research and bioinformatics tools on traditionally used and medicinally potential natural products . Considering the need to enrich more information about natural products and neurological disorders, researchers and clinicians working in the Natural Products/Pharmacology field were invited to contribute their valuable research to this Research Topic article collection. Research articles on pre-clinical and clinical studies of Natural Products/Traditional Plants in neurological disorders , Case studies/clinical reports emphasizing the role of natural products in neurological disorders, and Review articles focusing on \u201cNeuropharmacological Studies of Natural Products\u201d covering Clinical and translational research with bioinformatics tools, SAR and molecular docking studies and Mechanistic Insights were considered under the scope of this Research Topic.Puri et al., entitled \u201cNatural product-based pharmacological studies for neurological disorders,\u201d focused on targets associated with neurological disorders, traditional holistic approaches for managing neurological disorders and mechanistic approach of phytoconstituents in treating various neurological disorders. A mini-review entitled \u201cUnderstanding the role of \u201csunshine vitamin D\u201d in Parkinson\u2019s disease: A review,\u201d published by Behl et al., explained the role of sunshine vitamin D in Parkinson\u2019s disease. In the systematic review article entitled \u201cThe neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies,\u201d published by Hosseini et al., the authors have critically analyzed the role of melatonin in diabetic neuropathy and explained its mechanisms taking reference from pre-clinical data. A research paper entitled \u201cEvaluation of Mollugo oppositifolia Linn. as cholinesterase and \u03b2-Secretase enzymes inhibitor,\u201d published by Das et al., emphasized in vitro neuroprotective effect of Mollugo oppositifolia in Alzheimer\u2019s disease. The authors have identified phytochemicals in bioactive plant extract and performed in silico molecular docking studies to identify more potential and stable metabolites with potential for Alzheimer\u2019s disease targeting. Another research paper, \u201cLong-term oral administration of naringenin counteracts aging-related retinal degeneration via regulation of mitochondrial dynamics and autophagy,\u201d stressed the role of a CNS-acting flavonoid, Naringenin, in counteracting aging-related retinal degeneration.We received ten articles for consideration for publication in the thematic issue. After a thorough review, five articles were accepted out of 10 submitted articles. Amongst these, two articles are original research papers, one systematic review, one review, and one mini-review. A review article published by"}
+{"text": "The application of glial cell line-derive neurotrophic factor (GDNF) to cell cultures and animal models has demonstrated positive effects upon dopaminergic neuronal survival and development, function, restoration, and protection. On this basis, recombinant GDNF protein has been trialled in the treatment of late-stage human Parkinson\u2019s disease patients with only limited success that is likely due to a lack of viable receptor targets in an advanced state of neurodegeneration. The latest research points to more refined approaches of modulating GDNF signalling and an optimal quantity and spatial regulation of GDNF can be extrapolated using regulation of dopamine as a proxy measure. The basic research literature on dopaminergic effects of GDNF in animal models is reviewed, concluding that a twofold increase in natively expressing cells increases dopamine turnover and maximises neuroprotective and beneficial motor effects whilst minimising hyperdopaminergia and other side-effects. Methodological considerations for measurement of dopamine levels and neuroanatomical distinctions are made between populations of dopamine neurons and their respective effects upon movement and behaviour that will inform future research into this still-relevant growth factor. The discovery of glial cell line-derived neurotrophic factor (GDNF) as a secretion product from the rat B49 glioma cell line in 1993 heralded the arrival of a powerful promotor of dopaminergic cell survival with enormous potential for treating Parkinson\u2019s disease (PD). Lin et al  after biSide- and off-target effects are important to consider for future therapies as they affect the tolerability and utility of GDNF. Side-effects following intracerebroventricular (icv) GDNF injection in humans are documented as principally nausea, vomiting, paresthesias, hyponatremia, anorexia, and weight loss  channels  in addition to striatum (40%). ERK1 and ERK2 phosphorylation were increased in SN and striatum, respectively, and microdialysis showed an increase in DA release in response to K+\u2009and amphetamine  was unchanged following nigral GDNF injection in 4\u20136\u00a0month old rats, yet given a twofold increase in K\u2009+\u2009-induced DA release, there was calculated to be a 1.75-fold increase in TC (DA clearance) when measured electrochemically in vivo  which fine-tunes behaviour /tTA-responsive promotor system under CAMKIIa to overexpress GDNF at two- to threefold levels in cortex, hippocampus and brainstem in any cells that normally express CAMKIIa  showed increased TH activity and DA synthesis yet, unusually, no increase in K+\u2009-stimulated DA release via microdialysis  of the mouse Gdnf 3\u2032UTR has been excised via Cre-LoxP. Homozygous removal of the 3\u2032UTR resulted in a more than threefold increase in Gdnf mRNA and affected prepulse inhibition in mice, suggesting schizophrenia-like behaviour (M\u00e4tlik et al. In further support of the endogenous elevation route, the One important methodological consideration arose in measuring extracellular dopamine levels, as reported in Kumar et al. . ElectroThere is evidence for GDNF signalling via multiple pathways and for unexplored roles in maintaining normal striatal function outside of canonical RET signalling. NCAM1, integrins \u03b1v and \u03b21, and N-cadherin induce neurite outgrowth, proliferation, survival, and influence axon guidance (Chao et al. , respectively. This may affect the tolerability of future therapies in humans due to effects upon cognitive and behavioural functions.A clearer framework for working with GDNF in terms of overexpression, localisation, and off-target effects is now evident. This highlights the pitfalls of exogenous application and the benefits of endogenous upregulation as well as the marked effects of GDNF upon DA transport. DA overflow in systems with greatly increased dopamine transporter activity may not be an accurate marker of DA release as accurate measurement may be masked by increased reuptake kinetics see Fig.\u00a0. This is"}
+{"text": "RISPR-Cas9, have made zebrafish one of the most powerful model systems for breakthroughs in human diseases and provide the foundation for translational research [Our understanding of fundamental biological mechanisms and the pathogenesis of human diseases has been greatly improved by studying the genetics and genomics of zebrafish . The fieresearch .In this Special Issue of \u201cZebrafish: a powerful model for genetics and genomics\u201d, we present 16 research articles and reviews concerning zebrafish modeling in genetics and genomics that aid in understanding human diseases. Notable publications include three articles that illustrate the generation of novel transgenic zebrafish, which can be used in addressing important biological questions: (1) Mao et al. created a transgenic zebrafish to visualize adipocyte development, facilitating the characterization of white adipose tissues in vivo and the development of therapeutic interventions to treat metabolic diseases in humans; (2) Li et al. generated an animal system to monitor the in vivo dynamics of spatiotemporal calcium signaling useful for normal animal physiology as well as stressful and pathophysiological conditions; (3) Jeong et al. developed an optogenetic manipulation system for dissecting olfaction-related behaviors and their underlying neural circuitry.In addition to transgenesis, two studies have shown advanced applications of CRISPR-Cas9 technology that could assist users in patient-specific gene tailoring as follows: (1) de Vrieze et al. revealed an improved strategy in developing knock-in zebrafish models; (2) Schellens et al. demonstrated the therapeutic potential using the exon skipping approach for modeling retinitis pigmentosa.ift74 gene, developing gradual photoreceptor degeneration that is distinguishable from other previously published IFT-B mutants in zebrafish. (2) Berlingerio et al. demonstrated that cystinosis, a disease characterized by cystine accumulation in the lysosome resulting in nephropathy and vision problems in humans, was recapitulated in ctns gene mutant zebrafish. (3) Alexandro-Moreno et al. showed that primary congenital glaucoma, mainly associated with CYP1B1 gene mutations, was recapitulated in a cyp1b1 KO zebrafish and displayed a novel pathway involving the dysregulated expression of extracellular matrix genes. (4) Kim et al. identified potential regulators responsible for vanishing white matter disease by performing a comparative proteome between eif2b3 KO zebrafish and the WT control. These all show novel molecular processes that underlie disease etiology and, thus, could provide therapeutic clues for corresponding human diseases.What makes this Special Issue more interesting is the addition of articles that each showed a novel gene knockout (KO) zebrafish that recapitulated clinical symptoms associated with specific human diseases. (1) Zhu et al. induced ciliopathy via a mutation in the Additionally, several articles are included in this Special Issue to provide immediate benefit for researchers in regenerative biology, hematopoiesis, brain\u2013skin communications, or environmental health. Ellman et al. described a tutorial paper for setting up an apex resection model to study heart regeneration in lab settings, providing an improved development model and assessing the heart\u2019s capacity for regeneration using zebrafish. Huang et al. discovered that NELF (negative elongation factor), the promoter-proximal pausing controller of RNA polymerase II, is specifically involved in granulocyte development but not erythrocyte development, emphasizing the importance of NELF in regulating hematopoiesis. In addition, Ren et al. identified a biological mechanism that underlies environmental change, particularly acute cold resistance. Furthermore, Hong et al. developed a platform for screening MSH-related activity, identifying an effective chemical treatment for autism spectrum disorder.FOXC1 and PITX2 and discussed their analyses on the utility of zebrafish with the corresponding gene mutations for dissecting potential molecular mechanisms and therapeutic approaches.Finally, three review articles were included in the Special Issue in order to highlight the current status of disease modeling using zebrafish and the underlying molecular pathogenesis. Specific topics include hematopoiesis, rare neurological disorders, and Axenfeld\u2013Rieger syndrome (ARS): (1) Zhang et al. summarized a comprehensive review on erythropoiesis using zebrafish models to explore human anemias; (2) Son et al. described the disease modeling of rare neurological disorders, focusing on zebrafish models; (3) French C.R. wrote a review on the development of ARS induced by mutations in In summary, this Special Issue is a collection of 16 relevant articles that support the use of zebrafish modeling in genetics and genomics for treating human diseases. To further boost the benefits for the communities of researchers who use zebrafish models, we are accepting original research papers or review articles for the 2.0 version with a setup similar to this Special Issue: \u201cZebrafish: A Powerful Model for Genetics and Genomics 2.0\u201d."}
+{"text": "Recognizing the future leaders of Hematology is fundamental to safeguarding tomorrow's driving force in innovation. Indeed, early career researchers have faced a significant and potential \u201clong\u201d impact from the pandemic , 2.Therefore, this Research Topic aimed to showcase the high-quality work of internationally recognized researchers in the early stages of their careers. We highlighted research by leading scientists of the future across the entire breadth of Hematology, and present advances in theory, experiment and methodology with applications to compelling problems. Contributions to the Research Topic were by invitation only. All Rising Star researchers were suggested by established Editors within the Frontiers board in recognition of their influence on the future directions in their respective fields.All articles submitted to us for this Research Topic underwent a rigorous peer review process. Ultimately, 11 articles were published.Fouquet et al. highlighted the link between genotype and the unusual clinical phenotype.(i) An interesting case report in hematology was presented by analysis of a heterozygous somatic BLNK mutation associated with T-cell LGL (large granular lymphocyte) leukemia and autoimmune diseases. Liang et al. indicated the feasibility of the NGS approach and the evaluation of its therapeutic effect.(ii) Application of metagenomic next-generation sequencing (NGS) in the diagnosis of visceral leishmaniasis and its treatment evaluation was presented by a case report. Fattizzo and Motta covered a broad spectrum of novel and exciting treatment options in rare congenital and acquired anemias.(iii) A review article presented an update on emerging treatment strategies in rare anemias. Fu et al. presented an artificial intelligence method of excellent performance for the diagnosis and potentially automatic detection of malaria in the future.(iv) An original article reported an intelligent detection method for plasmodium based on self-supervised learning and attention mechanism. Selvakumar et al. focused on epidemiology and potential mechanisms for adverse long-term sequelae of iTTP, best practices in survivorship care, and presented a research agenda for the future.(v) A review article on immune thrombotic thrombocytopenic purpura (iTTP) provided up-to-date knowledge on long-term outcomes and survivorship. Ramadas and Sparkenbaugh reported novel insights into the activation of PAR1 by APC and thrombin, the APC-EPCR-PAR1 axis, and their potential roles in SCD.(vi) A mini review article discussed activation of APC-EPCR-PAR1 axis in sickle cell disease (SCD). Kerbauy et al. reviewed literatures on applying these novel techniques in autologous and allogeneic transplantation across different clinical entities.(vii) A review article focused on total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies. Lysandrou et al. described the study rationale and design, including patient screening, product manufacturing, infusion, and participant follow-up to data collection, management, and analysis.(viii) A study protocol article presented the phase I/II trial of induced HLA-G+ regulatory T cells in patients undergoing allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor. Ahmed et al. reported that many patients who were eligible for ide-cel were not able to secure a timely slot, with high mortality rates as a result.(ix) A brief research report article highlighted \u201cwaitlist mortality\u201d for myeloma patients with limited access to BCMA therapy. Whyte has introduced readers into the world of \u201cthromboinflammation\u201d or \u201cimmunothrombosis\u201d.(x) A mini review article explained the interactions of the fibrinolytic and innate immune systems. Shah et al. provided in-depth knowledge of the concept of point-of-care (POC) manufacturing or decentralized in-house production.(xi) A review article delineated promises and challenges of a decentralized CAR T-cell manufacturing model. Considering the multi-thematic character of this Research Topic, our hope is to inspire researchers and physicians to continue their explorations into novel advances in Hematology.EG: Writing \u2013 original draft. ML: Writing \u2013 review & editing. PC: Writing \u2013 review & editing. MA: Writing \u2013 review & editing."}
+{"text": "Workplace moral behavior  and immoral behavior  have received substantial attention over the past decades moral behavior, offering the diverse insights to the individual emotion-centric models and social cognitive process models, exploring the individual dynamic moral emotions and moral cognition before and after the conduct of workplace (im)moral behavior, and clarifying the respective boundary conditions. Totally, we have accepted 28 papers for publication in the Frontiers in Psychology, which deal with different aspects of workplace (im)moral behavior, exploring mechanisms of these behaviors from the perspectives of moral cognition and moral emotion, and investigating the relevant antecedents and outcome variables. Some studies examined positive leadership  and its impacts on subordinate performance and behavior . We also included articles that investigate immoral behaviors in the organizations such as abusive supervision and counterproductive behavior. These studies have systematically examined the role of immoral behavior in the organizations from both moral cognition and emotion perspectives, which provide a complete understanding of the mechanisms underlying the immoral behavior. Moreover, we included one systematic review of executives' unethical behavior. Here, we provide an overview of the articles that have been included in this Research Topic.Saeed et al., which examines the impact of ethical leadership on knowledge sharing through the social learning theory. In this study, psychological ownership serves as a mediating variable and professional commitment serves as a moderating variable. The data was collected from employees of 307 Pakistani listed companies. The findings reveal that ethical leadership had a positive effect on knowledge sharing via psychological ownership which was buffered by professional commitment, enhancing the understanding in the field of leadership and knowledge management by identifying the role of ethics.The study \u201cLinking Ethical Leadership to Followers' Knowledge Sharing: Mediating Role of Psychological Ownership and Moderating Role of Professional Commitment\u201d was conducted by Cheng, Guo, et al. employ social information processing theory and social learning theory to build a moderated mediation model. Based on the sample of 557 participants, the results suggest that responsible leadership could inhibit unethical pro-organizational behavior and customer-oriented perspective taking partially may mediate the negative link between responsible leadership and unethical pro-organizational behavior.What about the relationship between responsible leadership and unethical pro-organizational behavior? In their work \u201cStanding in Customers' Shoes: How Responsible Leadership Inhibits Unethical Pro-Organizational Behavior,\u201d Chen J. et al., have used the sample of 287 teachers to examine the relationship between moral leadership and innovation performance.In their work \u201cThe Impact of Moral Leadership on Physical Education Teachers' Innovation Behavior: The Role of Identification with Leader and Psychological Safety,\u201d Zada S. et al. utilized social learning theory and data from 347 employees in 56 teams to investigate the relationship among servant leadership, psychological safety, and knowledge hoarding. The findings suggest that servant leadership negatively affects knowledge hoarding by positively influencing psychological safety, and mastery climate moderated the relationship.The article \u201cServant Leadership Behavior at Workplace and Knowledge Hoarding: A Moderation Mediation Examination,\u201d written by Zada M. et al., examined the impact of servant leadership on the task performance of employees in virtual working environments during the COVID-19 crisis. Drawing on the conservation of resources theory, the findings revealed that servant leadership is positively related to task performance in a virtual environment during crises. The study also found that psychological empowerment partially mediates this relationship, and perceived supervisor support positively moderates the relationship between servant leadership and task performance.The study \u201cHow Classy Servant Leader at Workplace? Linking Servant Leadership and Task Performance During the COVID-19 Crisis: A Moderation and Mediation Approach\u201d by Liu L. et al. have examined one type of destructive leadership, the self-serving leadership. Drawing from the social identity theory and 377 survey data via a three-wave time lagged design, the findings showed that self-serving leadership may induce employees' deviant behavior, organizational identification partially mediates self-serving leadership and employees' deviant behavior, and employees' moral identity negatively moderates the relationship between self-serving leadership and employees' organizational identification.In their work \u201cThe Influence of Self-Serving Leadership on Deviant Behaviors in the Workplace: A Moderated Mediation Model,\u201d Zhu et al.. This bibliometric analysis has reviewed 428 articles published between the years 2000 and 2020 on executives' unethical behavior in the emerging markets.The study \u201cExecutives' unethical behavior with directions for future research,\u201d is written by Xu et al. have used conservation of resources theory to build a moderated mediation model with emotional exhaustion as a mediating variable and supervisor-subordinate guanxi as a moderating variable. The data was collected from 440 tourism employees. The results show that leaders' knowledge hiding is positively linked to employees' withdrawal behavior and emotional exhaustion.In their work \u201cThe influence of leader\u2013signaled knowledge hiding on tourism employees' work withdrawal behavior: A moderated mediating model,\u201d Su et al., employed the social cognitive theory and social exchange theory to explain how, when and why self-sacrificial leaders may trigger knowledge sharing. Totally, 481 pair sample has been used to test the theoretical model. The results showed that good guanxi between employees and their leaders, could lead employees to better understand leaders' self-sacrificial behavior and engage in knowledge sharing.Regarding the relationship between self-sacrificial leadership and employees' knowledge sharing, they study \u201cHow Does Self-Sacrificial Leadership Foster Knowledge Sharing Behavior in Employees? Moral Ownership, Felt Obligation and Supervisor-Subordinate Guanxi,\u201d conducted by Liu X. et al.. Drawing upon purposeful work behavior theory and using two-wave time lagged design, data was collected from 216 employee-supervisor dyads. The findings showed that duty orientation and achievement orientation have opposite relationship to pro-social rule breaking. Furthermore, job autonomy strengthens the positive effect of duty orientation and the negative effect of achievement orientation on pro-social rule breaking.The study entitled \u201cDoes Self-Sacrifice Make Me Great? Research on the Relationship Between Employee Conscientiousness and pro-Social Rule Breaking\u201d is written by Wang and Ma used social comparison theory and a sample of 331 employees, to examine the interaction between perceptions of coworkers' receiving idiosyncratic deals and respective deprivation. The findings showed the moderating role of conscientiousness, which may weaken the relationship between deprivation and social undermining.We have included another contribution related to employee consciousness. In their work \u201cWhen Do Coworkers' Idiosyncratic Deals Trigger Social Undermining? \u2013 The Moderating Roles of Cored Self-Evaluations and Conscientiousness,\u201d Zhang H. et al., examined the impacts of three helping behaviors  on helpers themselves. Drawing from the resource conservation theory and using a three-wave time-lagged design, the findings suggested that caring and coaching were more negatively associated with emotional exhaustion and helpers of these two styles were less likely to adopt subsequent deviant behaviors. This study has also identified the role of extrinsic career goals in the direct relationship between the three helping behavior and emotional exhaustion.They study \u201cWhen and How Workplace Helping Promotes Deviance? An Actor-Centric Perspective,\u201d conducted by Cheng, Hu, et al., uses the data collected from 218 salespeople in the internet technology service company and develops a contingent model to show how moral identity and impression management motives could moderate the links between pro-organizational motives, unethical pro-organizational behavior, and organizational behavior.The contribution \u201cA Contingency Perspective of Pro-Organizational Motives, Unethical Pro-Organizational Behavior, and Organizational Citizenship Behavior,\u201d written by Xiao J. et al., has examined the implicit coordination from the perspective of team mentality, and discussed the incentive mechanism of status competition by using knowledge sharing as a mediating variable and psychological safety as a moderating variable. The empirical study has used a sample of 367 employees from 44 companies. The findings revealed that prestige-type status competition was positively related to implicit coordination, while dominant-type status competition was negatively related to implicit coordination. Furthermore, knowledge sharing mediated the relationship between both types of status and implicit coordination, and psychological safety enhanced both relationships.The article \u201cStatus Competition and Implicit Coordination: Based on the Role of Knowledge Sharing and Psychological Safety\u201d written by Zhang M. et al. uncovered the situational factors that influence employees' unethical pro-organizational behavior to repay the organization. Based on the social exchange theory, the authors used multisource data from 139 human resource managers and 966 employees to examine why and how high-commitment work systems affect employees' unethical pro-organizational behavior. The findings revealed that high-commitment work systems promote employees' unethical pro-organizational behavior through relational psychological contract. Besides, the findings showed that balanced reciprocity beliefs strengthen the positive relationship between relational psychological contract and employees' unethical pro-organizational behavior.In the study \u201cResearch on the Relationship Between High-Commitment Work Systems and Employees' Unethical Pro-Organizational Behavior: The Moderating Role of Balanced Reciprocity Beliefs,\u201d Zhang Z. et al. conducted the study \u201cDoes Technostress Increase R&D Employees' Knowledge Hiding in the Digital Era?\u201d and introduced work exhaustion as a mediating variable for exploring how five sub-dimensions of technostress impact R&D employees' knowledge hiding. The authors have used job demand-resource theory to examine technostress\u2014an antecedent of knowledge hiding. The sample of 254 participants was collected through a two-stage survey. The findings showed that techno-invasion, techno-insecurity, and techno-complexity were significantly and positively associated with work exhaustion. Furthermore, work exhaustion mediated the relationship between aforementioned three variables and knowledge hiding, while workplace friendship negatively moderated the association between techno-invasion, techno-insecurity and work exhaustion, reducing the emergence of knowledge hiding, while it also positively moderated the association between techno-complexity and work exhaustion.Wu et al. examined the relationship between workplace suspicion and employees' silence, as well as the mediating role of knowledge hiding from a colleague's perspective. Drawing from resource conservation theory and self-regulation theory, data of 303 pair sample from 23 companies in China was collected through three-waves questionnaire method. The results revealed that workplace suspicion positively influenced employees' silence via knowledge hiding, and knowledge-based psychological ownership strengthened the mediating effect. However, face consciousness weakened the positive impact of workplace suspicion on knowledge hiding.The study \u201cWorkplace Suspicion, Knowledge Hiding, and Silence Behavior: A Double-Moderated Mediation Model of Knowledge-Based Psychological Ownership and Face Consciousness\u201d conducted by Zheng et al. uses 176 valid responses to examine whether employees' personal ethics and perceptions of corporate hypocrisy can be beneficial for reducing employees' mental fatigue. The theories used to develop the hypotheses are stakeholder theories and sociological theories. The findings showed that employees' mental fatigue reduces when internal or external corporate social responsibility (CSR) has a positive impact on employees' altruistic choice and employees' mental fatigue increases when CSR has a negative effect on ethical egoism.The study \u201cImpacts of Corporate Social Responsibility on Employees' Mental Fatigue\u201d written by Jiang et al. conducted the study of \u201cBenefits of Non-Work Interactions with Your Supervisor: Exploring the Bottom-Up Effect of Employee Boundary Blurring Behavior on Abusive Supervision\u201d and explored how employees' boundary blurring behavior can prevent themselves from being abused by supervisors. Drawing from the self-disclosure theory, authors have used a scenario-based experimental study and a multi-wave field study to find out that employees' boundary blurring behaviors inhibit the emergence of abusive supervision through the mediating effect of supervisor liking toward the employee.Existing research seldom employs a bottom-up perspective to examine how employees can reduce abusive supervision. In their work, Fousiani et al. explored the effect of morality and competence in recruiters' hiring decisions. The authors used the Big Two theoretical framework to examine how instrumental or relational goals of organizations might influence the importance of morality or competence of candidates during the hiring process. The authors conducted three studies  to test the proposed hypotheses. The findings showed that the primacy effect of morality might hold when organizational goals are relational but might get reversed when organizational goals are instrumental. They also found that perceived appropriateness of a candidate positively affects hiring recommendations.In the article \u201cAppearing competent or moral? The role of organizational goals in the evaluation of candidates,\u201d Carminati and H\u00e9liot, titled \u201cBetween Multiple Identities and Values: Professionals' Identity Conflicts in Ethically Charged Situations,\u201d adopted a qualitative approach. Forty-seven semi-structured interviews had been conducted among doctors and nurses working for the English National Healthcare Service. The findings showed that micro processes such as cognitive and emotional perspective taking, plus identifying with the other may trigger identity conflict.The contribution of Khan et al. examined the relationship between perceived overqualification and counterproductive work behavior (CWB) among textile sector employees, considering job boredom as a mediator and job crafting as a moderator. The findings showed a positive relationship between perceived overqualification and CWB. Furthermore, the study found that job boredom mediated the relationship between perceived overqualification and CWB, and job crafting moderated the positive association between perceived overqualification and job boredom.The study \u201cPerson\u2013Job Misfit: Perceived Overqualification and Counterproductive Work Behavior\u201d by Shen et al. titled \u201cHow I Speak Defines What I Do: Effects of the Functional Language Proficiency of Host Country Employees on Their Unethical Pro-Organizational Behavior\u201d investigates the relationship between functional language proficiency  and unethical pro-organizational behavior of host country employees in multinational corporations (MNCs). The authors used data from 309 full-time host country employees to test their predictions guided by social identity theory. The findings suggested that host country employees' functional language proficiency enhances their unethical pro-organizational behavior through their linguistic group identification and moral disengagement.The article by Liu J.-N. et al.. Drawing from planned behavior theory and 200 civil servants' data, the findings showed that public sector leaders' information-sharing behavior is positively related to their subordinates' taking charge behavior, and public service motivation mediates this relationship. The results also found emotional trust strongly moderates the effect of leaders' information-sharing behavior on subordinates' taking charge behavior.The article \u201cHow does leaders' information-sharing behavior affect subordinates' taking charge behavior in public sector? A moderated mediation effect,\u201d is written by Dai et al. have examined the role of positive workplace gossip through a moderated mediation model. Data from 327 employees in the Pearl River and Yangtze River Delta regions of China was collected to test the theory model. The results showed that positive workplace gossip may promote employee innovation.In their work \u201cIs not workplace gossip bad? The effect of positive workplace gossip on employee innovative behavior,\u201d Wang and Tang aimed to investigate the impact of daily supervisor abuse and coworker support on daily work engagement. Drawing from the conservation of resources (COR) theory, the study utilized a daily diary approach and collected data from 73 employees during five consecutive days in China. The results showed that daily abusive supervision had a negative impact on daily work engagement and that daily negative emotions mediated this relationship. Coworker support had a cross-level moderating effect between daily abusive supervision and daily negative emotions.The article \u201cHow Daily Supervisor Abuse and Coworker Support Affect Daily Work Engagement\u201d by Xiao W. et al. investigates the impact of crowdsourcing innovation community reference on creative territory behavior from the perspective of reference group theory. A two-stage survey has been used and 524 valid responses were collected. The results suggested that the crowdsourcing innovation community reference influences members' impression management behavior and then inhibits creative territory behavior. Interestingly, there are different community reference effects among members of different community age groups. These findings contribute to understanding the influence of the crowdsourcing innovation community on crowd participation decision-making and suggest implications for exploring the cooperation mechanism of crowdsourcing innovation.The study \u201cInfluence of Crowd-sourcing Innovation Community Reference on Creative Territory Behavior\u201d by Chen H. et al. examined the relationship between leader's aggressive humor and bystander's workplace withdrawal behavior. The study used the Cognitive-Affective Personality System Theory and collected data from 443 employees and their direct supervisors in the Chinese enterprises. The results showed that leader-aggressive humor positively affected bystander affective rumination and bystander workplace anxiety, which in turn mediated the relationship between leader-aggressive humor and bystander workplace withdrawal behavior. Additionally, organization-based self-esteem moderated the indirect impact of leader-aggressive humor on bystander workplace withdrawal behavior through bystander affective rumination and bystander workplace anxiety.In another perspective, the article \u201cWhy Does Leader Aggressive Humor Lead to Bystander Workplace Withdrawal Behavior?\u2014Based on the Dual Path Perspective of Cognition Affection,\u201d Dai et al. have explored the effect of positive workplace gossip on employee's innovative behavior; Zhang H. et al. have studied when and how workplace helping promotes workplace deviance from an actor-centric perspective; Zhang M. et al. have explained the dark side of high-commitment work systems and linked it to employees' unethical pro-organizational behavior. These findings point out the importance to review and manage workplace (un)ethical/(im)moral behaviors with a balanced but critical perspective.This Research Topic has made the following contributions. First, in this Research Topic, scholars attempted to conduct research from different perspectives and methodologies on the \u201cgood\u201d behaviors  and negative behaviors , which have enriched the research on the \u201cdark sides\u201d of workplace positive behavior and the \u201cbright sides\u201d of workplace negative behavior. For example, the study of Cheng, Guo, et al. have examined how positive leadership can prevent employees' workplace unethical/immoral behaviors. This contribution has greatly enriched the current understanding of how responsible leadership is related to employees' unethical pro-organizational behavior. Furthermore, this study has explicitly explained the impacts of positive leadership and the important role that positive leadership can play in inhibiting and governing the negative behaviors of employees.Second, prior research has explored the relationship between various types of destructive leaders' behavior  and workplace unethical/immoral behaviors such as counterproductive work behavior, and the relationship between positive leadership  and employees' positive workplace behaviors such as innovative behavior and prosocial behavior. However, how positive leadership can help prevent unethical organizational behaviors requires further development. In this Research Topic, Xu et al. have explored the influence of leader-signaled knowledge hiding on tourism employees' withdrawal behavior. Jiang et al. have advocated the benefits of employees' non-work interactions with their supervisors and verified the bottom-up effect of employee boundary blurring behavior on abusive supervision. Liu J.-N. et al. have investigated how leaders' information sharing behavior affect subordinates' taking charge behavior in public sector. Chen H. et al. have further studied the relationship between leader's aggressive humor and employee's withdrawal behavior from a bystander's perspective. Su et al. have demonstrated the impacts of leaders' self-sacrificial behaviors and supervisor-subordinate guanxi on employees' knowledge sharing. Wang and Tang have integrated daily supervisor abuse and coworker support in influencing employees' daily work engagement. These contributions point out that when managing leaders' or employees' workplace (un)ethical/(im)moral behaviors, one should not only look for the reasons and respective governance strategies from the actors' perspectives. In fact, the influence of others is an important source of the formation of individual behaviors in the workplace. Managers should improve the positive interpersonal interactions through building the healthy and meaningful relationship at the workplace, and reduce the contagion effects through lead by example, open communication, promotion of positive corporate culture, rewards on the ethical/moral behaviors, and so on.Third, this Research Topic focuses on the mechanisms by which relationships and interpersonal interactions between supervisors and subordinates and between coworkers influence each other's (un)ethical/(im)moral behaviors. We have included studies of top-down leadership behaviors and their impacts on employees' behaviors, and the studies of the bottom-up employees' behaviors and their impacts on leaders' behaviors. The (un)ethical/(im)moral behaviors in the workplace are examined through multiple directions. For example, Liu J.-N. et al.; Su et al.; Xiao J. et al.; Saeed et al.), knowledge hiding , and knowledge hoarding  have attracted increasing attention. The contributions have employed theoretical lens such as the conservation of resources theory, the self-regulation theory, the framework of \u201ccognition-motivation-behavior,\u201d and the psychological safety and psychological ownership perspectives, to examine the formation mechanism between knowledge sharing behavior and counterproductive knowledge behavior. In addition, these contributions have provided a systematic review related to the moral concern of knowledge hiding. Thanks to these studies, we are able to enrich the knowledge hiding research by diversifying the existing theoretical perspectives, realizing the interdisciplinary studies, introducing and integrating the moral ownership, moral self-regulation and other moral psychology, cognitive psychology and other disciplines in the theoretical perspectives, forming new insights to call for research on the novel knowledge hiding phenomenon . Furthermore, the contributions that have been included in this Research Topic have taken the lead in exploring how technostress increase R&D employee knowledge hiding in the digital era. These findings draw practitioners' attention to the ethical nature of knowledge hiding behaviors and the respective moral issues. This Research Topic offers practitioners with knowledge on how to better anticipate the harmfulness of immoral behavior and the dark sides of moral behavior, developing the knowledge governance practices from the perspectives of employees' moral emotion and moral cognition.Last, knowledge-related behaviors such as knowledge sharing (see for example All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Animal welfare and economic implications of infectious diseases in cattle demand an efficient surveillance as the foundation for control and eradication programmes. Bovine respiratory syncytial virus (BRSV), Parainfluenza virus type 3 (PI3V), Bovine herpes virus-1 (BoHV-1), Bovine viral diarrhoea virus (BVDV), and Enzootic bovine leukosis virus (EBLV) cause common and often underdiagnosed diseases in cattle that are endemic in most countries [ Th. Th31]. All assays were highly sensitive and able to discriminate the presence of antibodies from the 1\u200a:\u200a2 dilution. Nonetheless, the dilution that characterized the detection limit varied slightly for each antigen, with the 1\u200a:\u200a1024 dilution successfully discriminating positive samples from non-specific binding values for all five antigens tested. Albeit assays could discriminate positive samples in a wide range of dilutions, the MFI was diminished at low dilutions (1\u200a:\u200a8 or below). This counter-intuitive phenomenon (hook effect) occurs when an excess of antibodies impairs their effectiveness to form immune complexes . With hiet al. [et al. 2007 [et al. [Multiplexing in its various platforms will likely substitute monoplex assays for massive serological surveillance. As with ELISA, xMAP allows for the in-house development of assays, optimizing the antigens of interest and permitting the customization of antigen panels to suit specific needs. The development of an xMAP assay is no more complicated than that of an ELISA that uses the same antigens, in most cases yielding similar or even higher sensitivity. Several multiplex assays have been developed by other research groups to study bovine diseases. Fontana et al.  created al. 2007 ). Anders [et al.  devised  [et al. . NonetheThe viruses chosen for the development of the pentaplex assay in this study , have been targeted in eradication/control programmes in Europe and North America due to increasing disease prevalence  and the"}
+{"text": "With remarkable progress being witnessed in recent years in the development of sensors, these advances in sensor technology provide unprecedented opportunities for (1) the early diagnosis and prevention of human diseases by detecting critical biomarkers; (2) health assessments by monitoring and analyzing human physiological signals in healthcare and biomedical applications; and (3) the efficient evaluation of human-health-relevant environmental factors by monitoring and measuring environmental determinants.This Special Issue aims to provide an overview of recent advances being made in sensing technology, including sensors and smart devices, and their applications in healthcare, biomedical, and environmental research. The purpose of this Special Issue is to publish a collection of papers that highlight insightful and influential concepts, designs, algorithms, and techniques in this field. We expect these high-quality papers to be widely read and cited for improving the understanding of physiological mechanisms through accurate and sensitive detection, providing new perspectives and technology to solve health-related problems and state-of-the-art designs to integrate multifunctional sensors.Mingyu Sun et al.  proposedRamona B. Damalerio et al.  fabricatHamed Samimi and Hilmi R. Dajani  focused Haoran Liu et al.  proposedChuan Dai et al.  proposedAli Barzegar Khanghah et al.  presentePanayiotis Antoniou et al.  investigJie Huang and Daqing Huang  designedn = 19) were increased to either 25, 35 or 45 mmHg for 4 h before returning to normal pressure levels at 15 mmHg for the remaining 4 h. Changes in tissue hydration were assessed by differences in spectral slopes between 0.4 and 0.8 THz. They demonstrated that THz can noninvasively assess the corneal endothelium and provide valuable complimentary information for the study and diagnosis of corneal diseases that perturb the hydration of the tissue.Andrew Chen et al.  utilizedPengsu Mao  divided n = 8), fractal analysis (n = 3), recurrence quantification (n = 2), and the Lyapunov exponent (n = 2). This review demonstrated that, in adolescents assessed in a real context, entropy measures are preferred when studying the complexity of human movement, especially when examining multiscale entropy.Sandra Silva et al.  aimed toWe would like to express our profound appreciation for the authors and reviewers who made this Special Issue possible. Our reviewers and authors have dedicated tremendous effort into the preparation of this Special Issue, in order to allow it come to life and flourish."}
+{"text": "Pain Medicine community regarding the recent Cochrane review entitled \u201cSpinal cord stimulation for low back pain\u201d by Traeger et al.,We write to the When making broad recommendations about the use of SCS in the real world, the full context and breadth of available literature must be taken into consideration. The authors designed search criteria that included clinical trials comparing SCS to placebo or \u201cno treatment\u201d  studies with parallel-group design).While high-quality placebo-controlled studies of SCS for CLBP are indeed needed, there is an abundance of Level 1 comparative effectiveness data that supports the effectiveness of SCS for CLBP. These studies have long-term follow-up and answer key clinical questions, such as defining the optimal SCS waveform for a specific patient phenotype, and whether SCS provides outcome and cost benefits over revision decompression and/or fusion surgery. The summation of these data demonstrates large magnitudes of effect, although with indirectness and potential for risk of bias. As such, GRADE assessment should reveal moderate-certainty evidence of medium to long-term effectiveness of SCS for CLBP.2 statistical analysisTraeger et al.,The authors\u2019 conclusions about SCS\u2019s probable lack of efficacy rested singularly on the Hara et al.Surgery, the ultimate placebo and 2) Hippocrasy: How doctors are betraying their oath. Furthermore, while a pain physician was acknowledged at the end of the publication,Generalizations about CLBP care interventions, drawn from data limited by narrow search criteria, are problematic and misleading. The reader is left questioning whether Traeger et al.We respectfully urge the Cochrane Library to retract and revise the Traeger et al."}
+{"text": "Tan et al. and Zhu et al. A diversity of preclinical/translational research studies were also presented in the Research Topic. Lozon et al. presented a novel chemotherapy combination that was validated in vitro in colon cancer and lung cancer cell lines. Abdollah et al., Yang et al., and Lee et al. highlighted a promising anticancer activity for a variety of natural products against hepatocellular carcinoma. On the other hand, the work of Lee et al., Lin et al., Irshad et al., and Kuttikrishnan et al. presented mechanistic insights in pancreatic cancer, breast cancer, non-small-cell lung cancer, and leukemia. The Research Topic also encompasses two literature reviews by Bannoura et al. and Yuan et al.Continuous research efforts have significantly unraveled fundamental molecular pathways that have contributed to paving the way for the development of a multitude of therapeutic strategies, which have and expanded the arsenal of weapons against cancer. This has been tremendously reflected on the uplifting of the cancer survival curve and the improvement of the quality of life of cancer patients. The Research Topic herein was dedicated to highlighting the emerging talents of student researchers pursuing studies in the area of pharmacology of anticancer drugs. The articles in this Research Topic have shed light on the quality and diversity of student researchers across this field and focused on three main themes: 1) Remodeling Cancer Epigenome: Therapeutic Advances; 2) Cancer Immunosurveillance: From Mechanisms to Therapy; 3) Anticancer Drug Discovery and Translational Oncology. The studies herein include two reports of clinical trials by Zhu et al. employed a Markov decision-analytic model to compare the cost-effectiveness of T-DXd with chemotherapy in HER2-low ABC patients. While T-DXd showed improved quality-adjusted life years (QALYs), its incorporation led to increased costs and an unfavorable incremental cost-effectiveness ratio (ICER) compared to chemotherapy, making it devoid of cost-effectiveness in HER2-low ABC patients in the United States. The authors, however, believe that it may still provide health benefits to patients with HR+/HER2-low ABC.Trastuzumab deruxtecan (T-DXd), an antibody\u2013drug conjugate, has shown antitumor activity in patients with HER2-low advanced breast cancer (ABC) in clinical trials. However, the cost-effectiveness of T-DXd was not clearly established. In order to determine whether the benefits of this treatment outweigh its costs, Tan et al. suggested that pembrolizumab plus nab-paclitaxel might be a potential treatment option for patients with cholangiocarcinoma (CCA), which is a highly aggressive malignancy with poor overall survival. In this report, a metastatic extrahepatic CCA patient achieved durable response and good tolerance to a combination treatment of pembrolizumab plus nab-paclitaxel following progression on a chemotherapy of gemcitabine and capecitabine.In their case report, Lozon et al. contributed an original article highlighting the importance of safranal (SAF) as a promising candidate-sensitizing agent of human colon cancer cells (HCT116) and lung cancer cells (A549) to the cytotoxic effect of the topoisomerase inhibitor topotecan (TPT). The combination augmented TPT-induced alterations in DNA repair and boosted the incidence of double-strand breaks with subsequent induction of apoptosis. The sensitization only occurred when the cells were pretreated with SAF 24\u00a0h before TPT treatment. However, simultaneous exposure or adding SAF 24\u00a0h after TPT did not recapitulate the same results. Hence, the effect was sequence dependent.Abdollah et al. aimed to determine whether fucoidan\u2019s chemomodulatory benefits may be enhanced by using it in combination with the FDA-approved antiangiogenic drugs sorafenib and Avastin (bevacizumab) in order to augment their anticancer activity in hepatocellular carcinoma (HCC) cells. The authors reported that the combination treatment inhibited the PI3K/AKT/mTOR and KRAS/BRAF/MAPK pathways in addition to apoptosis induction in HCC both in vitro and in vivo.An article by Yang et al. identified a potential pharmacological mechanism by which Ganji Fang (GJF) can treat HCC at the systemic level. The underlying mechanisms were shown to involve immune control, cell migration, cell proliferation, apoptosis, and inflammation induction. Furthermore, it was demonstrated that the G0/G1 phase cycle arrest subsequent to the apoptosis after GJF treatment in liver cancer cells was triggered by blocking the PI3K/Akt signaling pathway. Pachymic acid has been shown to be the significant active component of GJF that exhibits anticancer action, and EPHA2 may be a potential key target for GJF in HCC.Lee et al. reported that WGM extracts induced cell death by targeting mTOR and MAPK signaling pathways in liver cancer cells, suggesting that they could be used as a pharmacologically safe natural dietary chemopreventive agent for HCC treatment.It was previously found that white genius mushroom (WGM), a popular edible mushroom in Taiwan, mediates strong antiproliferative activities against human Hep3B liver cancer cells. However, the underlying mechanisms have not been fully investigated. Lee et al. investigated the efficacy and molecular mechanisms of ivermectin/gemcitabine combination in pancreatic cancer. They observed that a combination treatment of ivermectin and gemcitabine suppressed pancreatic cancer both in vitro and in vivo more effectively than gemcitabine alone. Mechanistically, this combination was found to exert its effects by inhibiting cell proliferation via G1 cell cycle arrest and augmenting apoptosis by inducing mitochondrial dysfunction. Based on these findings, the study concluded that ivermectin, an antiparasitic drug, can exhibit synergistic effects with gemcitabine and may be repurposed to serve as a promising therapeutic agent for pancreatic cancer therapy.The article by Lin et al. demonstrated the anticancer effects of gallic acid, a phenolic acid known for its antioxidant properties, against triple-negative breast cancer cells in vitro. The study showed that gallic acid was able to inhibit the growth of HCC1806 cells and stimulate their apoptosis by triggering the production of reactive oxygen species, which modulate the PI3K/AKT/EGFR and MAPK signaling pathways.Irshad et al. employed integrative network pharmacology, molecular docking, and in vitro experiments to elucidate the mechanism of action of glycyrrhetinic acid (18\u03b1-GA), a triterpenoid found in licorice against non-small-cell lung cancer (NSCLC). Their network pharmacology study identified EGFR, AKT1, PI3KR1, MAPK1, IGF1, and SRC as crucial hub targets for 18\u03b1-GA against NSCLC. The authors further showed that 18\u03b1-GA augmented G1 cell cycle arrest, triggered apoptosis, reduced the migratory potential, and inhibited the EGFR-PI3K/AKT pathway in NSCLC cell lines.Kuttikrishnan et al. explored the role of neosetophomone-B (NSP-B), a meroterpenoid fungal secondary metabolite, on the FOXM1/BUB1B signaling pathway. The development and progression of various types of cancer, including chronic myelogenous leukemia, have been linked to the abnormal expression of FOXM1 and BUB1B genes. A TCGA data analysis elaborated that BUB1B is overexpressed in most cancers and linked with poor prognosis. Using gene expression profiling, the authors showed the significant downregulation of BUB1B in leukemia cells treated with NSP-B. In addition, they validated their in silico findings in vitro by showing that NSP-B suppresses the expression of FOXM1 and BUB1B in a dose-dependent manner, leading to compromised cell viability and apoptosis induction in leukemia cells.Bannoura et al. summarized the recent data on targeting KRAS G12D, which is among the most common mutations (45%) in pancreatic cancer that are associated with poor prognosis. The article discussed several modalities under development for targeting KRAS G12D, including small molecule inhibitors and immunotherapy.The minireview by Yuan et al. contributed a bibliometric article of the literature from the Web of Science Core Research Topic (2002\u20132021) on the emerging trends and research foci of the natural compound berberine in cancer. Berberine is a multitarget Chinese medicine monomer compound that is extensively studied for its antitumor/antiproliferative effects and its capacity to sensitize cancer cells to chemotherapy. The collected data showed that berberine exhibits anticancer capacity through a diversity of mechanisms, including halting the cell cycle, inhibition of tumor cell invasion and migration, and inducing autophagy and apoptotic cell death."}
+{"text": "Natural products have played important roles in drug discovery and development as more than 60% drugs are associated with natural products . Yunnan Chen et al., Lei et al., Yan et al., and Clements-Decker et al.), new synthetic approaches towards the key units of natural products , total synthesis of natural products , and structure-activity-relationship (SAR) studies on bioactive natural-product-like molecules . Taken overall, 10 contributions including 2 reviews and 8 original research articles comprise this Research Topic.This Research Topic presents a Research Topic of reviews and original research articles on isolation and structural characterization of novel natural products . A study on antioxidant and anti-inflammatory activity of constituents isolated from Dendrobium nobile (Lindl.) by Lei et al. shows that nineteen compounds, including two new vitamin E homologues, one new sesquiterpene, and two new dendrobines were isolated. New compound aldehyde-\u03b1-tocopherol demonstrated significant antioxidant activity compared with ascorbic acid (VC), as well as equal cytotoxic effect against Hela cell lines to cisplatin, indicating its potential application in the pharmaceutical and food industries. Yan et al. found fourteen C19-lycaconitine-type diterpenoid alkaloids, including six new alkaloids, grandiflolines A\u2013F, isolated from Delphinium grandiflorum L. New alkaloids grandiflolines A-C and E possess a characteristic \u03942,3 functional group in the A ring, while grandiflolines E and F feature a rare OH-16 substituent. New alkaloids exhibit potential inhibition activities of NO in LPS-activated RAW 264.7 macrophages. A review conducted by Clements-Decker et al. delved into the antimicrobial properties of lipopeptides derived from various bacteria strains. The study sheds light on the structures and recently discovered frameworks of lipopeptide families produced by these bacteria, which possess promising antimicrobial properties. Furthermore, utilizing the genome mining approach, underexplored sources of novel antimicrobial lipopeptides have been uncovered. A detailed understanding of the mode of action and biosynthesis included in the review provides a clear path for the development of potential antimicrobial therapeutics in the future.Rao et al. reported a new transitionmetal-free direct oxidative cyclocondensation reaction. The protocol highlighted the use of readily available o-aminobenzyl alcohols and N,N-dimethyl enaminones as starting materials, thus provided a flexible strategy for the preparation of 3-substituted or 3,4-disubstituted quinolones with broad substrate scope in moderate to excellent yields. The strategy enriched the quinoline synthesis method. Jiang et al. reported an effective palladium-catalyzed method for the synthesis of aryl acrylonitriles. This process uses simple and readily available arylacetonitriles and vinyl halides/triflates as raw materials, and the resultant aryl acrylonitriles can undergo a series of useful conversion reactions, such as reduction, hydrolysis and epoxidation.Wei et al. reported a general strategy for the total synthesis of arylnaphthalene lactone lignans (NALLs) including justicidins B and E and taiwanin C. Key features of this synthesis include an aryl\u2013alkyl Suzuki cross-coupling, a novel intramolecular cation-induced cyclization, and a base-mediated oxidative aromatization. Wei et al. explored the uses of dioxinones in synthesizing macrocyclic natural products and terpenoids. The review highlights the versatility and efficiency of dioxinones as reactive intermediates, making them valuable tools for the synthesis of diverse and complex natural products.Zhou et al. designed and synthesized a series of anti-ZIKV active compounds, acetylarylamine-S-DACOs, and conducted in-depth research on the action mechanism of the representative compound through molecular docking analysis and a series of biological experiments. The results confirmed the anti-ZIKV activity at the molecular and protein levels, and discovered that this selected compound targeted ZIKV RNA-dependent RNA polymerase (RdRp). Yin et al. created a series of podophyllotoxin derivatives containing nitrogen-containing heterocycles, which may have potential as anticancer drugs. After synthesizing several derivatives, imidazolium salts and triazolium salts were found to be the most effective against different types of human tumor cells. Additionally, experiments on cell cycle and apoptosis revealed that these compounds could trigger G2/M cell cycle arrest and apoptosis in HCT-116 cells.We hope that this Research Topic could provide an opportunity to school fellows of YNU to introduce their recent research findings in natural product chemistry to the chemical community, which could also provide an incentive for further scientific collaborations between school fellows of YNU and other researchers in this field."}
+{"text": "Mast cells have existed for almost 500 million years  in many The international Journal of Molecular Sciences recently published Special Issues dedicated to aspects of the pathophysiology of mast cells, such as \u201cMast cells in human health and diseases\u201d edited by Giovanna Traina , and \u201cMaThe emphasis of this Special Issue entitled \u201cThe Role of Mast Cells and Their Inflammatory Mediators in Immunity\u201d was to address aspects of mast cell involvement in immune and inflammatory processes not covered by previous volumes.A major review communicated via Dr. Domenico Ribatti and authored by Solimando et al. described in detail the production of interleukins by mast cells, as well as their important role in immune processes . Given tFor the longest time, the notion persisted that all mast cells are the same. Then, they were separated into mucosal-type (MMC), containing only tryptase, and those of the connective-tissue-type (CTMC), containing both chymase and tryptase. However, increasing evidence indicates that there are unique subpopulations with distinct histological and secretory characteristics. The submission via Dr. Lars Hellman by Akula et al. using quantitative transcriptome analysis describes a particular subtype of mucosal mast cell in bronchoalveolar lavage fluid (BALF) that contributes to inflammation in the lungs of asthmatic horses  that mayThe paper submitted via Dr. Claudia Gonz\u00e1lez-Espinosa by Mart\u00ednez-Aguilar et al. identifies the augmenting effect of lysophosphatidylinositol  on mast cell functions promoting inflammation through the differential participation of the GPR55 and cannabinoid 2 (CB2) receptors . PI servThe submission via Dr. Zenke by De Toledo et al. describes the important finding that human-induced pluripotent stem cell (hiPSC)-derived mast cells can mimic mastocytosis-like mast cells , suggestThe article by Drs. Tsilioni and Theoharides reports for the first time that nanomolar amounts of recombinant coronavirus spike protein stimulated human mast cells to secrete proteases via the activation of the angiotensin-converting enzyme 2 (ACE2) receptor, but stimulates the release of the proinflammatory cytokine IL-1b via the activation of TLR4; these processes are augmented by alarmin IL-33 . This noThe contribution communicated via Dr. Tsilioni by Jingshu et al. reported the development of a 3-D hydrogel formed by collagen I and culture human mast cells and showed that different A\u03b2 peptides could stimulate mast cells to secrete inflammatory mediators. This model could incorporate microglia and neurons that could better reflect the mechanisms involved in the pathogenesis of neuroinflammation and Alzheimer\u2019s disease .The submission submitted via Dr. Marcus Maurer by Dr. Buttgereit et al. describes that the mitochondrial Complex I can act as a critical innate inhibitory component of the mast cell secretion of pro-inflammatory mediators . ComplexFinally, the review by Theoharides and Kempuraj discusses the potential role of the ezrin, radixin, moesin (ERMS) family of proteins, especially moesin, in regulating the exocytotic mechanism of mast cell secretion of granule-stored mediators .These papers highlight key aspects of the potential role of mast cells in immunity and inflammation by presenting novel findings on the subtypes, regulatory mechanisms, and unique associations with innate and external triggers. However, there are still gaps in our knowledge, such as the effect of the microenvironment on the tissue mast cell phenotype and ways to regulate mast cell activation. An improved understanding may be obtained through the use of in vitro disease surrogate models using organoids  with hiP"}
+{"text": "Leishmania parasites and cancer cells. The information regarding common expressed proteins, as possible therapeutic targets, in Leishmania parasites and cancer cells is scarce. Therefore, the current study reviews proteins, and investigates the regulation and functions of several key proteins in Leishmania parasites and cancer cells. The up- and down-regulations of such proteins were mostly related to survival, development, pathogenicity, metabolic pathways and vital signalling in Leishmania parasites and cancer cells. The presence of common expressed proteins in Leishmania parasites and cancer cells reveals valuable information regarding the possible shared mechanisms of pathogenicity and opportunities for therapeutic targeting in leishmaniasis and cancers in the future.The association of leishmaniasis and malignancies in human and animal models has been highlighted in recent years. The misdiagnosis of coexistence of leishmaniasis and cancer and the use of common drugs in the treatment of such diseases prompt us to further survey the molecular biology of  Leishmania. Annually, approximately 1.5\u20132 million new cases are reported worldwide being 310 million people at risk. The mortality rate of the disease varies from 40\u00a0000 to 70\u00a0000 cases per year  are mostly restricted to the skin lesions with diverse appearances, from localized to body extended wounds or mucosal affectations. However, visceral leishmaniasis (VL) is characterized by severe organic symptoms and might lead to death    can also raise the risk of developing some types of cancers and may contribute to the appearance of malignancies which makes them possible models to study host\u2013parasite interactions and mechanisms of cancer  Liao, . Howeveret al., et al., et al., et al., et al., et al., et al., Leishmania parasites also modulate and destabilize the host chromatin structure leading to potential changes in relevant immune-related genes and responses  pathway  and PKC. The metabolic action of miltefosine affects the biosynthesis of glycolipids and membrane glycoproteins of the Leishmania parasite, leading to apoptosis  signalling , interleukin-12 (IL-12), IFN-\u03b3, inducible nitric oxide synthase and IL-2, and finally, inducing tumour cell death. Cancer therapy is an essential research area and protein kinases are major targets for drugs. The mTOR is a highly conserved serine/threonine protein kinase that is central regulating essential cellular processes and mTOR inhibitors are used in cancer therapy  and parasite survival inside macrophages through down-regulation of the nuclear factor-\u03baB and signal transducer and activator of transcription 3 oncogene factors  levels  led to the reduction of lesions size and decreased the load of parasites in skin in the L. amazonensis-infected BALB/c mice. However, the use of such an inhibitor also induced hepatotoxicity in BALB/c mice   were correlated with the development of oral cancer  selectively targeted proliferation and survival of tumour initiating cells in SCC and ovarian cancer cells. This compound prevented cancer cells from entering the S-phase under growth-factor stimulation without cell death induction  is an inhibitor of HSP90, which has been investigated in the treatment of cancer such as solid tumours and leukaemia. Alternatively, geldanamycin, and its analogues, 17-dimethylamino ethylamino-17-demethoxygeldanamycin (17-DMAG) and 17-AAG, may show a promising therapeutic activities against leishmaniasis . However, the delivery of 17-AAG is difficult because of its poor aqueous solubility  and is overexpressed in the promastigote forms compared to the amastigotes  and a combination of gossypol (a pan-ALDH inhibitor) and phenformin leads to cancer cell death  and beta (TOP 2B) which exhibit differences in their molecular weight, genetic regulation and the location of the active site. TOP II expression in cancer lines has been largely studied Doyle, . Althoug\u03b4) and epsilon (Pol \u025b). It also interacts with other proteins involved in cell-cycle progression which are not parts of the DNA polymerase complex. PCNA has demonstrated its role in the replication and repair of DNA, chromatin assembly and RNA transcription. Its importance in Leishmania pathology is related to its significant role in drug response in clinical isolates  dimers polymerize to form microtubules, which serve as a skeletal system for living cells and participate in several essential functions, such as mitosis or intracellular transport among others  has been suggested as potential drug target in leishmaniasis treatment    structure. Data produced by genome sequencing in protozoa has indicated the presence of TOM-40 homologues in in vitro\u2019. It seems that TOM-40 increases the replication of cancer cells through regulating the mitochondrial activity and improving cellular energy and redox status , the expression of OAT is up-regulated and the mechanism of this gene up-regulation is related to the activation of \u03b2-catenin signalling (Cadoret et al., et al., \u03b2-catenin signalling and the metabolism of glutamine are important factors in carcinogenesis especially in HCC (Cadoret et al., Leishmania parasites (Zigmond et al., OAT as a Leishmania parasites (Iribar et al., et al., et al., Selenoproteins are a group of enzymes bearing selenocysteine in their catalytic domain. Many of the Se-bearing proteins participate in oxidative stress protection as observed in et al., et al., Leishmania, with promising results. However, this compound seems not to target selenoproteins in these parasites, but rather interact with trypanothione reductase, a key enzyme of Leishmania polyamine-dependent redox metabolism (Ilari et al., et al., et al., et al., The role of selenoproteins and their metabolites including methylselenol, selenodiglutathione, Se-methylselenocysteine and selenomethionine has been underlined in the metabolism of lung cancer cells (Seng and Tiekink, Leishmania parasites has been previously reported (Hart and Opperdoes, et al., et al., Leishmania. Therefore, they might be related to the pathogenicity of these parasites (Blattner et al., et al., Leishmania isolates suggesting resistant strains require higher energy to protect against antimony-induced oxidative stress. Alternatively, the overexpression of such enzyme might lead to enhancing in pyruvate which can remove peroxides and participate to reduce oxidative stress (Biyani et al., Leishmania and mammalian cells, PGKs are encoded by two genes: gene B and gene C, and PGK-1 and PGK-2, respectively (Watson and Littlechild, et al., T. brucei PGK. Of these, 2-amino-N6-substituted analogues represented appropriate activity against the parasite kinase compared with the N6 compounds that lacked the C2 amino group, although activity was still weak (Merritt et al., PGKs are transferases involved in ATP production from ADP and 1,3-diphosphoglycerate. Their involvement in the glycolytic pathway and survival of et al., et al., et al., et al., et al., et al., et al., The importance of PGK-1 in cancer development resides on its involvement in drug-resistance and its dual action depending on the cellular environment. Under intracellular hypoxia conditions, it plays an oncogenic role. However, it decreases tumour growth when it is secreted extracellularly through angiogenesis inhibition (Daly Leishmania parasites and cancer cells. As an interesting issue, the regulation of these markers can be investigated in interactions that can be occurred between Leishmania parasites and cancer cells under \u2018in vivo\u2019 and \u2018in vitro\u2019 conditions. The reliable validation of the expression of such proteins in Leishmania parasites and cancer cells using further experiments is warranted to subsequently confirm their possible functions. Further investigation of the differentially regulation of common expressed proteins between cancer cells, normal human cells, low-pathogenic and high-pathogenic forms of Leishmania parasites might elucidate novel and attractive information concerning such proteins. The existence of common triggering factors reflects mutual features in the etiopathogenetic mechanisms underlying leishmaniasis and cancer. Given these similarities, lessons learned from strategies against cancer may be relevant to design adequate approaches to reduce and eliminate leishmaniasis. Herein, we focused specifically on the shared mechanisms at protein scale. Taken together, the introduction of common expressed proteins in Leishmania parasites and cancer cells might reveal valuable information regarding the possible common mechanisms of pathogenicity and therapeutic targets in leishmaniasis and cancers. Taking into account that current therapies for neglected diseases are based in drugs lacking effectiveness, the lack of new specific anti-Leishmania compounds and of research focused on this group of diseases, drug repurposing constitutes a useful tool to find effective candidates in leishmaniasis control and elimination. This review reinforces the likely functional similarities between many proteins in cancer and parasites, some of them being recognized therapeutic targets and thus the potential use of drugs with proven efficacy in the treatment of cancer for treating parasitic diseases and vice versa, opening new avenues to the one health approach.The up- and down-regulation of the aforementioned proteins were mostly related to the survival, development, pathogenicity, metabolic pathways and vital signalling in"}
+{"text": "Iron is essential for life, and the dysregulation of iron homeostasis can lead to severe pathological changes in the neurological system. Iron deficiency slows the development of the neural system and causes mental and emotional disorders ,2,3, whiIn this Special Issue, \u201cIron Metabolism, Redox Balance and Neurological Diseases\u201d, five original research articles and five scientific review papers are published. These papers highlight the most recent advances in different aspects of iron regulation and redox imbalance in various diseases, including the molecular mechanisms of iron-induced oxidative damage in disease pathogenesis, potential therapeutic targets and approaches for the regulation of iron metabolism and related damages, and challenges to current studies attempting to understand an aberrant iron metabolism in the pathology of different diseases and its potential clinical applications.In the original research articles, Han et al. revealed a novel role of iron in the maintenance of cell stemness via the Wnt/GSK-3\u03b2/\u03b2-catenin signaling pathway . The intBao et al. designed and characterized a mitochondrial-targeted pseudo-mitochondrial membrane potential (PMMP) constructed by antioxidant MitoQ , which sLiu et al. demonstrated that IRP2 not only regulated cellular iron homeostasis, but also medicated tissue iron distribution by managing the involvement of hypoxia-inducible factor 2 (HIF2) and nuclear receptor coactivator 4 (Ncoa4) . This stHan et al. investigated the underlying mechanisms of CY-09, a specific inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome, on ameliorating AD classical pathology and cognitive impairment in AD mice . Their fChen et al. revealed that the dopaminergic neuronal death and Parkinsonian symptoms in OTU domain-containing protein 3 (OTUD3) knockout mice might be caused by activating inositol-requiring enzyme 1\u03b1 (IRE1\u03b1) signaling, which mediated endoplasmic reticulum (ER) stress . The OTUIn the review articles, Luo et al. summarized the molecular mechanisms of ferroptosis in glioma cell growth, invasion, migration, and resistance, and introduced potential applications and challenges of manipulating ferroptosis in the development and treatment of gliomas . They alJim\u00e9nez-Jim\u00e9nez et al. systematically reviewed the role of antioxidant coenzyme Q10 (CoQ10) in AD and other dementias . CombineHolbein et al. described biological iron requirements, iron regulation, and the nature of iron dysregulation in detail in various disease conditions , includiLee et al. reviewed the interplay between intracellular iron homeostasis and neuroinflammation in neurodegenerative diseases . They inGao et al. summarized and elucidated the interplay between the dysregulation of iron metabolism, redox imbalance, and different neurological diseases  such as In conclusion, the original research and review articles in this Special Issue provide an updated overview of the advances on the mechanisms or treatments of neurological diseases related to iron dysregulation and redox imbalance. These papers offer fresh perspectives on the expanding knowledge and research possibilities in the field of iron metabolism, redox balance, and neurological diseases, and may stimulate future studies to better target the regulation of brain iron metabolism for the prevention and treatment of neurological diseases."}
+{"text": "Advanced Parkinson\u2019s disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally. Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigrostriatal dopamine neurons and its incidence is increasing fast globally  is defined as a condition where periods of poor mobility with or without dyskinesia are present and have an impact on functional independence of the affected person  in a water solution of carboxymethyl cellulose into the patient\u2019s proximal small intestine through a portable pump and a tube placed via percutaneous endoscopic gastro-jejunostomy (PEG-J)  of withdrawal  of 1.72\u00a0h in \u201cGood ON\u201d time. The trial also demonstrated positive and clinically meaningful results for the key secondary endpoint of \u201cOFF\u201d time (p\u2009<\u20090.0001) and other secondary endpoints including the MDS-Unified Parkinson's Disease Rating Scale Part II score (MDS-UPDRS motor experiences of daily living sub-score) (p\u2009<\u20090.0001); the Patient Global Impression of Change (PGIC) (p\u2009<\u20090.0001); and the Clinical Global Impression of Improvement (CGI-I) (p\u2009<\u20090.0001).ND0612 is a drug-device combination consisting of a sterile solution of levodopa/carbidopa continuously delivered via a dedicated subcutaneous pump (Olanow et al. ABBV-951 is a new soluble formulation of foslevodopa/foscarbidopa, both levodopa and carbidopa prodrugs, which can be delivered subcutaneously for up to 24\u00a0h/day. After administration, foslevodopa/foscarbidopa is quickly converted to levodopa/carbidopa by alkaline phosphatases, reaching and maintaining therapeutic steady-state plasma levels in a very short time (Rosebraugh et al. Research in PD has increasingly focused on the development of new and effective biological therapies for disease modification (Antonini et al. Limitations will still be related to the lack of direct comparative efficacy and safety studies among advanced treatments and the difficulty of identifying specific patients\u2019 profiles.Infusion therapies might also become more integrated with remote monitoring technologies and telemedicine, allowing healthcare providers to track patient responses, adjust treatments and offer support from a distance (Guerra et al. Along with the progressive increase in the number of options, the selection of more appropriate device-aided therapy for APD will be more complex, it will involve multiple specialties as well as the carers and affected ones. A shared decision approach is, therefore, essential. While treatment decisions need to be individualized, the choice of device-aided therapies can be guided by some general principles based on the patient\u2019s age, cognitive and behavioral status, dyskinesia and frailty.Understanding the comparative benefits of each treatment provides additional information that can help patients, caregivers and providers in the selection of the most appropriate therapy to ensure optimal symptom control and improved QoL (Martinez-Martin et al."}
+{"text": "Flow cytometry is a single-cell based technology aimed to quantify the scattering of light and the emission of multiple fluorescence signals by individual cells, biological vesicles, or synthetic microscopical particles when examined one by one at high speed using lasers or other suitable illumination sources ,2. In coThis new Special Issue entitled \u201cFlow Cytometry and Its Applications to Molecular Biology and Diagnosis 2.0\u201d of the International Journal of Molecular Sciences includes a total of five contributions: three original articles and two reviews, providing new information about advanced applications of flow cytometry in the fields of molecular and cell biology for basic and translational research.Rossi et al.  extensivDrug development has evolved rapidly, and in the last years, cell and gene therapies are becoming efficient alternatives to small chemical and biomolecule pharmacology. Several cell and gene therapies have reached regulatory approval, specially in the field of tumor immunotherapy, and such a breakthrough demands suitable bioanalytical techniques for fully characterizing the pharmacokinetics of these therapies. However, these different techniques may not always lead to concordant results, and this fact requires a deep understanding of the technical grounds of each technique, which data are generated, and how these data can be compared and interpreted. In their review, Hays et al.  critical+ extracellular vesicles (EVs). These results support that the conjugation of antitumor drugs to SiNPs is an efficient way for drug delivery that potentiates drug cytotoxicity, while reducing side effects.Among the new directions for cancer therapy, nanomaterials appear as a promising tool for drug delivery into specific cells or subcellular compartments. In this regard, fluorescent silica nanoparticles (SiNPs) appear to be a promising imaging platform, as they show intramitochondrial colocalization in biological cell models and can be used as efficient drug delivery systems when conjugated to a therapeutic molecule. Sola et al.  performeCampylobacter jejuni and other Gram-negative bacteria. In the first part of their in vitro experimental design, Montanari et al. showed that CDT-containing bacterial lysates induce lethal and sublethal alterations in intestinal (CaCo-2) and myeloid (U937) cell lines, including cell cycle arrest, mitochondrial dysfunction, and oxidative stress. These intracellular changes were accompanied by relevant changes in lysosomal exocytosis, secretory autophagy, and EV release. Based on these effect on the secretion processes, Montanari et al. investigated the presence of active CDT in EVs secreted by CDT-treated CaCo-2 cells and found that CDT-like effects were transferred from infected CaCo-2 cells to uninfected heterologous (U937) and homologous (CaCo-2) cells. Their results suggest that EVs from CDT-treated CaCo-2 cells are reliable CDT carriers and could potentially be used in the treatment of colorectal cancer.The paper by Montanari et al.  exploredEscherichia coli B strains deficient in key genes of the antioxidant defense, namely oxyR, sodA, and sod B. J\u00e1vega et al. applied this model for systematically assessing issues of ROS specificity of several relevant fluorescent probes and the involvement of different ROS in the oxidative stress induced on these strains by exogenous prooxidants. Their results suggest that the antioxidant-deficient Escherichia coli B strains can be used as ROS biosensors in flow cytometric studies of oxidative stress and confirm the specificity issues of ROS-sensitive fluorescence that have already been detected in eukaryotic models. In addition, J\u00e1vega et al. provided recommendations for the proper design of flow cytometric studies involving ROS detection.Analysis of reactive oxygen species (ROS) and oxidative stress is a very relevant application of flow cytometry. However, to ascertain the specific role of ROS in oxidative stress studies via cytomic methodologies, it is essential to detect and characterize these species accurately. While there is a large availability of fluorescent probes for ROS analysis via flow cytometry, these reagents exhibit important limitations in their specificity and sensitivity that may affect the accuracy of the analysis. J\u00e1vega et al.  presente"}
+{"text": "Real-world data from wearable devices has the potential to understand mental health status in everyday life. We aimed to investigate the feasibility of estimating mental health status using a wrist-worn wearable device (Fitbit Sense) that measures movement using a 3D accelerometer and optical pulse photoplethysmography (PPG).Participants were 110 patients with mental illnesses from different diagnostic groups. The study was undertaken between 1 October 2020 and 31 March 2021. Participants wore a Fitbit Sense on their wrist and also completed the State\u2013Trait Anxiety Inventory (STAI), Positive and Negative Affect Schedule (PANAS), and EuroQol 5 dimensions 5-level (EQ-5D-5L) during the study period. To determine heart rate (HR) variability (HRV), we calculated the sdnn , coefficient of variation of R-R intervals, and mean HR separately for each sleep stage and the daytime. The association between mental health status and HR and HRV was analyzed.The following significant correlations were found in the wake after sleep onset stage within 3\u2009days of mental health status assessment: sdnn, HR and STAI scores, HR and PANAS scores, HR and EQ-5D-5L scores. The association between mental health status and HR and HRV was stronger the closer the temporal distance between mental health status assessment and HR measurement.A wrist-worn wearable device that measures PPG signals was feasible for use with patients with mental illness. Resting state HR and HRV could be used as an objective assessment of mental health status within a few days of measurement. BecauseHowever, because of concerns about the time and effort involved in self-administered questionnaires, an objective and less burdensome method of monitoring mental health status using wearable devices has attracted attention. One way of estimating mental health status is to use heart rate (HR) variability (HRV), as HR is controlled by the autonomic nervous system (ANS) . The parThere is growing interest in the use of wrist-worn wearable devices that can measure movement using a 3D accelerometer and optical pulse photoplethysmography (PPG) to obtain biometric information in the real world, rather than in a special environment such as a laboratory. However, the validity of such data for the assessment of patients with mental illness has not been adequately demonstrated. HRV measures the variation in time between heartbeats and is usually calculated from electrocardiogram (ECG) R-R intervals; however, wearable devices record an optical PPG signal and therefore the peak of the R waves cannot be detected accurately. The accuracy of PPG-based HR data has been previously reviewed and validated in comparison with ECG data; PPG-based HR data is typically accurate within a 10% error range . As reseIn this study, we examined the feasibility and validity of using wearable devices to estimate mental health status in patients enrolled in the Mental Illness Registry, using standardized tests for anxiety, affect, and QOL as a reference. As a wearable device, Fitbit Sense was chosen because Fitbit device is the most researched , widely 2.2.1.A total of 110 patients who were enrolled in the Mental Illness Registry during the study period between 1 October 2020 and 31 March 2021 and provided their informed consent, participated in the study. Participants were either inpatients or outpatients at six sites: the National Center of Neurology and Psychiatry Hospital, Nara Medical University Hospital, Kansai Medical University Hospital, Nagoya University Hospital, Hokkaido University Hospital, and Akita University Hospital. The sample included patients with a wide range of clinical presentations from different diagnostic groups . Most paThe Ethics Committee of the National Center of Neurology and Psychiatry approved the study protocol and experimental procedures (B2021-086).2.2.This was a multisite observational study. Participants were either inpatients or outpatients at six sites: the National Center of Neurology and Psychiatry Hospital, Nara Medical University Hospital, Kansai Medical University Hospital, Nagoya University Hospital, Hokkaido University Hospital, and Akita University Hospital. The software setup for data acquisition was conducted in advance by the researchers. Participants had only to wear a Fitbit Sense on their left or right wrist for as long as they could tolerate it between the day of consent and their next visit to the hospital (for outpatients), or until their first visit to the hospital after discharge (for inpatients). While wearing the Fitbit Sense, participants were contacted via their smartphones to inquire about their current socioenvironmental situation and to ask them to complete the following self-administered questionnaires: the STAI FORM X-I, II  to meas  and cvrr , which are modulated by the ANS. We also assessed HR. The sdnn, cvrr, and HR were calculated using a sampling time of 5\u2009s with 30\u2009min as one epoch; if there were multiple epochs appropriately recorded, the average value was used as the representative value. Assuming that during the daytime HR is sensitive to activity, we excluded data in which the HR was greater than 90/min or fell below 50/min, and in which the difference between the maximum and minimum within one epoch was greater than 40/min or less than 5/min. During sleep, only the latter condition was used; data in which the difference between the maximum and minimum HRs within one epoch was greater than 40/min or less than 5/min were excluded because of the suspected possibility of measurement noise. The Fitbit device used in the present study records an optical PPG signal and thus the peak of the R waves cannot be detected accurately. Therefore, the interval between the pulse wave (estimated by 60/mean HR) was used as a surrogate for the R-R intervals obtained from an ECG.Sleep stage information in this study was provided by the Fitbit Research Library, which analyzed the 3D accelerometer and optical PPG data collected in this study. Unfortunately, the algorithm for determining sleep stage from 3D accelerometer and PPG data obtained from Fitbit is not publicly available. However, Beattie et al. provides an overview of the analysis using the generated features on a 30\u2009s time scale based on motion, HRV, and breathing rate parameters were used to develop an automated sleep staging algorithm . Specifi2.4.As reference, we used electronic self-reported assessments of anxiety, affect, and QOL. Patients reported their data using a smartphone. The following self-administered questionnaires were used: the STAI Form X-I and Form X-II to measure state and trait anxiety, the PANAS to measure positive and negative affect, and the EQ-5D-5L visual analog scale (VAS) and utility score to measure QOL.The STAI Form X-I and Form X-II were developed by Spielberger et al. ; they haThe PANAS consists of 20 items that comprise adjectives representing positive and negative affect . The rel5) possible health states, and utility scores are derived from a preference-based algorithm used to calculate quality-adjusted life years . In this study, an algorithm developed using survey results based on the composite time trade-off in Japan was used  were performed to examine associations between HR and HRV indices  and mental health status variables  for each sleep stage and the daytime to estimate which time period HR and HRV indices best reflected mental health status. Then, to explore the effect of focusing on the period showing the strongest association, the effect of temporal distance between the time of HR measurement and mental health status assessment on the association between them was examined using univariate correlation analyses (Pearson\u2019s product moment correlation) between HR and HRV indices and mental health status variables when HR and HRV data were restricted to within 7\u2009days and within 3\u2009days of the mental health status assessment. For the data set that was ultimately estimated to have the strongest association, multivariable regression analysis was performed with each HRV index, age, sex, chlorpromazine-equivalent of antipsychotics, imipramine-equivalent dose of antidepressants, and diazepam-equivalent dose of anxiolytics and hypnotics as independent variables, and each mental health status variable as a dependent variable, to adjust for possible confounding factors , 21.P-value of <0.05 was considered statistically significant for all tests.The statistical analysis was performed using JMP version 13.0.0 ; a 3.Of the 110 patients who consented to participate in the study, available data on HRV indices were obtained from 92 patients . For theThe exploratory analyses of correlations between HR and HRV indices and mental health status variables for each sleep stage and the daytime showed a significant correlation between sdnn and STAI Form X-II scores, between HR and STAI Form X-I and Form-II scores, between HR and EQ-5D-5L VAS and utility scores in the WASO stage; between HR and STAI Form X-I scores and EQ-5D-5L VAS scores in the light stage; between HR and STAI Form X-I scores, PANAS positive affect scores, and EQ-5D-5L VAS scores in the deep stage; and between HR and STAI Form X-I scores in the REM stage . As can Focusing on data obtained in the WASO stage, the correlations between HR and HRV indices and mental health status variables within 14\u2009days, 7\u2009days, and 3\u2009days of the time of mental health status assessment are shown in P\u2009=\u20090.035); HR and STAI Form X-I scores ; HR and PANAS positive affect scores ; HR and EQ-5D-5L VAS scores ; and HR and EQ-5D-5L utility scores .Multivariable regression analyses were conducted on the variables that showed significant intercorrelations for data obtained within 3\u2009days of mental health status assessment . After a4.In this study, we explored the feasibility of using PPG obtained by a wrist-worn wearable device to assess mental health status in patients with mental illness. Of 110 patients, 92 (83.6%) returned usable HR data. HR and HRV measured within 14\u2009days of the mental health status assessment were significantly associated with anxiety and QOL in different sleep stages, and the association was strongest in the WASO stage. Although exploratory, the results also suggest that HR and HRV in the WASO stage may reflect anxiety, positive affect, and QOL within 3\u2009days.ECG data on HR and HRV are one of the most important biomarkers of emotion . When anOur findings suggest that HR and HRV in the WASO stage better reflect current mental health status than data in other sleep stages and in the daytime. This may be because the resting state is maintained during the WASO stage, as it is less affected by daytime activities or ANS activity during REM sleep. In addition, the accuracy of wearable devices in estimating sleep stages in healthy individuals has been reported as reasonable , 14. OneA recent review  found thThe present study had several limitations. Although a common technique is to develop a peak detector algorithm to detect the peaks in the PPG signal, and the time between PPG peaks is used as a surrogate for the R-R intervals  in the pThis study examined the feasibility and potential of a wrist-worn wearable device to assess the mental health status of mentally ill patients. Although the results were exploratory and cross-sectional, they suggest the potential utility of this method. Additional validation studies, including longitudinal studies, are warranted. If it is possible to objectively monitor mental health status in the home by the wearing of a wrist-worn device for a relatively short period, this could reduce the burden on patients in cohort studies and improve their well-being.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of the National Center of Neurology and Psychiatry. The patients/participants provided their written informed consent to participate in this study.KN contributed toward conceptualization, methodology, investigation, project administration, and writing of the original draft. KMin and TF contributed toward data curation, provision of resources, and formal analysis. MM, MU, MK, NO, SM, KI, NH, AT, MO, MT, and KMis contributed toward conceptualization, methodology, and investigation. MOb, KT, and HO contributed toward conceptualization, data curation, and supervising the statistical analysis. All authors contributed toward acquisition of data, critical revision of the manuscript for important intellectual content, approval of the final version of the manuscript, and agree to be accountable for all aspects of the work and ensure that any questions related to the accuracy or integrity of any part of the work will be appropriately investigated and resolved.This research was supported by AMED under Grant number JP21dk0307103 and an Intramural Research Grant (3-1) for Neurological and Psychiatric Disorders of NCNP. KN confirms that he had full access to all the data in the study and takes final responsibility for the decision to submit for publication.KN reports grants from AMED during the conduct of this study and from Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd. and Janssen Pharmaceutical K.K., and personal fees from Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Meiji-Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., MOCHIDA PHARMACEUTICAL CO., LTD., Mitsubishi Tanabe Pharma Corp., Viatris Inc., and Eisai Co., Ltd. He has received payment for advisory work from Takeda Pharmaceutical Co., Ltd., Lundbeck Japan, and Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. MM has received research grants from Sumitomo Pharma Co., Ltd. and Kyowa Kirin Co., Ltd. MK has received grant funding from the Japanese Ministry of Health, Labour and Welfare, the Japan Society for the Promotion of Science, SENSHIN Medical Research Foundation, the Japan Research Foundation for Clinical Pharmacology, and the Japanese Society of Clinical Neuropsychopharmacology, and speaker honoraria from Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Meiji-Seika Pharma Co., Ltd., Eli Lilly Japan K.K., Merck & Co., Inc., Pfizer Inc., Janssen Pharmaceutical K.K., Shionogi & Co., Ltd., Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Lundbeck Japan, Viatris Inc., Eisai Co., Ltd., and ONO PHARMACEUTICAL CO., LTD., and has participated in advisory/review boards for Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Shionogi & Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. NO has received research support or speaker honoraria from, or has served as a joint researcher with, or a consultant to, Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., KAITEKI, Mitsubishi Tanabe Pharma Corp., Eli Lilly Japan K.K., MOCHIDA PHARMACEUTICAL CO., LTD., DAIICHI SANKYO CO., LTD., TSUMURA & CO., Takeda Pharmaceutical Co., Ltd., Meiji-Seika Pharma Co., Ltd., EA Pharma Co., Ltd., Viatris Inc., Ricoh Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Lundbeck Japan, Nihon Medi-Physics Co., Ltd., and Nippon Chemiphar Co., Ltd., outside the submitted work. KI has received speaker honoraria from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Meiji-Seika Pharma Co., Ltd., Merck & Co., Inc., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., TOWA PHARMACEUTICAL CO., LTD., and Viatris Inc., outside the submitted work. NH has received personal fees from Janssen Pharmaceutical K.K., Yoshitomiyakuhin Corporation, Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Novartis Pharma K.K., Meiji-Seika Pharma Co., Ltd., Lundbeck Japan, and Takeda Pharmaceutical Co., Ltd. AT received a research grant from Nippon Boehringer Ingelheim Co., Ltd. and personal fees from MOCHIDA PHARMACEUTICAL CO., LTD., Sumitomo Pharma Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. KMis has received research grants from Eisai Co., Ltd., Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Sony Corporation and has also received speaker honoraria from Eisai Co., Ltd., Nobelpharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck & Co., Inc., Otsuka Pharmaceutical Co., Ltd., and Viatris Inc. MT has received speaker honoraria from Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., DAIICHI SANKYO CO., LTD., Sumitomo Pharma Co., Ltd., Meiji-Seika Pharma Co., Ltd., Viatris Inc., Merck & Co., Inc., Eisai Co., Ltd., and Yoshitomiyakuhin Corporation outside the submitted work. KMin and TF were employed by TechDoctor Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "International Journal of Molecular Sciences includes original research and reviews on the molecular mechanisms of active, natural products  and phytochemicals in vitro and in vivo.The Special Issue \u201cMolecular Mechanisms of Natural Products and Phytochemicals in Immune Cells and Asthma\u201d in the Allergic asthma, an increasingly common immunologic disease in industrialized countries, is a chronic inflammatory condition of the airways that causes airway hyperresponsiveness (AHR). A Th1-Th2 cytokine imbalance has been hypothesized to underlie allergic asthma through a change in immune responses from a Th1 profile to a Th2  profile. Additionally, the recruitment of inflammatory cells such as T cells, mast cells, eosinophils, epithelial cells, macrophages and neutrophils is mediated via a number of chemokines and their receptors. Chemokines and their receptors are important therapeutic targets in asthma and allergic diseases because of their key role in immune cell recruitment and activation during inflammation [Two highly relevant papers have recently been published in the Special Issue of Bioactives and Nutraceuticals entitled \u201cMolecular Mechanisms of Natural Products and Phytochemicals in Immune Cells and Asthma\u201d. These two papers exhibit antiallergic and antiasthmatic effects of the active components in natural products.Lithospermum erythrorhizon on Mast Cells and Ovalbumin-Induced Allergic Rhinitis\u201d by Le et al. [Lithospermum erythrorhizon, N,N\u2019-dicoumaroylspermidine, inhibited the release of \u03b2-hexosaminidase, as well as the production of Th2 cytokines  by IgE-sensitized and BSA-stimulated RBL-2H3 cells. Using the allergic rhinitis mouse model, they showed that N,N\u2019-dicoumaroylspermidine reduced the number of inflammatory cells in nasal lavage fluid and the production of serum OVA-specific IgE. N,N\u2019-dicoumaroylspermidine isolated from Lithospermum erythrorhizon exhibits antiallergic properties, and it can be potentially effective for allergic rhinitis.The first article, \u201cAntiallergic Effects of N,N\u2019-dicoumaroylspermidine Isolated from e et al.  revealedGynostemma pentaphyllum Attenuates Airway Inflammation and Th2 Cell Activities in a Murine Asthma Model\u201d by Huang et al. [G. pentaphyllum. The study revealed that gypenoside A significantly reduced the expression of inflammatory genes and proteins in the lungs and bronchoalveolar lavage fluid and Th2 cytokine expression. Moreover, gypenoside A significantly inhibited the secretion of chemokines and inflammatory cytokines in tracheal epithelial cells. Gypenoside A is a natural phytochemical that can effectively attenuate airway hyperresponsiveness (AHR) and inflammation in asthma, mainly by blocking Th2 cytokines production. In summary, the two papers successfully demonstrate the antiallergic effects of phytochemicals from Lithospermum erythrorhizon roots and Gynostemma pentaphyllum.The second article, \u201cGypenoside A from g et al.  investigRecently, natural products and their phytochemicals play increasingly critical roles, especially multi-ingredient synergistic effects . The theWe hope that this Special Issue can provide a comprehensive overview of the current state of research on molecular mechanisms of natural products and phytochemicals in immune cells and asthma.In conclusion, the Guest Editor would like to thank all authors for their remarkable contributions and the Editorial Board for their support."}
+{"text": "The ripening process of fruits is complicated and coordinated and is characterized by obvious changes in pericarp color (green color loss and non-photosynthetic pigment increases), flesh texture , taste (variation of sugars and organic acids), and aroma flavour (volatile productions) of fleshy fruits . SpecifiTeixeira et\u00a0al. showed that the exocarp of green and mature grape berries is rich in chloroplasts, and they applied proteomic analysis of chloroplasts from the two phases. The authors observed that proteins associated with the Calvin cycle were stimulated in green berries, while those related to energy-generating metabolism were enriched in mature berries. Wang et\u00a0al. systematically identified a batch of lignin biosynthesis-related genes and constructed a co-expression network of these genes via weighted gene co-expression network analysis. Specifically, they found the major lignin biosynthesis genes involved in ripening process and stress resistance in banana. Liu et\u00a0al. reviewed NAC transcription factors, which show extensive participation in fruit yield and quality and regulate fruit ripening by directly acting on critical genes related to the biosynthesis and signal transduction of the plant hormones abscisic acid (ABA) and ethylene (ET). These articles provide the basis for the improvement of fruit development and ripening.The material basis and regulator underlying fruit development and ripening still remain challenges. Huang et\u00a0al. and Jiang et\u00a0al. reported that salicylic acid (SA) treatment could maintain the organoleptic quality and postharvest storability of pummelo and blueberry. Li et\u00a0al. recorded that pear had a greasy coating and yellowing process during postharvest storage, while 1-methylcyclopropene (1-MCP) could decrease the wax content of postharvest pear and delay the development of peel greasiness and yellowing by suppressing the transcription of a series of cluster genes associated with ethylene synthesis, ethylene signal transduction, wax accumulation, and chlorophyll degradation. Choi et\u00a0al. investigated the molecular details of kiwifruit ripening using ethylene and its action inhibitor 1-MCP. Through a time-course transcriptomic analysis, they found that the genes related to ET synthesis and signalling suffered from opposite influence from postharvest application of 1-MCP and ET, conversely, in the process of kiwifruit ripening. They identified that the ET transcription factor AcEIL might exhibit an essential function in ET-induced kiwifruit ripening. These articles suggest a practical foundation for improving the protective mechanisms in relation to fruit ripening and senescence.Postharvest ripening and senescence restrict the shelf life of horticultural crops. Both Lin et\u00a0al. compared two cultivars of hardy kiwifruit that have high frost hardiness and show similar trends in antioxidant capacities and nutritional compounds. The authors noted that the antioxidant capacity of the two hardy kiwifruit cultivars decreased but glucose increased progressively during maturation, in which the conversion from starch to total sugar was dominantly due to the expression of sucrose phosphate synthase (SPS) and fructokinase (FK). The predominant acids in the two hardy kiwifruit cultivars were quinic acid and citric acid from the early developmental to late maturity stages, respectively. These findings are conducive to a wider understanding of the physiological and biochemical basis of hardy kiwifruit for the cultivation of chilling-tolerant cultivars.Sensitivity to chilling can influence plant growth in the field and storability and quality during the postharvest storage period . AccordiLin et\u00a0al. assessed the effect of fucoidan application on cold storage quality, reactive oxygen species (ROS) homeostasis, and energy metabolism in cucumber fruit. The authors determined that the optimum concentration of coated fucoidan was 15 g/L, which could increase DPPH and -OH scavenging rates and reduce H2O2 accumulation. The authors suggested that the improved chilling tolerance in cucumbers with fucoidan treatment may be related to the increased antioxidant enzyme activities and ROS scavenging rates, as well as high levels of ATP, ADP, and energy charge. In accordance with the effects of fucoidan in cucumbers, Zhou et\u00a0al. confirmed that \u03b3-aminobutyric acid (GABA) could lighten CI symptoms in peach fruit and that the reduction efficiency of GABA on chilling injury was associated with the accumulation of ascorbic acid (AsA) and glutathione (GSH) contents and the amplified expression profiles of AsA-GSH recycling-related genes. Moreover, the authors indicated that several ERF transcription factors, which are potentiated by GABA treatment in peach fruit, regulate AsA and GSH contents to reduce chilling injury. Overall, the authors proposed potential strategies of fucoidan coating and GABA immersion in alleviating CI symptoms in postharvest horticultural crops.Xing et\u00a0al. investigated the mechanism of action of Sly-miR171d on chilling injury in tomato fruit. They found that down-regulated Sly-miR171d promotes GRAS24 expression, which obviously increased gibberellin production and C-repeat binding factor (CBF) expression and maintained cell membrane stability, therefore enhancing the chilling tolerance of tomato fruit. This study sheds light on the genetic improvement of postharvest tomato to chilling injury.In general, microRNAs (miRNAs) are a class of small, non-protein coding RNA molecules that function as negative regulators of target gene messages , and theIn summary, the articles in this Research Topic provide advanced information on ripening and chilling injury alleviation in horticultural crops. New insights into phytohormones, transcription factors and epigenetic modifications will impel our future applied research in the alleviation of crop ripening and chilling injury.CL: Conceptualization, Writing \u2013 original draft. ZY: Supervision, Validation, Writing \u2013 review & editing. SC: Writing \u2013 review & editing. CW: Supervision, Writing \u2013 review & editing. KW: Conceptualization, Writing \u2013 review & editing."}
+{"text": "We as dentists and surgeons would like to bring to the notice of our medical colleagues periodontal disease as yet another co-risk factor of pancreatic cancer.In a recent editorial by Dr Ga\u00ebtan Romain Joliat entitled \u2018Latest Advances and Future Challenges in Pancreatic Surgery\u2019, the authors stress on how development and improvement in the fields of chemotherapy, targeted therapy and immunotherapy will benefit patients with pancreatic cancers.P < .001) as well as in patients between 50 and 70 . Periodontal disease, tooth loss and root canal infections showed a positive association with an increased risk of developing pancreatic cancer. Previously, Heikkil\u00e4 et al. (2018), in their register-based cohort study of 68\u00a0273 adults, reported a higher pancreatic cancer mortality among individuals with periodontitis . An even stronger association was noted after adjustments . Fan et al. (2018) in their population-based nested case-control study have provided supportive evidence towards the role of oral periodontopathogenic microbiota in the aetiology of pancreatic cancer.Yu et al. (2022) also confirm the association between poor oral health and pancreatic cancer risk. They found a statistically significant association between periodontitis and an increased risk of pancreatic cancer in patients under the age of 50 , Fusobacterium nucleatum and Tannerella forsythia have a more potent role in the causation of cancers of the digestive tract than previously thought. They are able to evade the immune mechanisms and colonise the gastrointestinal tract, disrupting the epithelial integrity. Of these, Td is a notoriously invasive motile anaerobe with an equally harmful surface-bound chymotrypsin-like proteinase  virulence factor. The possible mechanisms by which it can promote carcinogenesis include (a) hydrolysis of bioactive peptides; (b) inhibition of apoptosis; (c) promotion of cellular invasion; (d) degradation of multiple host proteins; and (e) modulate immunity and inflammation.Evidence shows that periodontopathogens like  Females with periodontal disease were reported to be 3 times more likely to develop oesophageal cancer. Hence, periodontal disease could be a significant risk factor for cancer, especially in mature women.Additionally, research has found that certain potent periodontopathobionts are implicated in the tumorigenesis and progression of cancers affecting not only the oral cavity but also oesophageal, breast and gall bladder carcinomas. According to Nwizu et al. (2020), periodontal disease raises the general cancer risk by 14%.Patients with pre-existing gum disease are currently likely to have an increased risk for pancreatic cancer. As periodontal disease is a modifiable risk factor, it is of uppermost importance that regular and valid screening measures are employed for its early detection.9To further add to the knowledge, dentilisin acts against various immunomodulatory proteins critical for the regulation of tumour microenvironment and inflammation, thereby further contributing to tumour progression. It also has the ability to modulate immunomodulatory proteins, including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), both of which have been implicated in regulation of tumour microenvironment and metastasis of gastrointestinal cancers.MMPs are derived from host PMNs, endothelial, epithelial and smooth muscle cells in latent pro-MMP form. Of all MMPs, particularly activity of MMP-8 (collagenase) is elevated in patients suffering from gum disease as it causes destruction and digestion of type I collagen which is present in periodontal connective tissue.13 Elevated aMMP-8 levels in mouthrinse and patients\u2019 periodontal disease can be conveniently detected by aMMP-8 POCT  kits readily available in the market.P-8 POCT . These aThe authors recommend utilising non-invasive biomarkers like aMMP-8 for early detection of periodontal disease since it is a risk factor for carcinomas."}
+{"text": "Bone is a vital tissue as it carries out various metabolic functions: support of the body, protection of the internal organs, mineral deposit and hematopoietic functions. It has recently been observed that bone tissue also has endocrine functions, producing substances with hormonal activity such as osteocalcin and Fibroblast Growth Factor-23 (FGF-23) ,2.As is well known, bone tissue is continuously renewed through the bone remodelling process. The first phase involves bone resorption, mediated by osteoclasts, and the subsequent phase bone formation, mediated by osteoblasts. The continuous succession of these two phases keeps the skeleton young and allows the repair of microcracks .Bone metabolism, which is finely regulated by different biologic signals ,3, can bThe identification of mechanisms underlying the pathophysiology of metabolic bone diseases continues to be an area of significant research efforts, attracting scientists from different fields.For this Special Issue, we received different scientific contributions, spanning in vitro studies to clinical research articles and reviews of the scientific literature.The paper by Jansen et al., entitled \u201cIncreased bone resorption during lactation in pycnodysostosis\u201d , exploreNa et al., in the paper entitled \u201cAesculetin inhibits osteoclastic bone resorption through blocking ruffled border formation and lysosomal trafficking\u201d , showed Osteoporosis is generally considered more prominent among women than men. However, in the review by Rinonapoli et al., entitled \u201cOsteoporosis in men: a review of an underestimated bone condition\u201d , the autIn the review entitled \u201cMechanisms of bone fragility: from osteogenesis imperfecta to secondary osteoporosis\u201d , El-GazzRecent research suggests that the microbiota is involved in the regulation of bone metabolism, and that its alteration may induce osteoporosis. This is the topic of the review by De Martinis et al. entitled \u201cThe osteoporosis/microbiota linkage: the role of miRNA\u201d . In part"}
+{"text": "Natural killer (NK) cells are innate immune cells that demonstrate cytolytic activity against tumor cells, virus-infected cells and other physiologically stressed cells, such as senescent cells. The scientific community continues to discover novel biological aspects of NK cells in different organs, tumor microenvironments, and age groups. Recently, cancer immunotherapy has achieved exceptional success. Novel agents and combination therapies that modulate the immune system, including NK cells, provide promising routs for future treatment. International Journal of Molecular Sciences, entitled \u201cNatural Killer Cells and Immunotherapy\u201d, includes eight contributions: five original articles and three reviews that each provide new information on NK cell biology and immunotherapy. This Special Issue of the In their review \u201cThe Biological Role and Therapeutic Potential of NK Cells in Hematological and Solid Tumors\u201d, Velichinskii et al.  reviewedIn the review entitled \u201cPostoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery\u201d, Market et al.  introducSome immune cells exhibit unexplained features and functions in our immune system. Natural killer T (NKT) cells possess the common features of T and NK cells in terms of their immune responses. In particular, invariant NKT (iNKT) cells, expressing an invariant TCR \u03b1-chain, constitute a major population of NKT cells . In the Five original articles introduce the novel findings of NK biology and immunotherapy under different contexts.Cytokines are critical determinants of the phenotypic characteristics and functional activity of NK cells in immune response and development. In the article entitled \u201cPro- and Anti-Inflammatory Cytokines in the Context of NK Cell-Trophoblast Interactions\u201d, Mikhailova et al.  introducIn the article \u201cNK Cell-Dependent Antibody-Mediated Immunotherapy Is Improved In Vitro and In Vivo When Combined with Agonists for Toll-like Receptor 2 in Head and Neck Cancer Models\u201d, Gruijs et al.  investigIn a short communication article entitled \u201cA Chimeric IL-15/IL-15R\u03b1 Molecule Expressed on NF\u03baB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells\u201d, Bosch et al.  reportedIn the article \u201cEx Vivo Expanded and Activated Natural Killer Cells Prolong the Overall Survival of Mice with Glioblastoma-like Cell-Derived Tumors\u201d, Shida et al.  reportedIn the final article presented in this publication, \u201cNLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B\u201d, Lee et al. [As described in this Special Issue, NK cells are representative immune effector cells for the development of immunotherapies for hematological and solid cancer treatments. The possibility of using NK cells is growing rapidly, and will open up new opportunities and prospects for the development of immunotherapy in both hematological and solid cancer treatments; however, many questions remain to be elucidated in clinical trials and basic research. The results and discussions of these articles shed considerable light on NK biology and immunotherapy."}
+{"text": "Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) represent the two major forms of primary liver cancers. Despite the growing efforts to translate the increasing knowledge on molecular alterations of these cancers into treatment options for patients, the actual clinical outcomes remain unsatisfying .BTCs are fatal gastrointestinal cancers with very poor 5-year survival rates . The incHCC is the most common form of liver cancer . This deGuo et al.; Shen et al.; Yang et al.) and seven original research papers .Due to the ineffectiveness and development of resistance to current therapies, the need to identify and provide alternative therapeutic approaches is of paramount importance to alleviate the suffering of BTC and HCC patients. Therefore, the current Research Topic provided a structural platform to identify mechanisms of resistance, novel relevant therapeutic targets and prognostic/predictive markers as well as to demonstrate promising innovative treatment options. The call for papers attracted an astonishing number of 10 highly interesting publications and over 65 authors contributed to this Research Topic in the form of three structured reviews , non-invasive preoperative prediction of angiogenesis related markers in BTC , optimizing strategies for immunotherapy and the current status of adjuvant therapies in HCC are discussed , characteristics of extrahepatic cholangiocarcinoma (eCCA) are analyzed , and novel therapeutic strategies for BTC are demonstrated. .This Research Topic covers a variety of subject areas: promising new survival markers after surgery for BTC patients .High levels of vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) correlate with tumor progression and poor prognosis in eCCA patients . HoweverJansson et al.'s study, three preoperative immunologic plasma markers were identified - CSF1, TIE2, and TRAIL - that predict survival after surgery in a cohort of 102 BTC patients utilizing high-throughput multiplex immunoassay. CSF1 and TIE2 were found to be negative prognostic factors in BTC, while TRAIL was demonstrated to be a positive prognostic factor .BTC patients typically experience cancer recurrence within 5\u00a0years of surgery, but prognostic factors such as lymph node metastasis and tumor grading can only be observed after tumor resection . In JansShen et al.).Immunotherapy is a therapeutic option for HCC patients; however, the immune microenvironment of many tumors suppresses the effectiveness of this treatment .To address this Research Topic, Liang et al. also identified an efficacy enhancement of immunotherapy in HCC by combining anti-PD-1 antibodies with Abrine, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). In their study, Liang et al. showed that IDO1 is upregulated in HCC cells and can lead to tumor immune escape. They found that using Abrine along with anti-PD-1 antibodies can inhibit immune escape and increase CD8+ T cell infiltration, leading to a stronger immune response and anti-tumor effect .Taken together, this Research Topic provides insight into the latest efforts to overcome resistance mechanisms of current therapies, discover novel prognostic and predictive markers, and identify alternative anti-BTC/HCC strategies.We sincerely thank all the authors for their valuable contributions to this Research Topic."}
+{"text": "Molecular biomarkers are emerging as the key indices for the management of patients with significant diseases. Motivated by the systematic effort to define the human genome, the creation of rapid analytic technologies for evaluating nucleic acids and proteins has provided the technological \u201cboom\u201d for the development of molecular biomarkers. Collaboration and cooperation between stakeholders involved in biomarker development, application, and regulation may be the most expeditious route toward the translation of laboratory discovery into patient management. In summary, intensive research has originated multiple factors or biomarkers that are likely to be helpful in diagnosis, characterization, and therapy selection of different patients. A thorough understanding of the relevance of each biomarker will be the key to efficiently diagnose a disease and direct the patients towards the drugs more likely to be of benefit based on their particular profile. The papers selected for this special issue represent an excellent panel for addressing the molecular biomarkers as the future tools of medicine. This special issue contains thirteen papers.Circulating microRNAs and kallikreins before and after radical prostatectomy: are they really prostate cancer markers?,\u201d M. G. Egidi et al. presented 38 patients with prostate cancer. They suggested that two miRNAs (miR-21 and miR-141) could be involved in post surgical inflammatory processes. Postoperative serum kallikreins showed a significant decrease, highlighting the potential usefulness of kallikreins apart from PSA as potential prostate cancer markers.In the paper entitled \u201cA novel differential predict model based on matrixx-assisted laser ionization time of flight mass spectrometry and serum ferritin for acute graft-versus-host disease,\u201d. C.-Y. Zhang et al. investigated the possibility of pre warning the risk of an acute graft-versus-host disease (aGVHD) before and after allogeneic hematopoietic stem cell transplantation  by serum profiling combining with serum ferritinin. Their joint prewarning model could predict the risk of aGVHD, especially severe aGVHD before transplant which provide a reliable method to continuously monitor the condition of patients.In the paper entitled \u201cThe use of multidimensional data to identify the molecular biomarker for pancreatic ductal adenocarcinoma,\u201d L. Zhuang et al. presented that they have adopted an integrative approach to simultaneously identify biomarker and generate testable hypothesis from multidimensional omics data. They have found that PER2 expression was highly associated with the survival data, thus representing a novel biomarker for earlier detection of pancreatic ductal adenocarcinoma (PDAC).In the paper entitled \u201cClinical evaluation and cost-effectiveness analysis of serum tumor markers in lung cancer,\u201d R. Wang et al. showed that combinations of four tumor markers  improved the sensitivity for lung cancer and different combination panels had their own usefulness. NSE, CEA, and CYFRA21-1 were the optimal combination panel with highest Youden's index (0.64), higher sensitivity (75.76%), and specificity (88.57%), which can aid in clinical diagnosis of lung cancer.In the paper entitled \u201cImmune parameters in the prognosis and therapy monitoring of cutaneous melanoma patients: experience, role, and limitations,\u201d M. Neagu et al. reported the follow-up for 36 months of the immune parameters of patients diagnosed in stages I\u2013IV, namely, pre- and postsurgery immune circulating peripheral cells and circulating intercommunicating cytokines.In the paper entitled \u201cComparative gene expression profiling in human cumulus cells according to ovarian gonadotropin treatments,\u201d S. Assou et al. provided an exclusive study characterizing gene expression profiles in cumulus cells (CCs) of periovulatory follicles from patients undergoing HP-hMG and rFSH gonadotropin treatments during in vitro fertilization cycles. This project has characterized the expression of these genes as biomarkers of in vitro embryo quality.In the paper entitled \u201cAptamers: novel molecules as diagnostic markers in bacterial and viral infections?,\u201d F. M. Zimbres et al. urged an urgent need to discover novel diagnostic as well as therapeutic tools against infectious agents. They viewed that the systematic evolution of ligands by exponential enrichment (SELEX) represents a powerful technology to target selective pathogenic factors as well as entire bacteria or viruses. SELEX uses a large combinatorial oligonucleic acid library (DNA or RNA) which is processed by a high-flux in vitro screen of iterative cycles.In the paper entitled \u201cDistribution of ABO blood group and major cardiovascular risk factors with coronary heart disease,\u201d S. Biswas et al. viewed that the AB blood group decreases the risk of CHD in healthy controls; it might be due to the higher concentration of high density lipoprotein cholesterol (HDL-c), while the O blood group increases the risk of CHD due to lower HDL-c levels in Bengali population of eastern part of India.In the paper entitled \u201cImmunomodulatory effect of continuous veno-venous hemofiltration during sepsis: preliminary data,\u201d G. Servillo et al. reported that severe sepsis and septic shock are the primary causes of multiple organ dysfunction syndrome (MODS), which is the most frequent cause of death in intensive care unit patients. Many pro- and anti-inflammatory mediators, such as interleukin-6 (IL-6), play a key role in septic syndrome. Continuous renal replacement therapy (CRRT) removes in a nonselective way pro- and anti-inflammatory mediators. The authors investigate the effects of continuous venovenous hemofiltration (CVVH) as immunomodulatory treatment of sepsis in a prospective clinical study.In the paper entitled \u201cAcetylcholinesterase as biomarker in environmental and occupational medicine: new insights and future perspectives,\u201d M. G. Lionetto et al. viewed that Acetylcholinesterase (AChE) is a key enzyme in the nervous system (NS), since it terminates nerve impulses by catalyzing the hydrolysis of acetylcholine. As a specific molecular target of organophosphate and carbamate pesticides, AChE activity and inhibition are a human biological marker of pesticide poisoning. Thus, it is used to study the effects of the exposure to organophosphate and carbamate pesticides on NS in occupational and environmental medicine. This paper reviews and discusses the recent findings about AChE, including its sensitivity to other pollutants and expression of different splice variants. These insights open new perspectives for the use of this biomarker in environmental and occupational human health monitoring.In the paper entitled \u201cPolyisoprenylated methylated protein methyl esterase is both sensitive to curcumin and overexpressed in colorectal cancer: implications for chemoprevention and treatment,\u201d F. Amissah et al. discussed polyisoprenylated methylated protein methyl esterase (PMPMEase) which cocatalyzes the polyisoprenylation pathway required to process various monomeric G proteins. Mutation of these G proteins is considered to be responsible for 50% of colorectal cancers. This interesting finding suggests that elevated PMPMEase activity and its overexpression can be one of the candidate markers for early diagnosis of colorectal cancer. Susceptibility of this enzyme to curcumin also suggests that PMPMEase can be a potential candidate for targeted anticancer therapy.In the paper entitled \u201cEmerging therapeutic biomarkers in endometrial cancer,\u201d P. Dong et al. reviewed the current status of molecular therapies tested in clinical trials and mainly discussed the potential therapeutic candidates that are possibly used to develop more effective and specific therapies against endometrial cancer progression and metastasis.In the paper, entitled \u201cMouse prostate epithelial luminal cells lineages originate in the basal layer where the primitive stem/early progenitor cells reside: implications for identifying prostate cancer stem cells\u201d J. Zhou et al. have developed an in vivo cell fate tracing mouse model and an in vivo slow-cycling cell label mouse model to provide further insight into this question. Through genetic manipulation in the animals, their findings indicate that the basal cell lineage can produce more differentiated luminal cells; the putative mouse prostate stem cells (which are slow-cycling and responsible for tissue maintenance) likely reside in the basal layer.In the paper entitled \u201c Though the selected topics and papers are not an exhaustive representation of the entire area of molecular biomarkers and tools of medicine, yet they represent the rich and many-faceted knowledge that we have the privilege of sharing with the readers."}
+{"text": "The growing concern about cannabis use, the most commonly used illicit drug worldwide, has led to a significant increase in the number of human studies using neuroimaging techniques to determine the effect of cannabis on brain structure and function. We conducted a systematic review to assess the evidence of the impact of chronic cannabis use on brain structure and function in adults and adolescents.Papers published until August 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only neuroimaging studies involving chronic cannabis users with a matched control group were considered.One hundred and forty-two studies were identified, of which 43 met the established criteria. Eight studies were in adolescent population. Neuroimaging studies provide evidence of morphological brain alterations in both population groups, particularly in the medial temporal and frontal cortices, as well as the cerebellum. These effects may be related to the amount of cannabis exposure. Functional neuroimaging studies suggest different patterns of resting global and brain activity during the performance of several cognitive tasks both in adolescents and adults, which may indicate compensatory effects in response to chronic cannabis exposure.However, the results pointed out methodological limitations of the work conducted to date and considerable heterogeneity in the findings.Chronic cannabis use may alter brain structure and function in adult and adolescent population. Further studies should consider the use of convergent methodology, prospective large samples involving adolescent to adulthood subjects, and data-sharing initiatives. Cannabis is the illicit drug most widely available and used worldwide Animal studies have consistently demonstrated that delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis It is remarkable to note that although the onset of cannabis use is typically during adolescence, a few imaging studies have been conducted with adolescent users The growing concern about cannabis use has led to a significant increase in the number of human studies using neuroimaging techniques to determine the effect of the substance on brain structure and function, as well as to several recent reviews examining this topic Data for this systematic review was collected with an advanced document protocol in accordance with the PRISMA guidelines Electronic searches were performed using EMBASE (1980-August 2012), Medline (1966-August 2012), PubMed (1966-August 2012) and LILACS (1982-August 2012) databases. The following key words were used: cannabis; marijuana; marihuana; delta-9-tetrahydrocannabinol; THC; cannabidiol, CBD; neuroimaging; brain imaging; computerized tomography, CT; magnetic resonance, MRI; single photon emission tomography, SPECT; functional magnetic resonance, fMRI; positron emission tomography, PET; diffusion tensor MRI, DTI-MRI; spectroscopy, MRS. All the studies published up to August 2012 were included without language restriction.A general review of all neuroimaging studies investigating brain structure or function was initially performed. We obtained a total of 142 published papers . StudiesWe defined chronic cannabis users as persons who used cannabis several times a week and who had done so for at least two years. Recreational  cannabis users were defined as persons who had used cannabis sporadically (less than four times a month), and na\u00efve users or healthy controls were persons who had used cannabis less than 15 times in their lifetime, according to standardized strict criteria Any publication that reported data using two different neuroimaging techniques from the same subjects  or a study examining the same subjects with two different cognitive tasks  was considered as two studies in this review.Data was independently extracted by two reviewers. In case of disagreement, opinion from a third senior researcher was sought to assess whether study criteria were fulfilled. From the articles included we recorded names of authors, year of publication, socio-demographic  and cannabis use characteristics , imaging type and design, exclusion criteria , confirmation of abstinence from other drugs (whether checked by urine test), rest/active condition , type of cognitive task performed during functional imaging and psychopathological variables assessed . With regard to alcohol use, we assessed if subjects met criteria for alcohol abuse or for excessive alcohol consumption  based on the reported data. For structural and functional imaging data, the primary measures of interest were global and regional volume, and global and regional activity . The secondary outcome was its correlation with clinical variables. We collected the statistically significant results of each outcome variable, and recorded whether a multiple comparison correction was done to prevent bias towards false positives.a priori selection criteria Of the 142 studies identified, thirty-six did not meet the We identified 11 structural MRI studies that examined adult chronic cannabis users and met our selection criteria . StructuOf the seven studies comparing global brain volume measures between chronic cannabis users and healthy controls, there was only one study reporting significant differences et al. (2005) et al. (2011) et al. (2005) Among the six studies employing a whole-brain analysis approach With regard to the three studies that focused on specific regions of interest, all studies reported bilateral volumetric reductions in the hippocampus et al. (2011) et al. (2005) With respect to other brain regions, Cousijn et al. (2008) et al. (2011) et al. (2011) Four studies have used DTI to examine the integrity of white matter tracts in chronic cannabis users et al.  et al. (2011) Three volumetric studies in adolescent chronic cannabis users were included, two of which consist of the same sample et al. (2010) et al. (2011) et al. (2009) In terms of correlations, Medina 15O-PET 133Xe-SPECT 18F-FDG-PET 11C]- raclopride-PET 18F]FMPEP-d2 11C]-raclopride-PET studies et al. (2000) et al. (2001) et al. (2008) 11C]-raclopride-PET binding potential and glucose metabolism 11C]- raclopride-PET studies et al. (2012) et al. (2012) et al. (2011) We included eight case-control studies comparing resting rCBF in adult chronic cannabis users and non cannabis using healthy controls . The imaWe identified 16 studies in adult chronic cannabis users that compared regional activation during the performance of a cognitive task with healthy controls , four wiet al. (2006) et al. (2010) et al. (2012) Chang 15O-PET study, Block et al. (2002) et al. (2007) et al. (2006) In a H2et al. (2004) et al. (2005) et al. (2005) et al. (2004) 15O-PET during the performance of a modified Stroop test. However, they also reported a reduced dorsolateral prefrontal cortex activation and a greater activation in the hippocampus bilaterally et al. (2009) Eldreth et al. (2005) et al. (2011) 15O-PET, and Wesley et al. (2011) et al. (2005) et al. (2011) et al. (2011) et al. (2011) et al. (2010) et al. (2010) et al. (2010) et al. (2010) et al. (2010) Bolla et al. (2011) King et al. (2009) Gruber We included five case-control fMRI studies in adolescent cannabis users comparing brain activity with healthy controls during a cognitive task performance. As an exception, two of them et al. (2007) et al.  et al. (2007) et al. (2008) et al. (2010) et al. (2011) Padula et al. (2007) In a group of abstinent cannabis users, Tapert 1-rich areas implicated in several cognitive functions, which may be related to the amount of cannabis use; (2) Altered neural activity during resting state and under several different types of cognitive paradigms, that may reflect a different recruitment of brain areas during the tasks, particularly within the prefrontal cortex; and (3) The few studies conducted in adolescents suggest that both structural and functional alterations may appear soon after starting the drug use and may be related to gender.In this systematic review, we identified 43 studies suitable for inclusion regarding the impact of chronic cannabis use on brain structure and functioning, of which eight (19%) were in the adolescent population. Despite the high degree of heterogeneity among the studies reviewed herein, several relatively consistent findings emerged from this review. These findings, discussed in detail below, include: (1) Structural brain abnormalities, mainly in CBIn terms of structural findings, specific regional brain analyses demonstrated evidence of structural abnormalities when adult chronic cannabis users were compared with healthy controls. The most consistently reported brain alteration was reduced hippocampal volume Functional neuroimaging studies that have evaluated the resting state in active and abstinent adult chronic cannabis users suggest that resting global Functional imaging studies comparing activation in both adult and adolescent chronic cannabis users with healthy controls during the performance of different cognitive tasks indicated that chronic cannabis users would use similar brain areas that engage these cognitive processes but often demonstrating an altered pattern of brain activity A further important issue emerging out of this review is that few studies have investigated the effects of chronic cannabis use on the brain in adolescence subjects. In light of the popularity of cannabis among teenagers Results presented here have pointed out some important methodological differences that limit the generalisation of results and comparison between studies and have doubtless contributed to the slightly disparate array of findings. Despite the use of a strict definition of chronic cannabis user and robust application of inclusion and exclusion criteria in an attempt to avoid excessive heterogeneity between samples, studies often diverged on certain socio-demographic characteristics and cannabis use parameters, such as gender-bias, age of onset, lifetime use and abstinence period before the acquisition of imaging data. Moreover, it is well known that the THC content of smoked cannabis varies markedly between sources and preparations, with potency reported to have increased substantially over the past ten years With regard to other methodological limitations, some studies have reported modest sample sizes, sometimes below the threshold that would be currently regarded as acceptable  Table S1Click here for additional data file."}
+{"text": "The seventh annual Midsouth Computational Biology and Bioinformatics (MCBIOS) conference took place February 19 and 20, 2010 at Arkansas State University in Jonesboro, AR, presided over by Daniel Berleant, this year\u2019s President of MCBIOS.  Keynote speakers were Elaine Ostrander of NIH, renowned for her work on dog genomics, Clayton Naeve, CIO of St. Jude Children's Research Hospital, and Robert Cottingham, Leader of the Computational Biology and Bioinformatics Group, Oak Ridge National Laboratory. The record-breaking attendance exceeded 200 participants which necessitated parallel talk sessions for the first time. Student oral presentation award winners were Heidi Pagan (first place) of Mississippi State University (MSU), Juliet Tang (second place) of MSU, and Aleksandra Markovets (third) of Mississippi Valley State University. In addition, a record number of posters were also presented. Due to the number of posters, student poster awards were given in two categories, Biological Focus and Computational Focus. Winners were N. Platt and V. Chaitankar (1st place), G. Cooper and L. Pillai (2nd), and M. Ammari and C. Gearheart (3rd). Reflecting the integration of these foci in the field, winners in one category frequently scored high in the other category as well. MCBIOS is also pleased to have this year acquired legal status as a non-profit organization.A total of twenty eight papers describing research presented at the 2010 conference were accepted for publication in these proceedings out of a total of forty three papers submitted for consideration (~65%). The number of papers submitted for consideration was the largest submitted since the inception of MCBIOS with a 34% increase over last year\u2019s proceedings , and theet al. describe an expansion of the FDA-developed, ArrayTrackTM genomics tool, into a platform that supports microbial data to enable the rapid detection of food borne pathogenic bacteria during outbreak scenarios [et al. describe new SNP (single nucleotide polymorphism) and QTL (quantitative trait locus) libraries for the ArrayTrack system which provide users with extensive data including links to other resources, and motivated in part by the need to augment gene association study results with biological context [et al. report on the new web-based tool, IView, which graphically displays and makes searchable introgression data by marker name, chromosome number, or map position [Bioinformatics was largely born as a field through the need to analyze and understand sequence data. Partly as a result of ultra-high-throughput sequencing technology, the field has seen a strong resurgence recently with new computational methods being developed and applied to downstream applications such as the identification of human mutations -25 as wecenarios .  Xu et  context . Christoposition .Quest and colleagues working in the Cottingham laboratory address the problem of brittle genome annotation systems with an OWL-based approach that provides several significant advantages . Work reAn examination of substitution rates over evolutionary time by Ulrich Melcher compared viral and non-viral sequences to reveal that the rate of nucleotide interchanges in plant viruses is not constant, impacting phylogeny studies.  The evidence suggests that different evolutionary rules may apply to recent divergences than to those linked to distant speciation events .  et al. using a proteomics approach to evaluate the host protein expression differences. Two gene sets were found, each specific to one disease form which showed significant functional differences [et al. address the need for additional genomic information for Northern bobwhite, an avian species critical to ecosystem maintenance. Using next generation sequencing of cDNAs from a multi-tissue library, they generated ESTs which were pipelined into a unigene database and made publicly available at a searchable website [An in depth analysis of the two forms of Bovine Viral Diarrhea, a worldwide cattle disease, was completed by Mais Ammari ferences .  Arun R website .  et al [et al [Arabidopsis. The conserved gene evolution indicated that the study in the model species can be translational to human disease studies. Rowena Kelly et al [Aspergillus flavus resistance in Maize such as gene expression, proteomic, QTL genetic mapping studies and sequence data from the literature to help identify and select candidate A. flavus resistance genes.Cyriac Kandoth et al  mined thl [et al  carried ly et al  have conBiological information may be encoded in a one-dimensional sequence, but its manifestation takes place in three-dimensional space in the form of proteins, cells and tissues among other structures. Computational analysis and prediction of these structures is challenging, to say the least, and an active area of recent bioinformatics interest -48. Compet al. report on a method for modeling interactions between 8R-lipoxygenase and its substrate [et al., which can serve as an important training and practice tool for surgeons [et al.[To better understand and improve of the creation of anti-inflammatory drugs through inhibition of lipoxygenase, an essential enzyme in the inflammatory pathway, Shuju Bai ubstrate . A mixedsurgeons .  The pos [et al..  They ret al [et al [et al  compared density based clustering and Fuzzy C-Means clustering algorithms for border detection in dermoscopy images finding that density based clustering performed best with a low border error, high precision and recall; however, the Fuzzy C-Means clustering algorithm had poor performance especially in border detection.  Mete et al  proposed two new methods, boundary driven density based clustering based algorithms which performed better delineation with noisy images and an active contour model that gave the best detection with optimum parameters. Denise Koessler et al [Sinan Kockara et al  and Mutll [et al  examineder et al  developeThere are many areas within biology that are amenable to computational analysis, each of which is usually approached separately. Somewhat recently, the term \u201csystems biology\u201d has emerged to describe interconnected analyses, particularly those that help reduce complexity in these systems, as defined by the number of interconnections between component parts, into a more functional understanding . The term \u201csystems biology\u201d is often used broadly and not always consistently, but is an emergent area of high interest in bioinformatics -57. et al.[et al. report on the development of a Web-based gene-discovery bioinformatics tool, FAUN (Feature Annotation Using Nonnegative matrix factorization), which identifies implied gene relationships from biomedical literature, enabling hypotheses on functional characterization [A novel method for identifying subnetwork markers in a human protein-protein interaction network is described by Junjie Su et al..  They rrization .  et al., explores the important problem of inferring gene regulatory networks from time sliced microarray data. They claim that mutual information (MI) based approaches have inherent limits to their capabilities in this context which they were able to improve upon with algorithms based on modifications to the mutual information metric [ A paper by Vijender Chaitankar, n metric .Kumar and Nanduri present a downloadable database, HPIDB, which serves as a resource of host-pathogen protein-protein interactions integrated non-redundantly from public databases. The authors report on the flexibility of the database for querying and an output format which allows portage to downstream applications .Microarrays have long been a subject of bioinformatics analysis not only for better understanding transcription, a process affected by both genetic and epigenetic factors ,63, but A new non-stationary Dynamic Bayesian Network with a flexible lag choosing mechanism that detects potential genetic regulators and has improved structure prediction is reported by Yi Jia and Jun Huan .et al. address two interesting QC questions of whether expired Affymetrix GeneChip microarrays, an expensive resource, are still useful up to four years after expiration and if RNA stored at -80\u00b0C for the same period was suitable as template source.  In spite of a decrease in sensitivity, the authors found that these arrays generated data consistent with that from unexpired arrays and report favorably on the stability of the RNA [Zhining Wen  the RNA .There are a few other papers published in the proceedings but, for space, are not summarized here: -69.http://www.ISCB.org). For information regarding MCBIOS and our future meetings, see http://www.MCBIOS.org.MCBIOS 2011 will be held in College Station, Texas.  The 2010-2011 President of MCBIOS is Ulisses Braga-Neto of the University of Texas A&M, and Susan Bridges of Mississippi State University is now the President-elect. MCBIOS is a regional affiliate of the International Society for Computational Biology (The authors have no competing interests to declare.All authors served as editors for these proceedings, with JDW serving as Senior Editor. All authors helped write this editorial."}
+{"text": "Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulatory technique with putative cognitive enhancing and therapeutic applications. Since the year 2000, almost 1000 papers have been published on tDCS, reflecting the possible significance of a cheap, safe, and easily applied neuromodulatory technology. Whether or not this potential is tapped depends on understanding how tDCS affects brain functioning, a question explored in a recent publication by Stagg et al. ; presenttDCS is thought to decrease neuronal resting membrane potential beneath the anodal electrode by pumping in positive ions; vice versa for cathodal stimulation  underwent two tDCS sessions  in a counterbalanced order, separated by a week. tDCS electrodes were applied to left DLPFC and the contralateral supraorbit. In each session, participants underwent a 40-min resting-state ASL functional MRI scan in which there was a 10-min baseline, 20-min of concurrent tDCS-ASL and a 10-min post-stimulation period. Separately, but using the same protocol, a second group of participants (N = 12) were scanned once under sham stimulation only. Stagg et al. compared resting-state CBF between these three periods and examined changes in functional connectivity between the regions beneath each electrode and the rest of the brain. The same analyses were conducted using the sham stimulation group to confirm that the changes were not driven by nonspecific temporal drifts.Stagg et al. studied the effect of tDCS on cerebral perfusion using ASL. Subjects  to group 2 (stimulation\u2014baseline) should be conducted; finding a statistically significant effect in one sample, but not another is not a valid approach to establish the between-group effect (Nieuwenhuis et al., The electrical current used in tDCS studies is insufficient to generate neuronal action potentials. Instead, spontaneous firing changes resulting from alterations in neuronal resting membrane potential are thought to underlie the neuromodulatory effects of tDCS (Bikson et al., While the clinical potential for tDCS is high, it is obscured by our lack of insight into its neural effects. Studies such as Stagg and colleagues' build on previous findings and pave the way to an improved understanding. Only with this comprehension can the full clinical possibility of tDCS be utilized and directed toward improving treatment.Camilla L. Nord, N\u00edall Lally, and Caroline J. Charpentier wrote the manuscript together."}
+{"text": "Frontiers in Fungi and their Interactions details the exciting progress in developing vaccines and immunotherapy for fungi.Invasive fungal diseases have increased many fold over the past 50 years. Current treatment regimens typically require prolonged administration of antifungal medications that can have significant toxicity. Moreover, our present potent antifungal armamentarium fails to eradicate fungal pathogens from certain compromised hosts. Additionally, invasive fungal diseases continue to have unacceptably high mortality rates. A growing body of work has focused on the utility of vaccines and/or immunotherapy as a powerful tool in combating mycoses, either for the active treatment, as an adjuvant, or in the prevention of specific fungal pathogens. This Research Topic \u201cVaccines and Immunotherapy against fungi: a new frontier\u201d in Candida albicans (Vecchiarelli et al., Aspergillus fumigatus (Diaz-Arevalo et al., Cryptococcus neoformans (Hole and Wormley, Paracoccidioides brasiliensis (Travassos and Taborda, P. brasiliensis is also presented (Mayorga et al., Artocarpus heterophyllus, which modulates immunity against P. brasiliensis (Ruas et al., Histoplasma capsulatum (Nosanchuk et al., The critical requirement for understanding the degrees of engagement of host defense pathways in responding to fungal invasion has led to an increased focus on host-pathogen interactions. In this Research Topic, Carvalho et al.  review oIn sum, these articles broadly paint the current spectrum of investigations on host-pathogen interactions and provide a review of the state-of-the-art in vaccinology and immunotherapy against fungi. The information presented also underscores the rich areas for future study, all promising improved therapeutics against fungal invaders."}
+{"text": "APP are linked to early onset of familial Alzheimer\u2019s disease (FAD); APP processing generates \u03b2-amyloid (A\u03b2) peptides, which are the principal components of the amyloid pathology. Therefore, understanding the role of APP in neuronal function and dysfunction will provide crucial insights to AD pathogenesis.Genetic and biochemical studies establish a central role of the amyloid precursor protein (APP) in Alzheimer\u2019s disease (AD): Genetic mutations and gene amplification of We have a long-standing interest in studying the physiological functions of APP in neurons and synapses. Analysis of various loss-of-function mutants of APP and combining with a mixed-culture system allowed us to identify APP as a synaptic adhesion protein. We recently uncovered a potent role of APP in mediating adult neurogenesis in dentate gyrus: Loss of APP results in an aberrant increase in progenitor proliferation but impaired newborn neuron differentation, maturation and integration. Intriguingly, we found that APP is highly expressed in GABAergic interneurons and that specific deletion of APP in these neurons, but not in excitatory neurons, leads to similar neurogenesis defect. Our mechanistic and functional studies indicate that this activity is mediated by a general role of APP in regulating GABA release through its synaptic adhesion property.AD is an age-related disease. Adult neurogenesis declines sharply with aging. Increasing evidence supports a role of hippocampal adult neurogenesis in brain function and its impairment in AD. Therefore, perturbation of APP-mediated adult neurogenesis may contribute to neuronal dysfunction and AD pathogenesis."}
+{"text": "It is unique in its strict selection of a single member for activation, a process termed monoallelic expression. The conceptual advances that have emerged from studying var genes show striking common epigenetic features with many other clonally variant gene families or even single-copy genes that show a variegated expression in parasite populations. However, major mechanistic questions, such as the existence of a potential expression site and the identity of transcription factors or genetic elements driving singular gene choice, are still unanswered. In this review we discuss the recent findings in the molecular processes essential for clonal variation, namely silencing, activation, poising and switching. Integrating findings about all clonally variant gene families and other mutually exclusive expression systems will hopefully drive mechanistic understanding of antigenic variation.Phenotypic variation in genetically identical malaria parasites is an emerging topic. Although antigenic variation is only part of a more global parasite strategy to create adaptation through epigenetically controlled transcriptional variability, it is the central mechanism enabling immune evasion and promoting pathogenesis. The  The sites of host\u2013parasite interaction are constantly exposed to recognition by the host immune system. Protozoan pathogens have developed a wide range of sophisticated immune evasion strategies such as antigenic variation . Most var genes are in subtelomeric regions, whereas others are arranged in more chromosome central positions. Var genes consist of an Exon1, coding polymorphic sequences forming the extracellular domain, an Exon2, coding the semi-conserved intracellular domain, connected by a single highly conserved intron.The protozoan pathogen d stream A. Duringvar gene expression studies have wide implications for other plasmodial gene families and single-copy genes controlled by similar epigenetic mechanisms  A and B subtypes, as well as some members of the rifins, another clonally variant gene family. Inactivation of a second member of the Sir2 family, called Sir2B, showed some complementary de-repression effect on other, mostly upsC, var gene members , which is enriched in promoter regions of repressed var genes  to silent but not active P. falciparum than was anticipated   and Histone 3 lysine 9 acetylation (H3K9ac), which renders it permissive for transcription   in var gene is active within a single cell. The HB3 P. falciparum strain contains two nearly identical copies of the var2csa gene. Despite the fact that one copy lies on chromosome 12 and the other on chromosome 1, RNA FISH analysis showed that simultaneous expression of both copies occurs at the same site in the nucleus . Interestingly, an episomal promoter of the rifin gene families also colocalizes with the active var gene expression site when activated through drug selection . An alternative view is that an activation complex is recruited to the var gene in situ. This initiates the transcriptional activation cascade including its relocation away from the repressive zone. This scenario predicts that any perinuclear site outside the repressive centres may form an expression site. Depending on which model turns out to be accurate, var gene activation would occur before segregation from the repressive cluster or segregation would be a precondition for activation. In either case, the recent discovery of nuclear actin associated to var gene intron regions opens a new exciting avenue. Nuclear actin could provide a mechanical framework for spatial organization of active and silent genes .A different hypothesis for a mutual exclusive expression mechanism postulates the existence of a unique Var genes are only transcribed during the early stages of the blood stage cycle and intrinsic switching rates determined from in vitro cultured parasites can reach up to 2% per cycle (Roberts et al., var genes will be re-activated after the next round of invasion (var promoter in the late blood cell stages, while H3K9me3 is prevented from spreading into the promoter region (Lopez-Rubio et al., var gene locus in post-ring stages, whereas repressing marks are excluded from this site, presumably contributing to the poised state (Volz et al., P. falciparum awaits further investigation.invasion A. ChIP aSwitching between the clonally variant genes is central to antigenic variation and must be adapted to the host so the variant gene repertoire is not depleted too fast whilst effective immune evasion is still possible. It is important to keep in mind that the parasite needs to control its own proliferation so the host is not severely harmed by high parasitemia and effective transmission is guaranteed.var members (Horrocks et al., var genes during the non-transcribed phase can be experimentally erased by promoter titration (Dzikowski and Deitsch, et al., var genes is independent of previous stages. Another recent study on switch pathways used experimental evidence combined with mathematical modelling to conclude that var switching is non-random and necessitates a balanced process of parasite-intrinsic switching and immune-mediated selection (Recker et al., var gene switching patterns using silencing with drug-selectable markers in multiple isolates suggests that a var gene switching pattern is conserved throughout different genetic backgrounds (Enderes et al., et al., To this day, no genes modifying switch rates have been identified and no functional data is available on the molecular mechanism of switching. Nevertheless, descriptive studies demonstrated that transition rates can vary between var gene silencing may be modulated by external factors. For example, Sir2 depends on NAD levels for its activity. Low nutrition states of patients may influence Sir2 activity and hence alter the switch rate of distinct var subtypes. Experimental data from in vitro cultured parasites using peroxide or starvation stress can lead to a slight up-regulation of central var genes (Rosenberg et al., var gene expression pattern in patients (Merrick et al., Another critical question is whether the observed intrinsic switch rate is influenced by external factors, i.e. does the parasite react to its environment, or is the switching pattern hard-wired into the parasite's genome? Although no longitudinal data from human patients are available to support this concept directly, the epigenetic machinery controlling var expression studies from malaria patients, however, support the idea that host factors contribute to var gene transcriptional control. Unlike in vitro cultured parasites, ups A-type var genes were frequently expressed in P. falciparum-infected patients (Bachmann et al., et al., var genes mostly of the ups B and C-type. It will be crucial to investigate whether host factors modify the intrinsic switch rate of ups A-type var genes.The relative paucity of patient data related to this topic makes it difficult to investigate switching rates in the human host. Two recently published var genes cooperate with chromatin modifying enzymes in a complex interplay. On top of this, spatial regulation creates specific nuclear sub-compartments most likely critical for default silencing and monoallelic expression. Other factors such as non-coding RNA produced in subtelomeric regions adjacent or within var genes may contribute as well to antigenic variation (Epp et al., et al., Mutually exclusive expression relies on distinct layers of genetic and epigenetic control factors. Genetic elements, such as the promoter and the intron of var gene expression site remain to be explored. The biggest puzzle, however, in understanding mutual exclusive expression, is the absence of a putative activation factor. The concept of a limiting factor driving monoallelic var transcription has been postulated on many occasions but remains to be demonstrated. The notion that a unique enhancer element is the activating factor or expression site body would seem plausible, since there is exactly one copy in the nucleus of this haploid parasite. A transcription factor, whose expression is restricted to extremely low levels, may be considered but it seems difficult to really make sure that exactly one transcription factor is present. Considering that under special conditions more than one promoter can be activated we favour a model where potential positive feedback loops within the activating complex could ensure aggregation around the expressed var gene. In the absence of candidate genes for a monoallelic activating factor, identification of mutant parasites that have lost var gene expression remains the biggest challenge in the field. Traditional biochemical and mass spectrometric analysis of factors interacting with key genetic elements (Zhang et al., et al., et al., et al., Properties and composition of the hypothetical It remains enigmatic how one gene is active while others are silenced, when and how a specific gene is poised rather switched, but many exciting research avenues are left to explore in the field of mutually exclusive expression."}
+{"text": "Dear Editor,In your June 2011 issue, we found an interesting study by Farzanegan et al. entitled, \u201cEffects of lumbar discectomy on disability and depression in patients with chronic low-back pain.\u201d , 4. DeprThe association between depression and pain after low-back surgery is not consistent across studies. Depression and disability have been found to be highly influential in patients undergoing lumbar spine surgery. The psychological profile of depression has predicted poorer outcomes in patients with chronic sciatica pain and disability . The stu"}
+{"text": "In contrast to the current therapy, which antagonises the formation of proinflammatory mediators, the \u201cproresolving\u201d therapy promotes natural antiinflammatory processes. It is likely that several drugs and phytochemicals would act in this way, but this point has not been investigated and thus might be totally overlooked. In this paper, effects of curcumin (diferuloylmethane) were analysed, considering the ability of this natural compound to affect resolution of inflammation through modulation of its important inputs \u2013 activity and apoptosis of neutrophils. The presented data indicate that, besides its well-known ability to suppress mechanisms engaged at the onset and progression of inflammation, curcumin could support resolution of inflammation through decreased activity and enhanced apoptosis of neutrophils. This substance decreased the formation of oxidants in neutrophils, both under in vitro conditions and after oral administration to arthritic rats. Moreover, curcumin accelerated spontaneous apoptosis of neutrophils, as indicated by increased externalisation of phosphatidylserine, by intercalation of propidium iodide and by enhanced activity of the executioner caspase-3.Novel strategies of antiinflammatory therapy are based upon pharmacological agents capable to enhance the resolution \u2013  During the inflammatory process, different cytokines, growth, transforming and chemotactic factors are synthesised and several types of cells become activated. Neutrophils (polymorphonuclear leukocytes) are considered to be central cells of acute inflammation. These cells most rapidly reach the site of injury or infection and liberate antimicrobial proteins, proteases and produce reactive oxygen species. Prolonged or excessive liberation of these very effective and toxic substances could intensify the inflammatory process and enhance tissue damage. Therefore activity of neutrophils declines consecutively by the effect of antiinflammatory mediators  and programmed death of these cells (apoptosis) is initiated. These processes are essential for the termination (resolution) of the beneficial inflammation , luminol, isoluminol and PMA (phorbol-myristate-acetate) were obtained from Sigma  and methotrexate was from Pliva-Lachema . Human Annexin V/FITC Kit was purchased from Bender MedSystems , Caspase-Glo 3/7 Assay from Promega  and human purified caspase-3 was from Enzo Life Sciences .in vitro conditions, isolated human neutrophils were stimulated with 0.05 \u00b5M PMA and chemiluminescence was enhanced either with isoluminol (extracellular) or with luminol in the presence of extracellular scavengers \u2013 superoxide dismutase and catalase  and propidium iodide. Only Annexin positive cells were considered pre-apoptotic cells and double positive cells (Annexin+/propidium+) were considered late-apoptotic or dead cells.et al., Effect of curcumin on caspase-3 activity was evaluated in cell-free system by the luminescence method, using Caspase-Glo 3/7 Assay kit and human purified caspase-3  elevated the percentage of preapoptotic and apoptotic neutrophils A and incet al., 2, myeloperoxidase, collagenase, as well as to its ability to modulate activities of T lymphocytes and macrophages  were reduced more effectively than oxidants formed within neutrophils (involved in elimination of phagocytosed pathogens and fulfilling a regulatory role). Compared to previous studies (Limasset in vivo conditions \u2013 in arthritic rats. Neutrophils modified by inflammation produced several times more oxidants than did healthy controls and this hyperreactivity was suppressed by orally administered curcumin. Since the excessive formation of radicals was ascribed to the enhanced activity of NADPH oxidase in the presence of cytokines (Fairhurst et al., et al., et al., et al., et al., The decreasing effect of curcumin on neutrophil activity was further observed under et al., Curcumin-related inhibition of neutrophil oxidative burst was comparable with the activity of methotrexate \u2013 a drug widely used in the therapy of arthritic patients, which triggers synthesis of the endogenous anti-inflammatory mediator adenosine (Cronstein, The presented data indicate that, besides its ability to suppress mechanisms engaged at the onset and progression of inflammation, curcumin could support resolution of inflammation through decreased activity and enhanced apoptosis of neutrophils."}
+{"text": "Induction of premature (stress induced) cellular senescence of normal cells provides the mechanism eliminating proliferative capability of potentially carcinogenic cells and thereby is considered to be a barrier preventing neoplastic tranformation . On the Additional evidence on the role of perturbed dNTP pools in induction of DNA damage and replication stress was provided by Bester et al.,. Their sG12V, a classical model of oncogene-induced senescence. Among the enzymes down-regulated by activated HRAS were TS, ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2). Ectopic coexpression of TS, RRM1 and RRM2 or addition of deoxyribonucleosides to a large extent prevented DNA damage, decreased expression of senescence-associated phenotypes as well as attenuated the extent of proliferation arrest. Interestingly, overexpression of TS, RRM1 and RRM2 in quiescent NHFs had no effect on their proliferation arrest suggesting that unlike the OIS, quiescence is not induced by perturbation of dNTP pools. Moreover, in a separate study, Mannava et al.,[In the subsequent studies Mannava et al., provideda et al.,demonstraMost of the above findings were reproduced in a study of Aird et al., on a rolThe seminal findings on different cellular and oncogene models that perturbation of dNTP pools leads to DNA damage, replication stress, irreversible senescence -8,may ha"}
+{"text": "Cardiac hypertrophy is a distinguished feature of several physiological and pathological remodeling (Frey et al., Distinct underlying signaling pathways for physiological and pathological hypertrophy have been identified (Maillet et al., Unlike pathological hypertrophy, only a little studies described how miRNAs response to physiological hypertrophy (Soci et al., Traditionally, the adult mammalian heart is recognized as a post-mitotic organ with no regenerative capacity for cardiomyogenesis (Rosenzweig, With the strategies for checking myocyte hypertrophy and new cardiomyocyte formation, the miRNA basis of physiological hypertrophy will be revealed, which will help develop a miRNA-based therapy for heart failure."}
+{"text": "MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition. \u00a9 2010 Wiley-Liss, Inc.Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well-characterized common functional polymorphisms in the genes  Experimental manipulation of human and primate neurotransmission has provided insight into the distinct roles that the monoamine neurotransmitters serotonin (5-HT), dopamine (DA), and noradrenaline (NA) play in prefrontal cognition [Clarke et al., O-methyltransferase (COMT), one such enzyme [Karoum et al., COMT knockout mice show normal prefrontal NA levels and administration of the COMT-inhibitor tolcapone increases the release of DA, but not NA, in rat PFC [Gogos et al., Two major routes for the deactivation of monoamine neurotransmitters are reuptake by transporter molecules in the presynaptic cell membrane, and enzymatic degradation within the neuron or synapse. Both serotonin and NA transporters are abundant in PFC [Mantere et al., COMT, MAOA, and the serotonin transporter-linked polymorphic region (5HTTLPR) affect the level and/or activity of their products in defined manners, summarized in COMT Val allele was associated with worse performance on a measure of executive function, the Wisconsin Card Sort Test (WCST). While meta-analysis of similar studies shows little consistent cognitive effect [Barnett et al., MAOA and 5HTTLPR polymorphisms on cognition. MAOA genotype has been reported to significantly affect IQ among healthy Chinese women [Yu et al., 5HTTLPR polymorphism have been predominantly negative for standard neuropsychological measures such as IQ, response inhibition, and sustained attention [Fallgatter et al., Individual differences in cognitive function are highly heritable [Devlin et al., 158Met on cognitive performance at ages 8 and 10 in a population-based sample of more than 5,000 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) [Barnett et al., MAOA and 5HTTLPR. We also assess evidence for epistasis between the MAOA, 5HTTLPR, and COMT polymorphisms, in an attempt to broaden the candidate gene approach to include assessment of functionally interactive gene systems, here represented by the overlapping effects of these SNPs on synaptic neurotransmitter availability. We hypothesized that genes that exclusively affect serotonergic function (5HTTLPR) would show little effect on these prefrontally driven cognitive tasks, but that main genetic effects, and potential epistasis, would be demonstrated for variants affecting dopaminergic or noradrenergic availability , with 5 \u00b5M of each primer and 25 mM dNTPs in a total reaction volume of 25 \u00b5l. Amplifications were performed on a Perkin Elmer 9700 thermocycler  with one cycle at 96\u00b0C for 10 min followed by 30 cycles of 94\u00b0C for 15 sec, 60\u00b0C for 15 sec, 72\u00b0C for 30 sec, and a final 3-min extension at 72\u00b0C. The forward primer was labeled with the fluorescent dye 6-FAM, and amplicons were visualized on an ABI 3100 capillary sequencer. Allele sizes  were determined using Genotyper 2.5 (Applied Biosystems). MAOA 3, 3.5, and 4-repeat allele frequencies in girls were consistent with Hardy\u2013Weinberg equilibrium .DNA, obtained from blood and mouthwash samples, was extracted and processed [Jones et al., 5HTTLPR, low activity individuals were those with SS, SLG, or LGLG genotypes, medium activity were SLA or LGLA genotypes, and LALA genotypes were denoted high activity [Hu et al., COMT, Met/Met individuals were considered low, Val/Met individuals medium, and Val/Val individuals high activity, because Val allele carriers show higher COMT enzyme activity, and hence faster degradation of catecholamines at body temperature [Lachman et al., MAOA we excluded genotypes involving the rare 2- or 5-repeat alleles, whose functional effects are not yet clear [Sabol et al., MAOA is located on the X chromosome, boys carry only one allele. Boys with the 3-repeat allele were denoted low MAOA activity and those with 3.5- or 4-repeat alleles as high activity, since they show higher transcriptional efficiency and hence result in higher levels of synaptic MAOA [Sabol et al., Individuals were classified into high, medium, or low activity groups with respect to the functional effects of the polymorphism in each of the three genes. In each case, \u201chigh activity\u201d groups comprised the alleles leading to fastest clearance of the synaptic neurotransmitter and \u201clow activity\u201d the alleles leading to slowest clearance. For 5HTTLPR, and for MAOA in girls only. For boys, we compared cognitive scores in high versus low activity groups using t-tests. Main effects of COMT in this sample have been previously reported [Barnett et al., Main effects of genes on cognition were assessed by comparing cognitive scores between high, medium, and low activity groups using one-way ANOVA for the 5HTTLPR and MAOA genotypes, and a catecholaminergic one between COMT and MAOA genotypes. We assessed evidence for these interactions using general linear models with each cognitive measure as an outcome variables predicted by two genetic main effects and a gene\u2013gene interaction term. As before, all genotypes were coded as low, medium, or high activity. These analyses were conducted separately in boys and girls because MAOA is located on the X chromosome, and because COMT is known to have sexually dimorphic effects on a range of functional and neuropsychiatric phenotypes [Harrison and Tunbridge, Two possible sources of epistatic effects on cognition were considered: a serotonergic interaction between 5HTTLPR genotype. There were no cognitive differences between children for whom 5HTTLPR, MAOA, or COMT genotypes were or were not available . Allele frequencies were, for 5HTTLPR alleles S = 41.4%, LA = 51.5%, LG = 7.1%, and for MAOA, 2-repeat = 0.2%, 3-repeat = 34.0%, 3.5-repeat = 2.0%, 4-repeat = 62.4%, 5-repeat = 1.5%. COMT allele frequencies, as previously reported, were Val = 48.6%, Met = 51.4%. The number of children considered as low, medium, and high activity genotypes for whom at least one cognitive measure was available are shown in The number of children included in each analysis varied by the availability of cognitive data and genotypes: cognitive data were available on around two-thirds of those for whom DNA is available. As previously reported [Araya et al., MAOA on cognitive measures were assessed separately in boys and girls. t-Tests between high  and low (minimum n = 854) activity MAOA groups in boys showed no effects on any cognitive measure. Similarly in girls, one-way ANOVA between low, medium, and high activity MAOA groups  revealed no cognitive differences  such that better performance was seen in the high than medium activity group (Tukey's post hoc P = 0.03). One-way ANOVA revealed no cognitive differences between the three genotypes  within the low activity group.Groups defined by low, medium, and high serotonin transporter promoter activity were compared on all cognitive measures using one-way ANOVA. There were no differences between groups on measures of IQ or verbal inhibition see . NominalCOMT genotype and MAOA genotype, and a COMT \u00d7 MAOA interaction term, were fitted separately for girls and boys. In boys, there was evidence of interaction between COMT and MAOA only for working memory score . Nonetheless, this sample remains the largest so far examined with respect to MAOA and cognition, and the complete lack of difference in cognitive score between genotypes in either sex is again a decisive negative result.Although the lack of cognitive effects of MAOA, there was a modest but significant interactive effect of MAOA genotype and COMT genotype on working memory performance in boys but not girls. With few exceptions, cognitive genetic studies have thus far had inadequately sized samples to realistically assess possible gene\u2013gene (epistatic) interactions. The COMT \u00d7 MAOA interaction observed here for working memory is plausible given the dependence of working memory on prefrontal dopaminergic availability. That no similar effect was found for IQ is surprising: COMT genotype has a strong, male-specific effect on verbal IQ in this sample [Barnett et al., MAOA on IQ but not measures of executive function [Yu et al., In contrast to the absence of main effects of Separate analyses were carried out for boys and girls and for multiple cognitive phenotypes. Since scores on the four cognitive measures were correlated, strict correction for multiple comparisons using, for example, a Bonferroni correction, was not suitable. Nonetheless, while the large sample used in the study reduces the chances of Type II error, the possibility of Type I error remains present.MAOA has a widespread distribution in the brain [Grimsby et al., MAOA expression may be predominantly determined by genetic and epigenetic factors other than this VNTR, including a currently unknown locus with which it shows strong linkage disequilibrium [Balciuniene et al., COMT expression appears greater in PFC than other regions [Matsumoto et al., COMT is complex, with tissue-specific monoallelic expression [Gimelbrant et al., COMT SNPs that act in concert with the Val158Met polymorphism in influencing cognitive function in this sample [Barnett et al., COMT haplotype groups produced no meaningful change in results from those seen using just the Val158Met genotype .While both tasks that have a high working memory content [Owen, MAOA genotype affects working memory only in the context of high prefrontal catecholamine availability. There is, of course, a distinction between demonstrating a statistical interaction, and understanding the biological mechanism of interaction between two genes [Clayton and McKeigue, COMT and/or MAOA expression affect cognitive function. One such possibility is NA, which, like DA, is catabolized to some extent by both COMT and MAOA. At present, dopaminergic pathways remain the more obvious candidate, because COMT appears to play a relatively minor role in regulating NA in the PFC [Gogos et al., The gene\u2013gene interaction found here suggests that COMT \u00d7 MAOA effect on working memory was in accordance with our previous study [Barnett et al., COMT genotype affected a wide range of cognitive functions in boys but had no effect in girls. There is additional wide-ranging evidence to suggest that the effects of COMT may be different between the sexes [Harrison and Tunbridge, COMT knockout mice, which show sex-specific behavioral phenotypes [Gogos et al., COMT in human PFC [Chen et al., COMT are the bilateral relationships between COMT and estrogen-related compounds: estrogens mediate COMT expression [Xie et al., COMT metabolizes catechol estrogens, a process regulated by Val158Met variation [Worda et al., COMT, the location of the MAOA gene on the X chromosome complicates association studies, with the result that little is known about the relative expression and effects of MAOA in the two sexes.The sex-specific nature of COMT and MAOA, two genes involved in the functional deactivation of DA and other neurotransmitters, show interactive effects on working memory performance in normal children from a large, homogeneous, and representative sample. While neither gene has been unquestionably linked to psychiatric disorder, normal variation in brain function is likely to be partly determined by genetic variation in neurotransmitter pathways. Understanding genetic effects on normal brain function is a necessary stage in understanding the basis of abnormal function, but large samples are required to tease out relatively subtle effects on cognitive development at the population level.In conclusion, we present evidence that functional polymorphisms in"}
+{"text": "Impulsivity can be defined as a predisposition toward rapid, unplanned reactions to internal or external stimuli regardless of negative consequences of these reactions for the impulsive individual or for others , lack of premeditation (difficulty in thinking and reflecting on consequences of an act), lack of perseverance (inability to remain focused on a task), and sensation seeking (tendency and openness to try and enjoy exciting or dangerous activities). The BIS-11 assesses impulsivity on the subscales attentional impulsivity (inability to focus attention or concentrate), motor impulsivity (acting without thinking), and non-planning impulsivity (lack of future orientation or forethought). Both questionnaires are highly correlated with each other (r = 0.67), but correlations between their subscales are only weak and inconsistent, supporting the notion that both measures cover different aspects of impulsivity (Meule et al., Beyond the fact that self-report and behavioral measures seem to capture different aspects of impulsivity, conceptualizations also vary between the different self-report instruments. For instance, two of the most widely used impulsivity questionnaires are the Only a few studies have done this as yet. For instance, differential relationships between subscales of the BIS-11 and eating disorder symptomatology have been found in clinical samples. Patients with binge eating disorder had higher scores on the motor impulsivity subscale compared to healthy controls, but did not differ on the other two subscales (Nasser et al., Eating Inventory (formerly Three-Factor Eating Questionnaire, Stunkard and Messick, hunger subscale and attentional impulsivity. Furthermore, both attentional and motor impulsivity were correlated with disinhibition (Lyke and Spinella, Studies investigating non-clinical samples also revealed differential associations between BIS-11 subscales and various measures of eating behavior. For example, Lyke and Spinella  examinedconcern for dieting subscale of the Restraint Scale (Herman and Mack, eating concern subscale of the Eating Disorder Examination\u2014Questionnaire (Fairburn and Beglin, In a recent study by van Koningsbruggen and colleagues , only thr = 0.94, Spinella, While the BIS-11 contains 30 items, Spinella  developeFood Cravings Questionnaire\u2014Trait, Cepeda-Benito et al., Mood Eating Scale, Jackson and Hawkins, Night Eating Questionnaire, Allison et al., Perceived Self-Regulatory Success in Dieting Scale, Meule et al., Restraint Scale, Herman and Mack, Yale Food Addiction Scale, Gearhardt et al., In a range of studies, positive correlations could be found between the BIS-15 and various constructs that are related to overeating (Table external eating subscale of the Dutch Eating Behavior Questionnaire (van Strien et al., Up to now, only one other research group has examined relations between eating behavior measures and BIS-15 subscales. In this study (Hou et al., In sum, it appears that attentional impulsivity is most consistently related to various measures that are associated with overeating. Positive, but less consistent, relationships can also be found with motor impulsivity, particularly in patients with binge eating behavior. Non-planning impulsivity seems to be only weakly related to overeating. Neither subscale seems to be consistently correlated with BMI, which may be due to the fact that BMI is influenced by many factors other than eating behavior. Future research needs to address the question why attentional impulsivity in particular has such a prominent role in overeating. First evidence suggests that attentional impulsivity may increase the susceptibility that highly palatable food-cues attract attention and trigger eating behavior (Hou et al.,"}
+{"text": "Evidence-based medicine is supposed to be a conclusive summary of available empirical knowledge on certain medical issues and as such serving as the basis of guidelines and treatment recommendations. Meant to be self-explaining, the term actually appears to be crucial. It seems inconsistent and inconclusive since recommendations of single countries/institutions are based on different evidence measures\u2014some derive evidence from meta-analyses, whereas others exclusively follow randomised controlled studies. In a philosophical side trip, M\u00f6ller  criticalIn mild major, minor or subsyndromal depression, the total score of the Hamilton Depression Rating Scale (HAMD) so far is regarded as \u2018gold standard\u2019 in evaluating efficacy of antidepressant treatment. Nevertheless, in comparing the full scales HAMD17 and the Inventory of Depressive Symptomatology IDS-C28) plus diverse unidimensional subcales in a randomised, placebo-controlled trial in a representative patient sample, Helmreich et al. [8 plus diGRIA1, GRIA2 and GRIA4, Chiesa et al. [In the pathophysiology of depression, glutamate plays an important role. Exploring the association of major depressive disorder with some single nucleotide polymorphisms within the glutamatergic AMPA receptor subunits a et al.  in a relAlthough an association between affective disorders and the metabolic syndrome has been suspected, past studies did not bear clear results in this respect. Hence, Kahl et al.  have exaCognitive deficits play a major role in psychiatric disorders like depression and schizophrenia, but also in neurodegenerative diseases. In an fMRI study in healthy probands, Voss et al.  investigDTI also was used by Konrad et al.  to invesIn all, cognitive deficits are core symptoms of psychiatric disorders and responsible for an unfavourable outcome. The investigation of the neurobiological basis of these symptoms is needed to develop new regenerative treatment strategies in psychiatric and neurodegenerative diseases."}
+{"text": "A commentary onNeural correlates of moral sensitivity in obsessive compulsive disorderby Harrison, B. J., Pujol, J., Soriano-Mas, C., Hern\u00e1ndez-Ribas, R., L\u00f3pez-Sol\u00e0, M., Ortiz, H., et al. (2012). Arch. Gen. Psychiatry 69, 741\u2013749.Archives of General Psychiatry, Harrison et al. (In a recent issue of n et al.  providedThese brain areas were found to be active on healthy humans experiencing moral emotions such as indignation or moral disgust (see Moll et al., The results are striking in so far as they show that patients with OCD demonstrated significantly increased activation of the ventral frontal cortex, particularly of the medial orbitofrontal cortex. Moreover, significant positive associations were documented between the patients' DY-BOCS ratings of total symptom severity and the activation of the anterior insula (Harrison et al., The evidence from this study offers the opportunity to discuss two emerging related issues.First, it adds further support on a clinical model to the view that visceral and moral disgust share, at least in part, common neural and cognitive mechanisms Jones, . In factThus, their heightened moral sensitivity might reflect an enhanced disgust for immoral outcomes.This hypothesis is supported by previous evidence coming from neuroimaging studies. For instance, an overlapped recruitment of ventromedial prefrontal and orbitofrontal cortices have already been reported during the processing of both sensorial and moral disgust (Moll et al., A similar result was announced for the insula. For example, Wicker et al.  have disAll these findings suggest that, the heightened moral sensitivity in OCD can be grounded on the same neural mechanisms responsible for their altered sensitivity to outcomes which can induce sensory and emotional disgust (Shapira et al., Another remarkable aspect deserving some discussion is that OCD participants were not different from healthy control subjects in the subjective rating of the moral dilemmas, despite the difference reported in neural activation. This result, which probably argues some distinction between the patients' increased neural responses and their perceived emotional experience during a moral dilemma (Harrison et al., This suggestion is supported by the recent evidence of a negative correlation between interoception and anxiety (Pollatos et al.,"}
+{"text": "To the Editor:In our manuscript entitled \u201cSingle-neuron RNA-Seq: technical feasibility and reproducibility,\u201d published online on July 6th, 2012, we have made a few serious mistakes which need to be corrected:J. Neurosci. 31, 6939\u20136943.\u201dWe referenced several points and quoted statements from a recent study by Okaty et al., but we neither cited the paper nor placed quotation marks on the statements. The full citation should be \u201cOkaty, B. W., Sugino, K., and Nelson, S. B. (2011). Cell type-specific transcriptomics in the brain. We request to add a citation after \u201cThe analysis of each single-cell transcriptome consists of several independent steps\u201d in the first paragraph of Results, as \u201cThe analysis of each single-cell transcriptome consists of several independent steps ,\u201d given that these points were previously raised by Okaty et al. We request to add a citation to the first paragraph of Introduction, as \u201cstudies of gene expression and function in the brain were restricted to a relatively small number of genes (Luo and Geschwind, Moreover, gene expression may be regulated in opposing directions in different cell types, thereby appearing static in composite data.ToMoreover, as previously discussed by Okaty et al., \u201cgene expression may be regulated in opposing directions in different cell types, thereby appearing static in composite data (Okaty et al., We apologize to the readers of Frontiers in Genetics and to the authors of the Okaty et al., manuscript, for our failure to correct these mistakes during the review process of our manuscript."}
+{"text": "Frontiers in Pharmacology brings together a group of review and original articles focusing on IBS.Irritable bowel syndrome (IBS) is a very common functional disorder of the digestive tract. Despite the prevalence and the social impact of IBS, the exact etiopathogenesis is incomplete and the pharmacological treatment is unsatisfactory. In this research topic, Fabrizio De Ponti brilliantly outlined the drugs currently used in\u2014or in development for\u2014IBS, within a scenario in which the specific armamentarium of medications is unsatisfactory  activation on the production of kynurenine  in IBS  and selective  5-HT4 receptor agonist in vitro with strong in vivo gastrointestinal activity in guinea pigs, rats, dogs, and in healthy humans. TD-8954 may have value in the treatment in C-IBS sufferers.Beattie et al. investigated the Interleukin-6 (IL-6) is elevated in the plasma of D-IBS patients (Rana et al., 1 and/or CB2 receptor activation\u2014exert pharmacological actions which are potentially beneficial in IBS (Izzo and Coutts, 1 and CB2 receptor agonists in normalizing the accelerated transit (Kimball et al., 1 and CB2 responsiveness is maintained long after an initial inflammatory period and suggest a role of cannabinoid receptors in the underlying pathophysiology of PI-IBS.Cannabinoids\u2014via CBThe differentiated Caco-2 cells intestinal cell line, derived from a human colon carcinoma has been used for drug absorption studies as well as to evaluate the epithelial barrier integrity in relation to IBS as well as to investigate the intestinal permeability of IBS drugs (Catalioto et al., In summary, this research topic should provide a useful resource for IBS researchers, both basic and clinical. The pharmacological studies, together with new strategies for drug discovery, highlight that more research is urgently required to translate novel and innovative basic concepts into prescribing options for healthcare professionals. It is hoped that this collection of articles will inspire further research into IBS."}
+{"text": "The fundamental role of D-serine as a co-agonist at the N-methyl-D-aspartate receptor (NMDAR), mediating both physiological actions of glutamate in long term potentiation and nociception and also pathological effects mediated by excitotoxicty, are well-established. More recently, a direct link to a chronic neurodegenerative disease, amyotrophic lateral sclerosis/motor neuron disease (ALS) has been suggested by findings that D-serine levels are elevated in sporadic ALS and the G93A SOD1 model of ALS (Sasabe et al.,  It has only recently been recognized that D-amino acids play an important physiological role in the central nervous system. The evidence is most convincingly demonstrated for D-serine through its action as a co-agonist at the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, involved in synaptic plasticity , TAR DNA binding protein 43 (TARDBP) and fused in sarcoma (FUS). Arginine199 is highly conserved across species from bacteria to man and lies within the active site close to the FAD and substrate binding sites of the enzyme. The effect of the R199W-DAO mutation is very profound abolishing enzyme activity , the major biosynthetic for D-serine, in mammalian brain has been characterized extensively  was backcrossed with C57BL/6J mice and maintained as homozygotes (DAO\u2212/\u2212) in order to study the motor phenotype in more detail  has been identified in a mouse line, which shows abnormal locomotor activity  and in two overlapping ALS-like conditions, progressive bulbar palsy and primary lateral sclerosis , compared to normal controls and a control neurological group consisting of conditions associated with similar muscle loss   compared to controls, the greatest change being an increase of 57% in glycine which suggested a potential impairment in glycine transport (de Belleroche et al., An impaired clearance of both glycine, as indicated from these results (Lane et al., \u2212/\u2212, where D-serine synthesis is reduced. On the other hand, glycine facilitates NMDAR-mediated currents after afferent stimulation, diminished by GO but not by DAO (Li et al., \u2212/\u2212 knockdown or depletion of glycine by GO reduce LTP (Li et al., In hippocampus and amygdala (Li et al., The interplay between glycine site co-agonists has not been extensively characterized in brain stem and spinal cord. However, studies in rat hypoglossal motor neurons suggest that an increase in synaptically released glycine in response to metabolic stress may play a role in exacerbating NMDA receptor-mediated excitotoxicity in motor neurons (Kono et al., Experimental evidence obtained to date highlights the selective localization of DAO in spinal cord motor neurons, brain stem motor nuclei, cerebellum and other CNS centers involved in motor control. DAO is also found in glial cells in spinal cord and cerebellum. This distribution of enzyme activity is consistent with the lower levels of D-serine found in posterior brain compared to forebrain. The primary findings that implicate D-serine in ALS and potentially in neurodegeneration in general are that elevated levels of D-serine in spinal cord are found in ALS and the SOD1 mouse model of ALS (Sasabe et al., In order to further substantiate this concept, we have explored the potential toxic properties of the FALS-associated R199W-DAO mutation in cell culture and have shown that whether expressed in astrocytes or motor neurons the mutation promotes apoptosis but most interesting when expressed in glial cells the mutant protein is able to initiate apoptosis in neighboring neurons in co-culture that lack the mutation. The way in which this effect is transmitted between cells appears to be crucially dependent on the presence of an NMDAR co-agonist as the effect is blocked by the selective antagonist DCKA. In the situation where DAO is inhibited due to the presence of a mutation, D-serine levels are elevated (Sasabe et al., It is of considerable importance to note that increased synthesis of D-serine by neuronal and glial SR is known to be activated by cellular stressors such as AMPA, amyloid-beta and lipopolysaccharide (Wu and Barger, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Sir,Upsala Journal of Medical Sciences. This article provides an interesting analysis of estimating renal function in critically ill patients, but I believe there are several aspects that may warrant further discussion:I read with great interest the article entitled \u2018Significant differences when using creatinine, modification of diet in renal disease, or cystatin C for estimating glomerular filtration rate in ICU patients\u2019 by Lipcsey et al.  in the MFirst of all, the equations estimating glomerular filtration rate (GFR) are all notoriously flawed in the setting of rapidly changing renal function, that is, acute kidney injury. The creatinine-based formula for creatinine clearance is shown to over-estimate renal function when actual GFR is low, due to its multiple interfering factors and tubular secretion nature, but the cystatin C-based formula is also affected by muscle mass and adiposity . To compSecond, the duration of illnesses and timing of tests are also not taken into consideration in Lipcsey's article. Nejat et al. in their multicenter observation study have indicated that cystatin C rises earlier than creatinine in patients with acute kidney injury by 4\u20135 hours from a general ICU population .Finally, is there any better way of determining renal function in the critically ill with convenient point-of-care feasibility? Tidman et al. in their study of GFR determination in chronic kidney disease patients have provided a new thought: combining creatinine-based and cystatin C-based results for estimation . Though"}
+{"text": "Bevacizumab (Avastin) has rapidly gained status as a broadly active agent for malignancies of several different histologies in adults. This activity has spawned a range of uses in pediatrics for both oncologic and non-oncologic indications. Early analyses indicate that pediatric cancers exhibit a spectrum of responses to bevacizumab that suggest its activity may be more limited than in adult oncology. Most exciting, is that for low-grade tumors that threaten vision and hearing, there is not only evidence for objective tumor response but for recovery of lost function as well. In addition to oncological indications, there is a range of uses for non-oncologic disease for which bevacizumab has clear activity. Finally, a number of mechanisms have been identified as contributing to bevacizumab resistance in cancer. Elucidating these mechanisms will guide the development of future clinical trials of bevacizumab in pediatric oncology. Angiogenesis, or the formation of new blood vessels from pre-existing vessels is essential for normal organogenesis and tumorigenesis. The wide range of requirements for new blood vessel growth during development and in the setting of pathology is served by numerous angiogenic factors that recruit endothelial progenitors and other pro-angiogenic and vascular supporting cells, and promote endothelial cell proliferation and survival. Vascular endothelial growth factor (VEGF) is essential to both normal and pathology-associated angiogenesis and consequently, VEGF antagonism is the primary focus of anti-angiogenic therapies. Multiple isoforms of VEGF are generated through alternate splicing and post-translational modifications of the products of a multi-gene family comprised of VEGF-A, -B, -C, -D and placenta growth factor Ferrara, . Most of121, VEGF165, VEGF189, VEGF206)  as well as two co-receptor, Neurophilin 1 and 2. While binding to VEGFR-1 occurs with higher affinity than binding to VEGFR-2, it is VEGFR-2 that mediates the pro-angiogenic effects of VEGF on endothelial cells  in patients who had progressed after prior treatment  every 2\u2009weeks. Fifteen of the patients had no objective sustained response. Eight of the patients with GBM had stable disease for \u226512\u2009weeks with a median of 176\u2009days and median PFS of 4.2\u2009months. Median PFS for patients with DIPG was 2.3\u2009months. This study concluded that there is a lack of efficacy of combined bevacizumab and irinotecan in children with recurrent GBM and DIPG.Outcomes for children with high-grade gliomas (HGG) remain dismal with 5-year-survival rates of 5\u201315% for grade IV gliomas and 20\u201340% for grade III gliomas  every 2\u2009weeks. Seven had a radiographic response  and seven had clinical improvement . At the conclusion of the study, eight of the nine patients had not progressed . The 14th patient was progression-free at 45\u2009months. Significant responses to bevacizumab in children with LGG is consistent with reported activity for other anti-angiogenic therapies such as thalidomide-based regimens  are the most common childhood brain tumor. Treatment varies as a function of age and tumor location between surgical resection alone, or combined surgery and chemo or radiation therapy. Common indications for adjuvant therapy include recurrence in surgically inaccessible locations and threats to function particularly for deep-seated midline tumors growth of which can result in vision loss, or hypothalamic or brainstem dysfunction. While LGG are slow growing, biologically benign tumors, they possess increased vasculature . Although benign, these tumors tend to inexorably progress and often result in loss of all functional hearing by middle age. Standard treatment includes surgery and radiation however, these approaches are frequently ineffective at preserving hearing . Importantly, four of the seven evaluable patients had 57% improvement in word recognition beginning approximately 8\u2009weeks after initiation of therapy and four of those five also reported improvement in tinnitus. Mautner et al.  treated with bevacizumab (5\u2009mg/kg every 2\u2009weeks for 12\u2009months)  had a significant reduction in both MRI fluid-attenuated inversion-recovery (FLAIR) and T1-post-Gd contrast abnormalities. The average daily dexamethasone dose was reduced by 8.6\u2009mg. A retrospective review at Children\u2019s Hospital of Denver evaluated the response to bevacizumab of patients with DIPG (n\u2009=\u20094) , a severe complication of allogeneic stem cell transplantation. Yabe et al.  reportedVascular endothelial growth factor is a potent inducer of vascular permeability. Blocking it in patients with severe edema such as radiation necrosis and CLS may benefit some patients. Further studies are needed to further evaluate these findings.Bevacizumab has been used in several case reports of patients with angiomatosis, a neoplasm-like entity. Smith et al.  reportedBevacizumab has also been reported to benefit a patient with multifocal lymphangiomatosis or Gorham\u2013Stout disease (GSD), presenting as idiopathic osteolysis of the bones. GSD is possibly triggered by occult neoplastic cells that produce large amounts of IL-6 and VEGF. Grunewald et al.  reportedp\u2009=\u20090.002). Treatment of ROP with bevacizumab is now the standard of care at many centers. Albini and Murry reported a retrospective, non-comparative, open-label, interventional case series in 35 eyes of 33 patients with diseases such as CVN, Coat\u2019s disease, familial exudative vitreoretinopathy and sickle cell retinopathy who were treated with bevacizumab . One patient with sickle cell retinopathy and central retinal vein occlusion had significant improvement in central macular thickness over 6\u2009months after one injection (811\u201356\u2009\u03bcm). Similar effectiveness was also reported for treatment of CNV after Stevens\u2013Johnson syndrome , choroidal neovascularization (CNV), Coat\u2019s disease, and familial exudative vitreoretinopathy can lead to severe vision loss. Vision loss can occur for many reasons, including retinal ischemia and VEGF-induced neovascularization and vascular leakage of fluid, blood, and exudates. Mintz-Hittner et al.  conducteMaturo and Hartnick  reportedn\u2009=\u20091) including anaphylaxis, cerebral ischemia, posterior reversible encephalopathic syndrome, proteinuria, lymphopenia, and pneumonia.In adult studies, serious adverse events have been reported with the use of bevacizumab including CNS hemorrhage (1\u20135%), hypertensive crisis (<1%), and blood clots (6\u20139%) (Scappaticci et al., In the cases reported by Hwang et al.  who wereIn patients with NF2 treated with bevacizumab at 5\u2009mg/kg/dose, no thromboembolic events, hemorrhage, congestive heart failure, gastrointestinal perforation, reversible posterior leukoencephalopathy, or Grade III/IV events have been reported (Plotkin et al., Secondary amenorrhea was reported in a few patients. In the Phase I COG study, two of three post-menarchal females had a rise is LH and FSH, one subsequently missed her periods (Glade Bender et al., The patient treated for CAT syndrome was noted to have multiple punched out boney lesions after four doses of bevacizumab (Smith et al., Together, these studies indicate that bevacizumab is generally well tolerated in the pediatric population at doses up to 15\u2009mg/kg/dose. Serious side effects seen in adults have not been reported in the pediatric population.Targeting VEGF pathways clearly has a role in the treatment of a broad range of human disease. Some applications, like the treatment of post-irradiation edema or CLS, relate more to VEGF-mediated regulation of vascular permeability rather than to VEGF-stimulated angiogenesis. In these circumstances bevacizumab has demonstrated significant effect and it is likely that its use as a single agent for these indications will increase. In contrast, as detailed above, in cancer treatment when the angiogenic functions are the critical target for VEGF directed therapies, bevacizumab fails in most cases to produce a lasting clinical response. Identifying the mechanisms of resistance and appropriately modifying treatment approaches will be essential for the full realization of the potential of anti-angiogenic therapies. Here we will briefly review proposed mechanisms by which cancers adapt and evade VEGF antagonism.In discussion of and investigation into mechanisms of bevacizumab resistance, much has been made of an apparent change in the pattern of recurrence in bevacizumab-treated, versus conventionally treated, GBM. Some retrospective and prospective studies have reported an increase in the frequency of diffuse and distant recurrence after bevacizumab therapy from approximately 10\u201350% (Norden et al., The mechanisms that drive resistance to bevacizumab therapy are not yet fully defined. However, preclinical and clinical studies have revealed multiple intratumoral and systemic pathways that can contribute to tumor progression on bevacizumab therapy and these have been well reviewed by Bergers and Hanahan . In respIn addition to developing therapeutics that can target the multiple mechanisms of angiogenesis and tumor recurrence, a great clinical challenge as we advance anti-angiogenic therapies for cancer will be the application of laboratory and imaging techniques that can better define response early in therapy. This will be especially critical in the application of anti-angiogenic therapies to brain tumors where serial biopsy is not currently available. In this regard, serum evaluation for the up-regulation of pro-angiogenic factors, especially those associated with resistance like VEGF, PIGF, PDGF, FGF, IL8, CXCL12 may provide insight into shifts in response (Murukesh et al., In addition, imaging, particularly MRI-based spectroscopy, perfusion, diffusion, and oxygen consumption sequences may be able to detect functional changes in the vasculature relevant to anti-angiogenic responses and recurrent angiogenesis (Pope et al., Finally, PET imaging for therapy-induced changes in expression of specific components of angiogenic pathways as well as for changes in vascular function is an additional promising approach for detecting response to anti-angiogenic therapies that is just entering clinical evaluation (Chen and Chen, Together, sophisticated and combinatorial monitoring of response to anti-angiogenic therapies may support the timing of adjunctive interventions to circumvent resistance mechanisms and enhance efficacy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The MUS-81, SLX-1, and XPF-1 structure-selective endonucleases have been implicated in meiotic crossover (CO) formation in a variety of organisms, but their contributions to C. elegans CO formation have been unclear. In this issue of PLOS Genetics, Agostinho et al., Saito et al., and O'Neil et al. demonstrate that MUS-81 and XPF-1 function in two parallel pathways during the formation of meiotic crossovers in C. elegans and provide important insights into the interplay between endonucleases and the Bloom helicase ortholog during crossover formation.Saccharomyces cerevisiae have provided extensive genetic and biochemical support for this model. Although initiation by DSBs appears to be universal  and a progression of joint molecule (JM) intermediates that link DNA duplexes on homologous chromosomes  and S. cerevisiae Sgs1. Sgs1 disassembles early meiotic JMs, both to generate noncrossovers and to prevent formation of aberrant multi-chromatid JMs et al. report that him-6 mutants have defects in processing early intermediates, leading to chromosome fragmentation et al. propose that HIM-6 also has a late function in generating COs in conjunction with XPF-1 Drosophila BLM Additional potential similarities arise from studies of C. elegans meiosis  might work together to resolve HJs. However, it is possible that the proteins act on a different structure, such as nicked HJs (e.g., see reference Another important question concerns the exact nature of the pre-crossover JM. The authors suggest that these resolvases are acting on HJs, and resolution of chromatin bridges by GEN1 supports this suggestion. Agostinho"}
+{"text": "Kenneth Hugdahl's second affiliation is Department of Radiology, Haukeland University Hospital, Bergen, Norway.lower degrees of language lateralization as determined with fMRI (van Ettinger-Veenstra et al., higher degrees of lateralization.\u201dOn page 1 the final sentence in the second column should read: \u201cMoreover, individuals with n = 16 to find correlations between ear asymmetry and behavioral language tests in the non-forced condition of the Bergen DL task.\u201dOn page 7 the final sentence of the first column should read: \u201cFor the same reason van Ettinger-Veenstra et al.  might habut see Catani et al., On page 8 the final paragraph of the discussion should read: \u201cAs far as language is concerned, however, stronger lateralization seems to be associated with better performance in verbal abilities (Boles et al.,"}
+{"text": "Was\u2212/\u2212 mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22 to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.Wiskott\u2013Aldrich Syndrome (WAS) is a severe X-linked Primary Immunodeficiency that affects 1\u201310 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP) expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the  WAS gene is located on the X chromosome and encodes a 502 amino acid protein  is also an important regulator of WASP activation by inducing a stable acting form  is a rare X-linked Primary Immunodeficiency (PID) that affects 1\u201310 out of a million male individuals  is observed in some patients with substantial protein expression  cells  in T cells and T Cell Receptor (TCR)-dependent activation  and fungal infections  as compared to WASP-positive patients , followed by vasculitis , arthritis (29%), neutropenia (25%), inflammatory bowel disease (9%), and IgA nephropathy (3%). Henoch\u2013Sch\u00f6nlein-like purpura, dermatomyositis, recurrent angioedema, and uveitis have also been reported in some patients , most available therapies are not curative. Intravenous immunoglobulins (IVIG) and antibiotic prophylaxis are often used to reduce the risk of infections in WAS patients, but it is not clear whether these treatments effectively reduce the incidence of life-threatening infections  is available, BMT leads to 73\u2013100% survival . This adverse event gives rise to some concerns on the safety of RV-mediated GT for WAS. A multicenter clinical trial using a third generation LV carrying WAS gene driven by the endogenous promoter is on going in Milan, Paris, and London. Preclinical data in the murine model indicate that the LV-mediated GT approach is effective in restoring immune cell functionality . Two different Gene Therapy (GT) clinical trials have been approved: a Retroviral Vector (RV)-mediated gene transfer  family member Fas ligand (FasL) that is released and binds its receptor Fas in an autocrine fashion , Multiple Sclerosis (MS), and Systemic Lupus Erythematosus . In the last decade, it has been clearly defined that the lack of WASP causes defects in the cytoskeletal functions of B cells, including adhesion, migration, and homing  and a reduced or absent antibody production to polysaccharides and other T cell-independent antigens  co-engagement in Was\u2212/\u2212 B cells from chimeras could mediate tolerance breakdown, since the loss of Myeloid Differentiation primary response gene 88 (MyD88) signaling abolished the production of anti-dsDNA antibodies, germinal center formation, and development of systemic autoimmune disease , Recher et al.  which in turn activate pDCs to produce high levels of type I IFN , in the pathogenesis of systemic autoimmune diseases. In particular, IFN-\u03b1 produced by pDCs upon recognition of foreign nucleic acids via TLR7 and TLR9 contributes to tolerance breakdown in several autoimmune diseases, such as SLE, SS, and psoriasis (Ronnblom, Was\u2212/\u2212 mice abolish the production of anti-dsDNA antibodies (Becker-Herman et al., \u2212/low B cells (Ng et al., \u2212 B cells in WAS patients (Park et al., Was\u2212/\u2212 mice (Westerberg et al., Triggering of autoreactive B cells by self-nucleic acid-containing ICs can be another possible mechanism underlying the production of autoantibodies in WAS. In fact, it is known that self-nucleic acid-containing ICs can activate B cells through synergistic engagement of BCR and TLR7 or TLR9 (Leadbetter et al., In conclusion, together with the defects already described in the literature, these future lines of enquiry underline the greater than expected extent to which the WASP deficiency affects the immune system. Further research is necessary to define the underlying molecular and cellular mechanisms leading to autoimmunity, which represents the main collateral damage caused by WASP deficiency.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "While Frye and Jackson do a good job describing the common mechanisms of resistance found in food animals in the U.S., they err in stating that in the U.S. extended spectrum \u03b2-lactamases (ESBLs) \u201cthus far have only been found in human and not food animal isolates.\u201dEscherichia coli expressing CTX-M-type ESBLs in fecal isolates from healthy cattle at a livestock market and from a diagnostic isolate submitted to the Ohio Animal Disease Diagnostic Laboratory. Since then, CTX-M-type ESBLs have been found in E. coli collected from healthy dairy calves in the western U.S. (Davis et al., Salmonella enterica isolates from swine in Minnesota and from turkeys in 4 states (Wittum et al., E. coli from swine finishing barns in Michigan and Ohio and in Klebsiella pneumoniae from swine in Illinois (Mollenkopf et al., In fact, Wittum et al., in 2010 first reported the collection of E. coli isolate expressing CTX-M-type ESBLs from Pennsylvania has been reported (Doi et al., E. coli expressing OXA-type ESBLs (Davis et al., We are not aware of studies finding CTX-M-type ESBLs in isolates from broiler chickens, but a retail chicken meat"}
+{"text": "MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population. \u00a9 2012 Wiley Periodicals, Inc.Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The  Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids [Frankenburg, MTHFR gene includes two common polymorphisms  which both alter enzyme activity and homocysteine concentrations [Frosst et al., MTHFR C677T among 40 polymorphisms associated with schizophrenia susceptibility in the Han Chinese population [Yue et al., The MTHFR C677T functional polymorphism, and the metabolism of folate, methionine, and homocysteine have been extensively studied in relation to etiologically complex chronic diseases, and a relationship between MTHFR C677T and age at onset have been observed in for example, coronary artery disease, breast cancer, and Parkinson disease [Mager et al., MTHFR 677 T-allele predispose to an earlier age of onset in unrelated patients with schizophrenia of Scandinavian origin and found similar results in a family-based sample from western China [Vares et al., MTHFR polymorphisms in unrelated patients with schizophrenia to a combined analysis on age at onset. However, we were unable to replicate the findings outside the initial Scandinavian sample [Vares et al., The MTHFR C677T polymorphism and age at onset in two additional samples of Icelandic and Danish patients with schizophrenia, and combine the results with the previous Scandinavian results in a meta analysis.To determine whether the initial finding in unrelated individuals was restricted to populations of Scandinavian origin, or more likely due to chance alone, we here analyse the relationship between The Icelandic sample consisted of patients with schizophrenia, who were recruited all over Iceland as previously described [Stefansson et al., The sample from Denmark/Aarhus has also been previously described [Demontis et al., The samples from the initial report [Vares et al., P < 1 \u00d7 10\u22125, or frequency difference between chip types or typing centers with P < 1 \u00d7 10\u22126 were also excluded. Only samples with yield >90% were included, and the lower yield of each pair of duplicates was removed. Markers had control HW equilibrium P values > 0.001, and, in each group, yield in cases and controls was >95%.Genotyping of the Icelandic group using Illumina Human Hap300Beadchip genome-wide arrays was carried out as previously described [Stefansson et al., In Denmark/Aarhus, DNA was extracted from dried blood spots provided by the Danish Newborn Screening Biobank using the Extract-N-Amp Blood PCR kit . DNA was subsequently whole-genome-amplified using the RepliG mini kit  and genotyped on the Illumina Infinium HD Human610-Quad BeadChip  as previously described [Hollegaard et al., MTHFR C677T SNP was genotyped at the SNP Technology Platform in Uppsala, Sweden (http://www.genotyping.se), using the Illumina BeadStation 500GX and the 1536-plex Illumina Golden Gate assay (Illumina Inc.) as previously described [Vares et al., In the initial Scandinavian sample [Vares et al., For each study, we estimated the allele association between the C677T polymorphism and age at onset of schizophrenia with a general linear model. In this primary analysis, age at onset was treated as a quantitative trait, and modeled as a function of gender and the number of T alleles . The analyses were conducted in parallel, with R for the Icelandic and Danish/Aarhus sample  and with SAS/STAT\u00ae software (version 9.3) for the previously investigated Scandinavian samples [Vares et al., Meta analysis of the five studies was done with a simple random-effects model with Proc Mixed in the SAS/STAT\u00ae software . In the analysis, the allele association was modeled as a function of the fixed effect of the intercept and the random effect of study. The beta coefficients (regression slopes) for C677T from the primary analyses were used as the observed effect size, and the corresponding squared standard error (SE) was treated as known variance in the diagonal of the variance\u2013covariance matrix R. HW equilibrium was tested using Fisher's exact test as implemented in PEDSTATS [Wigginton and Abecasis, MTHFR 677T allele frequency varied from 27% (Sweden) to 36% (Iceland) in the samples . A negative association between 677T and earlier age at onset was also apparent in the Norwegian sample, although in this sample the association strength was weaker . We noted that this sample consisted of patients with an earlier age of onset than the other Nordic samples, and most patients became ill before the effect of the MTHFR C677T polymorphism was apparent in the original Scandinavian samples [Vares et al., MTHFR C677T polymorphism and age at onset of schizophrenia in the Icelandic sample (P = 0.86). Thus the initial finding of an age dependent association between the MTHFR C677T polymorphism and age at onset of schizophrenia in the Scandinavian population could not be replicated in two large and independent samples of similar origin. A meta-analysis of all five samples resulted in a pooled association estimate of 0.42 \u00b1 0.26 years earlier age at onset of schizophrenia per T-allele (mean \u00b1 SE), which did not reach statistical significance (P = 0.17).In the independent Danish sample (Aarhus), the age at onset decreased with on average 0.25 years per MTHFR 677T-allele and age at onset of schizophrenia in two independent samples of northern European heritage (Denmark and Iceland), or in meta-analysis including the initial Scandinavian samples. These results are in line with earlier analyses outside Scandinavia [Peerbooms et al., In the present study, we were unable to replicate our original finding of a negative association between the MTHFR 677T-allele and earlier age at onset in our original Scandinavian sample was primarily due to the Danish (Copenhagen) sample, and a similar tendency was present in the Danish (Aarhus) replication sample. Age at onset varied among the cohorts included in the study, and part of this variation may have been related to the different definitions of age at onset used . The heterogeneity in the definitions of age at onset is likely to have increased phenotype variation (and thus decreased the power to detect a true but weak association), but we observed no relationship between the definition of age at onset and association strength, neither in this nor in our previous analysis of multiple samples [Saetre et al., MTHFR polymorphism with respect to varying environmental conditions, such as availability of folic acid in food and/or practices of folic acid supplementation during pregnancy. Moreover, the power to detect an effect of the MTHFR 677T allele on late onset schizophrenia would be limited in the Danish (Aarhus) sample simply because of its younger age structure. Thus we cannot exclude the possibility of a weak negative association in populations of North European origin.The association between MTHFR 677T-allele has no significant effect on the age at onset of schizophrenia in the general population, irrespective of the geographical location, ethnicity or genetic background. Nevertheless, given the important role of MTHFR in the metabolism on folic acid, methionine, and homocysteine, it is possible that MTHFR gene variation not only affects schizophrenia susceptibility but may also modify symptom severity [Herran et al., However, given the data at hand, and previous analysis of samples of different geographical and ethnical origins [Peerbooms et al.,"}
+{"text": "Phosphodiesterase-5 (PDE5) inhibitors have shown a beneficial effect in a variety of clinical conditions, such as benign prostate hyperplasia, pulmonary arterial hypertension, female sexual arousal disorder, overactive bladder, and incontinence, Raynaud's disease, heart failure and stroke among others  pools (see Figure in vivo models of prostate cancer (Das et al., The accumulating body of evidence suggests that PDE5 inhibitors could interfere with the efflux functions of the ABC transporters, thus sensitizing cancer cells toward cytotoxic agents that are substrates of ABC transporters (Ding et al., In summary, there is evidence that suggests that PDE5 inhibitors may have an anticancer action either by increasing cGMP-PKG and coupled downstream events or by their ability to inhibit ABC transporter\u2014mediated s efflux of anticancer drugs. The safety, high tolerability, and wide availability of PDE5 inhibitors have made this class of drug an attractive tool to investigate their role in cancer chemotherapy. Since a detailed understanding of PDE5 inhibitors as anticancer adjuvants is limited, further studies are warranted to characterize their mechanisms and establish their role."}
+{"text": "DNA methylation is one of the essential epigenetic mechanisms that are closely correlated with the mechanisms underlying cell growth, differentiation and transformation in eukaryotes. Global changes in the epigenetic landscape are considered to be a hallmark of cancer. The initiation and progression of cancer are mediated through epigenetic modifications along with genetic alterations. Aberrant methylation of promoter regions is an epigenetic abnormality of the human genome that is highly characteristic of cancer. In this review, we aimed to summarize our current understanding of the alterations in the epigenetic landscape and investigate the potential use of DNA and RNA methylation in effective molecular treatment strategies. Complex diseases, such as malignant tumors and diabetes, are a common occurrence and represent a major public health concern. Despite the significant advances in cancer treatment, the overall cancer-related mortality is ~90%, due to late-stage diagnosis and failure to optimize treatment. Therefore, effective biomarkers for cancer diagnosis are urgently needed.Cancers such as lung, colon and breast cancer are frequently diagnosed at a late stage. Despite intensified efforts focused on improving the survival of cancer patients, only a moderate improvement is generally achieved. Failure of early diagnosis often leads to low treatment efficiency and poor prognosis; thus, the identification of a signal characterizing the early stages of formation and progression of cancer may reduce the incidence of this disease . Early fThe mechanisms underlying cancer development are complicated and cancer was originally perceived as a genetic disease. However, it was previously demonstrated that the initiation and progression of cancer involve epigenetic abnormalities, such as DNA methylation, histone modifications, nucleosome positioning and aberrant expression of non-coding RNAs, specifically microRNAs \u20137. The tcis-acting elements with trans-acting factors and gene expression. Various epigenetic experiments, involving genomic imprinting . Chromosome remodeling or reactivation of transposable elements was generated via demethylation of exons and introns or repetitive DNA sequences. An increased number of DNA hypomethylation loci in CpGs was shown to increase chromosomal instability and oncogene activation. For example, the hypomethylation of LINE-1 and Alu retrotransposons is frequently associated with lung cancer . The distribution of m5C within DNA is unique and may be used for genome-scale methylation analysis . For exaAs a specific pattern of gene expression in mammals, DNA methylation is essential for tissue development. Abnormal DNA methylation commonly disrupts molecular signaling mechanisms and leads to the development of various diseases, such as cancer. DNA methylation was the first epigenetic alteration to be identified in cancer . Therefoet al  were found to harbour methylated sites (ESR1 and 14-3-3-\u03c3 promoters were significantly different compared to healthy controls (et al (et al (The DNA methylation status is correlated with cancer and the methylation level is inversely correlated with mRNA expression levels. Jin et al  reporteded sites . In breacontrols . Glocknes (et al  reportedl (et al  comparedCDH1, APC, MGMT, RASSF1A, GSTP1, p16 and RAR-\u03b22, affect the activity of tumor suppressor genes, typically leading to transcriptional silencing. A number of important genes that undergo silencing interfere with important cancer-related cell pathways. Thus, the aberrant methylation of the promoters of cancer-related genes may be deemed as a potential biomarker contributing to early cancer detection and prediction of prognosis.The identification of patients with organ-confined carcinoma is key to early-stage diagnosis of cancer. Common organ-confined cancers, such as lung, hepatic, breast, cervical, colorectal and genitourinary tract cancers, result in patient death due to the lack of effective clinical diagnosis. In these cancers, the methylation of the promoter regions of tumor suppressor genes, such as SEPT9, is commonly detected in the plasma of patients with primary CRC and was submitted to the FDA for marketing application in 2010 as a molecular marker for early clinical stage CRC. SEPT9 as a DNA methylation biomarker was also associated with breast cancer; Gonzalez et al (SEPT9 expression may contribute to the pathogenesis of certain types of breast cancer. Another potential biomarker for breast cancer is the methylation of PITX2. The evaluation of the PITX2 methylation status among different breast cancer patient populations successfully increased the outcome prediction performance. Harbeck et al (PITX2 methylation in 399 breast cancer specimens and identified low-risk patients with hormone receptor-positive and node-negative disease. Hartmann et al (PITX2 in 241 breast cancer specimens and concluded that methylation of PITX2 was correlated with clinical outcome. Hrasovec et al (TMEM25 were correlated with CRC, with TMEM25 hypermethylation possibly playing a significant role in altering the expression of this gene in CRC.A series of novel DNA methylation biomarkers in the plasma and stool were developed for various detection purposes. Vimentin is transcriptionally silent in normal epithelia and aberrant vimentin expression has been used as a cancer marker in fecal DNA testing . In 2005ez et al  indicateck et al  investignn et al  also anaec et al  reportedThe elucidation of the mechanisms that underlie DNA methylation changes in cancer cells may help identify a number of cancer-specific methylation markers, assisted by promising detection methods, ultimately resulting in optimized clinical applications. The realization that DNA methylation may be involved in human malignancies and is ubiquitous in human diseases is likely to promote the development of novel diagnostic, preventive and therapeutic strategies.et al (et al (et al (RASSF1A to be an epigenetic marker for the detection of fetal DNA in maternal plasma. Epigenetic information passed from parent to offspring and DNA methylation from gametes was shown to be predominantly maternal (et al (The association between methylation and heredity is currently an emerging research topic. The presence of modified m5C affecting the phenotype of the offspring may be parentally inherited. Carone et al  indicatel (et al  reportedl (et al  considermaternal . Similarl (et al  recentlyThe modified DNA m5C that extensively occurs within the genome was extensively investigated over the last few decades; however, numerous putative methylated RNAs have been identified and characterized, regarding location, mechanism of formation and cellular function . Additio"}
+{"text": "Almost 40 years ago, Takatsuki et al. recognized the existence of a peculiar T cell leukemia in Kyoto, Japan that they named Adult T Leukemia (ATL). They reported a series of 13 patients in 1976 (Uchiyama et al., Almost 10 years ago, ours colleagues Kuan Teh Jeang and Mitsuaki Yoshida organized a special issue on HTLV infection in Oncogene. In setting up this issue, we cannot forget the memory our friend Teh.We called upon the expertise of different research groups from Europe, Japan, and USA. However, we regret that the format of this issue prevented us from soliciting many other colleagues. The following reviews will deal with many fascinating aspects of viral cycle, but summarizes also new approaches that should allow a better integrated research.A first group of articles provides information about HTLV-1 epidemiology and associated-pathogenesis. The article from Gessain and Cassar provides an updated view on HTLV-1 distribution, based on data obtained from 1.5 billion individuals originating from endemic areas (Gessain and Cassar, A second group of articles summarizes the interaction between the virus and the host's cells. Before causing diseases, HTLV-1 has to enter the cell. However, the mechanisms of HTLV-1 transmission and cell entry have remained elusive for a long period of time. Pique and Jones have summarized recent insights about those mechanisms both at the cell level but also between individuals (Pique and Jones, in vivo (Bai and Nicot, A third group of articles reports data on individual viral proteins that play important roles in the viral cycle and/or in pathogenesis. Nakano and Watanabe remind us the important role played by Rex, which uses cellular pathways to export unspliced or singly spliced viral mRNAs in the cell cytoplasm, therefore allowing expressing of structural proteins (Nakano and Watanabe, Finally, Duc Dodon and colleagues remind us that studying HTLV-1 pathogenesis requires animal models (Dodon et al.,"}
+{"text": "Frontiers in Neural Circuits in response to the \u201cSpecial topic\u201d entitled \u201cCortical NO interneurons: from embryogenesis to functions.\u201d Although it is practically impossible to address all aspects of NO interneurons, this special issue organized in four sections covers different facets of neocortical and hippocampal NO interneurons: from their diversity and embryonic origins to their functions in the cortical circuits and in neurovascular coupling.Neuronal processing and physiology of cortical circuits rely on a delicate interplay between glutamatergic excitatory neurons and GABAergic inhibitory interneurons in a spatially, temporally, and cell-type specific manner. Understanding these processes is further complicated by the large diversity characterizing the cerebral cortex (Ascoli et al., Studying the functional roles of NO-producing cortical interneurons has been challenging. NO being a highly diffusible gas (Wood and Garthwaite, stratum radiatum of the CA1 area exhibit characteristic properties of ivy cells and express NPY. In contrast to their counterparts in the stratum pyramidale (Fuentealba et al., stratum radiatum ivy cells display a different pattern of axonal and dendritic arborizations suggesting that these two subpopulations of hippocampal NO interneurons are involved in different microcircuits.This issue was revaluated in the whisker-to-barrel cortex by using NADPH-diaphorase histochemistry (Nogueira-Campos et al., Concomitantly with improvements in nNOS detection and the advent of genetic tools allowing lineage analysis of interneuron precursors, the developmental temporal and spatial origins of hippocampal and cortical nNOS neurons have been clarified with three studies showing that hippocampal and cortical type I NO interneurons originate from the medial ganglionic eminence (Jaglin et al., Another important question addressed in this special topic, is how NO interneurons are modulated by afferent signals and what their main neuronal targets are. Type I NO interneurons were found to express selectively the NK1 receptor whose activation by its natural agonist substance P induced their depolarization (Dittrich et al., Although NO is a well-established vasodilator, the relevance of NO interneurons in neurovascular coupling, the tight relationship between neuronal activity and local blood perfusion, has been questioned for decades (Cauli and Hamel,"}
+{"text": "Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development and synaptic plasticity that is fundamental to neural circuit formation and cognition. It is also involved in the control of appetite and body weight, with mutations in the genes for BDNF and its receptor, TrkB, resulting in remarkable hyperphagia and severe obesity in humans and mice. Recent studies have made significant progress in elucidating the source, action sites, and regulatory pathways of BDNF with regard to its role in the control of energy homeostasis, and have shed light on the relationships between BDNF and other molecules involved in the control of body weight. Here we provide a comprehensive review of evidence from pharmacological, genetic, and mechanistic studies, linking BDNF to the control of body weight. This review also aims to organize the main findings on this subject into a more refined framework and to discuss the future research directions necessary to advance the field. NTR). The Trk receptors have different neurotrophins as their preferred ligands, with NGF binding to TrkA, BDNF and NT4/5 binding to TrkB and NT3 binding to TrkC, while all of the neurotrophins can bind to p75NTR  is a member of the neurotrophin family of secreted signaling molecules that includes nerve growth factor (NGF), neurotrophin-3 (NT3), and neurotrophin-4/5 (NT4/5). Signal transduction can occur through the binding of two distinct classes of receptor proteins: the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, which includes TrkA, TrkB, and TrkC, or the p75 neurotrophin receptor , dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH), paraventricular hypothalamus (PVH), and brainstem Flier, . The ARCBdnf genes have nine exons, the first eight of which contain 5\u2032 untranslated regions (5\u2032 UTRs), with exon IX containing the entire coding sequence as well as the 3\u2032 untranslated region (3\u2032 UTR) , ventral tegmental area (VTA), substantia nigra and nucleus of the solitary tract (NTS) , after which the signal peptide is cleaved, leaving proBDNF  mice, which had increased risk of obesity resulting from increased food intake, concomitant with elevated serum leptin and insulin levels   infusion of neurotrophins on presynaptic cholinergic function  is the major site of thermogenesis. Sympathetic inputs from the stellate ganglion increase the expression of uncoupling protein 1 (UCP1) in IBAT, which allows the energy generated from \u03b2 oxidation of fatty acids to dissipate as heat in response to physiological stimuli such as cold exposure and overeating  expressing Cre recombinase indeed caused modest hyperphagia and obesity  was used to delete the Bdnf gene in SF1-expressing VMH neurons, the resulting mutant mice did not display any body weight phenotype (Dhillon et al., Cre transgenic mice will greatly facilitate elucidation of the role of VMH BDNF in the control of feeding behavior and body weight.The VMH is likely a site for the synthesis of BDNF protein that is critical for energy homeostasis. The Bdnf gene expression.Food deprivation also decreased levels of BDNF protein in the rat DVC, whereas refeeding or peripheral injection of the anorexigenic hormones leptin or CCK increased BDNF protein levels in this area (Bariohay et al., TrkB gene expression was reduced to a quarter of the normal amount, or the Bdnf gene was deleted in CaMKII\u03b1-expressing neurons, displayed markedly increased food intake on high fat diet compared to low fat diet (Xu et al., Bdnf mRNAs in the VTA and deletion of the Bdnf gene in the VTA induced hyperphagia on high fat diet but not low fat diet (Cordeira et al., Mice in which Bdnf mRNA encoding the same protein due to the presence of two alternative polyadenylation sites: short 3\u2032 UTR Bdnf mRNA and long 3\u2032 UTR Bdnf mRNA. One study indicates that BDNF protein regulating food intake is translated from long 3\u2032 UTR Bdnf mRNA, likely in dendrites (Liao et al., Bdnf polyadenylation site, such that the long Bdnf 3\u2032 UTR is truncated (Gorski et al., Bdnf mRNA (An et al., Bdnf mRNA in the VMH and nearby regions completely prevented these animals from developing hyperphagia and obesity (Liao et al., Bdnf mRNA to regulate appetite.Neurons produce two forms of NTR (Reichardt, NTR, lead to obesity in humans and mice (Lee et al., Not much is known about the action sites of BDNF with regard to its role in the control of energy homeostasis. BDNF exerts its biological effects through two receptors, TrkB and p75TrkB mouse knockouts. Once the neuronal populations are identified, researchers can focus on the mechanisms by which BDNF modulates the function of these neurons.Pharmacological studies have suggested several putative sites where BDNF acts to control energy homeostasis. Direct injection of BDNF into either the PVH or the VMH of adult rats was found to decrease food intake and increase energy expenditure (Wang et al., TrkB mRNA in the VTA (Cordeira et al., 1, such that peripheral injection of a D1 receptor agonist normalized the hyperphagia on high-fat diet (Cordeira et al., 1 is likely indirect, as the vast majority of TrkB-expressing neurons are striatal medium-sized spiny neurons that express the dopamine receptor D2 (Baydyuk et al., In addition to the hypothalamus and the brainstem, the mesolimbic dopamine system may be another target for BDNF to affect food intake, especially hedonic eating. Consumption of high fat diet was found to increase It is worth noting that one study reported that while central administration of TrkB agonists was anorexigenic in non-human primates, similar to what has been observed for rodents, peripheral administration was orexigenic, opposite to what is observed for rodents (Lin et al., db/db mice, diet-induced obesity mice and lethal yellow agouti mice, peripheral administration of BDNF has been shown to prevent or ameliorate the diabetic and obese phenotypes (Nakagawa et al., db/db mice, BDNF could potentiate the action of insulin in peripheral tissues, reducing serum glucose in obese, diabetic db/db mice (Ono et al., db/db mice by affecting blood glucose control, rather than food intake. BDNF administration also normalized fasted blood glucose levels, possibly through reduced hepatomegaly (Tonra et al., db/db mice, suggesting a long-lasting effect of BDNF on the control of glucose metabolism (Ono et al., db/db mice were restored to normal levels by BDNF treatment, with increased islet beta-cell area in BDNF-treated mice and a reversal of the decrease in pancreatic secretory granules, indicating a role for peripheral BDNF in restoring impaired pancreatic insulin production and secretion in db/db mice (Nakagawa et al., Obesity in mice with BDNF deficiency is associated with hyperglycemia and impaired glucose tolerance (Kernie et al., db/db mice led to increased insulin receptor activation in the liver and insulin-stimulated PI3K activity in the liver, skeletal muscle and IBAT. However, no direct effect of BDNF was found on cultured hepatocytes, L6 muscle cells or 3T3-L1 adipocytes, suggesting an indirect route of action. This may possibly be through regulation of central mechanisms leading to peripheral signaling, as suggested by the observation that centrally administered BDNF also had hypoglycemic effects, and led to similar increases in liver insulin receptor activation and insulin-stimulated PI3K activity (Nakagawa et al., db/db mice, indicating the activation of sympathetic pathways to regulate glucose metabolism (Yamanaka et al., CNS neurons may mediate some effects of peripheral BDNF administration on glucose homeostasis. Chronic subcutaneous BDNF administration in Bdnf mRNA levels in the VMH (Komori et al., Bdnf mRNA in dendrites, as leptin increased dendritic Bdnf mRNA translation in cultured hypothalamic neurons (Liao et al., Bdnf mRNA and BDNF protein, likely by activating BDNF-expressing neurons through a polysynaptic neural circuit.Several studies indicate that BDNF acts downstream of anorexigenic factors such as leptin and CCK to regulate food intake and body weight. Peripheral leptin administration was found to increase Bdnf mRNA (Liao et al., Bdnf mRNA, leptin injection activated LepRb normally in the ARC, DMH, and VMH, as indicated by phosphorylation of STAT3; however, leptin-induced c-Fos expression was impaired in the ARC and VMH and abolished in the DMH (Liao et al., BDNF signaling through the TrkB receptor is necessary for the anorexigenic action of leptin. Peripheral leptin injections reduced food intake in wild-type mice, but failed to do so in mice lacking long 3\u2032 UTR TrkB mutant mice and Mc4r\u2212/\u2212 knockout mice (Xu et al., TrkBF616A mice in which the phenylalanine residue at position 616 of the TrkB receptor is changed to an alanine residue, which makes the TrkB kinase sensitive to inhibition by the small molecule 1NaPP1 (Chen et al., Bdnf mRNA levels in the VMH (Xu et al., BDNF also interacts with the melanocortin system to regulate energy homeostasis. The initial consideration of this interaction arose from the appreciation of similar obesity phenotypes between Bdnf gene is a common allele (Shimizu et al., Cre transgenic mice and circuitry-mapping tools, it is becoming feasible to identify the neural circuits mediating the effects of BDNF on energy homeostasis. Identification of these circuits and elucidation of the mechanisms by which BDNF acts on them will greatly enhance our understanding of human obesity and hopefully bring us closer to a strategy for designing effective drug treatments for this disease.Strong evidence of a crucial role for BDNF in the control of energy homeostasis has been accumulated from genetic and pharmacological studies during the last decade or so. The Val66Met polymorphism in the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The mechanisms of eNOS-uncoupling seem multiple and complex. Recent research provides emerging evidence supporting an essential role of increased activity of arginases including arginase-I and arginase-II in causing eNOS-uncoupling, which results in vascular oxidative stress and inflammatory responses, and ultimately leading to vascular diseases. This review article will summarize the most recent findings on the functional roles of arginases in vascular diseases and/or dysfunctions and the underlying mechanisms in relation to oxidative stress and inflammations. Moreover, regulatory mechanisms of arginases in the vasculature are reviewed and the future perspectives of targeting arginases as therapeutic options in vascular diseases are discussed.Oxidative stress and inflammation in the vascular wall are essential mechanisms of atherosclerosis and vascular dysfunctions associated with risk factors such as metabolic diseases, aging, hypertension, etc. Evidence has been provided that activation of the vascular endothelial cells in the presence of the risk factors promotes oxidative stress and vascular inflammatory responses, leading to acceleration of atherosclerotic vascular disease. Increasing number of studies from recent years demonstrates that uncoupling of endothelial nitric oxide synthase (eNOS), whereby the enzyme eNOS produces detrimental amount of superoxide anion  Atherosclerotic cardiovascular disease and vascular complications associated with risk factors such as diabetes mellitus, hypercholesterolemia, hypertension, aging, etc., remain the most important challenge for our society  and nitric oxide (NO\u22c5) are important signaling molecules involved in the regulation of vascular functions, including vascular relaxations, inflammatory responses, and cell proliferation . 2O2 which is either detoxified to H2O by peroxiredoxins, glutathione peroxidases, and catalase or metabolized to the powerful oxidant molecules such as hydroxyl radical (OH\u22c5), peroxynitrite , flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and tetrahydrobiopterin (BH4). Electrons from NADPH are transferred in trans from the carboxyl terminal reductase domain of one eNOS monomer, via the flavins FAD and FMN, to the heme in the amino-terminal oxygenase domain of the other monomer, where BH4, oxygen, and l-arginine are bound  that competes with l-arginine for eNOS binding  and arginase-II (Arg-II), which is encoded by two separate genes. The human Arg-I gene which maps to chromosome 6q23, encodes a 322 amino acid protein  as well as intracellular l-arginine concentration (0.05\u20130.2\u2009mmol/L) far exceed the Km of eNOS (2\u201320\u2009\u03bcmol/L)  even in the presence of high extracellular concentration of l-arginine (0.4\u2009mmol/L)  does not have any benefits on vascular stiffness and left ventricular ejection fraction, but increases mortality .The underlying mechanisms of the detrimental effects of chronic \u22c5 production is well documented  and peroxynitrite increase Arg-I gene expression in porcine coronary arterioles  is also implicated in regulation of arginase expression and activity in endothelial cells. p38MAPK is a member of the superfamily of MAPKs which serves as cellular a stress sensor for a variety of cellular stresses including hyperglycemia, oxidative stress, and inflammatory cytokines  and Arg-II in endothelial cells (Yepuri et al., /\u2212\u2212 background show accelerated atherosclerosis (Vaisman et al., Arginase-II as therapeutic target in cardiovascular diseases has shown promising beneficial effects in genetic modified mouse models. Systemic deficiency of Arg-II reduces systemic and vascular inflammations in mice fed high cholesterol diet and high fat diet, and improves endothelial function in aging, reduces atherosclerosis, and improves insulin sensitivity and glucose homeostasis (Ming et al., It is however, interesting to notice that pharmacological agents that target arginase indirectly through blockade of signaling transduction pathways that regulate arginase gene expression or activity show beneficial effect on vascular functions. Early studies demonstrate that statins which inhibit arginase activity through inhibition of the small G protein or GTPase RhoA improves endothelial function (Ming et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To compare the efficacy of fine-needle non-aspiration cytology (FNNAC) with that of fine-needle aspiration cytology (FNAC) of thyroid lesions.FNAC and FNNAC techniques were studied in 50 cases of thyroid lesions. All the needle-sampling procedures were done by a single operator. The samples were assessed cytologically and evaluated using five parameters, that is, background blood or clot, amount of cellular material, degree of cellular degeneration, and degree of cellular trauma and retention of appropriate architecture.Wilcoxon signed rank test was performed using SPSS14 software. Differences between all the individual parameters as observed in FNAC and FNNAC smears were insignificant.After evaluation of FNAC and FNNAC on the basis of these scores, greater numbers of diagnostically superior samples were obtained by FNNAC; however, by FNAC more number of diagnostically adequate smears were observed. The numbers of unsuitable smears were also more by FNNAC technique. In vascular organs, an alternative method of fine-needle non-aspiration cytology (FNNAC) also known as cytopuncture was developed in France in 1982 by Brifford et al.[The study population comprised all patients who presented with thyroid swellings at the Department of Pathology (cytology section) from May 2005 to April 2007. After a thorough clinical examination, all the patients were subjected to both FNAC and FNNAC. A total of 50 cases of thyroid lesions were included in this study. The procedure was explained to the patient and verbal consent was obtained prior to performing the procedure. The patients were subjected to FNAC and FNNAC using 23-gauge needles and 10-cc plastic syringes. All the procedures were performed by a single operator. FNAC or FNNAC sampling was carried out randomly with lesions, irrespective of consistency and size of lesions. Every slide was assessed without the prior knowledge of techniques utilized. The study was thus single blind and also prevented the observer bias. The smears were scored according to criteria using a predetermined scoring developed by Mair et al..A cumulative score between 0 and 10 points was obtained for each specimen which was then categorized into one of the following three categories:Category 1\u2014(Score 0\u20132) Unsuitable for diagnosis.Category 2\u2014(Score 3\u20136) Adequate for cytological diagnosis.Category 3\u2014(Score 7\u201310) Diagnosis superior.P=0.05.The difference in the score for the individual parameter was assessed by Wilcoxon signed rank test using SPSS14 software. All the results were analyzed considering the statistical significance at a level of The non-aspiration technique yielded less diagnostically adequate but more diagnostically superior smears when compared with aspiration technique. A total of 19 cases were unsuitable for cytodiagnosis by non-aspiration as compared with 17 cases by aspiration technique .P value obtained by Wilcoxon signed rank test was not statistically significant in favour of non-aspiration sampling for any parameter. However, the average scores for each parameter favoured non-aspiration sampling than aspiration sampling [sampling .Non-aspiration sampling displayed more cellular material, less cellular trauma and degenerative changes, better retention of architecture and less likelihood of obscuring by blood. The average score per case was 6.04 by non-aspiration technique and was 5.90 by aspiration technique. FNAC, since its inception in 1847, has passed through two phases of initial scepticism and interim enthusiasm and has successfully reached the final stage of acceptance as identified by Orell in his aThe important advantage of FNNAC sampling is easy operation and absolute control over operating hand, especially for neck, breast, cutaneous or subcutaneous tissue. The FNNAet al.,[et al.[et al,[et al.[Results when compared for background blood contamination supported the non-aspiration technique Figures  and 2 buet al., the amouet al., and 4, b.,[et al. observed.,[et al. was greal.[et al, but the l.[et al, and 4 sil,[et al. but the l,[et al. and 4 wiet al.[For the five parameters studied objectively, there was no statistically significant difference observed between the two techniques, and a similar result has been found by Haddadi-Nezhad et al. Whereas et al.11et al.[et al.[In the present study, more diagnostically superior and less diagnostically adequate samples were obtained more by non-aspiration technique in comparison to aspiration technique. It was observed that the percentage of inadequate sampling was more with non-aspiration (38%) than with aspiration 34%) technique in contrast to the observations of Santos and Leiman[% techniqet al. With thel.[et al.Both the techniques have their own merits and demerits and neither is superior to the other. By combining both the techniques, better diagnostic accuracy can be achieved. However, FNNAC technique is easier to perform with better patient compliance."}
+{"text": "Dear Editor in Chief,With a great interest, we read a recently published paper in Frontier in Endocrinology journal by Vuolo et al., entitled \u201cVitamin D and Cancer\u201d  by b-galactosidase and sialidase of B and T cells, respectively, which can activate macrophage to phagocyte the neoplastic cells. Group-specific component protein (Gc) as DBP preserve vitamin D in body fluids and put it available for tissues. But an enzyme  produced by neoplastic cells deactivate and denaturize this factor and provide neoplastic cells to spread (Yamamoto and Naraparaju,"}
+{"text": "Arabidopsis and maize have identified a number of genes that are required for epidermal cell differentiation. However, the mechanism that specifies shoot epidermal cell fate during plant organogenesis remains largely unknown. Particularly, little is known regarding positional information that should restrict epidermal cell fate to the outermost cell layer of the developing organs. Recent studies suggested that certain members of the HD-ZIP class IV homeobox genes are possible master regulators of shoot epidermal cell fate. Here, we summarize the roles of the regulatory genes that are involved in epidermal cell fate specification and discuss the possible mechanisms that limit the expression and/or activity of the master transcriptional regulators to the outermost cell layer in plant shoots.Land plants have evolved a single layer of epidermal cells, which are characterized by mostly anticlinal cell division patterns, formation of a waterproof coat called cuticle, and unique cell types such as stomatal guard cells and trichomes. The shoot epidermis plays important roles not only to protect plants from dehydration and pathogens but also to ensure their proper organogenesis and growth control. Extensive molecular genetic studies in  The shoot epidermis is a single layer of surface cells that are morphologically characterized by anticlinal cell division patterns. The outer surface of the shoot epidermis is covered with a hydrophobic structure called a cuticle, which prevents water loss, pathogen attacks, and post-genital fusion of organs  was identified as an epidermis-specific homeobox gene that belongs to the HD-ZIP class IV family  after the embryos have undergone tangential cell divisions to generate outer protodermal cells and inner cells  caused severe phenotypes associated with defects in epidermal cell specification , a rice HD-ZIP class IV gene, was induced on the cut surface during callus regeneration  mutant, which develops multilayered epidermis by amplification of differentiated epidermal cells, expression of an HD-ZIP class IV gene was detected only in the outermost epidermal layer , which serve as precursor of cuticular wax  and zhoupi (zou) mutants are defective in cuticle formation in organs generated during embryogenesis . Plant embryos may require ALE1 and GSO1/GSO2-mediated signaling for efficient deposition of cuticle on the surface of the protodermal cells that develop in close physical contact with surrounding endosperm cells.crinkly4 (cr4) is a maize mutant with defects in the development of leaf epidermis and aleurone layer ] cause phenotypes defective in epidermal cell differentiation, lateral root initiation, and root initial cell maintenance  and TOADSTOOL2 (TOAD2) are leucine-rich repeat receptor-like kinases redundantly required for epidermal cell differentiation in the embryo  in the surface cells  is a calpain like cysteine protease that is conserved among land plants (Lid et al., DEK1 mRNA is expressed ubiquitously, suggesting that its activity is regulated post-translationally (Wang et al., Arabidopsis was not sufficient to upregulate the expression of ATML1 (Johnson et al., DEK1 activity affected cell division and growth also in internal tissues, suggesting that the action of DEK1 is not epidermis-specific (Johnson et al., dek1 may cause discontinuity and abortion of the epidermis (Johnson et al., Localization of some HD-ZIP class IV transcription factors was not limited to nuclei of heterologous cells (Zhang et al., in planta and it is possible that dimerization with other HD-ZIP class IV proteins changes the activity of ATML1 in a cell-type dependent manner, although ectopic expression of ATML1 alone was sufficient to induce epidermal cell fate in inner tissues (Takada et al., ATML1 was shown to heterodimerize with PDF2 atml1;pdf2 and DEK1 knockdown lines showed ectopic differentiation of mesophyll cells on the surfaces of leaves and cotyledons, respectively, (Abe et al., rpk1;toad2 embryos exhibited ectopic subepidermal marker expression in the outermost cell layer (Nodine et al., ATML1 decreased differentiation of green mesophyll cells in leaves (Takada et al., cr4 and dek1, which are defective in \u201csurface\u201d aleurone layer differentiation in the maize endosperm, cause ectopic differentiation of \u201cinner\u201d starchy endosperm cells on the surface of the endosperm (Becraft et al., Several lines of evidence show that acquisition of epidermal cell fate is associated with a loss of mesophyll or internal cell fate. First, epidermis-deficient Mesophyll cells possibly represent a primitive state of leaf cells, considering that ancestral aquatic algae are composed mainly of mesophyll-like cells. Land plants may have repressed mesophyll cell differentiation to evolve an epidermis on the surface. Evolutionary studies, including comparative genomics, may be useful for identifying molecular components that promote epidermal cell formation (Zalewski et al., Despite the extensive molecular genetic studies in model plants, positional signals that specify shoot epidermal cell fate remain unknown Figure . Most ofThe cuticle-bearing outermost cells should have distinct mechanical properties compared with inner cells. Moreover, cells located at the surface are unique, in that they are in constant contact with the environment. These unique properties could influence the differentiation of epidermal cells. Attempts to directly isolate epidermis-promoting biomolecules and to identify physical/environmental constraints influencing epidermal cell fate may shed new light on the issue.Shinobu Takada wrote the main manuscript text and Hiroyuki Iida prepared Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries Miller, , traumat It is estimated that as many as 300,000 U.S. troops in Iraq and Afghanistan have suffered head injuries Miller, . In the Largely due to population-wide increases in life-span, AD is rapidly becoming the public health crisis of our time. There are currently over three million Americans afflicted with the disease, a figure that is projected to increase to nearly nine million Americans and over 100 million world-wide by 2050  peptides], neurofibrillary tangles (NFTs), and widespread loss of cortical neurons Selkoe, . AlthougThe term \u201cTBI\u201d encompasses a wide variety of traumas. In fact, any form of brain injury is broadly classified as a TBI. Nevertheless, brain traumas can grossly be divided into two categories: (1) closed head injuries (where a rapid deceleration or blow to the head causes brain damage) or (2) penetrating head injuries (caused by a foreign object piercing the skull). Closed head injuries can come in the form of skull fractures, brain contusions caused by brain-skull impact, hematomas, and diffuse axonal injuries brought on by shearing forces. Notably, closed head injuries associated with concussions from contact sports and shockwave blasts from improvised explosive devices have garnered much recent attention. TBIs may range from mild to severe, with about 75% of injuries coming in the form of concussions or other mild TBIs  has been demonstrated in the acute response to brain injury (Roberts et al., A very recent study examined survivors of a single TBI 1\u201347 years after the trauma, and reported that NFTs and A\u03b2 pathology were present in approximately one-third of these patients. Such findings demonstrate the long-term consequences of a single TBI event (Johnson et al., As mentioned above, TBI is a strong epigenetic risk factor for development of AD later in life. Strikingly, several defining AD pathological hallmarks have been observed following TBI in patient brains and in numerous TBI animal models. In addition to neuronal and synaptic loss (Kotapka et al., A\u03b2 deposits and widespread axonal A\u03b2 accumulation have been found in patients' brains shortly after TBI (Roberts et al., de novo following brain trauma (Cribbs et al., In an attempt to clarify mechanisms of plaque appearance after brain trauma, several non-transgenic rodent and rabbit models have been utilized. While these animal models have proved useful to characterize axonal A\u03b2 accumulation after TBI, wild-type rodents and rabbits did not manifest cerebral \u03b2-amyloid plaques. This is likely owed to the fact that these TBI animal models have relatively low abundance of brain endogenous A\u03b2 species that do not reach a critical threshold for aggregation (Lewen et al., An important related concept is the idea of A\u03b2 pathology \u201cspreading.\u201d Interestingly, studies from Mathias J\u00fccker's laboratory and others have shown that intracerebral infusion of brain extracts containing aggregated A\u03b2 can initiate A\u03b2 deposition in brains of APP transgenic mice (Kane et al., TBI has also been shown to induce tauopathy. In that regard, it is important to note that a similar process has been described for spreading of NFTs by axonal transport after injection of abnormally folded tau filaments into a mouse model of cerebral amyloidosis (Clavaguera et al., In patients' brains as well as in experimental animal models, TBI has been associated with microglial activation (Carbonell and Grady, Depending on their activation state, microglia can be deleterious or beneficial in the context of cerebral amyloid deposition (Town et al., The development of clinically-relevant animal models is critically important to enable future study at the intersection of TBI and AD research. Animal models of AD fail to exhibit some of the key pathological earmarks of the human syndrome, even after significant brain injury (Uryu et al., By contrast, we have recently published a novel rat transgenic model of AD, line TgF344-AD. This transgenic line expresses mutant human APP and presenilin-1, which are each independent genetic causes of early-onset familial AD. Notably, this rat displays the full spectrum of human AD hallmarks, including cerebral amyloidosis, tauopathy, gliosis, and most importantly, large-scale apoptotic loss of neurons in cortical and hippocampal regions. Moreover, these animals display significant age-dependent cognitive disturbance (Cohen et al., The correlation between brain injury and neurodegenerative disease is now well-established (Szczygielski et al., These mechanistic investigations and the development of pre-clinical therapeutics will rely critically on a clearer understanding of both human pathologies. A key limiting factor is the large gap in our knowledge of the link between post-mortem observations in humans after TBI with animal model systems. Part of the uncertainty can be attributed to limitations inherent to experimental models of TBI. Therefore, it is expected that more precise modeling of pathological hallmarks in animal models will allow us to fill the knowledge gap. Specifically, it will be critical to develop models that accurately mimic the forces impacting the human brain under a variety of circumstances (Morales et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Computed tomography revealed a marked decrease in the size of the metastases following three therapeutic courses, and no lung metastases or new lesions were detected following nine therapeutic courses. The response was declared clinically complete. The patient refused additional treatment following nine therapeutic courses, and there was no recurrence 36 months after the final course of therapy. This case demonstrates the efficacy of IRIS plus bevacizumab as a first-line combination therapy against lung metastases of rectal cancer.This report presents the case of a 72-year-old male who had undergone abdominoperineal resection following a diagnosis of lower rectal cancer with multiple lung metastases. Pathologically, the resected specimen exhibited advanced rectal cancer with regional lymphoid metastases and was classified as stage IV disease. S-1 and irinotecan (IRIS) plus bevacizumab combination therapy was used to treat the lung metastases following the surgery. S-1 (100 mg/body) was administered orally on days 1\u201314 of a 28-day cycle, and irinotecan (125 mg/m As a result of marked improvement in systemic chemotherapy against unresectable and/or recurrent colorectal cancer, the median survival time of patients with metastatic colorectal cancer has improved to >20 months with administration of fluorouracil (5-FU), irinotecan and oxaliplatin . Accordi2) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion on days one and 15. Following three courses of therapy, the metastatic right lung tumor decreased in size to ~10 mm in diameter, and the left lung tumor had decreased in size to ~3 mm in diameter  with a diagnosis of rectal cancer. Patient medical history was otherwise unremarkable. On physical examination, all findings were unremarkable with the exception of slight pallor in the palpebral conjunctiva. Hematological investigations revealed anemia . Other laboratory tests and serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were all within normal limits. Colonoscopy revealed the entire circumference of an elevated tumor with central depression and erosion at the lower rectum. A biopsy specimen from the tumor was indicative of a moderately differentiated adenocarcinoma. Abdominal computed tomography (CT) revealed thickening of the rectal wall with regional lymph node swelling but no liver metastasis. Chest CT revealed two metastatic lung tumors measuring 25 mm (in the middle lobe of the right lung) and 10 mm in diameter (in the lower lobe of the left lung) . A diagndiameter . Followidiameter . Followidiameter . The reset al (et al (et al (Multidisciplinary therapies, including systemic chemotherapy against unresectable and/or recurrent colorectal cancer, have improved, and FOLFOX, CapeOX and FOLFIRI combination chemotherapies plus bevacizumab or anti-EGFR monoclonal antibody can improve the survival times of patients. In the present case, the patient received IRIS plus bevacizumab combination therapy against lung metastases of rectal cancer. Regarding IRIS chemotherapy, Muro et al  reportedl (et al  and Tourl (et al  identifil (et al , IRIS iset al (et al (et al (The effectiveness of IRIS plus bevacizumab combination therapy as a first-line therapy for metastatic colorectal cancer has been reported. In a phase II study, Komatsu et al  reportedl (et al  reportedl (et al  reportedTreatment of lung metastases from colorectal cancer is a debated issue. The overall survival of patients with completely resectable lung metastases is better than that of patients with unresectable lung metastases \u201317. The In conclusion, IRIS plus bevacizumab combination therapy is well tolerated and efficacious as first-line chemotherapy for metastatic colorectal cancer. As a CV port is not required and patients can be released from the infusion pump while at home, IRIS plus bevacizumab combination therapy could contribute to improved quality of life in patients with metastatic colorectal cancer."}
+{"text": "Normal aging is generally characterized by a slow decline of cognitive abilities albeit with marked individual differences. Several animal models have been studied to explore the molecular and cellular mechanisms underlying this phenomenon. The excitatory neurotransmitter glutamate and its receptors have been closely linked to spatial learning and hippocampus-dependent memory processes. For decades, ionotropic glutamate receptors have been known to play a critical role in synaptic plasticity, a form of adaptation regulating memory formation. Over the past 10\u2009years, several groups have shown the importance of group 1 metabotropic glutamate receptor (mGluR) in successful cognitive aging. These G-protein-coupled receptors are enriched in the hippocampal formation and interact physically with other proteins in the membrane including glutamate ionotropic receptors. Synaptic plasticity is crucial to maintain cognitive abilities and long-term depression (LTD) induced by group 1 mGluR activation, which has been linked to memory in the aging brain. The translation and synthesis of proteins by mGluR-LTD modulate ionotropic receptor trafficking and expression of immediate early genes related to cognition. Fragile X syndrome, a genetic form of autism characterized by memory deficits, has been associated to mGluR receptor malfunction and aberrant activation of its downstream signaling pathways. Dysfunction of mGluR could also be involved in neurodegenerative disorders like Alzheimer\u2019s disease (AD). Indeed, beta-amyloid, the main component of insoluble senile plaques and one of the hallmarks of AD, occludes mGluR-dependent LTD leading to diminished functional synapses. This review highlights recent findings regarding mGluR signaling, related synaptic plasticity, and their potential involvement in normal aging and neurological disorders. Over the next decades, a majority of developing countries will face one of the biggest challenges in history: accelerated aging of its populations. In human, aging is characterized by physical, psychological, and social changes. Interestingly, major individual differences are known to exist and low probability of disease and disability, high cognitive and physical capacity, and active engagement in life in general are associated to successful aging. Several animal models have been developed to investigate the processes behind this phenomenon  test was introduced in 1984, to study hippocampus-dependent memory in rats Morris, . CognitiEarly on, alterations in cholinergic neuronal activity were linked to memory impairments in the Long-Evans rat model  receptor subtypes , another form of synaptic plasticity has been closely related to memory formation -terminal domain of group 1 mGluR  isoform  and Alzheimer\u2019s disease (AD). Results published on animal models of those diseases and clinical trials conducted with patients will thus help to understand the processes involved in the aging of the brain.FMR1 gene transcription which encodes the Fragile X mental retardation protein (FMRP; Pieretti et al., FMR1 KO mice and FXS patients could dysregulate synaptic plasticity and lead to memory deficits (Luscher and Huber, Group 1 mGluRs have been implicated in the development of the FXS (Dolen et al., FMR1 KO mice, the lack of this protein synthesis suppressor may unbalance cellular mechanisms and exaggerate mGluR-dependent signaling (Dolen and Bear, FMR1 KO mice brain, mGluR5 is associated more with Homer 1a stimulating agonist-independent signaling pathways than long Homer isoforms (Ronesi et al., FMR1 KO mice, mGluR-LTD formation does not require the acute stimulation of protein synthesis which is probably related to the constitutive overexpression of proteins implicated in LTD formation and maintenance to compensate for the lack of FMR1 (Hou et al., FMR1 KO mice, LTP priming is reduced by mGluR decoupling from protein synthesis (Auerbach and Bear, The stimulation of group 1 mGluR with the specific agonist DHPG normally induces FMR protein translation in dendrites (Weiler et al., Drosophila fly model (McBride et al., in vivo treatment with group 2 mGluR antagonists in these mice (Choi et al., FMR1 KO mice by reducing mGluR-LTD with a 50% reduction in mGluR5 expression (Dolen et al., The first demonstration of mGluR modulation rescuing phenotypes in FXS animal models was attained by pharmacologically rescuing social interaction and memory impairments in the FMR1 KO mice brain (D\u2019Agata et al., Drosophila FMRP gene and presenilin, a protein mutated in the familial form of AD (McBride et al., 2+ from intracellular stores, it can also facilitate the hyperphosphorylation of tau by up-regulating protein kinase activities (Tsai et al., 2+ signaling, synaptotoxicity, and eventually synapse deterioration (Renner et al., A possible link between FXS and AD has been proposed since FMR protein binds to the amyloid precursor protein (APP; Sokol et al., After several decades of intense studies on processes involving ionotropic glutamate receptors in the aging brain, their metabotropic counterparts, and particularly post-synaptic group 1 mGluRs are becoming key targets to unravel synaptic plasticity processes underlying learning and memory. mGlu receptors, Homer proteins, and downstream signaling pathways likely all play critical roles in the maintenance of high cognitive abilities in old age. Further studies are thus highly warranted especially considering their apparent role in FXS and possibly AD.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Athenian statesman and poet Solon (638\u2013558 BC) believed that \u201cno man can be happy,\u201d being \u201cwretched all those who contemplate the sun.\u201d One century later, the lyric poet Pindar (c. 522\u2013443 BC) wrote that there has never been a man \u201cdevoid of trouble\u201d on earth, and there will never be one. In a recent Frontiers article, inspired by up-to date neuroscience evidence on the perception of pain, Lelard and colleagues investigated the interrelations between behavior and emotion in painful situations (Lelard et al., Unfortunately, we all know the unpleasant sensory and emotional experience of pain. What we can now explore scientifically in regards to pain has been complexly expressed through language and philosophy. The ancient Greeks used the word To determine how imagining oneself in painful situations might influence muscular and physiological responses, posturographic and physiological data were collected from participants viewing pictures of both painful and non-painful situations, while instructed to imagine themselves experiencing each situation. A displacement of center-of-pressure measure collected from a posturographic platform indicated that movement in the anteroposterior direction was shorter when subjects were presented with painful images. Responses of the tibialis anterior and soleus muscles, which have been associated with freezing responses in previous reports (Carpenter et al., Previous investigations have differentiated the \u201crepresentational characters\u201d that emerge while imagining a situation from the \u201cinstinctual characters\u201d that arise in more automatic bodily responses, and have suggested that these may emerge from cortical vs. subcortical activity, respectively (Giummarra et al., The article by Lelard and colleagues suggests that emotional content is capable of changing muscular responses in specific configurations with ecological significance (Lelard et al., Additional questions may inform future research. For example, in what situations might emotionally-laden stimuli evoke responses different from those observed in this study\u2014a muscular response indicative of fleeing rather than freezing? Would active suppression of empathy or perspective-taking for painful stimuli alter muscular responses? In addition, would suppression effectiveness differ for tasks with more visceral-response vs. representational-response evoking images? Possible experimental avenues for theoretical exploration that might support the implications of this study may exist in research examining individuals with unusual perspective-taking in healthy and pathological conditions\u2014i.e., those with mirror-touch synesthesia (Banissy and Ward,"}
+{"text": "They have important microbicidal activities, however in inflammatory conditions they may secondarily attack surrounding tissues. Overproduction of reactive oxygen species, prolonged or excessive liberation of MPO and other effective yet also toxic substances from neutrophils may participate in disturbed apoptosis, intensify the inflammatory processes and result in serious human diseases. The inhibitory effect of quercetin on PMA stimulated SO generation in isolated human neutrophils was found to be dose-dependent, without affecting the activity of intact isolated neutrophils. At comparable conditions, quercetin was more potent in inhibiting MPO release than SO generation. Our results indicate that quercetin could support resolution of inflammation through decreased activity of neutrophils,  The concentration of 10 \u00b5mol/l significantly inhibited only MPO release by 36%. Our results are in agreement with findings of Nosal et al.,  and Pere (et al.  where quet al., et al., et al., 2+-ATPase (Horakova, et al., et al.,Quercetin is believed to protect human organism against several degenerative diseases (Hollman & Katan, Our study provided evidence supporting the potential beneficial effect of quercetin in diminishing tissue damage at the site of inflammation by inhibiting MPO release and by decreasing the generation of superoxide and the subsequently derived ROS."}
+{"text": "The phenotype of DBA/2-mdx mice also seems to depend on the function of satellite cells. In this review, we summarize the methodology of direct isolation, characterization, and molecular regulation of satellite cells based on our results. The relationship between the regenerative capacity of satellite cells and progression of muscular disorders is also summarized. In the last part, we discuss application of the accumulating scientific information on satellite cells to treatment of patients with muscular disorders.Skeletal muscle has great regenerative capacity which is dependent on muscle stem cells, also known as satellite cells. A loss of satellite cells and/or their function impairs skeletal muscle regeneration and leads to a loss of skeletal muscle power; therefore, the molecular mechanisms for maintaining satellite cells in a quiescent and undifferentiated state are of great interest in skeletal muscle biology. Many studies have demonstrated proteins expressed by satellite cells, including Pax7, M-cadherin, Cxcr4, syndecan3/4, and c-met. To further characterize satellite cells, we established a method to directly isolate satellite cells using a monoclonal antibody, SM/C-2.6. Using SM/C-2.6 and microarrays, we measured the genes expressed in quiescent satellite cells and demonstrated that Hesr3 may complement Hesr1 in generating quiescent satellite cells. Although Hesr1- or Hesr3-single knockout mice show a normal skeletal muscle phenotype, including satellite cells, Hesr1/Hesr3-double knockout mice show a gradual decrease in the number of satellite cells and increase in regenerative defects dependent on satellite cell numbers. We also observed that a mouse's genetic background affects the regenerative capacity of its skeletal muscle and have established a line of DBA/2-background  One of the best-known examples of regeneration is the ability of newts to regenerate limbs and tails. This process was believed to utilize specialized multipotent cells that have the potential to produce all types of cells. The existence of this type of multipotent stem cells seemed to be the reason newts, but not humans, can regenerate limbs. However, a recent study of the axotl has suggested a different model  cells, and muscle-resident interstitial cells, that seemed to function as stem cells for muscle regeneration integrin \u03b21(+)Cxcr4(+)CD34(+)CD45(\u2212)Sca-1(\u2212)Mac-1(\u2212) fraction contained only myogenic cells  constitute a subgroup of the transforming growth factor (TGF)-\u03b2 superfamily, and are known as myogenic differentiation regulators. Gamell et al. reported that Bmp2 induces phosphorylation of Akt and migration of C2C12  were upregulated (>5-fold) in the activated state in our microarray results. The most highly upregulated gene (334-fold) was As mentioned above, satellite cells occupy a unique location and do not express the myogenic determination gene MyoD. Therefore, we hypothesized that the genes responsible for maintaining satellite cells are specifically expressed in quiescent satellite cells in skeletal muscle. To isolate such genes, we also prepared non-myogenic cells from skeletal muscle for comparison with quiescent and activated satellite cells, and 63 genes were finally identified as \u201cquiescence genes,\u201d which are highly expressed in quiescent satellite cells but not in cultured myoblasts and non-myogenic cells in skeletal muscle , but these genes are also expressed in non-myogenic cells in skeletal muscle. Another discrepancy is the expression of Notch-related genes in quiescent satellite cells. We identified Notch signaling-related genes (Notch3 and HeyL/Hesr3) as the most highly expressed genes in quiescent satellite cells, although Pallafacchina's results did not show the importance of Notch signaling in quiescent satellite cells. However, recent studies have clearly demonstrated the essential roles of Notch signaling for maintaining quiescent satellite cells in vivo as well as developmental stages (see below). On the other hand, quiescent satellite cells share common features in our and Pallafacchina's results, for example, some cell adhesion molecules and transcriptional factors. Although our reports had not mentioned it, Pallafacchina et al. intriguingly found up-regulation of anti-oxidative genes in quiescent satellite cells. In fact, our original data also included ant-oxidative genes in quiescent-stage specific manner. These results imply the importance of oxidative stress in quiescent satellite cells. Farina et al. analyzed gene expressions of quiescent satellite cells, activated satellite cells , and proliferating myoblasts   and Hesr  are known as primary targets of Notch signaling , which leads to a decrease in BrdU uptake  leads to the generation of mononuclear cells that proliferate  is a well-known inherited muscular disorder, and the causative gene, mdx mouse (the correct nomenclature is C57BL/10-DMDmdx) is the most widely used model animal of DMD  show similar phenotypes to humans; loss of muscle weight, increased fibrosis, accumulation of adipocytes, and decreased muscle force  and demonstrated that mdx/mTR mice exhibit severe muscular dystrophy and a decrease in the loss of satellite cell proliferation  . Recently, Cappellari et al. reported that Dll4 and PDGF\u03b2 signals convert myogenic cells to pericyte-like cells without erasing their myogenic memory (Cappellari et al., Satellite cells undoubtedly have the best potential to produce new myofibers in vitro reduces their regenerative activity, as described above (Montarras et al., in vitro (Gilbert et al., in vivo regenerative potential (Parker et al., Another problem is the difficulty of obtaining large numbers of satellite cells from a donor. In addition, expansion of satellite cells Another source of cells for therapy for muscle disorders is iPS cell-derived myogenic cells (Mizuno et al., mdx phenotype (Le Grand et al., The physiological self-renewal mechanism of satellite cells during regeneration must also be revealed. Some evidences have indicated an asymmetrical model of self-renewal of satellite cells (Conboy and Rando, In addition, another mechanism must be understood for the successful cell transplantation for muscle disorders. To date, we have not paid attention to the fusion process between transplanted cells and myofibers. When donor cells are transplanted, they have to cross the basal lamina and fuse with myofibers. Horsley et al. indicated the myotube-myoblast fusion process requires IL4/IL-4R signaling mediated by NFATc2 (Horsley et al., For 10 years, the isolation, characterization, and molecular regulation of satellite cells have been studied, and accumulating evidence is starting to reveal the molecular mechanisms for maintaining the satellite cell pool. In addition, recent studies are beginning to identify the roles of satellite cells in several different disorders. For instance, McCarthy et al. indicated that acute hypertrophy is not dependent on satellite cells (McCarthy et al., The generation of iPS cells has assisted the cell therapy approach to many disorders including muscular dystrophy (Takahashi and Yamanaka, Skeletal muscle is indispensable for motility. In addition, skeletal muscle has the potential to control other tissues. For instance, Bostrom et al. showed that a skeletal muscle-derived cytokine, irisin, converts white fat cells to brown fat-like cells (Bostrom et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A decline in skeletal muscle mass and function with aging is well recognized, but remains poorly characterized at the molecular level. Here, we report for the first time a genome-wide study of DNA methylation dynamics in skeletal muscle of healthy male individuals during normal human aging. We predominantly observed hypermethylation throughout the genome within the aged group as compared to the young subjects. Differentially methylated CpG (dmCpG) nucleotides tend to arise intragenically and are underrepresented in promoters and are overrepresented in the middle and 3\u2032 end of genes. The intragenic methylation changes are overrepresented in genes that guide the formation of the junction of the motor neuron and myofibers. We report a low level of correlation of gene expression from previous studies of aged muscle with our current analysis of DNA methylation status. For those genes that had both changes in methylation and gene expression with age, we observed a reverse correlation, with the exception of intragenic hypermethylated genes that were correlated with an increased gene expression. We suggest that a minimal number of dmCpG sites or select sites are required to be altered in order to correlate with gene expression changes. Finally, we identified 500 dmCpG sites that perform well in discriminating young from old samples. Our findings highlight epigenetic links between aging postmitotic skeletal muscle and DNA methylation. We found an overall global trend of genomic hypermethylation in human skeletal muscle between the young and old groups Fig. . In ordeet al., et al., et al., CpG islands (CGI) are present in 60% of gene promoters in the 450 K chip, and methylation deregulation in CGI overlapping the promoter has often been linked with cancer  negatively correlates with the corresponding promoter methylation level  was the transcription factor CTCF . This suggests that the dmCpG sites we identified within the aged group are relevant to muscle tissue. There were 54 enriched terms with a P < 0.01 (Table P = 2.05E-07) and axon guidance (P = 2.11E-07), which may be related to muscle innervation and aging. A decline of function in the neuromuscular junction has long been thought to contribute to the decline of muscle mass with age , cytoskeleton (P = 0.0003), and cytoskeleton organization (P = 0.001) are all linked to cytoskeleton function, and the latter plays an important role in proper muscle contractile function , homophilic cell adhesion (P = 8.43E-08), and cell adhesion (P = 1.70E-05), with cell adhesion being associated with fiber degeneration  (Table P = 6.16E-10) with 50 of 216 pathway members (23.1%) differentially methylated in at least one intragenic site .A recent report utilized genes identified as having dmCpGs with age to examine stem cell differentiation pathways  occurs with aging and is a major contributory factor in sarcopenia (Doherty et al., et al., et al., et al., et al., In aging human skeletal muscle, we identified a strong preference for the dmCpG sites to localize within a gene, and in the central and 3\u2032 end regions of genes, but surprisingly no preference for the promoter. Some studies have suggested that intragenic DNA methylation could regulate alternative splicing (Sati et al., A potential issue with the biopsy procedure used in our study is tissue heterogeneity between biopsies, which may impact the resultant molecular signatures. There are other cell types in muscle that might contaminate muscle-specific methylation signatures. Such sample variation may influence the results. However, it was previously demonstrated that there is remarkably little technical variation between discrete biopsies sampled from the right and left leg of the same individual with regard to fiber type differences, gene expression as assessed by microarray, fiber size, or even strength (Tarnopolsky et al., et al., In summary, we describe for the first time a genome-wide DNA methylation survey of a postmitotic tissue between young and old healthy human skeletal muscle. We also determined that there were several hundred robust dmCpGs that discriminated younger males from older males. Ontology analysis of the terms associated with dmCpGs provided several interesting hints of a potential role for epigenetic changes in the neuromuscular junction during aging. Resistance exercise can reverse specific aspects of the gene expression changes in aging to more youthful levels (Melov All methods and experimental procedures are available in online supplement."}
+{"text": "There is not too much success in the antioxidant treatment of heart deceases in humans. However a new approach is now developed that suggests that depending on their structures and concentrations antioxidants can exhibit much more complicated functions in many pathological disorders. It is now well established that physiological free radicals superoxide and nitric oxide together with their derivatives hydrogen peroxide and peroxynitrite  and reactive nitrogen species (RNS)) play a more important role in heart diseases through their signaling functions. Correspondingly this work is dedicated to the consideration of damaging signaling by ROS and RNS in various heart and vascular disorders: heart failure (congestive heart failure or CHF), left ventricular hypertrophy (LVH), coronary heart disease, cardiac arrhythmias, and so forth. It will be demonstrated that ROS overproduction (oxidative stress) is a main origin of the transformation of normal physiological signaling processes into the damaging ones. Furthermore the favorable effects of low/moderate oxidative stress through preconditioning mechanisms in ischemia/reperfusion will be considered. And in the last part we will discuss the possibility of efficient application of antioxidants and enzyme/gene inhibitors for the regulation of damaging ROS signaling in heart disorders. Heart disease (cardiopathy) and cardiovascular diseases are a group of numerous pathological disorders such as heart failure (congestive heart failure or CHF), left ventricular hypertrophy (LVH), coronary heart disease, cardiac arrhythmias, and so forth, in which signaling processes of reactive oxygen and reactive nitrogen species (ROS and RNS) play an important  role. Contemporary studies identified major sources of ROS and RNS productions: NADPH oxidases (Nox), xanthine oxidase, mitochondria, and nitric oxide synthases (NOS). As a rule, heart and cardiovascular diseases are characterized by ROS overproduction whereas the formation of major RNSs nitric oxide  and peroxynitrite (diamagnetic molecule) can decrease or increase depending on the nature of heart injury. Free radicals are usually considered to be the damaging factors in various pathologies, but on the other hand ROS and RNS are important signaling species in many physiological and pathophysiological processes. For example the critical role of these species has been shown in preconditioning and other survival processes (see below). A major aim of this work is to consider the role of ROS and RNS signaling in various heart and cardiovascular diseases.NADPH oxidases generate superoxide by the one-electron reduction of dioxygen:2O2+NADPHphox) was an important factor of the development of Ang II-induced cardiac hypertrophy independently of the change in blood pressure in mice. Similar effect of NADPH oxidase-derived superoxide was demonstrated by Nakagami et al. [Phagocyte NADPH oxidase Nox2 plays important role in heart injury. Bendall et al.  found thi et al.  Li et ali et al.  showed ti et al. . Similari et al.  demonstri et al. . \u03b2) induced NADPH oxidase activation and ROS overproduction that accelerated atherosclerosis, hypertension, and myocardial remodeling in apolipoprotein E-deficient (apoE(\u2212/\u2212) mice. It was found that Rac1 initiated hypertrophic response in the heart dependent on NADPH oxidase-generated ROS . Hingtgephox\u2009\u2009on internal membranes in epithelial cells. It was also found that in contrast to the other NADPH oxidase isoforms Nox4 produced mainly hydrogen peroxide and the very small amounts of superoxide. Cytosolic oxidase proteins or the GTPase Rac are not required for the activity of this enzyme. Serrander et al. [NADPH oxidase Nox4 is a NADPH oxidase isoenzyme which plays an important role in heart and vascular diseases. Martyn et al.  suggester et al.  also fou There is a lot of uncertainty in the studies of Nox4-dependent ROS production. Conclusion that Nox4 produces mainly hydrogen peroxide and not superoxide contradicts a majority of the other experimental data. It is possible that unreliable methods such as nitroblue tetrazolium (NBT) reduction were applied for superoxide detection in the above works \u201316. On t Nox4 is apparently located in different way in cardiac cells comparing to other NADPH oxidases. Thus Kuroda et al.  found th Surprisingly, Zhang et al.  found th Obviously these findings contradict those obtained by Kuroda et al. . In bothZhang et al.  suggestePrincipal reaction catalyzed by xanthine oxidase (XO) is the oxidation of xanthine into uric acid: ablished  and Chamablished  suggesteablished . Althougablished , 27.  However, it is now generally agreed that there is a significant increase in cellular XO level and activity in the cardiovascular system under pathological conditions even though these changes may not be easily detected under physiological conditions. For example Thompson-Gorman and Zweier measured xanthine oxidase-mediated free radical generation in isolated rat heart . They fo Similarly to NADPH oxidases xanthine oxidase stimulated many ROS-dependent heart disorders. Landmesser et al.  showed t\u03b1) and induced the activation of xanthine oxidase and superoxide generation leading to coronary endothelial dysfunction in a murine model. Yamamoto et al. [ Duncan et al.  found tho et al.  showed to et al.  demonstrMitochondria are an essential ROS producer in heart and vascular diseases although its significance as a ROS source comparing to NADPH oxidases and xanthine oxidase remains a subject for discussion. It is now well established that superoxide is generated by mitochondria due to electron leak from the two electron carriers of respiratory chain; these sources of superoxide are Complex I and Complex III . Many au\u03b1-induced mitochondrial superoxide production impaired respiratory complex I activity and led to mitochondrial damage in the left ventricle (LV) in rats. Mitochondrial depolarization and enhanced ROS production mediated by lipoxygenase and arachidonic acid were probably responsible for arrhythmias following ischemia-reperfusion injury [ Redout et al.  have stun injury . Howevern injury  found thNitric oxide synthases (NOS) catalyze conversion of L-arginine to L-citrulline and nitric oxide but under uncoupling conditions these enzymes also produce superoxide:oxidants . Thus Lioxidants  showed toxidants  found th As NOSs are able to produce both RNS and ROS, the effects of these enzymes on cardiovascular system can be very complicated\u2014they can enhance or diminish heart damage. Nitric oxide is the endothelium-derived relaxing factor (EDRF); therefore its function must be mainly favorable at the heart. However, the diffusion-controlled reaction of nitric oxide with superoxide produces the highly reactive peroxynitrite, a really harmful agent. Khadour et al.  have stuRegulation of superoxide/nitric oxide balance is important for the prevention of heart damage. This balance is partly achieved by the interaction of principal enzymatic ROS producers during pathological changes in heart. Thus Saavedra et al.  showed t Saraiva et al.  suggesteA brief episode of myocardial ischemia makes the heart remarkably resistant to a subsequent ischemia, the phenomenon named ischemic preconditioning. It has now been shown that ROS and RNS signaling play an important role in ischemic preconditioning and cardioprotection. For example it was found that 30\u2009min of ischemia triggered by acetylcholine and an opioid receptor in isolated rabbit hearts stimulated preconditioning which included the activation of ROS- and RNS-dependent cascade of the epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3-K), protein kinase B (Akt), nitric oxide synthase (NOS), and ROS-dependent opening of mitochondrial (mito)K(ATP) channels . This ca Kimura et al.  found th It is usually proposed that both K(ATP) channel opening and ischemic preconditioning protect the ischemic heart by acting at K(ATP) channels in the inner mitochondrial membrane. However Brennan et al.  found th Van-Cuong et al.  studied \u03b4, PI3K, and ERK kinases. It is thought that these processes stimulate the inhibition of mitochondrial permeability transition pore formation and trigger the entrance into the preconditioned state. In recent work Vigneron et al. [\u03b2 (GSK-3\u03b2), the opening of mitoK(ATP), and ROS generation activating the target of rapamycin (mTOR) pathway and induced cardioprotection. These findings suggest that cardioprotection involved a prosurvival mTOR pathway. Cohen et al.  have revn et al.  showed t Overproduction of ROS and deregulation of RNS production are important factors of the development of heart and cardiovascular diseases. Mechanisms of ROS and RNS generation by major producers, NADPH oxidases, xanthine oxidase, mitochondria, and nitric oxide synthases in these diseases as well as in preconditioning were discussed above and presented in \u03baB and cardiomyocyte hypertrophy in mice. As it has been already noted, Akt also participates in preconditioning [Among various enzymes, protein kinases B and C and mitogen-activated protein kinases (MAPK) play a very important role in ROS and RNS-dependent enzymatic cascades responsible for heart damage. One of these kinases is the serine/threonine protein kinase B (Akt). It has already been noted that Akt participates in Nox2-initiated Ang II-dependent cardiomyocyte hypertrophy . Recentlitioning , 65. Theitioning  found thitioning  proposed\u03b4, and PKC\u03b5 in heart damaging processes has been also demonstrated [\u03b4 or selective activation of PKC\u03b5 reduced oxidative damage in the heart following myocardial infarction. cGMP-dependent protein kinase (PKG) showed protective activity in the heart [ Participation of protein kinases PKC, PKCnstrated , 71, 87.he heart , 89.Gaitanaki et al. [\u03b2-Estradiol (E2) improved congestive heart failure (CHF) in rats by antioxidative mechanism that involved thioredoxin (Trx) upregulation, the inhibition of Rac1 mediated NADPH oxidase activity, and the apoptosis signal-regulating kinase 1(ASK-1)/JNK/p38-mediated apoptosis. Cai et al. [\u03b1 inhibited endothelium-dependent NO-mediated dilation of coronary arterioles from porcine heart by the ceramide-induced activation of JNK and subsequent production of superoxide by xanthine oxidase. Widder et al.  found thi et al.  showed ti et al.  demonstri et al.  showed ti et al.  studied i et al.  showed tvia a novel zinc-finger protein, MCPIP (MCP-1-induced protein). MCPIP stimulated enzymatic cascade through the activation of MAP kinases JNK and p38. These findings suggested that MCPIP induced ROS/RNS production that stimulated ER stress, autophagy and apoptosis. Hikoso et al. [\u03baB in cardiomyocytes in response to pressure overload. They demonstrated that I\u03baB kinase (IKK)-(NF-\u03baB) signaling cascade was protective in cardiomyocytes due to the attenuation of oxidative stress and JNK activation. Younce and Kolattukudy  studied o et al.  investig\u03b1) is upregulated in a number of cardiomyopathies inducing adverse cardiac remodeling and dilation due to the degradation of the extracellular matrix by matrix metalloproteinases (MMPs). Awad et al. [\u03b1 (rTNF) induced stronger superoxide production and increased expression of several MMPs in mouse neonatal cardiomyocytes comparing to cardiofibroblasts. Phosphatidylinositol 3-kinase (PI3K-\u03b3) mediated TNF-dependent superoxide production and MMP expression. Lu et al. [ It has been shown that tumor necrosis factor  proteins depend on ROS levels and can stimulate or decrease longevity of experimental animals. Klotho gene regulates cell senescence and aging. Mechanisms of ROS regulation in such gene/enzymatic processes were recently discussed [ It is known that several genes  regulate ROS formation in pathological states. Thus it has been shown that the suppression of iscussed .  These genes can also participate in ROS-dependent heart damage. Alcendor et al.  showed t\u03b11-adrenergtic receptor (\u03b11-AR) pathway together with protein kinases PKC\u03b5 and PKC\u03b4 and induced Akt-FOXO3a phosphorylation in rat cardiomyocytes. Sengupta et al. [ Guo et al.  showed ta et al.  showed ta et al. .Heart Diseases and Antioxidants), therefore we need to choose some principal studies. Antioxidants and free radical scavengers can suppress free radical-dependent heart disorders by direct reactions with reactive hydroxyl and peroxy free radicals or through the regulation of ROS signaling in gene- and enzyme-catalytic cascades. We will consider some important examples. For a long time antioxidants were considered important pharmacological agents for the treatment of heart diseases. It is impossible to discuss even a small part of works published on this problem  against ischemia-reperfusion injury in the heart. It has been proposed that Sildenafil, a selective inhibitor of phosphodiesterase type 5 induced powerful protection against myocardial I/R injury through the activation of cGMP-dependent protein kinase G (PKG). Das et al.  suggeste Thus antioxidants of various classes might be considered to be of potential use for the prevention and maybe treatment of heart and cardiovascular diseases.The data discussed in this work show that practically all pathological disorders in heart and cardiovascular system are associated with damaging ROS signaling. These damaging processes can be initiated by ROS overproduced by various sources such as NADPH oxidases, mitochondria, xanthine oxidase, and NO synthases , or norm\u03b1, or monocyte chemotactic protein-1 (MCP-1) are responsible for ROS overproduction. ROS overproduction might be also initiated by cellular disorders for example initiated by hyperthermia  increased the expression of thioredoxin (Trx) and the suppression of NADPH oxidase/ASK-1/c-Jun/p38 cascade causing a decrease in apoptosis and the stimulation of CHF recovery [ On the other hand ROS signaling in enzymatic/gene cascades might also decrease disorders in heart and cardiovascular system. As is seen from farction . 17\u03b2-estrecovery . Decreasrecovery , 78.  It is of interest that the participation of certain genes in signaling pathways frequently led to diminishing heart disorders. As is seen from  As ROS overproduction is one of the most important stimulators of heart disorders, it is logically to suggest that the application of antioxidants should be useful for fighting the heart and cardiovascular diseases. It has been shown above that the effects of antioxidants are very complicated and changed from direct interactions of antioxidants with reactive free radicals to the influence of enzymatic/gene pathways. For example protein kinases and the antioxidant/prooxidant genes can enhance or diminish ROS formation stimulating surviving and death of cardiomyocytes.  Another source of difficulty is dependence of the effects of antioxidants or prooxidants and various ROS inhibitors dependent on the levels of oxidative stress. As it was pointed out, low levels of ROS (low oxidative stress) might have prosurvival effects while high ROS levels (severe oxidative stress) will damage biomolecules. These effects can in turn be complicated by the survival effects of prooxidants-induced preconditioning and the induction of antioxidant enzymes (MnSOD and CuZnSOD).  Therefore a major question is how we might take into account all miscellaneous effects of antioxidants, prooxidants, and gene/enzymatic inhibitors for the selection of the right compounds and methods in the antioxidant (or prooxidant) treatment of heart diseases? Of course there is no simple answer. However, it is probably useful before beginning the treatment of patients to consider possible effects of the selected compound in major ROS and RNS signaling processes."}
+{"text": "Vitamin C and the Common Cold\u201d Linus Pauling included an interesting chapter on \u201chuman biochemical individuality\u201d that defined some important parameters on individual human genotypic versus phenotypic variation, based in part on studies from hemoglobin genetics . If we assume that there are about 26,600 human genes available to be expressed in each cell and that each gene is responsible for at least one inherited trait or genetic function (a number that is probably vastly underestimated), in a global human population exceeding 7 billion it then becomes exceedingly difficult to define \u201chuman genetic normalcy.\u201d These ideas form the basis for the evolving concept of \u201chuman genetic individuality\u201d and our ongoing efforts to better understand the genotypic basis of human phenotypic diversity in both health and disease  and miRNA abundance, speciation and complexity in defined brain anatomical regions from different human samples. These studies have been very valuable since the profiling of mRNA and/or miRNA can provide a powerful \u201csnapshot\u201d into the physiological status of a human cell or tissue in health and disease, and may even be predictive for the prognosis and/or diagnosis for the future outcomes of other AD patients. Steady-state mRNA and miRNA levels from different individuals clearly indicates that the abundance and speciation of these RNAs within clearly defined anatomical regions can significantly differ between samples analyzed, suggesting that genetic variation and extraneous effects, including age, gender, body mass index (BMI), apolipoprotein E (ApoE), beta-amyloid cleavage enzyme (BACE) and other AD-relevant allele status, life-style and intrinsic population effects can influence the profile of mRNA or miRNA abundance and complexity (Colangelo et al., APOE genotype (Tang et al., To illustrate one important example is the miRNA abundance and speciation of a small family of inducible, NF-kB-sensitive miRNAs in two different American populations\u2014Caucasian Americans and African Americans afflicted with AD Figure . A pathoVariation in miRNA patterns lends further strength to the idea that AD is not a single, definable neurological disease entity such as sickle-cell anemia Pauling, , but rat\u201chuman genetic individuality.\u201d If molecular-genetic and epigenetic profiles of AD brain samples are any indication of AD phenotypic variation then there may be real and significant inter-ethnic differences in AD epidemiology, incidence, disease course and progression. This further suggests that an equally wide variety of diagnostic and individualistic prevention and treatment strategies will be required to more effectively address such progressive, age-related neurological disorders of the human CNS, including the implementation of novel combinatorial therapeutic strategies such as anti-NF-kB and anti-miRNA approaches that have not yet been considered (Lukiw, Lastly, much independently derived data comparable to that shown in Figure d Lukiw, ."}
+{"text": "Dear Editor,I read with great interest the work published by Mogadam et al., entitled \"Comparison of Analgesic Effect between Gabapentin and Diclofenac on Post-Operative Pain in Patients Undergoing Tonsillectomy\" . I found"}
+{"text": "Synovial sarcomas commonly occur in the soft tissue of the extremities, while a primary occurrence in the mediastinum is quite rare. The current study reports the case of an 11-year-old male who presented with a neck mass, which computed tomography showed was due to a giant mediastinal mass involving the thyroid gland. The tumor was resected by thoracotomy and diagnosed as monophasic synovial sarcoma by histopathology. The patient received adjuvant combination chemotherapy and radiation therapy following surgery. At the 3-month follow-up, no local tumor recurrence was found. The present case report highlights the significance of recognizing the unusual presentation and clinical manifestation of synovial sarcoma to aid clinical management. Written informed consent was obtained from the patient\u2019s family. Synovial sarcoma is a type of mesenchymal tissue cell tumor that exhibits epithelial differentiation, which most frequently arises in the extremities, while a primary occurrence in the mediastinum is quite rare ,2. Prima2 in the left thyroid gland, however nothing of significance was revealed in the chest or abdominal regions. Computed tomography (CT) scans  scans  and 2 shmination  showed mmination \u20137, confimination  showed amination  was perfet al in 2002 as a type of mesenchymal tissue cell tumor that exhibits epithelial differentiation , which met al, of the Primary mediastinal synovial sarcoma is a type of malignant tumor with no specific differences from other mediastinal tumors with regard to clinical manifestation, imaging or histology, therefore, it is difficult to diagnose. With regard to clinical manifestations, mediastinal synovial sarcomas reveal various initial symptoms due to their different scopes of infringement. The common symptoms include chest pain \u20137, shortet al Although mediastinal synovial sarcomas have limited clinical data and no standardized treatments, complete surgical excision remains the cornerstone of therapy ,6,8,9. Aet al retrospe al(et al, adjuvan al(et al also fou al(et al. In the  al(et al, the 5-y al(et al recently al(et al,9,17. Th al(et al and 9 sh al(et al, it was  al(et al must be A previous study  showed tMediastinal synovial sarcomas are malignant tumors with a low incidence, no specific clinical manifestations and a lack of unified and effective treatments. These factors highlight the challenges preventing its diagnosis and treatment in clinics. The existing data supports surgery as the preferred treatment for mediastinal synovial sarcoma, but appropriate auxiliary treatments, including radiotherapy and chemotherapy, must be taken into consideration according to the factors affecting prognosis. In addition, the SYT-SSX fusion gene in synovial sarcoma must be further investigated in hope of identifying novel targeted therapies."}
+{"text": "Clustering and classification of large-scale chemical data are essential for navigation, analysis and knowledge discovery in a wide variety of chemical application domains. The maximum common structure (MCS) for a group of compounds is an important element of such classification, providing insight into activity patterns and enabling scaffold alignment for a more consistent 2D depiction. Most modern, exact MCS implementations use back-tracking  or cliqu"}
+{"text": "A goal of the COG Ewing Sarcoma (ES) Biology Committee is enabling identification of reliable biomarkers that can predict treatment response and outcome through the use of prospectively collected tissues and correlative studies in concert with COG therapeutic studies. In this report, we aim to provide a concise review of the most well-characterized prognostic biomarkers in ES, and to provide recommendations concerning design and implementation of future biomarker studies. Of particular interest and potentially high clinical relevance are studies of cell-cycle proteins, sub-clinical disease, and copy number alterations. We discuss findings of particular interest from recent biomarker studies and examine factors important to the success of identifying and validating clinically relevant biomarkers in ES. A number of promising biomarkers have demonstrated prognostic significance in numerous retrospective studies and now need to be validated prospectively in larger cohorts of equivalently treated patients. The eventual goal of refining the discovery and use of clinically relevant biomarkers is the development of patient specific ES therapeutic modalities. First described by James Ewing as an endothelioma of bone Ewing, , Ewing sIt was the advent of consistency in diagnosis that enabled cooperative groups worldwide to develop multi-center ES clinical trials. Over the past three decades these trials have systematically evaluated and optimized local and systemic treatment protocols for patients with ES , and increasing patient age have all been implicated as negative prognostic features. None of these are as significant as the presence of metastatic disease and studies have demonstrated variability in these individual features , and sub-clinical disease measurement. Fusion type will be discussed to demonstrate the importance of prospective evaluation and validation of biomarkers in the context of evolving therapy. The remaining categories were selected for in depth discussion after consideration of REMARK criteria. In the following sections we will highlight the features of each of these putative biomarkers that lead us to propose that their parallel evaluation and validation in the next series of prospective therapeutic trials is warranted. Several of these, including CNAs and cell-cycle proteins were recently discussed at a European Network for Cancer Research in Children and Adolescents (ENCCA) summit of 35 international experts   and RB1. Kovar et al. (CDKN2A deletions in 30% of tumors (N\u2009=\u20098/27) and 52% of ES cell lines (N\u2009=\u200912/23) and several retrospective studies have demonstrated an association between CDKN2A alterations and clinical outcome in ES patients. Wei et al. , while Tsuchiya et al. (CDKN2A deletions in 17% of tumor samples (N\u2009=\u20094/24). Patients in both studies were found to have worse disease-specific survival in univariate and multivariate analyses. Maitra et al. (CDKN2A downregulation by immunohistochemistry in 20% of patients (N\u2009=\u20094/20), and this correlated with metastatic disease at presentation and trended toward shortened survival. A meta-analysis examining the prognostic significance of CDKN2A alterations in ES based on six separate studies (N\u2009=\u2009188) concluded that the estimated pooled risk ratio (RR) for worse outcome with CDKN2A alterations was 2.17  and the estimated pooled RR of metastasis at diagnosis was 2.60   and 10% of primary tumors (N\u2009=\u20094/42)  and this over-expression was associated with advanced disease at diagnosis, poorer treatment response, and a worse overall survival. Significantly, this effect was independent of site, local treatment, or tumor necrosis. Similarly, a study by de Alava et al. (N\u2009=\u20096/55) and increased p53 protein expression was found to be the strongest prognostic factor that was associated with worse overall survival. Huang et al. (TP53 mutations in 13.3% of patient samples (N\u2009=\u20098/60), as well as CDKN2A homozygous deletions in another 13.3% of samples (N\u2009=\u20098/60). TP53 mutations and/or CDKN2A deletions were significantly associated with a poor response to chemotherapy (P\u2009<\u20090.0001) and, in a multivariate analysis, TP53 and/or CDKN2A alteration status as a single combined variable was identified as the most significant prognostic factor (P\u2009<\u20090.001). Finally, using immunohistochemistry and fluorescent in situ hybridization (FISH), Lopez-Guerrero et al. (P\u2009=\u20090.025), and worse progression-free survival (P\u2009=\u20090.012) and disease-specific survival (P\u2009=\u20090.006) in patients with localized disease.The potential of u et al.  detecteda et al.  identifig et al.  reportedo et al.  analyzedTP53 and CDKN2A as negative prognostic biomarkers in ES. Currently, COG and the ES Biology Committee are performing a large-scale analysis of TP53 and CDKN2A status in over 150 prospectively collected tumors from patients treated on the most recent AEWS0031 therapeutic study. Should this study confirm prior observations, analysis of these cell-cycle regulatory proteins will become a strong candidate for inclusion as a prognostic biomarker that can inform treatment decisions in future clinical trials.In summary, compelling data from several retrospective studies implicates alterations of Genomic instability with subsequent CNAs have been well-documented in ES and these alterations have been recently reviewed by Jahromi et al. . The recIn summary, independent studies of both small and large tumor cohorts have identified individual and global patterns of CNAs as putative prognostic biomarkers in ES. We anticipate that the continued improvement in next generation sequencing platforms will allow for greater characterization of structural variations in tumors, and will generate even more data to test associations between CNAs and clinical outcome. It is the recommendation of this committee that tumor and germline DNA be collected from all patients registered on future therapeutic studies of ES in order that CNAs and other genetic mutations can be evaluated as prognostic and predictive biomarkers in homogeneously treated patients. To that end, COG has discussed the prospective incorporation of CNA and genomic analysis in their upcoming ES trial for relapsed/refractory patients.Assessment of minimal residual disease (MRD) has been established as a critical part of therapeutic decision making in childhood acute lymphoblastic leukemia  protocols and therefore received similar therapy , and 19% of patients (N\u2009=\u200918/92) with non-metastatic disease at presentation. Circulating transcripts were identified in 20% of patients (N\u2009=\u200929/144) at diagnosis, and were more frequently observed in patients with large tumor burdens. In patients with localized disease, RT-PCR positivity in bone marrow and peripheral blood correlated with significantly poorer outcomes. In contrast, a study of peripheral blood samples from 26 children was unable to identify a significant progression-free survival difference in patients with detectable fusion transcript at diagnosis  with localized disease, 50% of patients (N\u2009=\u20093/6) with isolated pulmonary metastases, and 100% of patients (N\u2009=\u20096/6) with bone metastases. However, the study did not establish a correlation between marrow positivity for ES transcript and progression-free disease. Results of other smaller studies have been recently summarized by Wagner et al.  for molecular diagnosis, isolation of quality RNA has become less practical. Feasibility will only diminish as additional rare non-EWSR1 translocations are identified.To rigorously address whether the detection of circulating tumor transcript is of prognostic significance, the multi-center European EURO-E.W.I.N.G. 99 trial prospectively collected bone marrow samples for over 10\u2009years. As the first large prospective trial examining sub-clinical disease via RT-PCR in ES patients, the findings of this study will be critical to evaluate the feasibility and usefulness of this modality as a biomarker for ES. Based on our own experience with a much smaller cohort of patients in COG we, as a committee, are skeptical that RT-PCR-based assays will be clinically optimal for prognostication and treatment stratification. We base this assertion on our combined observations regarding issues of technical reproducibility of the assay between individual laboratories, and the technical expertise required to consistently obtain sufficient quality RNA for valid and reliable RT-PCR analysis. Although these issues could be addressed with the establishment of a central College of American Pathologists (CAP)-Clinical Laboratory Improvement Act (CLIA)-certified reference laboratory, the issue of RNA degradation in sample shipments would remain. In addition, RT-PCR-based analysis requires knowledge of the precise breakpoint. With the increasing use at many COG institutions of closed needle biopsy for diagnostic tissue collection and fluorescence In summary, although of potential prognostic significance, technical and logistic realities regarding tissue collection and RNA-based studies of blood and bone marrow specimens significantly diminish this committee\u2019s enthusiasm for RT-PCR analysis of sub-clinical disease in routine clinical practice. Should the aforementioned Euro-Ewing study validate RT-PCR of bone marrow as a significant prognostic variable, this issue will need to be re-addressed. At such time, consideration would need to be given to optimizing collection and submission of quality RNA and to creation of a CAP-CLIA certified COG reference laboratory.5 peripheral blood mononuclear cells. Ash et al. -directed therapy. Activating mutations in the EGFR gene are detectable in only a small minority of NSCLC patients but it is these patients who selectively respond to EGFR-directed therapy  patients who will respond to Epidermal Growth Factor Receptor (in vitro and in vivo models of ES are highly sensitive to the PARP1 inhibitor Olaparib alone and in combination with the drug temozolomide. Moreover, in a drug screening of several hundred cancer cell lines a marked and selective susceptibility of ES cell lines to Olaparib was also discovered (Garnett et al., The findings that only a small subset of patients with relapsed ES respond to IGF-1R targeted monotherapy serve as a sobering example of the critical need for predictive biomarkers in this disease. As trials investigating novel agents move forward, it is paramount that strategies that will permit evaluation of predictive biomarkers be simultaneously implemented. This will enable identification of patients who may preferentially benefit from such interventions in the future and allow for more selective inclusion and exclusion of patients in a manner that will lead to improved response rates. One potential treatment modality to emerge from recent pre-clinical investigations is PARP1 inhibition. PARP1 is a key enzyme involved in single-strand repair of DNA (Wang et al., Numerous prognostic biomarker studies for ES have been published in recent years. Of particular interest and potentially high clinical relevance are studies of cell-cycle proteins, sub-clinical disease, and CNAs. All of these have demonstrated prognostic significance in numerous retrospective studies and now need to be validated prospectively in larger cohorts of equivalently treated patients. The challenges in identifying and validating clinically relevant biomarkers in ES highlight a significant hurdle for the individualization of therapy in any rare cancer. Prospective therapeutic trials with standardized treatments remain the optimum source of biologic material and clinical correlative information to drive successful biomarker identification. Since these trials can take years to complete it is essential that biomarker studies be meticulously designed and incorporated up front in therapeutic studies. It is imperative that these studies are designed vigilantly to maximize levels of evidence and ensure adherence to REMARK guidelines. In addition, biomarkers that can be tested and validated on blood or fixed tumor specimens will have the best chance of translation into routine clinical practice. As new agents are developed, predictive biomarkers will need to be developed to assess the benefit of these therapies and rationally design treatment stratification based on likelihood of response. The choice of technical platforms must also be carefully considered in trials involving rare diseases. Although characteristics such as sensitivity are important when choosing a methodology, issues such as availability, cost-effectiveness, and sample requirements are equally important. Rare cancers require the participation of multiple institutions, and it is imperative that samples from each site are similarly collected and processed. Cooperative groups can play a critical role to ensure that biomarker studies are carefully selected, rigorously designed and, whenever possible, incorporated into therapeutic studies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Graft versus host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation. GVHD is characterized by an imbalance between the effector and regulatory arms of the immune system which results in the over production of inflammatory cytokines. Moreover, there is a persistent reduction in the number of regulatory T (Treg) cells which limits the ability of the immune system to re-calibrate this proinflammatory environment. Treg cells are comprised of both natural and induced populations which have unique ontological and developmental characteristics that impact how they function within the context of immune regulation. In this review, we summarize pre-clinical data derived from experimental murine models that have examined the role of both natural and induced Treg cells in the biology of GVHD. We also review the clinical studies which have begun to employ Treg cells as a form of adoptive cellular therapy for the prevention of GVHD in human transplant recipients. Although hematopoietic stem cell transplantation (HSCT) has been a successful therapeutic strategy for treating hematological malignancies for several decades, its broad application is limited by the high incidence of graft versus host disease (GVHD). GVHD is primarily a donor T cell-mediated syndrome whereby T cells in the graft elicit an immune response, resulting in host tissue damage . These cells, termed Treg cells, express the forkhead box transcription factor Foxp3, which is both necessary and sufficient for the suppressive ability of Treg cells  cells comprise 5\u201310% of the CD4+ T cell compartment and develop in the thymus  which are the sites of GVHD-associated tissue damage  which is a ligand for the CD1d molecule has been shown to expand donor-derived Treg cells in a dose-dependent manner and reduce GVHD-associated mortality (Duramad et al., in vivo expansion of nTreg cells and in vivo conversion and/or expansion of iTreg cells. Thus, it is difficult to exclude that these approaches may also result in the expansion of iTreg cell populations as well.Pharmacological strategies have also been tested in murine GVHD models to determine whether Treg cell numbers can be augmented after allogeneic HSCT. To that end, Shin et al.  demonstrde novo iTreg cell generation in recipient mice is negligible during GVHD (Chen et al., in vitro induction/expansion of this population followed by adoptive transfer into recipient animals. In initial studies, iTreg cells were stimulated with allogeneic dendritic cells or treatment with anti-CD3/anti-CD28 antibodies in the presence of TGF-\u03b2 and IL-2 to induce Foxp3 expression. Administration of in vitro-differentiated iTreg cells along with BM grafts containing alloreactive donor T cells did not result in any significant protection from lethal aGVHD (Koenecke et al., in vivo survival of these cells which was accompanied by instability of Foxp3 expression, resulting in a loss of suppressive function early post transplantation (Koenecke et al., While the majority of rodent models of GVHD have focused on the biology of nTreg cells, there has been much less attention devoted to the role of iTreg cells in GVHD biology. This has been due, in part, to the fact that there are no proven cell surface markers that distinguish nTreg cells from iTreg cells. Consequently, isolation of a pure iTreg cell population from donor animals for selective adoptive transfer studies is not currently feasible. Furthermore, in vivo is not clear, but one potential explanation is that the proinflammatory cytokine milieu that occurs during GVHD may also render iTreg cells more unstable. Supporting this premise are data demonstrating that in vivo-derived iTreg cell conversion is significantly enhanced when mice are treated with monoclonal antibodies that block signaling through IL-6 or IL-21 which serves to reduce inflammatory cytokine production (Bucher et al., in vivo, an alternative approach has involved the culture of CD4+CD25\u2212 T cells with the hypomethylating agent 5-azacytidine. Choi et al. (+ T cells both in vitro and in vivo, and that transplantation of these cells ameliorated GVHD severity.The reason that iTreg cells are unstable i et al.  reported+ Treg cell populations.We would note that instability of Foxp3 expression has also been noted to occur in nTreg cells in non-transplant models (Zhou et al., + Treg cells are classically defined as being a subset of the CD4+ T cell compartment. However, a CD8+ Foxp3+ Treg population has been described and found to be capable of suppressing T cell responses in animal models of autoimmunity and allergen exposure (Hahn et al., + Foxp3+ T cells have also been documented in the tumor microenvironment of patients with colon and prostate cancer, suggesting that they may be a mechanism by which tumors escape immune surveillance (Kiniwa et al., + Foxp3+ iTreg cells are induced early during GVHD (Beres et al., + counterparts, these cells were found to be dependent on TGF-\u03b2 and IL-2 for induction (Sawamukai et al., + or CD8+ iTreg cell population was required to prevent increased GVHD-associated mortality (Beres et al., + iTreg cells could be expanded in GVHD recipients using IL-2 antibody complexes in conjunction with Rapamycin as has been previously described with CD4+ Treg cells (Shin et al., + Foxp3+ T cells have been induced in vitro and found to suppress GVHD in a humanized mouse model (Zheng et al., in vitro or in vivo methodological approaches for translational application.Foxp3+ Treg cells to CD8+ T cells was significantly decreased at the mucosal interface of GVHD patients as compared to patients with intestinal inflammation unrelated to GVHD (Rieger et al., The approach that has been employed to address whether Treg cells may serve to modulate the severity of GVHD in man has been to correlate the absolute number and/or frequency of Tregs with the subsequent incidence and severity of aGVHD and cGVHD. Several reports have demonstrated a decreased frequency of Treg cells in the peripheral blood of patients with high clinical grades of aGVHD as compared to patients with lower grade aGVHD or no GVHD (Li et al., +CD25hi Treg cells as compared to individuals without GVHD. This was supported by a more recent study that reported increased peripheral Treg cell numbers in transplant recipients that developed cGVHD with no prior aGVHD diagnosis (Ukena et al., It is important to note, however, that not all studies have demonstrated a correlation between reduced Treg frequency and GVHD severity. Clark et al.  observedThe reason for the differences observed in these studies is not entirely clear. For the most part, however, studies that have failed to demonstrate that a reduction in Treg cell frequency and/or absolute numbers is associated with increased GVHD severity have relied on CD25 expression to delineate Treg cell populations, whereas those that have reported a positive correlation have tended to employ Foxp3 expression as a readout for this Treg cell population. Thus, it is possible that the reliance on different phenotypic markers may result in somewhat different populations being examined and be a potential explanation for these discordant results.+Foxp3+ Treg cells in the peripheral blood of the donor negatively correlated with the incidence of GVHD in the graft recipient. Several subsequent studies confirmed this correlation in recipients of HLA-identical sibling and unrelated donor stem cell grafts (Pabst et al., +CD25+CD127lo Treg cells as compared to bone marrow grafts, the frequency of peripheral blood Treg cells is reversed post transplantation. This was presumed to be due to the fact that PBSC Treg cells tended to be CD62Llo as a consequence of both granulocyte colony stimulating factor treatment for mobilization and the subsequent leukapheresis process (Blache et al., + Treg cells in the graft have been found to correlate with reduced GVHD incidence (Lu et al., + Treg cell population is more potent at suppressing GVHD than the corresponding CD62Llo population (Taylor et al., An alternative approach to examine the effect of Treg cells on GVHD severity in human allogeneic HSCT has been to assess the number of donor-derived Treg cells within the graft prior to transplantation. In this regard, Rezvani et al.  determin+CD25hi CD127\u2212 or CD4+CD25hiICOS+ Treg populations were likely to be most suitable for human adoptive transfer studies. Many groups have also identified in vitro expansion protocols that yield high number of Treg cells for adoptive transfer (Karakhanova et al., ex vivo-expanded cells also ameliorated disease in a xenograft model of GVHD (Chakraborty et al., Less than two decades after their discovery, Treg cells are now entering into clinical trials in allogeneic HSCT recipients. Pre-clinical murine models of GVHD have provided much insight into Treg cell-based therapy, but most mouse studies have been performed using Foxp3-GFP reporter mice where Foxp3-expressing Treg cells can be definitively isolated for adoptive transfer studies. This is not a luxury that is available in human studies where CD25 expression necessarily serves as a surrogate for Foxp3. However, since CD25 is upregulated on all activated T cells, further phenotypic characterization of these cells has been generally thought to be necessary for their use in man. To that end, Ukena et al.  comparedOne of the first reported clinical studies was conducted by Brunstein et al. who performed a phase I clinical prophylaxis trial with cord blood-derived Treg cells. The rationale for the use of cord blood-derived Treg cells was based, in part, on earlier studies, that had shown that they express similar levels of CTLA-4, Foxp3, GITR, and CD25 as adult peripheral blood Treg cells, and when stimulated by alloantigen, were potent suppressors of T cell expansion (Chang et al., A second clinical trial was performed by Di Ianni et al. , in whicThere has been one small study involving two patients in which expanded Treg cells were administered to patients with documented GVHD (Trzonkowski et al., + donor leukocyte infusions, used to treat relapsed hematologic malignancies post HSCT, resulted in Treg cell expansion in vivo. This same group then utilized this strategy to treat glucocorticoid refractory cGVHD patients. The administration of low dose IL-2 was associated with an amelioration of disease severity and this correlated with an increase in the number of Treg cells (Koreth et al., in vivo expansion of Treg cells may be a more clinically feasible strategy to enhance Treg reconstitution post transplantation, as compared to more costly expansion strategies.An alternative approach to harness the potential for Treg cell therapy in humans is based on the requirement of these cells for IL-2. Specifically, Zorn et al.  found thCollectively, these studies are exciting evidence that Treg cell therapy has now entered into the clinic. Going forward, well-designed trials will be necessary to determine whether these cells are indeed capable of preventing and/or treating patients with established GVHD.+ nTreg cells, CD4+ iTreg cells, and CD8+ iTreg cells in GVHD biology remain unclear. Elucidating the mechanisms by which the respective cell subsets function may provide insight for developing better therapeutic strategies. Furthermore, additional studies are required to ascertain whether CD4+ and CD8+ Treg cell populations function cooperatively or whether they have overlapping redundant roles in GVHD biology.Despite the significant progress that has been made in understanding the role of Treg cells in GVHD biology, a number of questions remain. First of all, the relative roles of CD4in vitro, have unstable Foxp3 expression. Since Foxp3 expression is necessary for suppressive function, further inquiry is needed to determine whether Foxp3 expression can be stabilized especially under pro inflammatory conditions which characterizes the GVHD milieu (Koenecke et al., Secondly, accumulating evidence indicates that Treg populations, particularly those that are expanded ex vivo expansion remain unresolved. Moreover, it is possible that alloantigen-specific Treg cells may be more potent in suppressing GVHD, and should be studied further (Albert et al., Finally, current Treg cell-based immunotherapy approaches rely on the expansion of polyclonal populations of Treg cells. The best source of Treg cells and the optimal culture conditions for The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neuropeptide W (NPW), which was first isolated from the porcine hypothalamus, exists in two forms, consisting of 23 (NPW23) or 30 (NPW30) amino acids. These neuropeptides bind to one of two NPW receptors, either NPBWR1 (otherwise known as GPR7) or NPBWR2 (GPR8), which belong to the G protein-coupled receptor family. GPR7 is expressed in the brain and peripheral organs of both humans and rodents, whereas GPR8 is not found in rodents. GPR7 mRNA in rodents is widely expressed in several hypothalamic regions, including the paraventricular, supraoptic, ventromedial, dorsomedial, suprachiasmatic, and arcuate nuclei. These observations suggest that GPR7 plays a crucial role in the modulation of neuroendocrine function. The intracerebroventricular infusion of NPW has been shown to suppress food intake and body weight and to increase both heat production and body temperature, suggesting that NPW functions as an endogenous catabolic signaling molecule. Here we summarize our current understanding of the distribution and function of NPW in the brain. In 1995, O'Dowd et al. . In 2002in situ hybridization histochemistry has revealed that NPW mRNA is expressed in a few restricted brain regions, including the rat periaqueductal gray (PAG), Edinger-Westphal nucleus (EW), and dorsal raphe nucleus , PAG, superficial gray layer of the superior colliculus, and subfornical organ. In general, NPBWR1 is most commonly expressed at high levels in the amygdala (Singh et al., In humans, RT-PCR analysis has demonstrated that NPBWR1 mRNA is highly expressed in the amygdala, hippocampus, neocortex, and hypothalamus (Lee et al., i et al.  reportedi et al.  used [12NPBWR1 knockout mice are hyperphagic and show decreased energy expenditure, suggesting that NPW may act as a modulator of feeding. icv infusion of NPW in male rats has been shown to increase food intake during the first 2 h in the light phase (Shimomura et al., ob/ob and db/db mice. Therefore, NPW may play important roles in feeding and energy metabolism, functioning as a substitute for leptin (Date et al., We have carried out a series of neuroanatomical studies to examine the neural relationship between NPW and other neuropeptides involved in the regulation of feeding. Very close neuronal interactions were observed between NPW-containing nerve fibers and orexin- or melanin-concentrating hormone-containing neuronal cell bodies and nerve fibers in the rat brain (Takenoya et al., 2 consumption and increased CO2 production, as well as an increase in body temperature (Mondal et al., Very recently, Skrzypski et al.  have demImmunohistochemical studies have reported that NPBWR1 is expressed in the PVN, pituitary gland, and adrenal medulla in the human, mouse and rat (O'Dowd et al., in vitro study has reported that log molar NPW23 concentrations, significantly alter prolactin, growth hormone and ACTH release from dispersed rat anterior pituitary cells (Baker et al., in vivo studies have revealed that icv infusion of NPW23 stimulates an increase in plasma prolactin levels (Baker et al., On the other hand, icv infusion of NPW23 stimulates prolactin release in the rat (Shimomura et al., Niimi and Murao  have repThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In western industrialized nations approximately 25% of all deaths are caused directly or indirectly by the consumption of psychotropic substances. Substance-related addictions therefore constitute the most frequently occurring psychiatric disease category (McGinnis and Foege, In their recently published manuscript Pascoli et al.  elucidatSince the first description of a patient, whose alcohol addictive behavior was positively influenced by high-frequency accumbal DBS (Kuhn et al., Although the mechanisms of deep brain stimulation are, despite its decade-long application, not yet fully understood it has been argued that the modulation of dopaminergic transmission \u2013 especially in the context of addictive disorders \u2013 underlies the therapeutic effect. While this assumption could only be demonstrated for the rat nucleus accumbens (Sesia et al., The influence of impaired dopaminergic functioning on cognition and neuronal plasticity has been much debated. It is assumed that an activation of accumbal D1 receptors by phasic dopamine release facilitates limbic afferents and promotes cortical synaptic plasticity. At the same time, D2 receptor activation might promote the reinforcement of prefrontal influences, which is especially relevant in the context of addiction given the reduced density of both striatal and accumbal D2 receptors in addicted patients (Lee et al., The results of Pascoli et al.  help expThe short-term application of psychotropic substances, in this case cocaine, apparently triggers a fast modification of D1-receptor expression in terms of focal synaptic plasticity and could, hence, bring forth a lasting shift in the D1/D2 ratio, which eventually might lead to a fortification of limbic and drug-associated afferents.Current pharmacologic approaches to ameliorate the dysregulated dopaminergic system are not sufficiently effective (Spanagel and Vengeline,"}
+{"text": "Cells with damaged and unrepaired genomes represent a potential threat for the organism and therefore their elimination is beneficial. The biological safeguard barriers responsible for elimination of such hazardous cells rely on two principles: intrinsic - achieved through cellular senescence/apoptosis, and extrinsic - performed by the immune system. The concept of immune system-mediated clearance of senescent cells is well established , howeverResearch performed in the last two decades shows that cellular senescence as an essentially irreversible block of cell proliferation can be triggered or bypassed via manipulation of expression levels of several dozens of genes indicating the complexity and redundancy of regulatory machineries controlling this antitumor barrier. While the regulatory circuits are not understood in much detail, the unifying feature of cellular senescence is the activation of cell cycle checkpoints that block cell-cycle progression at G1/S or G2/M boundary. Checkpoint activation reflects suprathreshold long-term expression, commonly triggered by persistent DNA damage response (DDR) signaling, of protein inhibitors of cyclin-dependent kinases (CDKs), the key drivers of cell-cycle progression. The multiple pathways leading to the induction of individual  inhibitors of CDKs (CDKi) form the basis for redundancy of mechanisms for induction and maintenance of senescence. The robustness of response, manifested as the possibility to impose senescence even in tumor cells lacking two pivotal senescence mediators p53 and Rb, stems from the fact that the regulatory circuits are interconnected by numerous cross-talks of signaling pathways and several feedback mechanisms [et al. reported recently [per se . Production of ROS in cells during inflammation contributes to aging and development of age-related diseases. Nox4 is a member of the NADPH oxidase family known to regulate production of ROS, especially superoxide forms to induce DNA damage and premature senescence. Weyemi et al. showed that knock-down of NOX4 decreased RAS-induced DDR [et al. reported that Ras-induced senescence is mediated via Nox1 and Nox4, and overexpression of both genes is sufficient to induce senescence via activated DDR [Cytokines secreted by senescent cells play here the important role not only in shaping the senescent phenotype by autocrine and paracrine signaling and reinforcing the cell-cycle block by secondary induction of diverse CDKi, but also, as Hubackova recently , by caus se Fig. . In thisated DDR .et al. did not explore the presence of cytokine-induced secondary bystander senescence in vivo, this can be anticipated based on the recent study of Braumuller et al. [et al. show that T-helper-1 cell cytokines TNF\u03b1 and IFN\u03b3 cooperatively induce senescence in mouse beta-cell tumors, both in vivo and in vitro, indicating a reciprocal relationship between the immune system and cellular senescence. Importantly, the concerted action of these two T-cell produced cytokines induced senescence in cancer cells indicating the role of immune surveillance in control of tumor cell proliferation by cytokine-induced senescence. Although not assessed in their study, it can be predicted based on previous reports that the observed senescence-inducing effect in response to both IFN\u03b3 and TNF\u03b1 is also triggered by DNA damage. TNF\u03b1 and IFN\u03b3 were also found to increase both intracellular and extracellular ROS production. Importantly, binding of NF\u03baB, a crucial mediator of cytokine effects, on NOX4 promoter was observed [Even though Hubackova r et al. . The cytobserved . Thus, NIt is becoming widely accepted that secretome of senescent cells can also modulate the microenvironment, in both normal or tumor tissues. However, due to the overall complexity and variability of the secreted cytokine species, dependent on specific cell types, (patho)physiological context and senescence-inducing stimulus, it is currently hard to predict all outcomes of senescence-associated cytokine signals on tissue homeostasis. Nevertheless, what can be conceived now, is that the genotoxic effects of several cytokine species produced by senescent cells can spread damage in tissues manifested as secondary (and tertiary) senescence and thus to contribute to aging and pathogenesis of aging-associated diseases. Therefore, the elimination of senescent cells from the organism may provide a rejuvenation effect, as has already been documented in progeroid mice ."}
+{"text": "IFT122, and demonstrated impaired ciliogenesis in patient fibroblasts. This report on IFT122 broadens the phenotype of CED and expands its allelic heterogeneity.Cranioectodermal dysplasia (CED) is a very rare autosomal recessive disorder characterized by a recognizable craniofacial profile in addition to ectodermal manifestations involving the skin, hair, and teeth. Four genes are known to be mutated in this disorder, all involved in the ciliary intraflagellar transport confirming that CED is a ciliopathy. In a multiplex consanguineous family with typical CED features in addition to intellectual disability and severe cutis laxa, we used autozygosity-guided candidate gene analysis to identify a novel homozygous mutation in  IFT122,WDR35,C14ORF179, and WDR19)  is a skeletal dysplasia characterized by typical craniofacial features in the form of dolichocephaly, sagittal craniosynostosis, and facial dysmorphism , and skeletal anomalies in the form of narrow thorax and short extremities, in addition to ectodermal dysplastic features in the form of thin sparse scalp hair and micro/hypodontia   and was absent from 374 Saudi control chromosomes.In this report, we describe a multiplex family containing three affected siblings born to healthy first cousin Saudi parents Fig.\u2003A. In addIFT122 as a novel CED disease gene (Walczak-Sztulpa et\u2003al. IFT122 in CED (Tsurusaki et\u2003al. In order to confirm the pathogenicity of this mutation, we cultured fibroblasts from the foreskin of the younger brother following circumcision and proceeded with stress-induced ciliogenesis assay, essentially as described before (Shaheen et\u2003al."}
+{"text": "Recent progress in the field of epigenetics has provided a new study angle for our research efforts on reproductive medicine and gynecologic malignancies. We have acquired valuable insight into the regulatory mechanism and biological effects of DNA methylation and histone modification, the two major epigenetic pathways. The newly acquired knowledge effectively complements that gained from the genetic standpoint and holds great potential for the prevention, diagnosis, risk assessment, and treatment of these diseases. Specifically, the DNA methylation and imprinting mechanisms are implicated in fertilization, early embryonic development, placental function, and pathogenesis of preeclampsia and intrauterine growth retardation. Aberrant DNA methylation and chromatin modification lead to gene-specific silencing of numerous tumor suppressor genes, DNA repair genes, and steroid hormone receptors. This special issue presents a collection of peer-reviewed papers focusing on these areas. While the issue is not intended as an exhaustive representation of all of the potential topics, they nevertheless provide insightful and multifaceted information that we consider a pleasure to share with the readers.This special issue includes 9 articles: three of which are related to the IGF-II imprinting in placenta and the effects of reproduction procedures on imprinting; two describe epigenetic mechanisms and genetic test for infertility; another paper documents the effects of in vitro maturation on histone acetylation in oocytes and early cleavage embryos; two address DNA methylation changes in cancers; one paper discusses rational design of primer for methylation assays.Effects of in vitro maturation on histone acetylation in metaphase II oocytes and early cleavage embryos,\u201d Wang et al. document a reduced expression of histone acetyltransferase GCN5 (GCN5) and histone deacetylase 1 (HDAC1) in two-cell embryos but a normal level of these enzymes after the two-cell stage. The results indicate that in vitro maturation could affect protein and gene expression related to histone acetylation in oocytes and early cleavage embryos. However, by function of selection, parts of the changes could be recovered in late embryo development. In the first paper entitled \u201cImprinting and promoter usage of insulin-like growth factor II in twin discordant placenta,\u201d Luo et al. analyze the imprinting and promoter usage of IGF-II in placenta of normal twins and twins with weight or phenotype discordance and conclude that promoter 3 specific LOI of the IGF-II gene may be closely related to phenotype discordance, but not to weight discordance. In the second paper entitled \u201cOxidative stress and DNA methylation in prostate cancer,\u201d Donkena et al. present a comprehensive review on the effects of oxidative stress on DNA methylation and cancer progression, life style and diet as factors involved in ontogenesis and epigenetic interference for cancer prevention, and DNA methylation as a biomarker for cancer detection. Updates on the application of DNMT inhibitors to chemotherapy are also provided. In the third paper entitled \u201cPreimplantation genetic screening: an effective testing for infertile and repeated miscarriage patients?,\u201d Wang et al. compare results from different laboratories on preimplantation screening of aneuploidy and assess the efficacy, risks, and benefits of the procedure. They conclude that the use of preimplantation genetic screening should be reconsidered.In the fourth paper entitled \u201cStudy on the imprinting status of insulin-like growth factor II (IGF-II) gene in villus during 6\u201310 gestational weeks,\u201d Chen et al. compared the rate of loss of GF-II imprinting in the placental villous tissues between normal and abnormal embryo development and observed a significantly increased loss of imprinting in the abnormal group, suggesting that the imprinting status of IGF-II may be functionally related to embryo development.In the fifth paper entitled \u201cEffects of assisted reproduction technology on placental imprinted gene expression,\u201d Katagiri et al. investigate the impact of assisted reproduction techniques (ART) on imprinted gene expression in human placenta. Different changes in the mRNA levels of imprinted genes are observed in the ART group compared with the spontaneous conception group, suggesting that ART may modify epigenetic status.In the sixth paper entitled \u201cSpecificity of methylation assays in cancer research: a guideline for designing primers and probes,\u201d Barekati et al. discuss the critical parameters to be considered for a rational design of PCR primers used for the detection of methylated DNA. The authors also provided applicable tools/algorithms and useful websites.In the seventh paper entitled \u201cEpigenetic regulatory mechanisms associated with infertility,\u201d Minocherhomji et al. review the epigenetic mechanisms involved in spermatogenesis and infertility. Topics discussed in detail include the regulation and potential role of epigenetics in infertility by high-order chromatin organization, epigenetic control of genes associated with pericentromeric regions of chromosome 9 and Y, and noncoding RNAs. In the eighth paper entitled \u201cIn the ninth paper entitled \u201cHypermethylation of SOX2 promoter in endometrial carcinogenesis\u201d, Wong et al. report their studies on the methylation profiles of SOX2, a gene encoding the stem cell-related transcription factor SOX2 in endometrial carcinomas. Compared to normal control tissues, cancer tissues show hypermethylation and decreased expression of SOX2. The authors conclude that epigenetic silencing mechanisms may play a crucial role in transcriptional regulation of SOX2 and loss of SOX2 expression.Shi-Wen JiangShi-Wen JiangBrian BrostBrian BrostSean DowdySean DowdyXing XieXing XieFan JinFan Jin"}
+{"text": "Physiotherapists play an inherent role in the multidisciplinary palliative care team. Existing knowledge, attitudes, beliefs and experiences influence their team participation in palliative care.The objective of this study was to assess the changes in knowledge, attitudes, beliefs and experiences among student physiotherapists who attended a palliative care training program.Preliminary quasi-experimental study design, conducted at an academic institution.Fifty-two student physiotherapists of either gender  of age (20.51\u00b11.78 years) who attended a palliative care training program which comprised lectures and case examples of six-hours duration participated in this study. The study was performed after getting institutional approval and obtaining participants\u2019 written informed consent. The lecture content comprised WHO definition of palliative care, spiritual aspects of life, death and healing, principles, levels and models of palliative care, and role of physiotherapists in a palliative care team. The physical therapy in palliative care-knowledge, attitudes, beliefs and experiences scale - modified from palliative care attitudes scale were used for assessing the participants before and after the program.t-test and Wilcoxon signed rank test at 95% confidence interval using SPSS 11.5 for Windows.Paired P<0.05) were noted for all four subscales- knowledge (7.84\u00b14.61 points), attitudes (9.46\u00b18.06 points), beliefs (4.88\u00b13.29 points) and experiences (15.8\u00b111.28 points) out of a total score of 104 points.Statistically significant differences (The focus-group training program produced a significant positive change about palliative care in knowledge, attitudes, beliefs and experiences among student physiotherapists. However, communication and coordination within the palliative care team has to be improved to minimize the negative impact of symptom distress on patient well-being and quality of life. Also, physical therapists must develop strategies for patient empowerment and methods for assessing and evaluating qualitative aspects of physical therapy in palliative cancer care.et al.,[According to Glazer-Waldman et al., the attiet al., if patieet al.[et al.[Previous studies that evaluated effects of training in palliative care utilized the educational program as part of a curriculum development among other healthcare professionals like critical care medicine trainees, medical et al. which wal.[et al.et al.[Effects of education and training programs on knowledge, attitudes, beliefs and practice were studied by other authors in the fields of nursing and child health.14 In phyet al. studied et al. who founExisting knowledge, attitudes, beliefs and experiences influence their team participation in palliative care. The objective of this study has been to assess if any change that occurred in knowledge, attitudes, beliefs and experiences among physical therapy students who attended a 6-hour educational training program on palliative care.The study ethical conduct was approved by the Institution and written informed consent was obtained from all participants prior to commencement of the study.Study design: This study used a pre-post quasi-experimental design, in which data were collected from a convenience sample of physical therapy students who attended a formal training program on palliative care and role of physical therapy.Participants: Final year physical therapy students of the institution attended upon free registration. The physical therapy curriculum had four years of academic training followed by six months of internship in undergraduate degree program. The students had previous experience of evaluating and treating pain in their third and early fourth year of academics during their clinical postings in multispeciality government hospital focused in treatment of cancer patients. Participants were given an initial description and instructions on filling the questionnaires by a qualified physical therapist.Training program: The training program was an elective educational intervention which comprised a lecture, case examples and active demonstration which consisted of WHO definition of palliative care, spiritual aspects of life, death and healing, principles, levels and models of palliative care, and role of physiotherapists in a palliative care team- for a total duration of six hours, where direct contact training of physiotherapists in palliative care emphasizing on introduction to palliative care, principles and models of assessment and care of persons at hospice, supportive, palliative, end-of-life and bereavement perspectives, goal planning and strategic implementation of physical therapy treatment methods in palliative care was done. Interaction duration of 15 min was allowed both between participants and also with the invited speaker (first author), who was a qualified physical therapist, experienced in pain relief methods for seven years.The training program required free registration of the participants and was conducted annually on a not-for-profit basis by the institution. The training program is one of its kinds listed in International Association for Hospice and Palliative Care website.et al.[Outcome measurement: The data was collected pre and post-training through a self-administered questionnaire- physical therapy in palliative care-knowledge, attitudes, beliefs and experiences scale . The scale is a 37-item self-report measure consisting of both qualitative and quantitative data. The full version of the questionnaire is given in et al. on critiThe PTiPC-KABE scale was was pilot-tested for test-retest reliability and was then used for assessing the participants before and after the program as a primary outcome measure. To avoid bias and to maintain participant anonymity, coding and decoding during data mining and analysis was done by another independent blinded physical therapist.Evaluation of test-retest reliability of PTiPC-KABE scale: For this purpose, we randomly selected 24 physical therapy students by Lots method from the same sample and we administered the questionnaire twice with a time-gap of 1 h, 2 h before the commencement of the actual study.Participants who could not understand English, who refused consent or who returned incomplete questionnaires were excluded from analysis. Completed questionnaires were collected by another qualified physical therapist, who was blinded to the study. The data were initially mined and entered for analysis by another blinded physical therapist.t-test and Wilcoxon signed rank test. Test for normality was done using Kolmogorov-Smirnof test. All analyses were done using SPSS 11.5 for windows at 95% confidence interval.Evaluation of test-retest reliability was done using intra-class correlation coefficient (ICC) for the total scores of two trials of the PTiPC-KABE scale. A mixed-methods model of primary analysis was done to compare pre-post scores using paired Of the total 82 physical therapy students- who attended the training program, 76 provided consent and were willing to participate in this study. 24 filled for the initial test-retest reliability of the scale (ICC=.80-.90) for the total score and the rest 52 were considered for this pre-post study. A total of 52 participants- 12 male (23.1%) and 40 female (76.9%) with age 20.51\u00b11.78 years- filled the questionnaire twice- before the commencement of training program and after the completion of the training program.P<.05) changes post-program was observed for all items of the PTiPC-KABE scale after we adjusted for acquiescence bias of Likert scaling. We combined the moderately agree and strongly agree into \u201cagree\u201d and same for disagree option. No response was given a score of \u201czero\u201d, disagree was given \u201cone\u201d, neutral/ unsure was given \u201ctwo\u201d and agree was given \u201cthree\u201d. Such a scoring helped us to have a continuous data for computation purposes. We also inverted the scores for the items with negative impact on palliative care such as items 10, 17, 24, 27-33. Thus a total score can thus be derived after adding all the raw scores.Statistically significant , attitudes (9.46\u00b18.06 points), beliefs (4.88\u00b13.29 points) and experiences (15.8\u00b111.28 points) subscales of PTiPC-KABE scale when analyzed using paired t-test .t-test [There was an overall statistically significant change in total score of 36.61\u00b114.35 points out of a total of 104 points (35.2% change) when analyzed using paired t-test .Our study is the first of its kind reported on physiotherapist population and effects of a palliative care training program. One of the positive consequences of such training programs is the development of curricular content to suit student needs. Such educational interventions pave way to develop better curricular models and to integrate into regular professional and post-professional education.et al.[Marion et al. describeGoals of care should guide use of technology; and decision-making should be patient- centered.Know how to use prognostic scoring systems and recognize their limitations; be familiar with the ethical principles and guidelines for forgoing life-sustaining treatments; know how to withdraw life-sustaining treatments in ways that avoid distress; know how to monitor, identify and treat symptoms of distress, discomfort, anxiety or pain; and, know how to use opiates and sedatives to titrate to effect.Respect patients as individuals with diverse preferences; value the role of families in shared decision-making; respect ethnic and religious differences; and, be aware of their own values regarding death.Listen and communicate effectively and empathically; form trusting relationships with patients and families; explain details of illness, treatment strategy and goals of care simply; collaborate with the patient and family in balancing benefits and burdens; make recommendations and decisions in the face of uncertainty; give advice based on the patient\u2019s preferences; talk comfortably about death, dying and loss; support families or other intimates during their bereavement; and, work effectively in collaboration with multidisciplinary teams.et al,[We see these- knowledge and attitudes among physical therapists largely shown to influence their practice patterns and levels of care. Earlier reports by Weed and Zimny, Zimny anet al, commenteet al.[et al.[Population-based interventions are much better as educational interventions aimed at team training in palliative care. Sato et al. found pol.[et al. showed pet al.[The study had few limitations- the lack of established validity of the questionnaire used and lack of long-term follow-up of participants to observe knowledge translation into action process. We understand that measurement error of the said questionnaire would be nullified in pre-post designs if the scale has appreciable test-retest reliability. Accordingly the test-retest reliability was excellent. Further research on validation is in progress. Long-term carry-over effect of gained knowledge and its implication into actual real-life situation in palliative care is also under scrutiny currently. Long-lasting improvements in knowledge was found to be absent among medical and nursing students education previously by Velayuthan et al. who alsoet al.[The implementation of the above suggested findings, however, face their own barriers. Lai et al. listed tet al.,[There are already well-established multidisciplinary palliative care training centers for healthcare professionals in operation in Kerala as described by Seamark et al., to name According to Fins and Nilson, as acadeet al.[et al,[et al.[Considering that physical therapists have largely favorable attitudes toward evidence-based practice as reported by Jette et al. and a tret al. and a wil.[et al, there isl,[et al. This knoPhysical therapists, let\u2019s now move on, from ignorance to knowledge.The focused training program on palliative care had positively influenced a group of physiotherapy students in this study by bringing about a significant change in their knowledge, attitudes, beliefs and experiences."}
+{"text": "Further expanding the major findings of the landmark study by Harrison and colleagues showing that late-life pharmacological inhibition of the enzyme mammalian Target Of Rapamycin (mTOR) -a conserved integrator of nutrient and growth factor signaling- is sufficient to significantly extend lifespan in mice on rapamycin feeding , Selman If activation of AMPK (and/or inhibition of mTOR/S6K1) constitutes the best metabolic response to avoid that a normal growth rate would compromise somatic integrity in progeroid animals , 5, it iEven if findings from Colman and colleagues demonstrating significant lifespan extension in rhesus monkeys can definitely substantiate CR as an effective pro-longevity strategy for humans , many peMetformin treatment has been recently found to selectively target tumor-initiating cancer stem cells (CSCs) in breast cancer cell cultures -31, likeTranslation of in vitro results into in vivo applications may significantly alter, however, the assumed CRM nature of the biguanide metformin. A recent study by Anisimov and colleagues published in a previous issue of Aging (Albany NY) may certainly establish that metformin should be defined as geroprotective or gerosuppressant rather than bona fide CRM. Long-living female mice from the outbred SHR strain were fed metformin in drinking water beginning at 3, 9 or 15 months of age and they were then analyzed for reproductive aging, mean & maximal lifespan and incidence of malignant tumors . MetformEarlier studies from the same group showed that metformin treatment increased mean lifespan of SHR mice by >37% and increased maximum lifespan by >10 months . MetformIf metformin both prevents cancer and extends lifespan in cancer-prone (e.g. neu-N transgenic mouse model of mammary cancer) strains of rodents, metformin's ability to prolong lifespan without affecting cancer in non-cancer-prone strain of rodents (e. g. SHR) may suggest that metformin can prolong life (and delay aging) by mechanisms unrelated to its ability to suppress cancer. It may not, however, if this discrepancy simply relies with the cellular response that oncogenes and tumor suppressors have on the phenotype of energetic metabolism. Derived from the FVB/N strain, neu-N transgenic mice express the nontransforming rat neu cDNA under the control of a mammary-specific promoter . As a coWhen considering recent studies describing that pre-malignant intraepithelial neoplasias such as ductal carcinoma in situ (DCIS) of the breast do contain pre-existing carcinoma precursor cells , 64, it It remains to be elucidated how metformin treatment, if started early and/or late in life, might significantly impact on late-onset diseases, like Alzheimer dementia, coronary artery diseases or, perhaps more importantly, certain familial forms of cancer. In this regard, an ideal scenario relates to genetic susceptibility to breast and ovarian cancer in women arising from a mutation in the BRCA1 gene, which is one of the most widespread genetic diseases , 77. WomAnisimov and colleagues studied markers of cellular senescence in fibroblasts from skin of SHR mice treated with metformin since the 3rd and the 9th months of life . AlthougAs mentioned above, one of the hallmarks of senescent cells is that the senescence growth arrest is essentially permanent and cannot be reversed by known physiological stimuli . TherefoPioneeringly revealed by current Anisimov's studies, a previously unrecognized ability of metformin to regulate the senescent phenotype in vivo may provide crucial insights to definitely distinguish a/the molecular mechanisms underlying metformin-promoted anti-aging and/or anti-cancer effects. On the one hand, studies of human tissues and cancer-prone mice argue strongly that cellular senescence suppresses cancer in vivo -114. SenAn unexplored scenario relates to metformin's ability to induce and/or enhance senescence responses in tumor cells themselves. Senescence-inducing stressors such as oxidative damage, DNA damage and/or oncogenes normally reach sufficient intensity to trigger senescence at the pre-malignant tumor stage. In agreement with a role of senescence in cancer prevention, the subsequent invasive progression of pre-malignant lesions almost inevitably involves one or more events that inhibit or impair the senescence pathway . Pret al [et al [et al [Landmark studies of Lin et al  and Campl [et al  have recl [et al . Senescel [et al ? Althougl [et al ; b.) phal [et al  to promol [et al , 129. Inl [et al , Skp2 inl [et al -132 gettl [et al , 134, itl [et al . Becausel [et al ), a molel [et al -139. Finl [et al -142, it l [et al  and to pl [et al .Cellular senescence can drive are-related pathologies other than cancer. If metformin reduced abundance of senescent cells is central to metformin's ability to actively regulate lifespan extension, it would be interesting to test if metformin treatment may decelerate rapid accumulation of senescent cells and/or the rapid development of age-related phenotypes including growth retardation, loss of weight, lipodystrophy (i.e. loss of adiposity), hair loss and bone density defects. A mouse model of Hutchinson-Gilford progeria syndrome  can be extremely informative because it develops phenotypes that overlap with those of HGPS children and do not include cancer even when causing a significant alteration in the number and proliferative capacity of epidermal stem cells , 146. AdThe key question that remains to be answered in Anisimov's studies relates to the molecular mechanism(s) through which metformin treatment increased lifespan and delayed tumor formation in female SHR mice. An ever-growing experimental body of evidence strongly suggests that metformin, at the cellular level, works as an efficient deactivator of the mTOR/S6K1gerogenetic pathway owing its ability to activate the metabolic rheostat AMPK . Althoug"}
+{"text": "This strategy might yield a novel class of more efficacious anti-epileptics with fewer side effects by specifically addressing disease pathophysiology. Moreover, this strategy may have ramifications for other adult seizure syndromes in which GABA receptor-mediated depolarizations play a pathogenic role, such as temporal lobe epilepsy.Neonatal intensive care has advanced rapidly in the last 40\u2009years, with dramatic decreases in mortality and morbidity; however, for neonatal seizures, neither therapies nor outcomes have changed significantly. Basic and clinical studies indicate that seizures in neonates have long-term neurodevelopmental and psychiatric consequences, highlighting the need for novel pharmacotherapeutics. First-line treatments targeting GABAA receptors, like barbiturates and benzodiazepines, are limited in their efficacy and carry significant risks to the developing brain. Here, we review the use of current GABA agonist therapies for neonatal seizures and suggest other treatment strategies given recent developments in the understanding of disease pathogenesis. One promising avenue is the indirect manipulation of the GABAergic system, via the modulation of neuronal Cl Seizures are the most common neurological emergency in the neonate, with an estimated prevalence of 1.8\u20135 seizures/1000 live births in the US Jensen, . In factA receptor, or by antagonism of NMDA receptors. Although these drugs are effective in adults, they do not control neonatal seizures well. When given as monotherapy, phenobarbital controls seizures in less than half of newborns  often secondary to an increased neuronal accumulation of Cl\u2212, though \u2212 homeostasis. Among these are the bumetanide-sensitive Na+-K+-Cl\u2212co-transporter NKCC1, which transports Cl\u2212into the cell, and KCC2, which normally extrudes it  is actively enrolling patients in a randomized, double-blind, controlled dose-escalation study of bumetanide as an add-on therapy to treat refractory seizures caused by hypoxic-ischemic encephalopathy. The estimated study completion date is December 2015. A second trial (NCT01434225) is being performed by a large, multi-center European group in an \u201copen-label,\u201d dose-escalation fashion to assess the effect of bumetanide in addition to phenobarbital for the treatment of neonatal seizures caused by hypoxic-ischemic encephalopathy. Data from these pilot studies will be utilized to guide the design of larger Phase III trials that will determine the efficacy of bumetanide in the treatment of neonatal seizures.GABA via NKCC1-knockdown or KCC2-overexpression may result in cortical neurons with fewer and shorter dendrites (Cancedda et al., \u2212 gradients in GABA transmission. Nevertheless, in the context of our enhanced understanding of the mechanisms of GABA signaling in the neonatal brain, novel therapies that target Cl\u2212 homeostasis are promising new targets for the treatment of neonatal seizures (Loscher et al., \u2212 homeostasis should also be considered. One unexplored mechanism of Cl\u2212 modulation is the manipulation of neuronal Cl\u2212 gradients via targeting of the serine-threonine regulatory kinases of NKCC1 and KCC2 (Kahle et al., in vitro, and does so via changes in transporter phosphorylation at critical regulatory residues (Figure \u2212 homeostasis, such as temporal lobe epilepsy, in which abnormal expression of Cl\u2212 channels also renders GABA excitatory (Palma et al., There are some concerns about the modulation of depolarizing GABA responses based on its importance during neurodevelopment. Studies suggest the \u201cpremature\u201d shift of Es Figure  (Kahle es Figure . Given tThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor:i.e.: \u2018every cell has a sex\u2019 In 2001, The United States Institute of Medicine (IOM) Committee on Understanding the Biology of Sex and Gender Differences concluded that \u2018Sex\u2026should be considered when designing and analysing studies in all areas and at all levels of biomedical and health-related research\u2026\u2019 and stated an apparent paradox It is unchallenged that there are health differences between males and females and that social and cultural factors could contribute to the observed differences. Anyway, the sex-dependent differences also have a biological base which sometimes has not been deeply investigated. Scientists studying health differences between male and female aim to both considering social/cultural environment and investigating biological/molecular mechanisms different between sexes. Some experimental studies have elucidated important differences in cell death control et al., via an apoptosis-inducing factor-dependent pathway (a caspase-independent pathway) in male neurons while proceeds via a cytochrome C-dependent pathway (a process mediated by caspase activation) in female neurons in vivo studies. In particular, it has been demonstrated that microRNA-23a, by binding the mRNA of the caspase inhibitor named XIAP, induces its translational repression in females, leading to enhanced caspase signalling in the ischaemic female brain. This effect has been shown to be independent of circulating oestrogen levels , contributing to female cellular higher resistance after ischaemic brain injury. Gupta NC et al. in vitro study. In addition, at least to some extent, sex-matched or sex-unmatched cell controls may be necessary in many experimental settings. In conclusion, sex-related differences in cell death mechanism may have strong implications for experimental studies and sexual dimorphism dependent on chromosomal rather than hormonal differences have important implications for planning preclinical studies and clinical interventions.However, it is currently emerging that some cell death programs are differentially controlled by sex-related hormone-independent cellular genetics. Differences in cell death sensitivity in male and female may then occur in the absence of an hormonal context. This is not an immediately obvious finding; Penaloza C"}
+{"text": "Frontiers in Neurology, on the treatment of West syndrome (WS) by using valproate as monotherapy, prompted us to rethink about the past and present treatment strategies and the outcome in this severe epileptic syndrome.The recent article by Chandra et al. , publishEven though the study by Chandra et al.  leaves sHistorically, some previous studies in children with WS, which employed valproate as monotherapy, proved effective in controlling either hypsarrhythmia and/or the epileptic spasms \u20136. BesidOverall, the treatment strategies in WS [either the first-line treatments  or the more classical non-golden treatments ] are based on the assumption that an early initiation of therapy coupled with a rapid control of seizures in these patients may prevent the arrest or the decline in cognitive development.clinical spasms with onset in infancy is wider than previously thought and is currently comprised under the umbrella term of Infantile Spasms syndrome (ISs), which defines an epileptic syndrome (occurring in children younger than 1\u2009year\u2009\u2013 rarely older than 2\u2009years), with clinical  spasms usually occurring in clusters whose most characteristic EEG finding is hypsarrhythmia . WS refers to a form (a subset) of ISs, characterized by the combination of clustered spasms and hypsarrhythmia on an EEG. Additional (less common) phenotypes falling within the ISs include the so-called infantile spasms single-spasm variant (ISSV: in which spasms may occur singly rather than in clusters), hypsarrhythmia without infantile spasms [HWIS: in which hypsarrhythmia can be  recorded without any evidence of clinical spasms], and infantile spasms without hypsarrhythmia  . There  Osborne . Notably Osborne . In thisFor all the above reasons, the results of Chandra et al.  highligh"}
+{"text": "Atrial fibrillation (AF), as a sustained arrhythmia, is featured by uncoordinated atrial activation with the consequent deterioration of mechanical function in the atrium (Mestroni, Three classical models have been proposed for the genesis of AF, including focal activity, single-circuit reentry, and multiple-circuit reentry model (Fatkin et al., Although AF is a most prevalent type of arrhythmia, its genetic etiology remains unclear (Franco et al., Pitx2a, Pitx2b, and Pitx2c (Schweickert et al., Pitx2d is also expressed in human, functioning as a dominant negative protein (Cox et al., The Pitx2 gene mainly encodes three distinct isoforms including The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Rhizobia are also controlled by systemically regulated or autoregulated processes on top of the basic innate immunity response. The induction of systemic immunity responses like ISR (induced systemic resistance) by some beneficial rhizosphere bacteria or the SAR (systemic acquired resistance) response provoked by pathogens are results of multiple response cascades employed by the plant host to respond to microbial and other environmental interactions. However, the entire response network is by far not yet revealed. For example, bacteria-induced plant responses resulting in improved resistance towards pathogens can also be due to the perception of secondary metabolites, like the surfactin lipopeptide, produced by certain biocontrol Bacilli  such as chitin or lipochitooligosaccharides, peptidoglycan, lipopolysaccharides or flagellum structures, and the initiation of efficient plant defence reactions  type is tightly regulated in response to cell density or the cell \u201cquorum\u201d  or pathogenic (Pseudomonas aeruginosa) bacteria provoked at concentrations as low as nano- to micromolar significant changes in the accumulation of over 150 proteins. Auxin-responsive and flavonoid synthesis proteins were induced and also a secretion of plant metabolites that mimic QS compounds were found, which may have the potential to disrupt QS signaling by associated bacteria. In tomato plants, a specific induction of systemic resistance proteins after inoculation of the roots with C4- and C6-side chain AHL-producing Serratia liquefaciens MG1 was discovered independently  in MG1-inoculated plants. Furthermore, Serratia plymuthica HRO-C48, producing C4-/C6- and OHC4-/OHC6-homoserine lactones, is able to induce ISR-like systemic protection of bean and tomato plants against the fungal leaf pathogen Botrytis cinnera; this response was greatly reduced with mutants impaired in AHL-production  N-acyl AHL-compounds in a different manner: C4- and C6- homoserine lactones alter the expression of selected hormonal regulated genes which results in changes of the plant's hormone content, in particular an increased auxin/cytokinin ratio   Urban) (G\u00f6tz et al., Lotus corniculatus produce lactonases which degrade AHLs and prevent their uptake and transport. In barley, it could further be demonstrated that C8- and C10-AHLs are taken up in a cell energy dependent manner by ABC-transporters into the root and transported via the central cylinder into the shoot (Sieper et al., The first demonstration of specific responses of a plant to bacterial AHLs was demonstrated for the legumes o et al.  found thu et al.  and Jin u et al.  demonstrRhizobia (P\u00e9rez-Montano et al., Gypsophila was shown to influence QS, type III secretion system and gall formation activity by Pantoea plantarum (Chalupowicz et al., Serratia marcescens 90\u2013166 (Ryu et al., Interestingly, several plants have been demonstrated to produce AHL-mimic substances or to develop other activities influencing QS of plant associated bacteria (Gao et al., Pseudomonas aeruginosa, was shown to selectively impair the regulation of the nuclear transcription factor NF-\u03ba B which controls innate immune responses in mammalian cells (Kravchenko et al., N-acylhomoserine lactones as modifying bacterial effector molecules.Uptake of AHL-compounds and specific perception of AHLs in animal cells were also studied intensively in recent years (Teplitski et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We discuss the cellular machinery required for CIL and the molecular signals that regulate it. We focus on our recent finding that in prostate cancer cells, Contact inhibition of locomotion is regulated by a balance between EphA and EphB receptor signalling. We show that, as recently described for chick heart fibroblasts, microtubule dynamics are required for Contact inhibition of locomotion in prostate cancer cells and we propose that stabilization of microtubules could account for defective Contact inhibition of locomotion between cancer cells and noncancer cells.Contact inhibition of locomotion (CIL) occurs when a cell stops migrating in a particular direction upon contact with another cell. Many cancer cells show Contact inhibition of locomotion when contacting one another but display contact-unimpeded migration following collision with noncancer cells. Here we review current understanding of Contact inhibition of locomotion, from Abercrombie's historical studies of cells in tissue culture to more recent analyses of Contact inhibition of locomotion  This indicates that CIL has occurred. However, when PC-3 cells are treated with EphA2/EphA4 siRNA, the difference between free migration and migration following contact was significantly reduced, indicating that these cells do not display CIL . There is no significant difference between the free and contact Cx values of taxol-treated cells indicating that taxol treatment leads to failure of CIL  and suggests that defective CIL in heterotypic collisions between PC-3 cells and fibroblasts is mediated by EphB3 and EphB4 signalling. DU-145 cells may not display defective CIL because they do not have increased expression of EphB receptors and so EphA signalling predominates and CIL occurs in heterotypic collisions between DU-145 cells and fibroblasts (Astin et al., Reverse-transcription PCR profiling of the Eph receptor and ephrin expression in PC-3 and DU-145 cells indicated that PC-3 cells have increased expression of EphB3 and EphB4 compared to DU-145 cells (Astin Here we show that CIL between prostate cancer cells is regulated by EphA receptors, specifically EphA2 and EphA4. These receptors appear to act together to coordinate CIL. By contrast, PC-3 cells display contact-unimpeded migration following collisions with fibroblasts. We find that this is due to their increased expression levels of EphB3 and EphB4, which engage ephrin-B2 expressed on fibroblasts. Knockdown of these two EphB receptors can restore CIL between PC-3 cells and fibroblasts. We propose that during cell\u2013cell collisions, cell migratory responses are regulated by a balance between repulsive EphA versus attractive EphB signalling.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Recently, we have shown that Cdc42 is activated downstream of EphB receptors while RhoA is activated following EphA receptor activation (Astin et al., et al., et al., et al., et al., Our finding that EphB4 is increased in the more metastatic cell line, PC-3, compared to the less metastatic prostate cancer cell line, DU-145, is consistent with previous reports (Xia in vitro and in vivo (Abercrombie & Heaysman, et al., et al., et al., Since Abercrombie's early observations on the social behaviour of migrating cells in tissue culture, several studies have shown that CIL is an important process in defining the migratory behaviour of cells"}
+{"text": "Endothelial dysfunction is the hallmark of hypertension, which is a multifactorial disorder. In the cardiovascular system reactive oxygen species play a pivotal role in controlling the endothelial function and vascular tone. Physiologically, the endothelium-derived relaxing factors (EDRFs) and endothelium-derived contractile factors (EDCFs) that have functions on the vascular smooth muscle cells. The relaxation induced by the EDRFs nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarization factor (EDHF) could be impaired in hypertension. The impaired ability of endothelial cells to release NO along with enhanced EDCFs production has been described to contribute to the endothelium dysfunction, which appears to lead to several cardiovascular diseases. The present review discusses the role of oxidative stress, vascular endothelium, and vascular tone control by EDRFs, mainly NO, and EDCFs in different models of experimental hypertension. Hypertension is a multifactorial disorder that involves many mechanisms leading to risk factors for cardiovascular diseases. Endothelial dysfunction is defined as the imbalance between the production and bioavailability of endothelium-derived relaxing factors (EDRFs) and endothelium-derived contractile factors (EDCFs), associated with increased bioavailability of oxygen reactive species (ROS) and decreased antioxidant capacity characterized as oxidative stress. In this review we will discuss the involvement of oxidative stress and vascular endothelium as well as the importance of vascular tone control, relaxation, and contraction in hypertension.4), flavin-adenine-dinucleotide, flavin-mononucleotide, and nicotinamide-adenine-dinucleotide-phosphate  and hydrogen peroxide (H2O2) increase arginase activity/expression in the endothelial cells. This should lead to NOS uncoupling with reduced NO production and augmented superoxide anion (O\u22122) production. As shown by Romero et al. , which convert L-arginine and molecular oxygen to L-citrulline and NO, using such co-factors as tetrahydrobiopterin  or Ser1179 (bovine) activates eNOS  or Thr497 (bovine) decreases its activation  revealed higher baseline NO and H2O2 concentrations than normotensive rats  -mediated activation of NADPH oxidase (Heitzer et al., 495 residue in the Ca2+/CaM binding domain by PKC (Mount et al., 495 dephosphorylation results in eNOS uncoupling and O\u22122 production rather than NO generation (Lin et al., 495 eNOS phosphorylation site is more phosphorylated in hypertension or contains uncoupled eNOS remains unknown.Increased ROS bioavailability, decreased antioxidant capacity, or both occur in many models of hypertension such as SHR (Suzuki et al., 4 supplementation reverses the effect of uncoupled NOS induced by TERPY (Bonaventura et al., We have investigated the vascular mechanisms involved in the vasorelaxation induced by NO donors that present potential capacity to replenish vascular NO upon reduced NO bioavailability. Most of the studies using NO donors are performed on endothelium-denuded arteries to avoid interference of endogenously produced NO (Bonaventura et al., A and ETB receptors. ETA receptors are expressed on smooth muscle cells and promote contraction. ETB receptors are located on endothelial and smooth muscle cells, with opposite effects. Smooth muscle ETB activation evokes contraction, whereas endothelial ETB activation induces relaxation (Taddei et al., The altered function of endothelial cells leads to enhanced contraction (Endemann and Schiffrin, The SHR aorta exhibits a characteristic endothelial dysfunction that is not due to decreased EDRF release, but it is the result of simultaneous EDCF release. Indomethacin, a non-selective COX inhibitor, restores the blunted relaxation in SHR aorta to the level of normotensive (L\u00fcscher and Vanhoutte, 2, TXA2, and ROS are proposed as COX-derived EDCFs. Increased endothelial [Ca2+]i is required to evoke EDCF-mediated responses. Dysfunction in Ca2+ handling within the endothelium is important for the exacerbation of endothelium-dependent contractions in SHR aorta (Tang et al., Endoperoxides, PGI2O2 modify the vascular activity of NOS and COX in concentration-dependent way (Cai et al., 2 evokes vasorelaxation, whereas in aging animals or SHR it induces contraction (Vanhoutte, Independent of the genesis of hypertension, specific ROS such as HInhibitors of COX (Taddei et al., In conclusion, the data presented in this work suggest that decreased NO availability along with enhanced EDCFs production contribute to the endothelium dysfunction and impaired vascular relaxation in hypertension Figure . ConsideThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Our article reports a meta-analysis of available evidence on high-dose chemotherapy followed by autologous stem cell transplantation for primary breast cancer. A previous publication by Berry et al. reported a closely related meta-analysis and the authors regret not citing this article:Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous stem cell support as adjuvant therapy in breast cancer: Overview of 15 randomized trials. J Clin Oncol 2011;29:3214-3223Berry et al. provide evidence that high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) support prolongs relapse-free survival but does not improve overall survival in patients with high-risk primary breast cancer. In our subgroup analysis, age and hormone receptor status had a significant interaction with OS. In the study by Berry et al., OS was statistically different by treatment arm in the subgroup for women with both hormone receptor-negative and HER2-negative tumor, for whom there was a 33% reduction in the risk of death. The hypothesis suggest that this breast cancer category presents increased sensitivity to dose intensification of alkylating agents and should remain the subject of clinical HDCT studies.While our meta-analysis evaluated publication bias and heterogeneity in the included studies, our analysis did not include an analysis of individual patient data, which Berry et al. did carry out. The lack of an analysis on individual patient data can be considered as a limitation of our meta-analysis."}
+{"text": "Physiotherapy is concerned with identifying and maximizing movement potential, within the spheres of promotion, prevention, treatment and rehabilitation. Physical therapists practice in a broad range of inpatient, outpatient, and community-based settings such as hospice and palliative care centers where as part of a multidisciplinary team of care, they address the physical and functional dimensions of the patients\u2019 suffering. Physiotherapy treatment methods like therapeutic exercise, electrical modalities, thermal modalities, actinotherapy, mechanical modalities, manual physical therapy and assistive devices are useful for a range of life-threatening and life-limiting conditions like cancer and cancer-associated conditions; HIV; neurodegenerative disorders like amyotrophic lateral sclerosis, multiple sclerosis; respiratory disorders like idiopathic pulmonary fibrosis; and altered mental states. The professional armamentarium is still expanding with inclusion of other miscellaneous techniques which were also proven to be effective in improving quality of life in these patients. Considering the scope of physiotherapy in India, and in palliative care, professionals in a multidisciplinary palliative care team need to understand and mutually involve toward policy changes to successfully implement physical therapeutic palliative care delivery. World Confederation for Physical Therapy (WCPT) defines Physical Therapy as; \u201c\u2026 providing services to people and populations to develop, maintain and restore maximum movement and functional ability throughout the life-span. Physiotherapy includes the provision of services in circumstances where movement and function are threatened by the process of ageing or that of injury or disease. Full and functional movement are at the heart of what it means to be healthy. Physiotherapy is concerned with identifying and maximizing movement potential, within the spheres of promotion, prevention, treatment and rehabilitation. Physiotherapy involves the interaction between physiotherapist, patients or clients, families and care givers, in a process of assessing movement potential and in establishing agreed upon goals and objectives using knowledge and skills unique to physiotherapists\u201d.Physical therapists practice in a broad range of inpatient, outpatient, and community-based settings, including the following:Hospitals Outpatient clinics or officesRehabilitation facilitiesSkilled nursing, extended care, or subacute facilitiesHomesEducation or research centersSchools and playgrounds Hospices or palliative care centersCorporate or industrial health centersIndustrial, workplace, or other occupational environmentsAthletic facilities Fitness centers and sports training facilities.Physiotherapists play an inherent role in the multidisciplinary palliative care team emphasizing on improving function and quality of life in patients who are deemed to require physical and functional dimensions of care. PhysicalFunctional dimension is defined as one\u2019s perceived ability to perform accustomed functions and activities of daily living, experienced in relation to expectations and adaptations to declining functionality. Functionet al.[Inspite of most of population being rural, the current status of medical personnel and facilities in our country is scarce; with only 34% of physicians and 25% of all hospital beds are available in rural areas. Nursing is considered as a low-status job and is not a much-sought-after profession for young people. Hence the need for an efficient allied health professional to fill in the current needs of palliative care team sees the emergence of physical therapists, with their thorough professional background and clinical expertise, as invaluable members in the team of care.Physicians address the physical dimension to their extent and nurses in functional dimension. Addressing both the aspects simultaneously can be more beneficial for the patient. Considering the current healthcare scenario in India as reported by Seamark et al. Inspite The objective of this paper is to update the palliative care clinicians, physical therapists and other team members on the role of a physical therapist in a palliative care team by detailed view of physical therapy treatment methods and their evidence for application into conditions requiring palliative care.It comprises passive movement, assisted active movement, active movement, assisted-resisted active movement, and resisted movement techniques. The techniques can be applied in anatomical planes or as functional movement direction. The techniques can be performed on land or in water. The latter is termed as \u201chydrotherapy\u201d. Best examples of therapeutic exercise techniques are relaxation, massage, suspension therapy, muscle- re-education, progressive resisted exercise, floor aerobics, active mobility exercises, mobilization and stabilization exercise, proprioceptive neuromuscular facilitation (facilitation and inhibition techniques); breathing exercise; postural training; work simulation, work conditioning and work hardening; graded activity program and cognitive-behavioral training. ExerciseLow-frequency modalities like neuromuscular electrical stimulation  and functional electrical stimulation, iontophoresis, high-voltage pulsed galvanic current, transcutaneous electrical nerve stimulation (TENS) and diadynamic currents; medium frequency modalities like Russian currents and Interferential therapy. High frequency modalities are usually grouped under deep-heating modalities under thermal modalities. Electrical modalities are very useful adjuncts in pain management.Cryotherapy ; superficial heating agents ; hydrotherapy (whirlpool and contrast bath). Thermal modalities are effective adjuncts to exercise and/or electrical modalities.Traction therapy, compression therapy, therapeutic taping and continuous passive motion. Compression therapy can be very useful in managing lymphedema.Ultraviolet, LASER, Extracorporeal Shock Wave therapy are useful in selected situations.Biofeedback is useful in patients with limited cognitive abilities and neuromuscular dyscontrol.Massage, deep transverse frictions, myofascial release, trigger point therapy, muscle energy techniques, motor control retraining.Joint mobilization using passive physiological and passive accessory (joint play) movements, combined movements, mobilization with movements, manipulation (high-velocity low amplitude thrust techniques).Neurodynamic techniques of neural tissue loading and nerve massage.Manual physical therapy techniques are used in a variety of settings ranging from hospital-based to home-based. The effects of the techniques depend upon the skills of the handling therapist.Orthosis- splints/ braces: supportive devices for the body parts.Prosthesis: artificial limbs.Mobility aids: locomotor training devices like wheelchair, prone crawlers.Walking aids: canes, crutches and walkers.Assistive devices are useful for training functional activities for patients with limited function.et al,[et al,[Pate et al, and Bryal,[et al, reportedl,[et al,Toot in additet al,[Laakso emphasizet al, said, inOxford Textbook of Palliative Medicine, as follows;The importance of physical therapy is widely stated in the most-read textbook- Physiotherapy aims to \u201coptimise the patient\u2019s level of physical function and takes into consideration the interplay between the physical, psychological, social and vocational domains of function\u2026\u2026 The physiotherapist understands the patients underlying pathological condition, but this is not the focus of treatment. The focus of physiotherapy intervention is, instead, the physical and functional sequelae of the disease and/or its treatment, on the patient.\u201d[patient.\u201dPhysiotherapy aims to: maintain optimum respiratory function; maintain optimum circulatory function; prevent muscle atrophy; prevent muscle shortening; prevent joint contractures; influence pain control; optimize independence and function; and, education and participation of the carer.The following section describes the role of physical therapy in common conditions that require palliative care.Physical therapists have a very important role to play in holistic care of patients diagnosed with cancer as stated by Flomenhoft and RashPhysical therapy treatment techniques have also been reported in cancer-related fatigue by Watson and Mock, breast c2023et al,[et al,[Narayanan and Koshy emphasizet al, said thal,[et al, performeThe Chartered Society of Physiotherapy (CSP)\u2019s evidence summary emphasizes the effectiveness of physical therapy in the palliative care of older people. Physicalet al,[Multiple sclerosis (MS) is the met al, also fouet al,et al,[Weih et al, performeet al,[et al.[et al,[et al,[The use of motor imagery (MI)\u2014presumed to be a visual and kinesthetic neural representation of the overt behavior\u2014has relied on two major assumptions. The first assumption is that the internally generated movement patterns involve the same neuronal correlates as the overt behaviors . Second, it assumes that using MI will lead to cortical and subcortical neuronal modification that is of benefit to a person who has experienced a stroke. Mental practice as an effective technique for locomotor training and rehabilitation was also employed in most neurological conditions as found in their comprehensive review by Malouin and Richards.[Ginis et al, reportedl,[et al. Katz et l.[et al, earlier l,[et al, in theirl,[et al, mentioneRichards.The role of physical therapy in palliative care of patients with respiratory disorders ranges from home-based care such as training symptom control for cough and breathlessness to providing interventions such as airway clearance techniques in the intensive and critical care units in hospital-based rehabilitation. The renowned professional body for respiratory and cardiac conditions, the American Thoracic Society emphasisPulmonary rehabilitation is a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy. ATS has listed four essential components of pulmonary rehabilitation as; (1) exercise training , (2) education , (3) psychosocial and behavioral intervention , and (4) outcome assessment. This was also mentioned by Lanken et al,[en et al, that pulThe therapeutic efficacy of pulmonary rehabilitation was demonstrated convincingly in many systematic reviews and randomized controlled trials and hence physical therapy in the form of exercise training in globally accepted and widely practised position statements and treatment guidelines.et al,[Nici et al, mentioneet al,[Of the respiratory disorders requiring palliative care, the most life-limiting condition is idiopathic pulmonary fibrosis. Raghu et al, stated tet al, reportedet al, physicalKeenleyside and Vora recommenLeGrand stated tSachs and Weinberg explaineet al,[Emery et al, found exCiesla elaboratThe reported benefits of formalized exercise training to an informal recreational physical activity in chest physical therapy also extended to include systemic conditions like chronic renal failure to have positive effects on quality of life by Eng and Ginis. Also selet al,[et al,[et al,[et al,[Palliative care improved outcomes in patients living with HIV or AIDS. Home palliative care and in-patient hospice care improved a number of patient outcomes, particularly in terms of pain and symptom control, anxiety, insight and spiritual well-being. Harding et al, also stal,[et al, and hencl,[et al, 2005, O\u2019l,[et al, found aeet al,[et al,[et al,[et al,[Earlier proponents like O\u2019Brien et al, and O\u2019Brl,[et al, advocatel,[et al, in anothl,[et al, found cosound mind and a sound body\u201d and authors like Wilfey and Kunce[et al,[Exercises as a treatment for altered psychological states have been through over the years grounded on the principle, \u201cand Kunce and Tuckand Kunce found eace[et al, also fouThough exercise had been a part of behavioral medicine for treating altered physiological states like obesity, diabetes, cardiovascular risk modification and smoking according to Martin and Dubbert, through et al,[et al,[et al,[et al,[Exercise therapy programs such as aerobic exercise training was shown by McCann and Holmes to positet al, confirmeet al, for anxiet al, who founl,[et al, found chl,[et al, found exl,[et al, found adSteptoe and Cox found thTkachuk and Martin in their84Though theoretically not part of physical therapy, physical therapists are trained in the following techniques and they do perform these in their regular practice.Tarler-Benlolo emphasizet al,[EMG Biofeedback, exercise91et al, and exeret al, was showet al, and, Qiget al,Other complementary therapies which are often included in physical therapist\u2019s treatment armamentarium are acupuncture, aromatherapy, reflexology, relaxation and massage.Massage therapy as a complementary therapy technique for feet and handPhysical therapy was shown to have positive influence on quality of life and perceived well-being in a wide range of patient populations requiring palliative care such as cancer, HIV, neurological disorders, cardiopulmonary conditions and mental illnesses.The scope of physiotherapy practice is influenced by the ratio of qualified physiotherapists to the population. The number of physiotherapists per head of population in India is 1:212,000. This oftet al,[Meier et al, suggesteFuture studies are warranted on the following aspects;Assessment of knowledge, attitudes, beliefs and experiences toward palliative care among physical therapistsEvolution of a palliative care training program for physical therapists.Qualitative research on experiences of palliative care team members with physical therapistsInfluence of physical therapy on patient and caregiver perceptions and quality of life in other palliative care conditions.The authors wish to recommend three approaches to improve physical therapy in palliative care.Improving professional knowledge and skillsChanging professional attitudes toward care at end-of-lifeRecognizing the palliative care healthcare system in India.Coming together is the beginning, keeping together is progress, working together is success\u201d\u201c- Henry Ford."}
+{"text": "Mitochondrial outer membrane permeabilization (MOMP) is the ultimate step in dozens of lethal apoptotic signal transduction pathways which converge on mitochondria. One of the representative systems proposed to be responsible for the MOMP is the mitochondrial permeability transition pore (MPTP). Although the molecular composition of the MPTP is not clearly understood, the MPTP attracts much interest as a promising target for resolving two conundrums regarding cancer treatment: tumor selectivity and resistance to treatment. The regulation of the MPTP is closely related to metabolic reprogramming in cancer cells including mitochondrial alterations. Restoration of deregulated apoptotic machinery in cancer cells by tumor-specific modulation of the MPTP could therefore be a promising anti-cancer strategy. Currently, a number of MPTP-targeting agents are under pre-clinical and clinical studies. Here, we reviewed the structure and regulation of the MPTP as well as the current status of the development of promising MPTP-targeting drugs. Traditionally, MPTP has been regarded as a multimeric complex, which putatively consists of the voltage dependent anion channel (VDAC) in the OMM, the adenine nucleotide translocase (ANT) in the IMM, cyclophilin D (CyP-D)\u2014a mitochondrial matrix protein that exhibits peptidylprolyl cis-trans-isomerase activity, and some other proteins such as hexokinase (HK) ; pro-apoptotic multidomain proteins (Bax and Bak); pro-apoptotic BH3-only proteins  , promotes binding of Bcl-XL to VDAC, leaving Bax free from Bcl-XL. Free Bax interacts with Bak and/or Bax to form pore structures for the release of cytochrome c  -4-hydroxyphenyl]-2-naphthalene carboxylic acid) are well known to induce clinical remission in patients with APL  is an expanded porphyrin which displays an elevated oxidizing potential, thereby triggering excess generation of ROS  and dithiodipyridine (DTDP) can cause thiol oxidation of a critical cysteine residue (Cys 56) of ANT, through which BMH and DTDP may induce MOMP and cell death irrespective of the expression level of Bcl-2 (Costantini et al., Resveratrol, a polyphenolic compound from grapes and wine, can inhibit mitochondrial ATP synthesis and trigger MOMP (Fulda et al., Curcumin is a major constituent of turmeric powder from the plant Curcuma longa. Among several anti-cancer mechanisms of curcumin are the modulation of Bcl-2 family proteins and cellular ROS, inhibition of the NF-\u03ba B survival pathway, and inhibition of cyclooxygenase-2 (Divya and Pillai, Betulinic acid, a natural pentacyclic triterpenoid of the lupane class, is known to trigger mitochondrial apoptosis in cancer cells (Fulda et al., Berberine, an alkaloid derived from plants of the Berberidaceae family, has been shown to exert direct effects on mitochondria, including the interaction with ANT (Pereira et al., L on the OMM to prevent them trapping Bax, allowing free Bax to form OMM channels (Neuzil et al., in vitro data, which warrant further clinical trials with \u03b1-TOS (Neuzil et al., \u03b1-TOS, a vitamin E analogue, competes with ubiquinone in binding to Q sites of respiratory complex II, which results in the displacement of ubiquinone from complex II, disrupts the electron flux, and consequently generating ROS (Dong et al., Honokiol is a small molecule polyphenol isolated from the genus Magnolia (Fried and Arbiser, Again, GSK3 plays a role in the opening of the MPTP through the phosphorylation of CyP-D. In 206 osteosarcoma \u03c1\u00b0 cells with an extreme Warburg phenotype, constitutively active ERK was shown to oppose this signaling by phosphorylating and inhibiting GSK3 (Masgras et al., Mitochondria have pivotal opposing roles in energy generation for cell survival and cytochrome c release for apoptotic cell death. Although the concept of the MPTP is still evolving, mounting evidence indicates that the MPTP is directly responsible for cytochrome c release, leading to apoptotic cell death. Targeting the MPTP for cancer treatment has two advantages: tumor specificity and bypass of the resistance mechanisms. Metabolic reprogramming and mitochondrial alterations in cancer cells could provide important clues for developing tumor-specific anti-cancer agents. MOMP finally occurs as a consequence of upstream pro-apoptotic signaling events, which are frequently deregulated in many cancers and which become resistant to most classical anti-cancer agents that target upstream regulators of MOMP (Fulda et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Understanding the role of different proteins in controlling synapses formation and stabilization may help elucidating, at the network level, the mechanisms by which inhibitory transmission controls network excitability and oscillatory behavior, crucial for information processing in the brain.Aim of this e-book is to highlight recent advances in these processes, bringing together leading experts in the field, who have made major contributions to our understanding of the cellular and molecular mechanisms regulating the appropriate assembly, location, and function of pre and postsynaptic specializations at inhibitory synapses.This e-book comprises nine reviews, one perspective and three research articles organized in a logic way following the information flow from the pre to the postsynaptic site.via protein\u2013protein interactions across the synaptic cleft.In the first article, Jovanovic and Thomson  (School via postsynaptic calcium signals, triggered by the depolarizing action of GABA and activation of voltage-dependent calcium channels.Grantyn et al.  (Instituvia transcriptional and post-translational modifications.Early in postnatal life, the depolarizing action of GABA is crucial for the construction of neuronal circuits. This process depends on intracellular chloride homeostasis which is under control of the cation-chloride co-transporter KCC2. In addition, by interacting with actin cytoskeleton, KCC2 exerts, independently of its role on chloride homeostasis, a crucial role on spines morphogenesis. Chamma et al.  (INSERM In the following research paper, Bhumbra et al.  (DepartmA receptor antagonists or gating modifiers. GABA transient may limit the activation of postsynaptic receptors and their binding reaction to mono-ligand state, promoting low probability channel opening and fast deactivation kinetics.Once released from presynaptic terminals, GABA diffuses in the synaptic cleft and binds to postsynaptic receptors. This process is very fast and occurs in non-equilibrium conditions. Barberis et al.  (Departmtransporters may exert a homeostatic control on GABA release is put forward in a perspective article by Conti et al. (The intriguing hypothesis that GABA i et al.  (DepartmA receptor isoforms, physiologically relevant to phasic and tonic inhibition. The highest potency would be compatible with extrasynaptic receptors, containing the \u03b1 6 subunit and exposed, during spillover of GABA from synapses, to low agonist concentrations, while the lowest potency would be compatible with synaptic GABAA receptors containing the \u03b12/\u03b13\u03b2\u03b3 subunits, exposed, during vesicular release, to high agonist concentrations.In the following review, Mortensen et al.  (DepartmA-mediated conductance. They suggest that the \u03b2 3 subunit may be an important pharmacological target for the treatment of striatal disorders.Using a genetic approach, Janssen et al.  (DepartmA receptors and other ligand-gated ionic channels or G-protein coupled receptors co-localized on the postsynaptic membrane. The interaction may occur via a direct coupling between two receptors or via the activation of intracellular signaling pathways. Usually the interaction results in a reduced GABAergic inhibition with consequent disinhibition. A similar receptor\u2013receptor interaction may occur also at extrasynaptic sites to regulate tonic GABAA-mediated inhibition.Next, Shrivastava et al.  (DepartmSasso\u00e8-Pognetto et al.  (DepartmA receptors in front of presynaptic releasing sites, by directly interacting with several types of \u03b1-containing subunits. Its heterogeneity, obtained through alternative splicing and post-translational modifications, associated with complex biophysical properties of its domains leads to the construction of diverse structural scaffolds that can accommodate different GABAA receptor subtypes. Gephyrin is also recognized as a crucial hub for multiple signal transduction pathways and trans-synaptic signaling that ultimately impact on synaptic dynamics and synaptic plasticity.The complex and still \u201cenigmatic\u201d role of the scaffolding molecule gephyrin at GABAergic synapses is exquisitely reviewed by Tretter et al.  (DepartmPapadopoulos and Soykan  (Max-PlaA receptors subunits mRNA in the hippocampus and cortex of post mortem brains of individual suffering from alcohol dependence. Interestingly, the observed changes refer mainly to extrasynaptic GABAA receptors, which mediate tonic inhibition responsible for regulating basic neuronal excitability.Finally, Jin et al.  (Departm"}
+{"text": "Actin is a protein abundant in many cell types. Decades of investigations have provided evidence that it has many functions in living cells. The diverse morphology and dynamics of actin structures adapted to versatile cellular functions is established by a large repertoire of actin-binding proteins. The proper interactions with these proteins assume effective molecular adaptations from actin, in which its conformational transitions play essential role. This review attempts to summarise our current knowledge regarding the coupling between the conformational states of actin and its biological function. Proteins are essential building blocks of the living systems. They are involved in all the biological functions playing structural and/or regulatory roles. In most of the cases proteins are required to be adaptive, i.e., to change their structure and function under certain cellular conditions. A frequent example of this adaptation is the up and down regulation of their activity, which occurs in many cases through interactions with other proteins and/or small regulatory molecules. The conformational elasticity of the proteins is essential for their adaptive properties. In many cases the details of the relationship between the various conformational states and the functions of proteins are well established. In some cases the characterisation of the coupling between the structural transitions and the modifications in the biological function is not complete. As proteins are often central components of cellular machineries, the detailed description of their conformational dynamics is desirable.The interest in actin has extensively increased since its discovery by Straub  . In theiAfter some debate since the first report on actin as an intranuclear entity dated back to the 60s Lane,  actin alActin is not restricted to metazoans but can also be found in plants. Since the discovery of the actomyosin complex in plants [Vorobeva and Poglazov, Actin has a large repertoire of interacting partners including metal ions, nucleotides and actin-binding proteins, which attribute versatile functions to actin [Sheterline et al., It is essential to understand how actin can adapt and modify its conformation for the various biological processes, what cellular components are effective to regulate these conformational transitions and how these different structural states are coupled to the complex and tightly regulated mechanisms through which actin fulfils its manifold biological activity. Here we review the present knowledge on the conformational dynamics of actin from structural, spectroscopic and cellular biology studies of complexes that actin forms with its interacting partners. We will also attempt to discuss how these conformational differences contribute to the functional segregation of actin structures in living cells.Since its discovery in 1942 Straub,  from aceActin exists in both monomeric (globular or G-actin) and polymeric (filamentous or F-actin) form .. The fiUnder physiological ionic conditions actin monomers assemble into filaments. Actin polymerisation proceeds through kinetically distinct steps. It is initiated by the slow formation of actin nuclei (dimers/trimers), which serve as seeds for the subsequent filament elongation. During elongation more actin monomers associate to than dissociate from either of the two ends, which results in the net growth of both filament ends. The steady-state phase is characterised by a dynamic equilibrium where the length of the actin filaments remains constant, while actin monomers continually associate to and dissociate from the ends. In this dynamic equilibrium a stationery population of free actin monomers is established, called critical concentration, whose value lies between the critical concentration of the barbed and pointed end. Besides structural polarity, determined by the arrangement of actin protomers within the filament, actin filaments also exhibit a kinetic polarity, which is defined by the different monomer association and dissociation rates at the two ends. The barbed or plus end binds actin monomers faster than the pointed or minus end. Although its ATPase activity is not crucial for actin polymerisation, actin self-assembly is associated with the ATPase cycle, which powers treadmilling process Wegner, .The first high-resolution structural model of the actin filament at a resolution of 8 \u00c5 was proposed by [Holmes et al., fs range reflect the rearrangements of atoms/molecules, and these structural changes can be resolved by X-ray crystallography, electron microscopy (EM), cryo-EM and femtobiological approaches [Egelman, ns correlation times are related to the change in the restricted segmental motion of a monomer/protomer or a few neighbouring protomers and can be determined by time-dependent fluorescence anisotropy [Ikkai et al., Rather than being rigid structures, both monomeric and filamentous actin have remarkable conformational flexibility and adopt many various structural states in response to interaction with their partner molecules [Orlova and Egelman, Egelman, . The ns KD = 10\u221210 M) than ADP (KD = 10\u22128 M) [Neidl and Engel, KD \u223c10\u22129 M) is thought to be occupied by magnesium in cells [Estes et al., \u22121) [Schuler, Pi). This results in the appearance of an ATP/ADP-Pi cap at the barbed end, while the rest of the filament contains ADP-bound actin protomers [Brenner and Korn, Pi almost simultaneously, which results in homogeneous ADP-bound actin protomers along the whole filament [Yao et al., The main ligands that bind to the central cleft of the actin monomers are an adenosine nucleotide and a divalent cation  inset a Schuler, , which iSchuler, . In the The Holmes model postulated the importance of an interstrand hydrophobic plug-pocket interaction in filament integrity [Holmes et al., The importance of this cross-strand hydrophobic interaction and loop mobility in actin filament integrity was supported by disulfide cross-linking studies. These experiments showed that mutant G-actin\u2014in which the loop is locked to the protein backbone\u2014could not polymerise [Shvetsov et al., 2+-ADP actin monomers had lower steady-state phosphorescence emission anisotropy, and thus greater torsional flexibility than filaments polymerised from Mg2+-ATP actin monomers [Rebello and Ludescher, Cys374 in S1 and substantially greater intermonomer flexibility of filaments that were assembled from ADP-actin monomers than those assembled from ATP-actin monomers. These data suggest that more tenuous interprotomer connections are formed when the filament is polymerized from ADP-bound monomers [Nyitrai et al., The influence of the different nucleotides on the conformational dynamics of actin filaments was first demonstrated by the analysis of EM images of negatively stained actin filaments, and by dynamic elasticity and viscosity measurements of solutions of F-actin. These measurements suggested that actin filaments formed from ATP-actin monomers were more rigid than actin filaments assembled from ADP-actin monomers [Janmey et al., Lp = 9 \u03bcm), which suggests similar bending flexibilities [Isambert et al., 3\u2014which mimics the \u03b3-phosphate [Combeau and Carlier, Pi-state resulted in higher flexural rigidity of F-ADP-Pi-actin (Lp = 13.5 \u03bcm) compared to F-ATP, or -ADP-actin [Isambert et al., A detailed light microscopy analysis of the thermal fluctuations of fluorescently labelled F-actin showed that there was no difference in the persistence length of actin filaments assembled from either ATP-actin or ADP-actin monomers  [Hild et al., Gln137 close to the \u03b3-phosphate of the bound ATP. As Gln137 is implicated in the ATPase mechanism these structural rearrangements may be related to the regulation of ATPase activity of actin [Oda et al., Consistently, FRET measurements showed that the replacement of ATP by ADP in the nucleotide-binding cleft resulted in conformational changes that bring 3-F-actin and ADP-F-actin showed that the structure of S2 is more disordered in the ADP-state which results in breaking one of the longitudinal bonds and destabilization of the filament [Orlova and Egelman, Actin self-assembly and ATPase activity were also shown to alter the conformation of the DNase I binding loop (or D-loop)  inset c 2+-F-actin were shown to be higher compared to Ca2+-actin filaments using spectroscopic and EM approaches [Orlova and Egelman, 2+-F-actin than for Mg2+-F-actin [Nyitrai et al., Tightly bound cations can modify the conformational state of actin as well. Both the torsional and bending flexibilities of Mg2+-G-actin and Mg2+-G-actin in the range of 6\u201326 \u00b0C, while above 26 \u00b0C a conformational transition was detected in Ca2+-actin monomers [Nyitrai et al., 2+-F-actin was found to be lower than that of Ca2+-F-actin in the range between pH 6.5 and pH 7.4 [Hild et al., 2+-F-actin. The interprotomer connections were more rigid at both pH 6.5 and 7.4 in Mg2+-F-actin than in Ca2+-F-actin [Hild et al., Temperature-dependent FRET measurements revealed no difference between the flexibility of the outer domain (S1 and S2) of Ca2+-actin filaments was proved to be unaffected (Lp \u223c8 \u03bcm) when the filaments were polymerized at different pH values (between pH 5 and 9) [Arii and Hatori, 2+-F-actin increased from \u223c4.5 \u03bcm to \u223c9 \u03bcm as the pH increased from 5 to 9, suggesting higher mobility of actin protomers within Ca2+-F-actin at lower pH values [Arii and Hatori, 2+-actin and Mg2+-actin filaments as the pH decreased [Kron and Spudich, The persistence length of MgThe polymerisation of actin filaments was accelerated and the helical pitch between the protomers was increased by lowering the pH [Zimmerle and Frieden, The observations described above demonstrate that small ligands\u2014such as nucleotides and cations\u2014and also external conditions\u2014such as the pH\u2014modify the conformation of actin. Despite the large amount of accumulated data the biological function of these structural modifications remained somewhat ambiguous. Some observations indicated that ATP hydrolysis altered the thermodynamic and mechanical properties of actin filaments and their interactions with actin-binding proteins. These results led to the hypothesis that ATP hydrolysis may serve as a biological clock in living cells. The maturation of the filaments is sensed and reflected by the change in the nucleotide state, and thus in the conformation of actin filaments [Allen et al., In many cases, when the conformation of actin filaments is changed upon ligand-binding, the effects propagate along the filaments through the interaction of neighbouring actin protomers, i.e., through long-range allosteric interactions. Such allosteric interactions were reported for many actin-binding compounds Oosawa,  and are Amanita phalloides, is the best characterised so far. Phalloidin binds tightly to actin filaments, reduces the rate of Pi release [Dancker and Hess, Pi-actin , which suggests different interprotomer interactions in F-actin in the ADP-Pi state compared to the ATP-, or ADP state [Orban et al., Several actin-binding natural products that have cytotoxic activity exhibits cooperativity [Wieland and Faulstich, Jaspis johnstoni)\u2014also binds to actin filaments competitively with phalloidin [Bubb et al., Another cyclic peptide, jasplakinolide\u2014that can be found in a marine sponge  can alter the regulation of the cytoskeleton and/or bind directly to actin [Richard et al., Apart from these examples many other poisonous chemicals (such as for example jararhagin) [Costa and Santos, D. discoideum has 17 [Romans and Firtel, D. melanogaster and mammals have 6 genes [Fyrberg et al., The tuning of the conformation and thus cellular function of actin can be achieved by the various actin isoforms which coexist in living cells. Actin is expressed as a variety of isoforms generated by gene duplications. Yeasts have 1 actin gene [Gallwitz and Seidel, S. cerevisiae and D. discoideum actin filaments based on 3D helical reconstruction from EM images show that these actin filaments are similar in terms of the overall three-dimensional morphology, which confirms that these parameters were conserved through the evolution [Orlova et al., S. cerevisiae actin filaments than in muscle actin [Orlova and Egelman, S. cerevisiae actin protomers than in muscle actin [Orlova et al., S. cerevisiae actin filaments by time-dependent phosphorescence anisotropy decay measurements indicated higher torsional flexibility for yeast F-actin than for muscle F-actin [Prochniewicz and Thomas, S. cerevisiae G-actin compared to muscle actin in the barbed end, in the region of S1 and S2 and in protomer-protomer contact areas within the actin filaments as well [Stokasimov and Rubenstein, S. cerevisiae F-actin [Orlova et al., D. discoideum F-actin in the Ca2+-bound form displays less extensive interstrand contacts between the two long pitch helix than muscle actin, while these contacts are more massive in D. discoideum F-actin in its physiologically relevant Mg2+-bound form [Steinmetz et al., D. discoideum Mg2+-F-actin is longer (Lp = 4.2 \u03bcm) than that of the D. discoideum Ca2+-F-actin (Lp = 1.6 \u03bcm) or the muscle Mg2+-F-actin (Lp = 2.3 \u03bcm). Therefore, the enhanced interstrand connectivity seems to provide the structural basis for the altered bending flexibilities of the actin filaments.Available structural analyses of rabbit muscle, 2+-actin filaments were thermodynamically more stable than the \u03b1-skeletal Mg2+actin filaments. On the other hand, \u03b1-cardiac Mg2+-actin filaments are more stable than the \u03b1-cardiac Ca2+-actin filaments [Orban et al., The muscle specific \u03b1-skeletal and \u03b1-cardiac actin isoforms differ only in four amino acids [Vandekerckhove and Weber, Although the experiments of recent years have shed light on many aspects of the isoform specific functional variations of actin, the understanding of how these conformational dynamics differences of polymers assembled from different actin isoforms contribute to the isoform specific functions demands further investigations.Apart from small ligands and peptides described above actin interacts with a large number of partner proteins. These proteins can change the conformation of actin when regulating its biological functions. Although the coupling between these structural-functional changes is not completely understood yet, there are indications that the actin-binding protein induced structural modifications are established for certain biological functions. In the next session we attempt to provide examples for these conformational changes.2+-F-actin [Orlova and Egelman, Pi is bound to myosin) the binding of myosin subframent-1 was not cooperative and was accompanied by a smaller change in the microsecond rotational dynamics of F-actin than in the rigor state [Prochniewicz et al., Myosins interact with actin in all of their known biological activities. As a classic example, myosins play special and central role in the manifestation of muscle contraction [Geeves et al., A recent study has found evidence that the effect of the myosin on the conformation of actin depends on the myosin isoform as well [Prochniewicz et al., The field focusing on the functions of various myosins is large and growing. It is well established that the specialised forms of myosins play essential roles in many biological functions in synergic interactions with actin. Despite the decades of investigations the information regarding the conformational effects of myosins on the structural and dynamic properties of actin filaments is limited, indicating that further investigations will be needed to properly describe and understand the biological functions of these interactions.2+-ATP actin monomers in a nucleotide dependent manner (KD(Mg-ATP) = 2 \u03bcM, KD(Mg-ADP) = 80 \u03bcM) [ is a small (5kDa) WH2-domain (Wiskott-Aldrich syndrome protein-homology 2) containing protein. It sequesters actin monomers by forming a 1:1 nonpolymerisable complex with them, which does not participate in actin assembly at either end of the filament [Cassimeris et al., 2+-ATP-G-actin at intermediate rates (100\u2013400 s), which suggests that the conformational dynamics of G-actin is restricted upon T\u03b24-binding [De La Cruz et al., Trp and the Tyr band of the near-UV CD spectrum of Mg2+-ATP-G-actin [De La Cruz et al., Tyr residues around the nucleotide binding cleft led to the proposal that the nucleotide binding cleft is narrower in the T\u03b24-G-actin complex. In support of this, FRET measurements showed that T\u03b24-binding decreased the distance between probes attached to Lys61 (S2) and Cys374 (S1) and to Lys61 (S2) and \u025b-ATP, while increased the distance between Gln41 (S2) and Cys374 (S1). This indicates that T\u03b24 rotates the D-loop towards the bound nucleotide away from S1 enclosing the nucleotide binding cleft [Dedova et al., Extensive spectroscopic and biochemical analysis revealed that T\u03b24-binding was accompanied by significant changes in the conformation of actin monomers [De La Cruz et al., KD = 0.1 \u2212 1 \u03bcM [Pantaloni and Carlier, Profilin is an essential actin binding protein that plays important role in controlling actin dynamics and actin-based motile processes. The structure of different profilin isoforms in complex with actin isoforms were solved by X-ray crystallography [Schutt et al., The high-resolution crystal structure of the profilin-actin complex shows that binding of profilin to G-actin results in the rotation of the two major domains by 4.7\u00b0 relative to each other in a \u2018clamp\u2019-like fashion, closing around the profilin and opening up the nucleotide-binding cleft [Schutt et al., ADF/cofilin (actin-depolymerising-factor) (AC) family of proteins can be grouped into five functionally distinct classes of actin-binding proteins  which are characterized by the presence of the ADF homology (ADF-H) actin-binding module [Lappalainen et al., An extensively studied member of the AC protein family is ADF/cofilin that contains a single ADF-H domain. ADF/cofilin binds both G-, and F-actin, preferentially their ADP-bound form in a 1:1 and 2:1 stoichiometry, respectively [Hayden et al., Gln41 (S2) and Cys374 (S1) [Dedova et al., Lys61 (S2) and Cys374 (S1) [Blondin et al., The recently solved crystal structure of twinfilin's ADF-H domain in complex with a G-actin molecule reveals that the binding interfaces are located in the groove between S1 and S3 of actin [Paavilainen et al., Pi release from ADP-Pi-F-actin [Blanchoin and Pollard, The binding of ADF/cofilin to actin filaments exhibits a high degree of kinetic cooperativity [Hawkins et al., Gln41 (S2) and Cys374 (S1) in neighbouring protomers and an increase in their mobility, which suggests a more flexible protein matrix around the probes and loosening of the intermonomer contacts within the long-pitch strand of F-actin [Scoville et al., The atomic model of ADF/cofilin-decorated F-actin revealed extensive contacts of the bound ADF/cofilin molecule with the outer domain of actin protomer [McGough et al., The analysis of the thermally driven fluctuations of fluorescently labelled actin filaments revealed that ADF/cofilin increased the bending flexibility and decreased the persistence length of actin filaments by 5-fold [McCullough et al., 2+-dependent severing activity, with gelsolin remaining bound to the barbed end of the severed filament [Hesterkamp et al., The gelsolin family consists of seven different proteins characterized by repeats of gelsolin-like (G) domains, including gelsolin, adseverin, villin, capG, advillin, supervillin and flightless I, which are involved in the regulation of actin dynamics [Silacci et al., Cys374. Further cross-linking and fluorescence measurements showed that the nucleation by gelsolin was promoted by conformational changes between the D-loop and the C-terminal of protomers, which propagate along the filament from the gelsolin capped barbed ends [Khaitlina and Hinssen, Helical reconstruction of cryo-EM images showed that by binding to the side of F-actin gelsolin bridges two neighbouring actin protomers within the short pitch helix, and induces distortions within the actin filament which may sufficiently weaken the noncovalent interactions to break and sever the filaments Bearer, . EM recoBoth in vitro and in vivo, the rate of the spontaneous polymerisation of actin is limited by the instability of the initial actin dimers/trimers. In cells, to overcome this kinetic barrier and regulate precisely the spatiotemporal initiation of actin structures, membrane-associated stimuli-dependent nucleation factors catalyze the de novo formation of actin filaments by unique mechanisms. The first identified nucleation machinery includes the WASP/WAVE/Scar proteins (Wiskott-Aldrich syndrome protein/WASP family verprolin homologous/suppressor of c-AMP response) which activate the Arp2/3 complex to generate a branched daughter filament from a pre-existing mother filament Pollard, . RecentlS. cerevisiae was also proposed to induce conformational changes within yeast actin filaments, which was indicated by the increase of the pyrene excimer fluorescence in formin-nucleated actin filaments [Wen and Rubenstein, The mechanisms by which nucleation factors catalyze filament assembly and regulate barbed end dynamics has been extensively studied over the past few years. For detailed information we direct the readers to recent reviews [Kerkhoff, Minor changes in the highly conservative amino-acid composition of actin can have deep impact on the structure of actin, its function and interactions with its partner molecules  [Bookwalter and Trybus, Mutations in actin are frequently manifested in the form of skeletal [Sparrow et al., Under in vitro conditions, the M132V nemaline actin mutant obtained from human biopsies was demonstrated to have lower polymerization capability and increased velocity in the actomyosin motility assay [Marston et al., The T278I mutation of the ACTG1 gene coded cytoskeletal \u03b3-actin can also cause autosomal dominant hearing loss [van Wijk et al., In the case of the familial hypertrophic cardiomyopathy some mutant actin  presented slower folding in vitro. The incorporation of the monomers into the filamental structure affected adversely as well [Vang et al., Besides mutations in actin itself, mutations in genes encoding actin-associated proteins also lead to genetic conditions. Dystrophin and its homologous utrophin are members of the spectrin-superfamily. These proteins are associated with the costameric cytoskeleton in striated muscle that circumferentially locates around the myofibrils in register with the Z-disk and physically couples the force-generating myofibrils to the sarcolemma Ervasti, . The mutThe effects of dystrophin and utrophin on the structural dynamics of actin filaments were studied with transient phosphorescence anisotropy. The results showed that both of these proteins altered the rotational dynamics of actin filaments [Prochniewicz et al., It is difficult to pinpoint in a simple model the biological function related to the conformational changes in actin monomers or filaments. The difficulty comes from two sources. Actin has various and complex biological functions and apparently it can effectively and relatively quickly adapt to many intracellular situations and binding partners. On the other hand there are a large number of molecules from small cations to proteins which contribute to the broad conformational landscape of actin. While these conformational changes are extensively studied in vitro, very little is known about the conformational dynamics of actin in the cellular environment. One of the aims of the previous sections of this review was to provide examples of these specific interactions and environments, and to give an overview regarding the role of the conformational state of actin.Although the described interactions were specific some of them could provide bases for a more general model regarding the regulatory function of actin conformation. Recent observations suggested that formins, a group of actin nucleation factors, could substantially change the conformation of actin filaments by making them more flexible [Bugyi et al., So far, the conformational dynamics of actin, and the effects of different factors were investigated in depth under in vitro conditions. Considering the rich variety of actin functions and the large amount of data accumulated in these studies some of the couplings between the structural changes and biological functions were revealed. In many other cases the complete understanding of the roles of intramolecular mechanisms in actin demands further studies. Cellular actin networks interact simultaneously with more proteins that can induce different changes in the conformational dynamics of individual actin monomers or filaments. How are these changes superimposed\u2014enhanced or dampened\u2014and determine the overall conformational dynamics of actin networks? How does the conformational dynamics of actin filaments play a role in the establishment of the functional properties of relevant actin networks? Recent advances in the development of novel technologies (such as fluorescence lifetime imaging microscopy (FLIM) or fluorescence anisotropy decay imaging microscopy (FADIM) [Suhling et al., fs to ms and can be measured by different approaches  of the rotation. The rotational correlation times describing the rotational motion of G-, or F-actin are distributed to a broad time scale; from ches see .mechanical property of actin filaments, it measures the resistance of the filament to an external twisting torque.mechanical property of actin filaments, it measures the resistance of the filament to bending forces.K) of F-actin by the following equation:describes the flexural rigidity of actin filaments. It equals the arc length of the filament over which the tangent angle at every point along the arc length correlates in three-dimensional motion. The persistence length is the distance over which the filament bends due to thermal fluctuations. The persistence length is related to the flexural rigidity (kB is the Boltzmann-constant and T is the absolute temperature. Actin filaments belong to the semiflexible polymers with typical persistence length of 0.1 \u2013 20 \u03bcm.where"}
+{"text": "The human genome harbors an impressive number of genes encoding enzymes that primarily metabolize or transport drugs or other xenobiotics (XMEs). Genetic and functional variation in these genes is tremendous and has complex consequences, depending, for example, on whether enzyme structure or expression is affected, or whether the produced metabolite is pharmacologically or toxicologically active or not. Despite numerous impressive examples of the impact of genetic variation on pharmacokinetics and drug response, today's knowledge is incomplete regarding most XME genes and fragmentary even for many well-investigated XMEs. This is one of the reasons why clinical pharmacogenetic studies are often controversial and clinical application in personalized medicine is presently limited. Advanced technology and ongoing large-scale projects are rapidly uncovering the existing genetic variation in all populations on earth, ultimately enabling the personal genome in the very near future. A wealth of mostly rare novel variants is awaiting functional characterization either by high-throughput expression/phenotyping techniques or by prediction using improved algorithms to estimate functional relevance.With this Research Topic we would like to give an up-to-date overview about the current knowledge in this field by covering both, known hard facts as well as cutting-edge advancement in novel genetic and genomic variation of XMEs and their functional consequences. Five major subtopics which include 20 research or review papers are included in this E-book. These are the following:Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine Lee, , review.Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance : resolving the puzzle (Stephens et al., MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? (de la Torre et al., Molecular interactions between NAFLD and xenobiotic metabolism (Naik et al., Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain (Ag\u00fandez et al., Clinical implications of XME gene variantsCYP3A4 in three South African populations (Dr\u00f6gem\u00f6ller et al., Characterization of the genetic variation present in Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the Chilean population: comparison with Caucasian and Asian populations (Roco et al., Pharmacogenomic diversity among Brazilians: influence of ancestry, self-reported color, and geographical origin (Suarez-Kurtz et al., Inter/intraethnic variability of XME gene variantsImpact of the interaction between 3\u2032-UTR SNPs and microRNA on the expression of human xenobiotic metabolism enzyme and transporter genes (Wei et al., CYP2C19 (Helsby and Burns, Molecular mechanisms of genetic variation and transcriptional regulation of Regulation of XME gene expressionImpact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia (Gervasini and Vagace, Multilocus genotypes of relevance for drug metabolizing enzymes and therapy with thiopurines in patients with acute lymphoblastic leukemia (Stocco et al., Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer (Vianna-Jorge et al., High-resolution melting analysis of the common c.1905+1G>A mutation causing dihydropyrimidine dehydrogenase deficiency and lethal 5-fluorouracil toxicity (Borr\u00e0s et al., Polymorphisms of phase I and phase II enzymes and breast cancer risk (Justenhoven, CYP2C8 gene rs11572080 with regard to colorectal cancer risk (Ladero et al., Analysis of the functional polymorphism in the cytochrome P450 Pharmacogenetics in cancer therapy"}
+{"text": "Easton (In speech-related fields, researchers had begun formulating ideas for modularizing speech movements even prior to Bernstein's influence. Cooper et al. , for ins. Easton  had firs. Easton  shifted . Easton , with liMeanwhile, researchers in other areas have built a substantial volume of experimental and modeling research around the neuromuscular organization and biomechanics of non-speech movement, including work on complex fine motor systems such as the fingers (e.g., Overduin et al., The great majority of evidence for modularization derives from experiments on non-human spinal structures (see Tresch et al., In our view, neuromuscular modules are built specifically to drive body structures that are biomechanically efficacious, enabling them to operate feed-forward, i.e., with little or no central feedback control. This has often been assumed as a premise underlying modularization (e.g., Loeb et al., While there remains some controversy around whether these modules are best defined in terms of their neural (e.g., d'Avella and Bizzi, Developing a theory of speech production that accords with current work on neuromuscular modularization, we believe, has the potential to link a number of fields and methodologies surrounding a central question in cognitive science, with implications for all aspects of speech research, from phonetics and phonology to the phylogenetic and ontogenetic development of speech. In addition to bringing another complex motor system into the broader discussion of neural modules, modularizing speech at the neuromuscular level promises a major advance for speech models, constituting a \u201cmissing link\u201d between speech movement primitives (Ramanarayanan et al.,"}
+{"text": "The arbitrariness of the linguistic sign is a fundamental assumption in modern linguistic theory. In recent years, however, a growing amount of research has investigated the nature of non-arbitrary relations between linguistic sounds and semantics. This review aims at illustrating the amount of findings obtained so far and to organize and evaluate different lines of research dedicated to the issue of phonological iconicity. In particular, we summarize findings on the processing of onomatopoetic expressions, ideophones, and phonaesthemes, relations between syntactic classes and phonology, as well as sound-shape and sound-affect correspondences at the level of phonemic contrasts. Many of these findings have been obtained across a range of different languages suggesting an internal relation between sublexical units and attributes as a potentially universal pattern. Linguistic theory widely adopts Saussure's  essentiaEmpirical evidence for such phenomena primarily comes from signed languages  sometimes further imitating the emotional impression they have on us, e.g., the German \u201cUff\u201d which transposes the ejected breath (ff) with which we instinctively express a reaction of relief into written German .According to Wundt , some onOrganon model, they also fulfill the conative/appealing function as in the calling (German \u201che\u201d) or the request to keep silent (German \u201cssst\u201d).Following Schrott and Jacobs , in inteTesting cross-cultural agreement in the understanding of phonological iconicity of interjections, Sauter et al.  asked nakyoro kyoro for \u201clooking around\u201d or \u201cspinning\u201d; Tamil thuru thuru for \u201ceager\u201d or \u201cactive\u201d). Following Dingemanse, sensory imagery is perceptual knowledge that derives from sensory perception of the environment and the body. Although scarcely represented in Indo-European languages, Atoda and Hoshino  but lack the central feature of compositionality to qualify as morphemes. They even appear across language borders in non-cognate-words of remote languages  also seem to depict sensory imagery and therefore might qualify as iconic mappings.According to Bergen , availabSapir  initiateMore recently, Pe\u00f1a et al.  reportedShrum et al.  extendedmaluma with a curvy round shape and takete with a spiky angular shape. The effect was subsequently labeled as \u201ckiki/bouba effect\u201d and replicated across a wide range of unrelated languages such as Himba (Bremner et al., Substantial evidence for phonological iconicity as a cross-linguistic phenomenon was derived from a seminal experiment of K\u00f6hler . Within Maurer et al.  found thDevelopmental and cross-linguistic studies strongly suggest an innate origin of iconic mappings. However, dependent variables used are offline measures and especially adults' judgments might reflect metacognitive strategies.To overcome this problem, Westbury  implemenUsing an implicit learning categorization task combined with EEG, Kovic et al.  presenteLikewise, Ramachandran points to possible synkinetic mappings of hand and jaw movements, controlled in two adjacent areas in the Penfield motor homunculus (Ramachandran and Hubbard, Building on their research on sound-size correspondences, Taylor and Taylor  asked moFocusing on real text instead of artificial word material, F\u00f3nagy  contrastIn a more general approach, Heise  extendedAryani et al.'  softwareAnother account of systematic mappings of phonology to affective dimensions was proposed by Zajonc et al. , who conSystematic form-meaning mappings are abundant in many languages, although not always necessarily iconic in nature. Yet, these latter ones hold strong implications for the essence of human language and its origin.Given the relatively small inventory of phonemes and the potentially infinite number of concepts to be expressed, the Saussureian principle of arbitrariness certainly remains a general key feature of human language Gasser, , allowinFay et al.  point inStrictly arbitrary relations between levels of phonology and semantics as assumed by psycholinguistic models (e.g., Levelt et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Schizosaccharomyces pombe. This simple model has contributed significantly to our understanding of how the cell cycle is regulated, and serves as an excellent model for studying aspects of cytokinesis. Here we will discuss the state of our knowledge of how the contractile ring is assembled and disassembled, how it contracts, and what we know of the regulatory mechanisms that control these events and assure their coordination with chromosome segregation. \u00a9 2011 Wiley-Liss, Inc.Cytokinesis is the final stage of the cell cycle, and ensures completion of both genome segregation and organelle distribution to the daughter cells. Cytokinesis requires the cell to solve a spatial problem  and a temporal problem (to coordinate cytokinesis with mitosis). Defects in the spatiotemporal control of cytokinesis may cause cell death, or increase the risk of tumor formation [ S. pombe model, giving references to reviews addressing aspects of fission yeast biology that are beyond the scope of this overview. As their common name implies, cells of the fission yeast Schizosaccharomyces pombe divide by medial fission, reminiscent of cell division of animal cells. The cells take the form of a cylinder capped by hemispherical ends. During interphase, cells grow mainly at their tips, with cell length being a measure of cell cycle progression. Upon commitment to mitosis, cells stop elongating and reorganize the actin and tubulin cytoskeletons in preparation for nuclear and cell division [McCully and Robinow,S. pombe. This has led to the use of this simple model system for studies addressing the regulatory and mechanistic aspects of cytokinesis, which have provided many insights into the regulation of this critical stage of the cell cycle. Cytokinesis is regulated by a group of protein kinases known as the septation initiation network (SIN). The SIN is essential for cytokinesis, and is coregulated with mitotic events, to ensure the coordination of mitosis and cytokinesis (see below). S. pombe. We will briefly introduce the S. pombe has a single, essential mitotic cyclin-dependent kinase (CDK), named cdc2p: its function is conserved in distantly related yeasts such as S. cerevisiae where it is named CDC28, and in human cells, where it is known as CDK1 [Beach et al.,Reorganization of the actin and tubulin cytoskeletons for mitosis and cytokinesis depends upon commitment mitosis and CDK activity [reviewed by Marks et al.,S. pombe [He et al.,S. pombe [reviewed by Martin,Unlike mammalian cells, fission yeast undergo a \u201cclosed\u201d mitosis, in which the nuclear envelope does not break down, and the spindle forms inside the nucleus [Hagan and Hyamsmid1 and pom1 [Huang et al.,The PH-domain protein mid1p, is a key factor of positioning CR at the medial cell cortex [Chang et al.,The second is nuclear export of mid1p at the G2/M transition, which targets mid1p to the cortex proximal to the nucleus [Sohrmann et al.,An elegant study from the Pollard lab [Wu et al.,When cells enter metaphase, F-actin and myosin II (myo2p) independently appear on the medial cortex and then interact with each other to form the CR [Naqvi et al.,for3-null mutant [Nakano et al.,de novo polymerization of F-actin is the dominant pathways for CR assembly in S. pombe. Actin subunits depolymerized from actin patches in cell tips are bound to profilin cdc3p [Balasubramanian et al.,S. pombe differs from animal cells, where assembly of the CR is induced after inactivation of CDK1 and anaphase onset. Formation of the S. pombe CR early in mitosis is mediated by mid1p, which acts as an organizing scaffold for the actin polymerization machinery and myo2p to the future division site. Mid1p has a C-terminal PH domain with low similarity to the metazoan cytokinesis proteins of the anillin family, which directly bind to both F-actin and myosin II [reviewed by D'Avino,In addition to myo2p, an IQGAP-like actin-crosslinking protein rng2p, the formin cdc12p, and the F-BAR protein cdc15p are also incorporated into cortical mid1p nodes in early metaphase, independently of F-actin [Wu et al.,mid1 mutant cells, although CR formation is not initiated at metaphase, myo2p associates with a cable-like F-actin structure elongating from the cell cortex during anaphase, resulting in formation of an abnormally shaped CR, which is frequently displaced from the cell middle [Huang et al.,S. pombe division is symmetrical while another system, probably SIN-mediated, supports CR-assembly. Interestingly, at least two other species of the Schizosaccharomyces genus, S. japonicus and S. octosporus do not have a clear ortholog of mid1p and in these organisms CR assembly is initiated during anaphase [Alfa and HyamsS. pombe, which is required for formation of the septin ring and cell separation in S. pombe [Berlin et al.,In S. pombe ortholog of the conserved CDC14-family of phosphoprotein phosphatases; it is implicated in many cellular processes, and is regulated by phosphorylation and localization [Cueille et al.,S. pombe. The CR is assembled stepwise during mitosis [Wu et al.,Flp1p/clp1p is the Drosophila POLO [Ohkura et al.,plo1, cdc7, or spg1 promotes CR and septum formation from any stage of the cell cycle, uncoupling the usual dependency of cytokinesis upon entry into mitosis [Fankhauser and Simanis,The SIN is a group of protein kinases which are essential for cytokinesis. Signaling requires the activity of three protein kinases, each of which has a regulatory subunit (kinase-regulator); cdc7p-spg1p [Fankhauser and Simanis,The SIN has been implicated in assembly of contractile actin ring (CR) [Hachet and Simanis,S. pombe SPB is composed of cytoplasmic and nuclear components which are separated by the nuclear envelope and connected by fine striations [Ding et al.,Laser ablation of SPBs in fission yeast during mitosis suggests that at least one SPB must be intact during anaphase B for cytokinesis to occur [Magidson et al.,sid4 or cdc11 block association of SIN proteins with the SPB, and prevent SIN signaling. Ectopic activation of the SIN in a sid4 mutant fails to promote septum formation, indicating that SPB association of SIN proteins is important for signaling [Balasubramanian et al.,The SIN proteins associate with the SPB via a tripartite scaffold comprised of ppc89p, sid4p and cdc11p [Chang and Gould,in vitro [Furge et al.,During interphase, spg1p, byr4p, and cdc16p are all observed at the SPB; cdc16p and byr4p are interdependent for localization [Sohrmann et al.,Spg1p in its GTP-bound form interacts with cdc7p during mitosis [Sohrmann et al.,spg1 and cdc7 [Guertin et al.,cdc7 mutants and some alleles of spg1 [Sparks et al.,The protein kinase sid1p and its regulatory subunit cdc14p appear at the new SPB only after the inactivation of CDK and onset of anaphase B [Guertin et al.,Biochemical analysis has shown that cdc16p, spg1p, mob1p, and cdc13p (the mitotic cyclin for cdc2p) all bind to the N-terminal domain of cdc11p [Morrell et al.,par1, the B\u2032 regulatory subunit of PP2A [Jiang and Hallberg,fin1 [Grallert et al.,The transition from the symmetric to the asymmetric configuration of the SIN and the initiation of septation requires inactivation of mitotic CDK [Yamano et al.,zfs1 and scw1 are RNA binding proteins [Beltraminelli et al.,cdc7 mutant at the permissive temperature [Mulvihill et al.,A number of putative regulators of the SIN have been identified genetically; S. pombe SIN in another yeast, Saccharomyces cerevisiae, is called the mitotic exit network (MEN). In addition to a role in cytokinesis, the MEN is required for the inactivation of CDK, and exit from the mitotic state into G1; for reviews, see [Burke,The biological counterpart of the ee Burke,. Many coee Burke,. Some coee Burke,. The kinee Burke,.As mentioned above, the SIN seems to be important for stabilizing the CR after onset of anaphase and to sustain assembly of CR components until cytokinesis is finished. The SIN and flp1p/clp1p, are both implicated in a cytokinesis checkpoint, which blocks the next round of mitosis in response to perturbed assembly of the CR [Le Goff et al.,Overexpression of C-terminal truncated cdc12p, probably corresponding to a dominant active form lacking the auto-inhibitory domain, induces cdc15p- and CR-dependent cytokinesis even in interphase cells [Yonetani and Chang,S. pombe, only a small subset of these can trigger reorganization of F-actin, CR formation and septation when their activity is altered [Matsuyama et al.,Though whole genome-based screening shows that more than 200 proteins are localized to the division site in After the completion of nuclear division, the CR constricts, which is followed by the primary septum synthesis. At present, it is unclear whether CR constriction is an active, motor-driven process, or whether it occurs passively, as the septum is deposited behind it. Previous studies have shown the following: Mutant cells that are unable to assemble a coherent CR deposit septum materials at the cell cortex [Streiblova et al.,S. pombe, the Arp2/3-complex is not required for CR assembly [Wu et al.,Araidopsis thaliana [Boutte et al.,Drosophila early embryo [Cao et al.,S. pombe cells the Rab11-homolog ypt3p localizes to the medial region during cytokinesis, dependent on an intact actin cytoskeleton [Cheng et al.,S. pombe.As the primary septum is synthesized, actin patches accumulate around the region of septation. In ace2 produces multicompartmented cells [Alonso-Nunez et al.,The primary septum is composed of linear chains of 1,3-\u03b2-glucan [Humbel et al.,S. pombe CR with those of mammalian cells, and speculate upon possible mechanisms for its assembly and constriction. We will begin with a brief review of the mechanics of cytokinesis in mammalian cells.In this section, we will discuss the assembly, constriction and disassembly of the CR, with particular emphasis on the mechanical and structural aspects of these processes. We will also compare the properties of the In animal cells, cytokinesis is brought about by membrane ingression, which has been named the cleavage furrow (CF). The CF is thought to be induced by geometrical asymmetry of the cortical tension in the cell. Several mechanisms for CF formation have been proposed [reviewed by Wang,Caenorhabditis elegans oocyte Centralspindlin also reduces Rac GTPase-activity, which inhibits the formation of an Arp2/3-complex-dependent branched actin network and thereby ensures formation of the formin-dependent CR, which is composed of straight F-actin [Canman et al.,C. elegans oocyte [reviewed by Werner and Glotzer,In animal cells, the central spindle and overlap region of astral microtubules (MTs), which extend from opposite spindle poles, promote CR assembly at telophase. Centralspindlin, a protein complex consisting of MKLP1, a kinesin-6 dimer, and Rho-family GTPase-activating protein (RhoGAP) subunits, plays the central role in this system [Mishima et al.,Sulfolobus acidocaldarius [Lindas et al.,Cytokinesis is accomplished by the scission of a \u201cbridge\u201d connecting the daughter cells. Dynamic reorganization of membranes including scrambling of outer and inner sides of plasma membrane, SNARE\u2013mediated vesicle fusions, and membrane scission by ESCRT complex is required for this step [reviewed by Prekeris and Gould,de novo at mitosis (and does not arise from conversion of interphase actin cables or patches), but they are differ significantly with regard to how CR F-actin is formed: from dozens of cdc12p nodes or from a small number of cdc12p spots. Recent studies have shown that the cdc12p spot formation depends on its FH3 domain and the actin-bundling protein ain1p, and is dispensable for CR assembly [Yonetani et al.,In this section, we will address two questions: first, what is the origin of CR F-actin? Second, is the CR formed by a spot/leading cable mechanism, or from a band of nodes? Considerable effort has been devoted to analysis of CR assembly [Vavylonis et al.,de novo assembly. The cortical flow of preformed F-actin is supported by direct observations of flux of fluorescently labeled actin [Cao and Wang,de novo assembly of CR F-actin was observed as accumulation of actin at the equator of blebbistatin-treated mitotic cells where the cortical flow is abolished [Guha et al.,At least two nonexclusive mechanisms seem to be involved in recruitment of actin to the equatorial region during cytokinesis in animal cells: cortical flow and S. pombe cells. The CR actin filaments have mixed polarities, and interdigitating myosin-like thick filaments between them were also observed in animal cells [Sanger and Sanger,S. pombe is discussed below.It is generally accepted that the CR is comprised mainly of actin and myosin II. However, their precise configuration in the ring remains undetermined. EM observations in several dividing cells have revealed that CR F-actin generally aligns parallel with the equator beneath the plasma membrane at the division site [Schroeder,As mentioned above, cortical F-actin filaments oriented perpendicular to CR, which would not be involved in CR constriction according to the purse-string model, are often detectable. Filaments with this orientation have escaped detection by EM observation. Given the high turnover rates of actin and myosin II in CR, this perpendicular F-actin may also be dynamic, probably more than CR F-actin, and hence may be difficult to preserve during severe fixation. Functional dissection of these filaments might substantiate alternative mechanisms for cortical ingression during cytokinesis Wang,. Along sDrosophila and HeLa cells [Field and Alberts,Some actin-binding proteins (ABPs) localized selectively at CR are thought to characterize the special properties of CR F-actin bundles. The actin-bundling protein \u03b1-actinin localizes to the CF in dividing NRK cells and is involved in accumulation of CR F-actin [Mukhina et al.,It is noteworthy that the equatorial accumulation of F-actin is not always evident in dividing cells, whereas ABPs or myosin II are clearly detectable in most cases [e.g., Neujahr et al.,It also remains possible that myosin II contributes to organization of CR F-actin bundles. Myosin II is implicated in rearrangement of the actin cytoskeleton in protruding lamellae of fibroblast cells [Verkhovsky et al.,In the purse-string hypothesis, myosin II motors are presumed to generate a force driving CR constriction via interaction with CR F-actin. Inhibition of the ATPase activity of myosin II using blebbistatin blocks cytokinesis in mammalian cells without affecting CR F-actin assembly [Straight et al.,S. pombe has two myosin II isoforms, myo2p and myo3p , both of which localize to the CR [Bezanilla and Pollard,S. pombe cytokinesis remains unclear. F-actin accumulates at the division site in myo2-null cells but fails to form a ring [Kitayama et al.,myo2-E1 allele), significantly reduces the actin-binding and motor activity of myo2p [Lord and Pollard,myo2-E1 mutant cells, node condensation into a ring abolished at restrictive temperature and is delayed at the permissive temperature [Coffman et al.,myo2-E1 cells constrict twofold slower than those in wild-type cells [Stark et al.,myo3 exacerbates the phenotype of myo2-E1 cells, the two myosin-IIs seem to share overlapping functions in cytokinesis [Motegi et al.,C. elegans, UNC-45 colocalizes with myosin II during cytokinesis in the early embryos [Barral et al.,S. pombe rng3p belongs to the same UCS -family and associates with myo2 and other four myosin proteins cotranslationally [Amorim and Mata,myo2-E1 cells [Lord et al.,Folding of the myosin head domain requires a co-chaperone of the (UNC-45/CRO1/She4p) family of proteins. In Dictyostelium or Drosophila S2 cells, accumulation of individual myosin-II filaments at the equatorial region has been visualized as small rods less than 1 \u03bcm in length by fluorescence microscopy [Yumura and Fukui,One of the observable characteristics of myosin II molecules is to assemble into bipolar thick filaments through their tails [Kaminer and Bell,FRAP analysis has shown that CR F-actin and cortical F-actin turn over rapidly both in fission yeast and mammalian cells [Pelham and Chang,S. pombe cells, the sole ADF, named as adf1p, localizes to the CR and is essential for accumulation of F-actin at the division site during cytokinesis [Nakano and Mabuchi,Xenopus ADF/cofilin, XAC, localizes to the leading edge of the CF in a fertilized egg and also participates in its formation [Abe et al.,In S. cerevisiae, the CR is not essential for cytokinesis, and septation alone manages to carry out the closure of bud neck [Bi et al.,It is unequivocal that in dividing animal cells net inward forces are generated along the equator, whether by the CR or by other mechanisms, and they drive the constriction of the medial cortex [Rappaport,in vitro. Fine and time-resolved EM observation of CR and the medial region of dividing fission yeast cells may also help to address this issue. An attractive model for generation of the contractile force has been proposed, which posits that polymerization and depolymerization of CR F-actin can produce mechanical force for the ring contraction in the presence of end-tracking crosslinkers even without myosin II motors [Zumdieck et al.,Whatever the actual function of CR constriction is, its mechanism(s) is still an open question. As discussed above, the purse-string model should be challenged by examining whether myo2p assembles into minifilaments Schizosaccharomyces pombe has proved to be an informative model for the study of cytokinesis and its coordination with mitosis. Many of the structural components required for cytokinesis are well conserved through evolution, so the fission yeast provides an excellent background in which to test the in vivo effects of defined mutations; when proteins are involved in multiple processes, hypomorphic alleles may permit separation of these functions. Though we have learnt a great deal about how cytokinesis occurs in S. pombe through a judicious mixture of cell biology, genetics and biochemical analysis, it is clear from the foregoing discussion that much remains to be done. Scientifically speaking, the next few years should be very exciting!The fission yeast"}
+{"text": "Microorganisms transform inexpensive carbon sources into highly functionalized compounds without toxic by-product generation or significant energy consumption. By redesigning the natural biosynthetic pathways in an industrially suited host, microbial cell factories can produce complex compounds for a variety of industries. Isoprenoids include many medically important compounds such as antioxidants and anticancer and antimalarial drugs, all of which have been produced microbially. While a biosynthetic pathway could be simply transferred to the production host, the titers would become economically feasible when it is rationally designed, built, and optimized through synthetic biology tools. These tools have been implemented by a number of research groups, with new tools pledging further improvements in yields and expansion to new medically relevant compounds. This review focuses on the microbial production of isoprenoids for the health industry and the advancements though synthetic biology. Escherichia coli or Saccharomyces cerevisiae, which serves as a microbial cell factory  and recombined control elements  were screened to select the E. coli strain that produced sevenfold more mevalonate , human 5-phosphomevalonate kinase (hPMK), yeast 5-diphosphomevalonate decarboxylase (yPMD), and E. coli IPP/DMAPP isomerase , by introducing heterologous genes for IPP isomerase  from Nostoc punctiforme, which were inserted into the chromosome of E. coli. This plasmid-free strain created astaxanthin as its only carotenoid at 1.4\u2009mg/g dcw  method\u201d to put together multiple genes in a single step, Nishizaki et al.  improved lycopene production. \u201cMultiplex automated genome engineering\u201d (MAGE) was proposed by Wang et al. They modified 24 genetic components at once from a degenerate pool of synthetic DNA, achieving a fivefold increase in lycopene production in just 3\u2009days , was achieved  was overexpressed to produce \u03b1-santalene, a skin cancer chemopreventative, at 0.21\u2009mg/g dcw  and kaurene synthase-like (SmKSL) as well as GGPP synthase (BTS1) and FPP synthase (ERG20) in S. cerevisiae (Zhou et al., Biosynthetic pathways for various diterpenes and sesquiterpenes have also been engineered for improved production through synthetic biology. To maximize production of several sesquiterpenes, Asadollahi et al. replaced the nativeS. cerevisiae, but production levels of the Taxol intermediate, taxadiene, were low. Several changes to taxadiene synthesis in yeast were introduced, including an alternate geranylgeranyl diphosphate synthase from S. acidocaldarius and a codon-optimized taxadiene synthase from Taxus chinensis, ultimately resulting in a 40-fold titer increase to 8.7\u2009mg/l (Engels et al., E. coli as a host, Ajikumar et al. (Application of synthetic biology tools to microbial production of the cancer chemotherapy drug paclitaxel will decrease its cost and increase its availability. Paclitaxel, known as Taxol, is a potent chemotherapy drug, which is very difficult to chemically synthesize (Chandran et al., r et al.  divided de novo design of biosynthetic pathways (Ajikumar et al., The past decade has witnessed the potential of synthetic biology to make the microbial isoprenoid production become industrially relevant. However, further improvements in yield and expansion to new medically important compounds can be attained through the development of additional tools. An incomplete understanding of the complexity of biosynthetic pathways limits the ability to fully forward engineer microbial production (Nielsen and Keasling, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Lower limb injuries in sport are increasingly prevalent and responsible for large economic as well as personal burdens. In this review we seek to determine which easily implemented functional neuromuscular warm-up strategies are effective in preventing lower limb injuries during sports participation and in which sporting groups they are effective.Seven electronic databases were searched from inception to January 2012 for studies investigating neuromuscular warm-up strategies and injury prevention. The quality of each included study was evaluated using a modified version of the van Tulder scale. Data were extracted from each study and used to calculate the risk of injury following application of each evaluated strategy.Nine studies were identified including six randomized controlled trials (RCT) and three controlled clinical trials (CCT). Heterogeneity in study design and warm-up strategies prevented pooling of results. Two studies investigated male and female participants, while the remaining seven investigated women only. Risk Ratio (RR) statistics indicated 'The 11+' prevention strategy significantly reduces overall  0.54 to 0.84) and overuse  lower limb injuries as well as knee  injuries among young amateur female footballers. The 'Knee Injury Prevention Program' (KIPP) significantly reduced the risk of noncontact lower limb  and overuse  injuries in young amateur female football and basketball players. The 'Prevent Injury and Enhance Performance' (PEP) strategy reduces the incidence of anterior cruciate ligament (ACL) injuries . The 'HarmoKnee' programme reduces the risk of knee injuries  in teenage female footballers. The 'Anterior Knee Pain Prevention Training Programme' (AKP PTP) significantly reduces the incidence of anterior knee pain  in military recruits.Effective implementation of practical neuromuscular warm-up strategies can reduce lower extremity injury incidence in young, amateur, female athletes and male and female military recruits. This is typically a warm-up strategy that includes stretching, strengthening, balance exercises, sports-specific agility drills and landing techniques applied consistently for longer than three consecutive months. In order to optimize these strategies, the mechanisms for their effectiveness require further evaluation. Historically, stretching as part of a warm-up strategy before exercise has been strongly advocated to prevent injury . Howeveret al. [et al. [Neuromuscular training programmes are hypothesized to improve joint position sense, enhance joint stability and develop protective joint reflexes, ultimately preventing lower limb injuries. H\u00fcbscher et al.  recentlyet al. . However [et al.  systematThe aims of this systematic review were: (1) to evaluate the efficacy of functional neuromuscular warm-up strategies which do not require additional equipment in preventing lower limb injury in order to guide clinical and sporting practice; and (2) to identify the common elements of successful strategies in order to guide future research.Embase, SPORTDiscus, Google Scholar, PubMed, ISI Web of Knowledge, Scirus and PEDro were searched for articles from inception to June 2011 and updated in January 2012. Search terms included (movement training OR neuromuscular OR proprioceptive OR proprioception OR plyometric) AND (training OR program OR programme) AND prevent* AND (injury OR injuries). Limits included English language (due to the cost of translation) and human studies. The reference list of retrieved articles was manually checked for potentially relevant studies.Inclusion/exclusion criteria are shown in Table et al. [et al. [A modified version of the nine item van Tulder et al.  was used [et al.  criteria [et al. . Two indDetails of study design, participant characteristics, interventions, statistical analysis, results and study limitations were extracted and tabulated from each included study by one reviewer (KH). Additionally, two reviewers (KH and CB) extracted data related to participant numbers and injury incidence for the various types of lower limb injuries reported. Review Manager version 5.0 was used to calculate risk ratios (RR) and their 95% Confidence Intervals (CI) for all comparisons as well as to produce forest plots to represent this data visually. The number needed to treat (NNT) was calculated only for variables producing a statistically significant RR . Sensitivity analysis was completed to identify if the use of equipment improved injury prevention. To complete this, the effectiveness of a selection of eight studies, five randomized controlled trials (RCTs) -16 and tThe initial search identified 766 articles Figure . DuplicaTable Details of each study are summarized in Table RRs for the effectiveness of neuromuscular warm-up strategies in preventing undefined lower limb injuries are shown in Figure None of the strategies evaluated were able to produce significant reductions in hip or thigh injuries, with calculated risk ratios shown in Figure P = 0.046). The AKP PTP [RRs for the effectiveness of neuromuscular warm-up strategies in preventing knee injuries are shown in Figure  AKP PTP  was ableRRs for the effectiveness of neuromuscular warm-up strategies in preventing lower leg and ankle injuries are shown in Figure This systematic review investigated the effectiveness of neuromuscular warm-up strategies for injury prevention. Based on available data a number of strategies appear to be effective in preventing lower limb injuries. Specifically, 'The 11+'  strategyThe quality assessment criteria revealed that the studies had various methodological weaknesses affecting their internal validity. Firstly, sample sizes were often too low to evaluate specific injuries . If evaluating the effectiveness of neuromuscular warm-up programmes on more specific injuries, sample size calculations prior to commencement and recruitment of larger samples are recommended. Additionally, future studies should ensure blinding of assessors, concealment of treatment allocation, intention to treat analysis and more adequate randomization procedures to reduce the impact of issues relating to internal validity. External validity was also limited, in particular the applicability of the findings to age groups other than between 13 and 26 years.There is also a need to determine the mechanism of effectiveness of neuromuscular warm-up strategies and determine whether injury reduction is the result of each individual component or due to a combination of exercises. No studies were identified which compared two different components or combinations of neuromuscular warm-up strategies and, in general, programmes targeted varying risk factors associated with a variety of specific injuries. Addressing this through further research will enable more emphasis on effective components of injury-specific interventions and facilitate the development of more successful neuromuscular warm-up strategies for injury prevention, specifically in reference to specific lower limb injuries.et al. [et al. [et al. [et al. [et al. [There is limited homogeneity between the prevention strategies and the methods of recording injury incidence, making data pooling for meta-analysis inappropriate. Injury incidence was reported by a certified athletic trainer , a coachet al. , Gilchri [et al. , LaBella [et al. , Kiani e [et al.  and Brus [et al. . This poAdverse effects were only noted in four studies ,28,31,33The effectiveness of three neuromuscular warm-up strategies in preventing the total number of lower limb injuries was evaluated in studies included in this review. Of these, only 'The 11+'  and KIPPThe PTP  may haveHip and thigh injuries were recorded during the evaluation of two neuromuscular warm-up strategies, 'The 11+'  and 'TheKnee injury rates were recorded in all of the nine studies, with six of these recording ACL injuries. Based on available data, four neuromuscular warm-up strategies were found to be effective in preventing knee injuries. These included individual studies showing 'The 11+'  and 'HarSuccess of the AKP PTP  may relaet al. [et al. [et al. [et al. [et al. [et al. [et al. [Despite investigating the same warm-up strategy , Mandelbaum et al.  demonstr [et al.  showed o [et al.  was a CC [et al.  performe [et al.  there wa [et al.  informed [et al.  while th [et al. ,28-34.The PTP , and KLIThe 'HarmoKnee'  programmet al. [The effectiveness of four neuromuscular warm-up strategies which did not require additional equipment in preventing lower leg and ankle injuries were evaluated in studies from this review. Based on the results, no neuromuscular warm-up programme was able to reduce lower limb injury risk significantly. However, it should be considered that the KIPP  indicateet al.  which evet al.  results A previous systematic review comparing balance work  and neuromuscular exercises  revealed that ankle sprains were reduced by 36% and 50%, respectively . AdditioAccording to the present systematic review, several practical neuromuscular warm-up strategies which do not require additional equipment that is not readily available at the usual amateur competition or training venues are effective to varying degrees at preventing lower limb injuries. However, in some instances a large number of participants would need to undertake a strategy before one injury is prevented. This is the case with the PEP  strategyImportantly, this systematic review highlights several areas that may account for significantly better injury prevention when incorporating neuromuscular warm-up strategies. These include: (1) incorporation of stretching, strengthening and balance exercises, sports-specific agility drills and landing techniques; (2) completing the strategy for longer than three consecutive months; and (3) completing of the strategy at all training sessions. In addition to these programme specifics, further evaluation of the '11+'  programmFurther studies need to determine whether 'The 11+' , KIPP 3, 'HarmoKThe current systematic review identified five practical neuromuscular warm-up strategies which do not require additional equipment and which may effectively reduce the risk of lower limb injuries. Specifically 'The 11+' reduced overall and overuse lower limb injuries and knee injuries in young amateur female football players, the 'KIPP' reduced non-contact overall and overuse lower limb injuries in young amateur female football and basketball players, the 'HarmoKnee' programmThe authors declare that they have no competing interests.KH and CB were the primary initiators of the study while all authors made substantial contributions to data analysis and interpretation. All authors were involved in drafting and revising the manuscript and approved the penultimate version. The final version was approved and submitted by DM.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/75/prepub"}
+{"text": "Cannabis sativa (cannabis) should be considered doping in sports. Results from a 2010 report in the United States  the main psychoactive constituent and responsible for the observed toxic effects after smoking, while other cannabinoids are responsible for minor effects, such as cannabinol (CBN), which is 10% as psychoactive as THC Huestis, . THC is The non-psychoactive cannabidiol (CBD) is anxiolytic in humans following a single dose (Zuardi et al.,"}
+{"text": "Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways. Thanks to those receptors astrocytes are not only capable to respond to the classical neurotransmitters glutamate and \u03b3-aminobutyric acid (GABA) released from synapses [through metabotropic glutamate receptors (mGluRs) mGluR1-5 and GABAB receptors respectively; Pasti et al., 2+ signals through the astrocytic syncytium . Their activation leads to the intracellular activation of phospholipase C (PLC), followed by the production of the messenger molecule inositol trisphosphate  transients mediated by channels, exchangers, and transporters  whole-cell Ca2+ transients have led to the idea that unlike neurons, astrocytes display exclusively particularly slow responses, and that their signals are not suited to be restricted to small cellular compartments, as happens for example, in dendritic spines. However, in vivo experiments have shown that faster local responses of astrocytes in the somatosensory cortex can occur upon hind limb stimulation  channel. TRPA1 mediated spotty Ca2+ signals seem to play an important role in setting the basal intracellular Ca2+ concentration of hippocampal astrocytes . But what is the impact of this on neuronal functioning? Numerous studies in different brain regions have uncovered a multitude of ways in which astrocytes can modulate neuronal excitability and synaptic transmission. In the following section we will review several of these different pathways.The excitability of neurons is one of their most fundamental properties. Dynamic modulation of excitability is a powerful way of implementing state-dependent changes in neuronal computation. Several studies have shown that astrocytes can regulate neuronal excitability. Astrocytes can achieve this through several mechanisms: by regulation of the extracellular ionic composition, by maintaining a tonic extracellular transmitter concentration, by regulation of basal synaptic transmission, and by the induction of phasic events in neighboring neurons. We will shortly discuss these different mechanisms.+. Both hippocampal astrocytes  receptor mediated current, and a decrease in neuronal excitability , or long-lasting (long-term plasticity). Short-term plasticity (a change in synaptic strength lasting up to 10s of seconds) is thought to underlie critical computational functions of neuronal networks  ions (Dingledine et al., 2+ into the postsynaptic neuron, which can activate second messenger cascades leading to either LTP or LTD (Malenka and Bear, d-serine is a more likely co-agonist for the NMDAR then glycine (Mothet et al., d-serine in the brain seems to be the astrocyte. Astrocytes release d-serine into the extracellular space through vesicular fusion, and this astrocytic d-serine release is necessary to obtain sufficient NMDAR activation for induction of LTP in hippocampus (Yang et al., d-serine release (Zhang et al., Most forms of long-term synaptic plasticity depend on activation of postsynaptic NMDARs. The NMDAR classically is described as a coincidence detector of pre- and post synaptic neuronal activity. This is because for activation it needs both binding of presynaptically released glutamate as well as a postsynaptic depolarization to relieve it from block by magnesium (Mgd-serine as shown in hippocampus was described in the hypothalamic supraoptic nucleus (SON; Panatier et al., d-serine for postsynaptic NMDARs is greatly reduced, leading to a shift in the activity dependence of LTP and LTD (Figure A similar dependence of NMDAR mediated long-term plasticity on astrocyte-derived D Figure .d-serine can actively gate LTP in the rat barrel cortex in vivo (Takata et al., d-serine release from the astrocytes upon activation. These findings highlight the importance of d-serine as a modulator of plasticity both in vitro and in vivo. Furthermore, since cholinergic input into the cortex has been suggested to gate cortical plasticity (Bakin and Weinberger, Interestingly, a recent study showed that astrocytic release of d-serine can also induce synaptic plasticity independent of its role at the NMDAR (Kakegawa et al., d-serine from Bergmann glia. This d-serine subsequently activated postsynaptic \u03b42 glutamate receptors, which in turn caused internalization of postsynaptic AMPARs. Interestingly, interfering with this form of LTD disrupted motor coordination in vivo, showing its relevance for cerebellar development. From the study by Kakegawa et al. (Apart from acting as a NMDAR co-agonist, a recent study has shown that astrocytic release of a et al.  it is noa et al. . Furthera et al. . Therefoa et al.  and hippin vivo (Navarrete et al., Another gliotransmitter that can mediate long-term plasticity is glutamate. Previously, we mentioned that astrocyte stimulation at hippocampal Schaffer collateral synapses can induce short-term potentiation through astrocytic glutamate release followed by activation of presynaptic mGluRs (Fiacco and McCarthy, in vivo, by application of the cannabinoid receptor agonist \u03949-THC, leads to LTD of Schaffer collateral synapses instead of LTP. This LTD also requires astrocytic glutamate release, but is mediated by activation of postsynaptic NMDARs, followed by endocytosis of postsynaptic AMPARs (Han et al., Additionally, a recent study showed that pharmacological activation of astrocytes 1Rs (Sj\u00f6str\u00f6m et al., 1Rs together governed the induction of t-LTD. We showed that activation of presynaptic NMDARs during induction of t-LTD is mediated by astrocytic glutamate release (Min and Nevian, 2+ signaling. This in turn leads to glutamate release from the astrocyte, which activates presynaptic NMDARs. Activation of the presynaptic NMDARs induces a long-lasting decrease in synaptic release probability, although the signaling cascade downstream from presynaptic NMDAR activation is still unclear (Figure In the neocortex, we have recently shown that astrocytic release of glutamate is necessary for the induction of spike-timing-dependent depression (t-LTD; Min and Nevian, r Figure .2+ signals, and therefore presumably the astrocytic glutamate release, is not correlated with respect to the pre- and post-synaptic action potentials (Min and Nevian, 2+ block of the presynaptic NMDARs to hamper their efficient recruitment. However, it was recently shown that presynaptic NMDARs in the developing sensory cortex incorporate the NR3A subunit, which renders the receptor insensitive to Mg2+ block (Larsen et al., One interesting question rising from these results is how the presynaptic NMDARs are efficiently activated. Because the timing of the astrocytic CaThese results show that astrocytes form a crucial part of the retrograde signaling cascade for induction of t-LTD. Since endocannabinoid mediated forms of LTD occur in numerous brain regions and serve important functions (Heifets and Castillo, 7 receptors. Activation of these postsynaptic receptors leads to insertion of AMPARs, and thereby to a long-lasting postsynaptic increase in the efficacy of excitatory synapses (Gordon et al., 2+ signaling and subsequent release of ATP through mGluR activation. This protocol can lead to a similar long-lasting postsynaptic upscaling of the synaptic efficacy (Gordon et al., Astrocytes also play a role in homeostatic control of synaptic transmission. This was first shown in cultured neurons, where glial release of the cytokine TNF\u03b1 increases the synaptic expression of AMPARs, thereby controlling the weight of all excitatory synapses (Beattie et al., Finally, long-term synaptic plasticity is costly in terms of energy. As mentioned before, astrocytic supply of energy to neurons is essential for maintaining synaptic transmission (Rouach et al., d-serine, they can directly induce synaptic plasticity by releasing glutamate or other gliotransmitters, and they can mediate homeostatic plasticity. In addition, dynamic regulation of metabolic support by astrocytes is crucial for synaptic plasticity.In conclusion, astrocytes play a role in several forms of long-term plasticity. Astrocytes can either set the threshold for LTP/LTD induction by controlling the extracellular concentration of In the previous section, we have discussed how astrocytes can modulate neuronal functioning. Based on the above described astrocyte-neuron interactions, we will summarize some possible roles that astrocytes could play in neuronal computation. We suggest that the functional role of astrocytes adds to the computational power of neuronal networks.d-serine, astrocytes are ideally positioned to mediate metaplasticity. The level of astrocytic d-serine release will determine the possible amount of NMDAR activation and therefore of NMDAR mediated postsynaptic Ca2+ influx upon synaptic activity. Since many forms of LTP and LTD require NMDAR mediated Ca2+ influx for their induction, astrocytes can shift the threshold for LTP and LTD induction (Figure d-serine and therefore, the induction threshold for LTP and LTD (Panatier et al., d-serine release upon astrocyte activation by cholinergic inputs opens the window for subsequent LTP induction in the in vivo neocortex (Figure d-serine release is a physiologically important metaplasticity signal in the brain. It can translate the activity state of the neuronal network into a modulatory signal that determines the corresponding learning rule: during a high activity state due to arousal or heightened attention the neuronal and astrocyte networks are highly active supporting the induction of LTP. Future behavioral studies should determine what the importance of this astrocyte mediated metaplasticity is for learning and memory formation.Metaplasticity is a higher-order form of synaptic plasticity, defined as a change in the ability to induce synaptic plasticity (Abraham and Bear, n Figure . A clearx Figure . Therefo2+ signaling spreads along an astrocytic process and results in the release of gliotransmitters at neighboring synapses. Heterosynaptic short-term plasticity could play a role in switching between synaptic ensembles during information processing. As described earlier, astrocytes mediate heterosynaptic short-term depression at excitatory synapses onto CA1 pyramidal neurons (Zhang et al., Single astrocytes form non-overlapping domains (Bushong et al., Heterosynaptic long-term plasticity has been implicated in the homeostatic control of synaptic inputs to a neuron (Chistiakova and Volgushev, 2+ signaling, directly translates into synaptic plasticity. For example, we found that astrocyte activation with a voltage-clamp depolarization protocol results in increased Ca2+ signaling in the astrocyte, but that this activity alone does not change synaptic transmission strength at excitatory cortical synapses. An additional activation of the presynaptic axon was necessary in order to induce LTD (Min and Nevian, It is important to note that not every activation of an astrocyte, manifested by increases in Ca2+ transients gradually increases during the induction of t-LTD (Min and Nevian, The induction of many forms of synaptic plasticity requires a repeated presentation of a certain stimulus pattern (Petersen et al., 2+ signals in the processes of astrocytes can be used to perform chemical computations similar to linear and non-linear Ca2+ signaling in neurons. Efficient Ca2+ buffering (Neher, 2+ microdomains that limit the release of gliotransmitters in space and time. Only certain patterns of Ca2+ signals might cause a high enough concentration of Ca2+ in the astrocyte processes to trigger vesicular release. This could be accomplished by local Ca2+ buffer saturation and a specific spatial relationship between Ca2+ release sites in the ER and the vesicular Ca2+ sensor triggering exocytosis (Marchaland et al., 2+ signaling in astrocytes is needed to understand their chemical computation.How can an astrocyte act as a thresholding unit? The sophisticated Cag Neher, , receptog Neher,  and extrin vivo. However, recent advances in genetics have made it possible to specifically alter astrocyte signaling in vivo while keeping neuronal signaling intact. This has led to some important insights into astrocyte involvement in information processing. For example, it is now clear that astrocyte derived adenosine modulates the build-up of sleep pressure as well as the cognitive effects of sleep deprivation (Halassa et al., 1 receptor, Han et al. (in vivo (Saab et al., in vivo experiments with the subcellular astrocyte-neuron signaling mechanisms as described in this review.As described above, there is ample experimental evidence for an active role of astrocytes in neuronal plasticity. The most important question remaining is the functional relevance of the above described astrocyte-neuron interactions. This has proven very hard to address, since experimental approaches until recently were unable to specifically modify and study the role of astrocytes in neuronal computation and behavior n et al.  showed tn et al. . Finallyin vitro experiments and behavioral readouts in vivo is the use of mathematical models. As mentioned earlier, progress has been made with mathematical models of astrocyte Ca2+ signaling. In addition, several models have included bidirectional signaling between astrocytes and neurons on the synaptic level, leading to new insights into the function of this bidirectional signaling. For example, a study by Nadkarni et al. (One possible way to bridge the gap between cellular mechanisms observed with high-resolution i et al.  suggestsi et al. . In anoti et al. . Such moAn example of a recently developed neuron-glia network model comes from a recent study by Wade et al. . Here, i2+ dynamics, thereby potentially enhancing the computational power of neuronal networks. The challenge for the future is to understand how and when astrocyte mediated signaling processes are involved in computation in the brain. To answer this fascinating question will require a combination of state-of-the-art experimental techniques with advanced computational modeling.In conclusion, research on the involvement of astrocytes in neuronal signaling in the last years has resulted in a rich array of possible astrocyte-neuron interactions. It is now evident that beyond their permissive role in synaptic and network function astrocytes can perform integration of neuronal signals by means of their CaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To the Editor: Kaba et al. (We conducted a retrospective subanalysis of results from a multicenter therapeutic trial assessing HEV seroprevalence among HIV/hepatitis C co-infected patients in France (The difference between our study, which demonstrated low HEV IgG prevalence in IDU patients, even in southern France, and the results from Kaba et al. ( In Response: The letter of Larrat et al. (,\u2013Seroprevalence studies of different populations, especially those with differing immune responses, cannot lead except by chance to the same result. Of note, we recently reported that HEV seroprevalence was 2.3% among injection drug users infected with HIV ("}
+{"text": "Dear Editor:et al. about the relationship between down-regulation of osteopontin and breast tumour progression in vivois highly interesting [The article by Chakraborty eresting . Recent et al. in a recent study have reported that nearly 67% of oral squamous cell carcinomas and nearly 54% of all oral carcinomas in situ lesions are immunoreactive for osteopontin [et al. suggests that osteo-pontin may be an important marker of early invasion in lingular squamous cell carcinomas [For instance, Devoll eopontin . Similarrcinomas . In factBesides oral malignancies, osteopontin has also been implicated in the etio-pathogenesis of numerous other systemic malignancies such as non-small cell lung cancers and breast cancers . Clearly"}
+{"text": "Dictyostelium discoideum) and plants  gene family, which is 70% identical to glycogen synthase kinase-3 from mammals,  and rice (LOC_Os05G33050) also possess homologous proteins comprising ARM repeats and a BTB/POZ domain  signaling (Samuel et al., AtPUB19 showed that it is upregulated in response to drought, salt, cold and ABA (Liu et al., ATPUB18 as a negative regulator has been put forward in ABA-mediated stomatal closure and drought responses (Seo et al., ATPUB22/23 in Capsicum annum known as CaPUB1 was found to be highly inducible in response to various abiotic stresses such as drought, cold and salt (Cho et al., A biological role for the U-box/ARM protein Nicotiana, two U-box/ARM proteins NtCMPG1 and tobacco ACRE276 and their functional homolog in Arabidopsis, AtPUB17 has been implicated as positive mediators of plant defense and stress signaling (Gonzalez-Lamothe et al., Another report suggested the role of AtCHIP, an Arabidopsis U-box/ARM protein in response to extreme temperature conditions. Subsequently, AtCHIP was reported to be involved in the ABA stress signaling pathway by mediating interaction with protein phosphatase 2A (Yan et al., On the basis of facts described above, it can be concluded that animal and plant ARM repeat proteins share many resemblances. Therefore, it is possible that at least some transcription effectors involved in Wnt signaling are evolutionary conserved. These elements include nuclear accumulation in response to extracellular signal, phosphorylation and degradation. Apart from the common response, plants possess specific signaling pathways mediated by ARM proteins. In plants, ubiquitination is critically involved in the function of ARM proteins. The proliferation of \u03b2-catenin-like ARM proteins in plants suggest their significance in the regulation of diverse biological fuctions in them. Further study of these proteins in plants would contribute to our understanding of the molecular factors involved in response to abiotic stress.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Obesity is a major public health concern and there are increasing calls for policy intervention. As obesity and the related health conditions develop during childhood, schools are being seen as important locations for obesity prevention, including multifaceted interventions incorporating policy elements. The objective of this systematic review was to evaluate the effects of policies related to diet and physical activity in schools, either alone, or as part of an intervention programme on the weight status of children aged 4 to 11\u00a0years. A comprehensive and systematic search of medical, education, exercise science, and social science databases identified 21 studies which met the inclusion criteria. There were no date, location or language restrictions. The identified studies evaluated a range of either, or both, diet and physical activity related policies, or intervention programmes including such policies, using a variety of observational and experimental designs. The policies were clustered into those which sought to affect diet, those which sought to affect physical activity and those which sought to affect both diet and physical activity to undertake random effects meta-analysis. Within the diet cluster, studies of the United States of America National School Lunch and School Breakfast Programs were analysed separately; however there was significant heterogeneity in the pooled results. The pooled effects of the physical activity, and other diet related policies on BMI-SDS were non-significant. The multifaceted interventions tended to include policy elements related to both diet and physical activity (combined cluster), and although these interventions were too varied to pool their results, significant reductions in weight-related outcomes were demonstrated. The evidence from this review suggests that, when implemented alone, school diet and physical activity related policies appear insufficient to prevent or treat overweight or obesity in children, however, they do appear to have an effect when developed and implemented as part of a more extensive intervention programme. Additional evidence is required before recommendations regarding the focus of policies can be made and therefore, increased effort should be made to evaluate the effect of policies and policy containing intervention programmes upon weight status. Obesity among children is associated with significant psychological, social and health consequences including insulin resistance, cardiovascular disease, low self-esteem and poorer education and employment outcomes ,2. The rTo date the systematic reviews which have examined the effect of obesity related school policies have evaluated diet and physical activity outcomes rather than weight status -16. JaimGuidance from The Cochrane Collaboration and the National Health Service Centre for Reviews and Dissemination informed the development of the review protocol, which is available upon request ,18.Two search strategies were developed for this systematic review, one for diet related and one for physical activity related policies  [Dialog Datastar], British Education Index [Dialog Datastar], Australian Education Index [Dialog Datastar], Cumulative Index to Nursing and Allied Health Library (CINAHL Plus) [Ebscohost], and The Cochrane Library [Wiley Online]. The search strategy was developed in Medline ; source of funding; ethics approval; recruitment; summary characteristics of the study population; details of the intervention ; treatment of any control group; definition of obesity; duration of follow-up/exposure; and results. Standard tools were used to assess the quality of the studies -24. The d) in body mass index standard deviation score (BMI-SDS), were calculated for each study using standard calculations and the R package MAd ), where \u2018m\u2019 is the average number of participants in each school and \u2018ICC\u2019 is the intra-cluster correlation . An ICC et al.,31. Furt2 statistic [Random effects meta-analysis of each cluster was undertaken in Stata  to obtaitatistic .The study identification process and reasons for exclusion are illustrated in Figure\u00a0Ten studies examined diet related policies, five physical activity related policies, and six examined policies with both diet and physical activity related components (henceforth known as combined policies) Table\u00a0. Despiteet al.[All the included studies examined BMI as an outcome categorised as overweight or obese, or adjusted to standard deviation scores (BMI-SDS), percentiles (BMI%), growth rates or Healthy Fitness Zone (BMIHFZ) . The Heaet al.. One stuet al..Study quality is summarised in Table\u00a0Due to the nature of policy interventions, the randomised controlled trials and controlled before and after studies could not meet some of the quality criteria generally applied to these study designs. Blinding of the outcome assessment may not always have been possible and, for some studies, loss to follow up was greater than 20%. However, each study employed a valid design, in terms of the use of second sites as controls, random allocation and protection from contamination.The demographics and baseline weight status of the participants of each study are listed in Table\u00a0Fifteen studies utilised the Center for Disease Control and Prevention (CDC) 2000 BMI reference categories and an additional paper appears to have used this categorisation but did not report it . Two stuet al.[Key results from each study are presented in Table\u00a0et al. and Thomet al.. Table\u00a04Thirteen studies evaluated diet related policies, including five evaluating the NSLP ,44,47,50The pooled result of participation in the NSLP was a small non-significant rise in BMI-SDS  -0.193 to 0.269)  and the effects of these policies have not been combined. However, the individual results and effect sizes are detailed in Table\u00a0et al.[et al.[et al.[Six studies evaluated policies with both diet and physical activity related components, one of which did not report the quantitative results just the direction and significance and therefore effect sizes could not be calculated -59,63,64le\u00a0et al. reportedl.[et al.,64. The l.[et al., was siget al.[The aim of this systematic review was to examine the effect of school diet and physical activity related policies upon anthropometric outcomes among children aged 4\u201311\u00a0years. Twenty-one studies were identified which examined a range of policies which were clustered as either diet related or physical activity related or both (combined policies) for analysis. Within the diet related policies cluster, eight studies evaluated the NSLP and SBP and as these policies target a subset of the population they were analysed separately from the other diet related policies. The NSLP was associated with a non-significant rise in BMI-SDS results, whereas the SBP was associated with a significant decrease in BMI-SDS and the other diet related policies were associated with a non-significant decrease in BMI-SDS, however, significant heterogeneity remained in the NSLP and SBP sub-clusters reducing the validity of these results Figures\u00a0, 3 and 4et al. as imporet al.,26,31. Get al.. Five ofet al.,47,55,632\u2009=\u200965.6%. Millimet and Tchernis [A strength of this review was the broad search strategy. School policy evaluation may be reported by a variety of disciplines and inside and outside of peer-reviewed journals and therefore through the variety of databases searched, the grey literature search and the inclusion of literature such as dissertations all the relevant studies were sought. Primarily, this demonstrated that there is a paucity of scientific evaluations of school policies as only 21 eligible studies were identified from the 6,894 retrieved, yet among the eligible studies where were a variety of designs, quality and policies which impinge upon the review. Among the 21 studies reviewed only five utilised experimental study designs which prevented the consideration of causal pathways in this review Table\u00a0. Loss toTchernis  and MillTchernis  used comet al.[et al.[et al.[et al.[et al.[et al.[et al.[et al.[In order to calculate effect sizes, assumptions about the outcome correlations in studies using independent and non-independent samples were made; these assumptions were relaxed in a sensitivity analysis, reported in Additional file et al. and Choml.[et al. both foul.[et al. found a l.[et al. found thl.[et al. argue thl.[et al. argue thl.[et al. recentlyl.[et al. using rol.[et al. with thol.[et al. did not l.[et al.,67.et al.[This review evaluated the effect of school policies upon an objective measure of weight status (BMI-SDS) unlike previous reviews which have evaluated physical activity and diet outcomes, which may be more subjective -16. Theret al. found siet al.. SubsequThe evidence from this systematic review suggests that diet and physical activity related policies need to be located within more complex approaches to preventing childhood obesity which focus on multiple factors  and at multiple levels of influence  as advocated by the Centers for Disease Control and Prevention guidelines . No poliThe complex web of factors which influence weight have been illustrated in the obesity systems map which also highlights the range of levels of influence from micro to macro . Within 95% CI: 95% confidence interval; AVHPSP: Annapolis valley health promoting schools program; BMI: Body mass index; BMI%: Body mass index percentile; BMIHFZ: Body mass index healthy fitness zone; BMI-SDS: Body mass index standard deviation score; CDC: Centers for disease control and prevention; ECLS-K: Early childhood longitudinal study \u2013 kindergarten cohort; FMI: Fat mass index; HAES: Health at every size; ICC: Intra-cluster correlation; IOTF: International obesity task force; MeSH: Medical subject headings; NSLP: National school lunch program; PE: Physical education; SBP: School breakfast program; UK: United Kingdom; USA: United States of America; USDA: United States Department of Agriculture.The authors declare that they have no competing interests.AJW was involved with the conception and design of the review, undertook the searches and participated in the study identification, data extraction and quality assessment, he then undertook the analysis and drafted the manuscript. WEH was involved with the conception and design of the review, advised on and supervised the analysis and assisted with drafting the manuscript. CAW was involved with the conception of the study and had input into the final manuscript. AJH participated in the study identification, data extraction and quality assessment and proofread the final manuscript. SL contributed to the drafting of the final manuscript and interpretation of the results. KMW was involved with the conception and design of the review, participated in the data extraction and quality assessment, assisted with the interpretation of results and drafting of the final manuscript. All authors read and approved the final manuscript.Search strategy.Click here for fileSensitivity analysis.Click here for fileEffect size calculations.Click here for fileDiet related policies meta-analysis with Rappaport, Daskalakis and Sendacki [ replacing Foster, et al. [.Sendacki  replacin, et al. .Click here for file"}
+{"text": "Exome sequencing now allows us to reliably identify these mutations using a single genomic test, and we have recently implemented exome sequencing in the diagnostic follow-up of these patients.Germline coding de novo mutations in genetic disease and the associated risk factors such as local genomic structure and paternal age. Next, I will describe our recent work using a diagnostic family-based exome sequencing approach to test this de novo mutation hypothesis in 100 patients with unexplained ID, as well as targeted follow-up studies of several candidate ID genes in 750 additional patients. A total of 79 unique coding de novo mutations were identified and validated in 52 patients. Damaging de novo (n = 10) as well as X-linked maternally-inherited (n = 3) mutations were detected in known ID genes, resulting in a minimal diagnostic yield of 13% in this cohort. In addition, potentially causative de novo mutations in novel candidate ID genes were detected in 22 patients. For three of these candidate genes, recurrent de novo mutations were identified in patients with similar phenotypes, confirming that they are true ID genes. To further expand the possibilities of exome sequencing for mutation detection, we have recently implemented automatic CNV detection on exome data, and compared its performance to that of high-resolution genomic microarrays. This analysis shows that exome sequencing can reliably detect the large majority of pathogenic de novo CNVs, responsible for approximately 15% of ID.In this presentation, I will first discuss the role of de novo mutations therefore represent an important cause of ID, and exome sequencing is an effective diagnostic strategy for their detection.In conclusion,"}
+{"text": "PLoS Genetics, Joyce et al. report the first comprehensive RNAi screen of genes regulating somatic chromosome pairing in Drosophila Many generations of biologists have been intrigued by the myriad structures that eukaryotic chromosomes can adopt and have questioned how their form relates to function Drosophila presents a unique opportunity for identifying molecular regulators that establish, maintain, and antagonize homolog pairing because its homologous chromosomes are almost always paired in somatic cells. Metz described somatic cell homolog pairing in 1916 Suppressor of Hairy Wing (Su(Hw)) and Topoisomerase II as pairing promoting factors Cap-H2, was shown to be necessary and sufficient to antagonize pairing of homologs in the context of polytene chromosomes Cap-H2 mutant Drosophila males have chromosome unpairing defects in meiosis I, also providing evidence for a Cap-H2 anti-pairing activity Recent evidence has raised the exciting possibility that both pairing and anti-pairing forces may act on chromosomes to regulate the spatial juxtaposition of homologous sequences . Two preThe ability to perturb homolog pairing by RNAi depletion The pairing and anti-pairing genes code for cell cycle, protein turn-over machinery, and chromatin proteins, among others. Previous studies suggested that cell cycle regulation and chromosome pairing are related by showing that entry into S-phase and G2/M disrupt pairing Perhaps the most exciting broad conclusions from this study are that chromosome pairing is much more complicated and dynamic than anyone had anticipated, and that an abundance of \u201cpairing promoting\u201d and \u201canti-pairing\u201d factors provide opposing forces. The authors suggest that the degree of homolog pairing in somatic cells, at the gene level and at the whole chromosome level, is likely determined by the relative activities of pairing and anti-pairing factors . It is n"}
+{"text": "Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment. The former can be divided into two progeny stem cells or differentiated progenitors and thus controlling the self-amplification of stem cells, whereas the latter produces one differentiated progenitor and another daughter [in vivo, and the microenvironment plays an important role in the function preservation of stem cells [Stem cells, which are rare in most tissues, are defined as cells with the ability to perpetuate themselves by self-renewing and to differentiate into a variety of specialized cells in a tissue or organ ,2. Both daughter . Generaldaughter . Stem ceem cells .CSCs are a small subpopulation of tumor cells with an infinitely proliferative potential existing in tumor tissues . They plCSCs and stem cells have a host of similar characteristics, such as self-renewal, indefinite self-replication, asymmetric cell division, generating a large number of differentiated cells and expressing specific molecules ,18. Addiet al.[+/CD38\u2212) [+/CD38\u2212 cells can form tumors that phenotypically resemble the patient\u2019s original tumor [Growing evidence has shown that tumors are derived from and maintained by a rare population of dysregulated stem cells. The CSC hypothesis was first raised by Mackillop et al. in 1983.+/CD38\u2212) . After tal tumor ,24, indial tumor . This noal tumor , lung [2al tumor ,28, liveal tumor , ovary [al tumor , colon [al tumor , pancreaal tumor   [Further evidence of CSCs comes from histology and immunocytochemistry studies. For example, many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases, which implies that the cell that produced them had the capacity to generate multiple cell types. Ginestier et al. showed tl.[et al. confirmel.[et al., brain [l.[et al., and livl.[et al. were alsl.[et al., are botl.[et al.,48. In 2ma (NPC) . Furtheret al.[et al.[According to label-retaining cell (LRC) trial, adult stem cells can be identified based on their ability to retain nucleoside analog, such as bromodeoxyuridine. In accordance with this principle, Zhang et al. found thl.[et al. confirmeet al.[Growing evidences suggests the existence of a dynamic equilibrium and bidirectional conversion between CSCs and cancer progenitors . On the et al. demonstrin vivo, whereas most daughter cells exited from the cell cycle are not able to proliferate in vitro; (2) Differentiation to a limited extent in vitro, and the capacity can be analyzed by special surface markers at the different differentiation stages. During this process, the cellular morphology was often bizarre and maturation is incomplete. Another study [Cancer progenitor cells display low a self-renewal capacity and a higher probability of terminal differentiation compared with CSCs . Variouser study  showed t+ stem cells from CML patients were insensitive to STI571 in vitro, thereby these immature Ph+ progenitor cells can survive, while the overall sensitivity of CML CD34+ progenitor cells to STI571 is mainly determined by cell cycle status [Growing evidences indicated that drug-targeted therapies to control tumors either at CSCs or cancer progenitor cells level exhibited different sensitivity. Chronic myeloid leukemia (CML) stem cells were insensitive to tyrosine kinase inhibitors like imatinib, dasatinib and nilotinib, while sensitive to leukemia progenitor cells \u201362. The e status .high/+ CD24low/\u2212 expression was found in breast tumor-initiating stem-like cells. However, it was not clear whether CD44 and CD24 consistently distinguished tumorigenic from non-tumorigenic cells. Subsequently, these CSC-like cells were verified intrinsically resistant to conventional chemotherapy [et al.[et al.[+ stem and early progenitor cells lost their CD133 expression, giving rise to late progenitors and finally differentiated progeny. These lineage programs for cell fate determination can be restricted by PcG proteins, such as Bmi1, which regulates tumor initiation in CD133+ stem and early progenitor cells, while regulates tumor maintenance of proliferation, differentiation and cell fate determination in CD133\u2212 proliferative progenitors. Likewise, Stewart et al.[Increasing evidences showed that the surface protein markers expressed by CSCs and cancer progenitor cells were somewhat dissimilar. In 2003 , CD44higotherapy  and ioniotherapy . Jiang ey [et al. suggestel.[et al. showed trt et al. found th+/CD38\u2212 cells, in leukemia is similar to normal hematopoietic progenitor cells [To date, the cell of origin of CSCs remains to be a pendent and troubled problem around the world. There are two hypotheses for the origin of CSCs . One staor cells . The eviIt has been proposed that CSCs and normal stem cells can interconvert into each other. The more important consequence of this event is that normal stem cells can generate CSCs that ultimately induce a new tumor. Emerging evidence has supported this notion, as CSCs share many properties of normal stem cells. For examples, both have the capacity of self-renewal and non-directional differentiation potential, and many classic cancer related signal transduction pathways also regulate the development of normal stem cells. In this scenario, cancer cells could simply utilize the existing stem cell regulatory pathways to stimulate their self-renewal. In addition, both stem cells and CSCs have telomerase activity and amplified telomere repeats, while most adult human somatic cells lack detectable telomerase. Another theory associates stem cells with the formation of tumors, which is most often related with tissues with a high rate of cell turnover. In these tissues, it has long been expected that stem cells are responsible for tumor formation. Tissue with fast renewal, such as epithelial tissue and those of the hematopoietic system, are sites with high incidence of cancer. The faster tissues renew, the higher the rate of mutation that will occur during replication and transcription. Although it is not clear which target cells mutate and transform to tumors, experimental data obtained from a variety of tumors show that certain colon cancers and leukemia result from an accumulation of multiple mutations of stem cells . Due to Some researchers presume that CSCs may be obtained by the mutation of committed progenitor cells with an ability of self-renewal. For example, leukemia stem cells can be transformed from granulocyte-macrophage progenitors with the assistance of MLL-AF9 fusion protein . Anotheret al.[+ cells could generate additional lgr5+ cells as well as all other adenoma cell types, thus exhibiting activity of CSCs in mouse intestinal adenomas [et al. found that the yellow fluorescent protein (YFP) could been expressed in around 1% of basal papilloma epithelial cells in mice, and these YFP-labeled tumor cells were capable of generating all cell types that comprised the tumor [Despite the lack of direct experimental evidence, some studies show that CSCs may be the fusion of stem cells and other cells . These net al.. The CSCet al., which het al., A549 luet al., colon cet al. and glioet al.. Terminaet al.\u201383. Howeadenomas ; (2) theadenomas ; (3) usihe tumor .At present, the molecular mechanisms underlying regulating the development of CSCs remain to be unexplored. Various signaling pathways have been suggested, and some of them are reviewed as follows.The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms, which regulates widely the development and homeostasis of vertebrate and invertebrate embryos and adult individuals through the local interaction between cells, and controls how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs . Notch aStudies indicate that Notch signaling is likely to be implicated in the pathogenesis of many human tumors, including leukemia  and pancWnt proteins are secreted signaling molecules of Wnt signaling, and nuclear \u03b2-catenin function as a key mediator. One indicator of Wnt pathway activation is the nuclear accumulation of its main effector \u03b2-catenin, which is one component of a transcriptional activation complex that includes members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of DNA binding proteins . In normet al.[et al.[Wnt signaling pathway regulates many developmental processes through transcriptional regulation  and its et al. demonstrl.[et al. documentl.[et al.,112.in vivo[+ glioma CSCs [et al.[in vitro (7). The signal transducer and activator of transcription 3 (STAT3) is a crucial transcriptional regulator involved in tumorigenesis. Inhibition of STAT3 with specific inhibitors or targeting STAT3 with specific shRNAs disrupts proliferation and maintenance of GSCs [Other molecular pathways or factors that play a critical role in the development of CSCs include following: (1) mTOR signaling pathway, which is frequently aberrantly activated in human cancers, and significantly correlated with biological cell behaviors . Recent in vivo. In addiin vivo; (2) Fibin vivo. In addiin vivo and gastin vivo. Studiesin vivo. Using toma CSCs . In addioma CSCs ; (4) Recoma CSCs  suggest oma CSCs ; (5) Epioma CSCs . This nooma CSCs ; (6) Baos [et al. in 2008  of GSCs ,125.Once a cancer has been diagnosed, treatments vary according to cancer type and severity. Surgery, radiation therapy, chemotherapy or hormonal therapy represents traditional approaches designed to remove or kill rapidly-dividing cancer cells. However, there has been hardly any substantial progress with new therapies regarding clinical endpoints, despite significant advances in molecular mechanisms of cancer. Cancer remains a major public health issue. Conventional anti-cancer treatments target the more mature cancer cells that form the bulk of the tumor, but do not target the CSCs, which are relatively quiescent and intrinsically resistant, thus possibly accounting for treatment failures . To target al.[Tumor metastasis is a complex process, and is also the main cause of the death of cancer patients in clinic. It is the key to improve the prognosis of patients by removing CSCs selectively with no significant toxicity . Severalet al. confirm et al.; (3) Somet al.. In breaet al.. Subsequet al.. Cell diet al., especiaet al.,140; (4)et al..et al.[Another way to control the tumor progression is to induce differentiation of CSCs. Study by Piccirillo et al. showed aet al.. The CSCet al.. The bioet al.[et al.[et al.[Recent studies have found that CSCs are the main reason for tumor growth, recurrence and metastasis . Dingli et al. in 2010 et al.. (3) Manet al.. (4) Meal.[et al. and Lianl.[et al. have obsl.[et al.,152,153,l.[et al..Despite recent clinical studies have begun to monitor the behavior of CSCs during chemotherapy, it is still an urgent requirement of more clinical studies to assess how responses to therapy correlate with CSC biomarkers. Development of new CSC-targeted strategies is currently hindered by the lack of reliable markers for the identification of CSCs and the poor understanding of their behavior and fate. Although cancers represent a major therapeutic challenge, with better understanding in the CSCs, the more specific markers to look for this lethal disease. There is no doubt that the application of CSC theory to study the tumorigenesis mechanisms will lead a paradigm shift in the cancer research and the understanding of the essence of cancer, supplying a new way to effectively diagnose tumor sites and find functional proteins as potential therapy targets."}
+{"text": "VSG by RNA polymerase I (Pol-I), with silencing of other VSGs, and periodic switching of the expressed gene, typically via DNA recombination with duplicative translocation of a new VSG to the active site. Thus, telomeric location, epigenetic controls and monoallelic transcription by Pol-I at an extranucleolar site are prominent features of VSGs and their expression, with telomeres, chromatin structure and nuclear organization all making vitally important contributions to monoallelic VSG expression control and switching. We discuss VSG transcription, recombination and replication control within this chromosomal and sub-nuclear context.African trypanosomes are lethal human and animal parasites that use antigenic variation for evasion of host adaptive immunity. To facilitate antigenic variation, trypanosomes dedicate approximately one third of their nuclear genome, including many minichromosomes, and possibly all sub-telomeres, to variant surface glycoprotein (VSG) genes and associated sequences. Antigenic variation requires transcription of a single  Given the important role of tracts of imperfect 70\u2009bp repeats in VSG recombination reactions (Fig.\u2009VSG switching (Glover et\u2009al., Although RAD51-dependent mechanisms of T.\u2009brucei nuclear DNA replication and suggest a link with antigenic variation. The first link between the DNA replication machinery and VSG transcriptional control was based on studies of T.\u2009brucei ORC1/CDC6 (Godoy et\u2009al., VSGs in insect-stage cells (Tiengwe et\u2009al., et\u2009al., et\u2009al., procyclin loci in bloodstream-form cells following knockdown of MCM-binding protein (Kim et\u2009al., T.\u2009brucei replication has yet to be demonstrated. These findings implicate DNA replication in VSG transcriptional control, but the basis of this, and in particular whether there is a common mechanistic action of ORC1/CDC6 and MCM-binding protein, remains unclear. Association of ORC1/CDC6 with telomeres (Benmerzouga et\u2009al., P.\u2009falciparum and other organisms, both at telomeres and elsewhere (Sasaki and Gilbert, T.\u2009brucei ORC1/CDC6 is remarkably small relative to Orc1 orthologues and lacks the N-terminal bromo-adjacent homology domain involved in binding HP1, which acts in heterochromatin-mediated silencing in other organisms (Flueck et\u2009al., et\u2009al., A number of studies are providing insights into the machinery, co-ordination and regulation of VSG expression are also possible. Loss of ORC1/CDC6 is likely to reduce the number of replication origins and hence replication efficiency, which in turn is likely signalled by the cell-cycle checkpoint machinery; in other eukaryotes ORC mutations trigger a Rad9-dependent checkpoint, arresting cells in S-phase (Ide et\u2009al., T.\u2009brucei, the equivalent histone residue, H3K76, is di-or tri-methylated by two enzymes, DOT1A and DOT1B, respectively (Janzen et\u2009al., et\u2009al., VSG transcriptional control and VSG switching dynamics present in dot1b mutants, may be due to a link between replication and checkpoint signalling (Stockdale et\u2009al., VSG expression and switching may relate to chromosome dynamics after replication. ORC in other eukaryotes is implicated in sister chromatid cohesion; pre-replication complexes can direct loading of cohesin, and ORC provides a cohesin-independent route for sister chromatid association in budding yeast (Diaz-Martinez et\u2009al., T.\u2009brucei cohesin knockdown, which also causes elevated BES switching (Landeira et\u2009al., Two less direct explanations for the roles of ORC1/CDC6 and perhaps MCM-binding protein in VSG BESs (Boothroyd et\u2009al., et\u2009al., VSGs in their previously transcribed or silent states clearly depends upon the replication process. However, mechanistic data are currently lacking here, and we do not yet know the timing, rate or direction of replication through BESs or other VSG loci.Other studies also suggest that DNA replication acts in antigenic variation. The DNA DSBs found within the VSG allelic exclusion and recombination, both essential aspects of antigenic variation in T.\u2009brucei, are critically dependent upon the telomeric environment. Emerging evidence also reinforces the importance of distinct chromatin territories within the nuclear space, although cause or consequence is less certain here. The sub-telomeric context likely provides an environment that experiences more frequent breaks, which allowed T.\u2009brucei to effectively co-opt and potentially modify a natural response to DNA breaks to achieve efficient antigenic variation. These typically heterochromatic loci also facilitated the massive expansion of the VSG gene family without multi-gene expression. Modifications have been achieved through exploiting minichromosomes to increase the maximum telomeric VSG-count by approximately 10-fold, by expansion of recombinogenic 70\u2009bp repeats flanking VSG genes and, potentially, through BRC-repeat expansions within BRCA2. Clusters of large numbers of silent telomeric VSGs likely now facilitate the homology search and improve access to templates for repair. T.\u2009brucei has also co-opted the Pol-I machinery for VSG expression, leading to the formation of a novel extranucleolar, telomere-associated Pol-I compartment.The available evidence indicates that VSG loci, and it will be important to determine the cis-regulatory sequences, the trans-acting factors and how they interact to drive VSG exclusion and switching. An approach focussed on T.\u2009brucei homologues of DNA repair, transcription regulatory and chromatin-associated factors identified in other systems has been fruitful. However, an important goal for the future is to seek factors that play more direct and specific roles in VSG expression control, some of which may represent exploitable drug-targets. Such factors should further illuminate the mechanisms underlying monotelomeric VSG expression and recombination, the processes that make T.\u2009brucei such a persistent parasite.There are a complex variety of chromatin states that could impact transcription, recombination and replication at"}
+{"text": "Digestive malignancies remain one of the leading causes of cancer-related death worldwide despite the fact that increasing clinical and biological knowledge has emerged. Among all the newly discovered cancer cases, colorectal cancer, stomach cancer, liver cancer, and esophagus cancer rank in the front and the mortality rate for them also tops the list. The poor prognosis of digestive tumors is partially due to late diagnosis, delayed initiation of treatment, and unsatisfactory reaction to cancer therapies. Many molecular markers have been discovered for early diagnosis and better therapeutic outcomes from which we do benefit a lot. However, diagnosis and treatment of alimentary cancers require further optimization. We believe further study of novel molecular targets for early detection and better treatment would be helpful to reduce mortality rate and to improve the prognosis of malignant diseases of digestive system.In this current issue, we focus on recent advances in the research of novel molecular targets which would help reveal the possible mechanism of tumorigenesis, progression, metastasis, and recurrence of digestive malignancies. The potential value of these molecular targets in cancer therapy is also highlighted. We present 10 articles on novel molecular targets in digestive system of which six articles discuss the molecular markers in hepatocellular carcinoma, three articles discuss the molecular makers in gastric carcinoma, and one makes a comprehensive review on one anticancer target in digestive system cancer therapy.In the paper entitled \u201cH-Ras oncogene expression and angiogenesis in experimental liver cirrhosis,\u201d by G. \u00d6. Elpek et al. evaluated the relation between H-Ras expression and angiogenesis in liver cirrhosis which can progress to liver carcinoma. The oncogene H-Ras is elevated in liver cirrhosis and correlates significantly with angiogenesis.\u201cLEPREL1 expression in human hepatocellular carcinoma and its suppressor role on cell proliferation\u201d by J. Wang et al. found that LEPREL1 was downregulated in hepatocellular carcinoma (HCC) tissues both in mRNA and protein levels, and the down-regulation was not associated with conventional clinical parameters of HCC. LEPREL1 could serve as a potential tumor suppressor gene by inhibiting HCC cell proliferation.The research paper \u201cExpression of potential cancer stem cell marker ABCG2 is associated with malignant behaviors of hepatocellular carcinoma\u201d by G. Zhang et al. found that ABCG2 could probably function as a liver cancer stem cell marker because of its close relationship with tumorigenesis and also because it could promote cell proliferation, drug resistance, and metastasis. This molecule may represent an attractive target for the innovation of cancer stem cell-directed therapy for HCC.in vitro and in vivo,\u201d S. He et al. found that the interference of NET-1 could enhance the anticancer effect of sorafenib. The interference of NET-1 could lead to impaired ability of proliferation and migration and could induce apoptosis in HCC cell line. NET-1 may be a promising molecular target to develop adjuvant therapy in combination with the only effective targeted drug, sorafenib for HCC.In \u201cStudy of RNA interference targeting NET-1 combination with sorafenib for hepatocellular carcinoma therapy Another two articles talked about the function of microRNA in HCC. X.-Y. Huang et al. showed that miR-29 was upregulated in HCC and correlated with poor outcomes of HCC. It might function by promoting cell proliferation and inhibiting cell apoptosis. The work by Z. Wang et al. clarified the association of miR-499 and miR-34b/c polymorphisms with susceptibility to HCC and got to the final conclusion that rs3746444 was not associated with susceptibility to HCC while rs4938723 was associated with increased HCC risk.\u201cMast cells positive to tryptase and c-kit receptor expressing cells correlates with angiogenesis in gastric cancer patients surgically treated\u201d by M. Ammendola et al. studied the angiogenesis in gastric cancer and found that MCTP and c-kitR-EC correlated positively with microvascular density. Drugs against c-kitR and tryptase could be promising agents in antiangiogenic therapy.\u201cSignificance of glutathione peroxidase 1 and caudal-related homeodomain transcription factor in human gastric adenocarcinoma,\u201d J. J. Han et al. demonstrated GPX1 and CDX2 might participate in the carcinogenesis, differentiation, and progression of gastric adenocarcinoma, and CDX2 might be an independent prognostic factor.\u201cIndirect comparison showed survival benefit from adjuvant chemoradiotherapy in completely resected gastric cancer with D2 lymphadenectomy\u201d by Q. Yang et al. confirmed the role of adjuvant chemoradiotherapy in D2-resected gastric cancer patients with discussion of underlying molecular mechanism of this benefit.The review article \u201cPP2A-mediated anticancer therapy\u201d by W. Chen et al. made a general review of the tumor suppressor PP2A by focusing on PP2A structure and the possible mechanism of its participation in anticancer therapy.In summary, this special issue presents several intriguing achievements in the field of novel molecular targets in digestive malignancies which we hope could be utilized in the future for early diagnosis and treatment."}
+{"text": "Pichia anomala, Acinetobacter spp. and Pseudomonas putida; specialists such as Dunaliella salina, Saccharomyces cerevisiae, Lactobacillus spp. and other lactic acid bacteria; freshwater autotrophs Gonyostomum semen and Microcystis aeruginosa; obligate anaerobes such as Clostridium acetobutylicum; facultative pathogens such as Rhodotorula mucilaginosa, Pantoea ananatis and Pseudomonas aeruginosa; and other extremotolerant and extremophilic microbes such as Aspergillus spp., Salinibacter ruber and Haloquadratum walsbyi. Some microbes, such as Escherichia coli, Mycobacterium smegmatis and Pseudoxylaria spp., exhibit characteristics of both weed and non-weed species. We propose that the concept of nonweeds represents a \u2018dustbin\u2019 group that includes species such as Synodropsis spp., Polypaecilum pisce, Metschnikowia orientalis, Salmonella spp., and Caulobacter crescentus. We show that microbial weeds are conceptually distinct from plant weeds, microbial copiotrophs, r-strategists, and other ecophysiological groups of microorganism. Microbial weed species are unlikely to emerge from stationary-phase or other types of closed communities; it is open habitats that select for weed phenotypes. Specific characteristics that are common to diverse types of open habitat are identified, and implications of weed biology and open-habitat ecology are discussed in the context of further studies needed in the fields of environmental and applied microbiology.Competition between microbial species is a product of, yet can lead to a reduction in, the microbial diversity of specific habitats. Microbial habitats can resemble ecological battlefields where microbial cells struggle to dominate and/or annihilate each other and we explore the hypothesis that (like plant weeds) some microbes are genetically hard-wired to behave in a vigorous and ecologically aggressive manner. These \u2018microbial weeds\u2019 are able to dominate the communities that develop in fertile but uncolonized \u2013 or at least partially vacant \u2013 habitats via traits enabling them to out-grow competitors; robust tolerances to habitat-relevant stress parameters and highly efficient energy-generation systems; avoidance of or resistance to viral infection, predation and grazers; potent antimicrobial systems; and exceptional abilities to sequester and store resources. In addition, those associated with nutritionally complex habitats are extraordinarily versatile in their utilization of diverse substrates. Weed species typically deploy multiple types of antimicrobial including toxins; volatile organic compounds that act as either hydrophobic or highly chaotropic stressors; biosurfactants; organic acids; and moderately chaotropic solutes that are produced in bulk quantities . Whereas ability to dominate communities is habitat-specific we suggest that some microbial species are archetypal weeds including generalists such as:  As the collective metabolism and ecological activities of microorganisms determine the health and sustainability of life on Earth it is essential to understand the function of both individual microbes and in their communities. The cellular systems of an insignificant portion of microbial species have been intensively characterized at the levels of biochemistry, cell biology, genomics and systems biology; and a substantial body of (top-down) studies has been published in the field of microbial ecology in relation to species interactions, community succession and environmental metagenomics. There are, however, some fundamental questions that remain unanswered in relation to the behaviour of microbial species within communities: what type of biology, for instance, enables microbes to dominate entire communities and their habitats and thereby determine levels of biodiversity in specific environments?et\u2009al., et\u2009al., et\u2009al., et\u2009al., dominate their respective communities. In the field of plant ecology it is open habitats (such as freshly exposed fertile soil) that facilitate the emergence of weed species both within specific ecosystems and across evolutionary timescales. We propose that weed behaviour is equally prevalent in some microbial habitats, that open microbial habitats promote the emergence of microbial weed species, and that microbial weed biology represents a potent ecological and evolutionary mechanism of change for some microbial species and their communities.Plant species that primarily inhabit freshly disturbed habitats \u2013 known as weeds \u2013 are characterized by vigorous growth; tolerance to multiple stresses; exceptional reproduction, dispersal and survival mechanisms; a lack of specific environmental requirements; production of phytotoxic chemicals; and/or other competitive strategies . The bioThis article focuses on the following questions: (i) what types of substrate or environment facilitate the emergence of dominant microbial species, (ii) are there archetypal weed species that can consistently dominate microbial communities, (iii) what are the stress biology, nutritional strategies, energy-generating capabilities, antimicrobial activities and other competitive strategies of microbial weeds, (iv) which components and characteristics of microbial cells form the mechanics of weed biology, (v) what are the properties of open  habitats that promote the emergence of weed species, and (vi) how are microbial weeds conceptually distinct from plant weeds, and other ecophysiological groups of microorganism?et\u2009al., et\u2009al., et\u2009al., et\u2009al., Aureobasidium pullulans, Candida spp., Debaryomyces hansenii, Metschnikowia pulcherrima, Pichia guilliermondii, Pichia manshurica, Rhodotorula mucilaginosa and Zygowilliopsis californica  and generalists such as Aspergillus, Pichia and Pseudomonas species , Haloquadratum walsbyi , and Gonyostomum semen and Microcystis aeruginosa (eutrophic freshwater) ability to dominate can be restricted to a specific type of habitat. Most of these microbes do not populate their respective habitat as a one-off or chance event; they can consistently dominate their microbial communities and do so regardless of their initial cell number . Furthermore dominating species span the Kingdoms of life and, collectively, can be observed in most segments of the biosphere; from bioaerosols to solar salterns, oceans and freshwater to sediments and soils, the phyllosphere and rhizosphere, to those with molar concentrations of salts or sugars (see Table\u2009S1). The phenomenon can also be observed during food-production, food-spoilage and waste-decomposition processes where resource-rich habitats are available for colonization (see Table\u2009S1). The materials present in and the microbes living on these substrates are ultimately derived from the natural environment so community successions resulting in single-species dominance are likely to be commonplace in comparable open habitats within natural ecosystems . Environments in which P.\u2009putida is a major ecological player (Table\u2009S1) typically contain an array of chemically diverse aromatics and hydrocarbons that induce chaotropicity-mediated stresses  environments including soils, plant necromass, saline and very high-sugar habitats (Table\u2009S1). At least 20 species of Aspergillus and the closely related genus Eurotium are xerotolerant  strains are capable of reasonable growth rates close to 0\u00b0C  may be attributed, in part, from enhanced energy-generating capability. Aspergillus species (like many fungi) can utilize a range of polyols \u2013 as well as trehalose \u2013 as compatible solutes based on their individual strengths as protectants against osmotic stress, desiccation rehydration, chaotropes etc.  accumulates carotenoids in response to light which can protect against oxidative stress that is a potential hazard in salterns exposed to high levels of ultraviolet , also uses the \u2018salt-in\u2019 compatible-solute strategy, and \u2013 along with S.\u2009ruber \u2013 has light-activated protein pumps that generate proton-motive force and thereby boost energy generation  can successfully compete with the multitude of halophilic Archaea found in 5\u2009M NaCl environments . This alga preferentially utilizes glycerol as a compatible solute, is able to accumulate glycerol to molar concentrations  either primarily use glycerol as a compatible solute or preferentially accumulate this chaotrope at low temperature , the acidic surface-film of sphagnum moss (as well as other plant tissues) and various surfaces within the human body and other animals  a polyextremophile that is psychrophilic, highly salt-tolerant, and can growth over the majority of the pH range known to support microbial life  ohmeri and Pichia sydowiorum that exhibited the greatest tolerance to the widest range of solute-imposed stresses (Table\u2009D.\u2009hansenii and Hortaea werneckii), and/or otherwise lacked the capacity for vigorous growth on the high-sugar substrate at 30\u00b0C  of the parent plant have a favourable water activity and high nutrient availability and are therefore potentially habitable by a wide range of microbes , accumulate a compatible solute (glycerol) that affords protection against this chaotrope (see below), and at the same time generate energy without any loss of ATP-generation efficiency  \u2013 which is activated under cellular stress. This regulatory system enables the coordination of an array of stress responses in an energy-efficient manner (Table\u2009S.\u2009cerevisiae responses to osmotic stress [via the high-osmolarity glycerol-response (HOG) pathway], oxidative stress, and challenges to protein and membrane stability are exceptionally efficient  which can be prevalent in relatively low-nutrient aquatic and non-aquatic habitats . Despite their copiotrophic phenotype, pseudomonads utilize a number of strategies to maintain growth and metabolism under phosphate-, iron- or nitrogen-depleted conditions  metabolic versatility in nutrient utilization can enhance the competitive ability of microbes , and polysaccharides . In order to out-compete other species in such habitats, microbes must utilize these macromolecular substrates that typically have a low bioavailability, require specialist enzymes to degrade, can be toxic, and/or are energy-expensive to catabolize. Facultatively saprotrophic microbes such as Aspergillus, Pichia, Rhodotorula and Acinetobacter species are able to access and catabolize recalcitrant polysaccharides; some weed species can produce exceptional amounts, or high-affinity versions, of inducible saprotrophic enzymes, such as xylanases  can retain activity over a wide range of environmental stresses  high chaotropicity  weeds are able to dominate their habitats due largely to the production of phytotoxic inhibitors that can be exuded from leaves, roots and plant necromass and which inhibit the germination and/or growth of other plant species  is unique to microbial weed species Tables\u2009 and 2. Wet\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., octanol-water <\u20091.95 typically partition into the aqueous phase of cellular macromolecules and can act as potent chaotropic stressors  also inhibits the growth of competing species by acidifying the environment which it achieves via the production of a number of organic acids , including efflux pumps  is conferred by an array of mechanisms : killer toxins, hydrolytic enzymes and volatile substances  have an unusually high resistance to the net chaotropicity of the ammonia, ethanol, butanol, acetone and other chaotropic substances in their habitat  that are highly effective at expulsion of hydrocarbons such as toluene as well as many other stressors and toxins  are inhibitory to competing species  gives an insight into the complexity of the microbial warefare that takes place in open habitats: 57 compounds were detected including terpenes, alcohols, ketones and esters . This is a product of its metabolic versatility, exceptional tolerance to hydrocarbons and other solutes, and antimicrobial activities  that emerges as a dominant genus; and in the green layer at lower pH (2\u20132.5), R.\u2009mucilaginosa has the competitive advantage (Table\u2009S1). Phyllosphere, rhizosphere and other habitats can also remain continuously open if they are replenished with organic substances from ions released from soil particles, extracellular polymeric substances and compatible solutes from microbial cells, root diffusates, animal wastes, diverse sources of necromass, etc.The concept of an open habitat is a fundamental, well-established principle in the fields of plant and animal ecology. For microorganisms, open habitats can be defined according to the diversity, interactions and community succession of their inhabitants in contrast to other types of microbial habitat that are defined by physicochemical characteristics, substrate type or nutrient concentration Table\u2009. Hydrocas Tables\u2009 and 6. O\u22121 mole\u22121 chaotropic activity, <\u2009pH\u200911 or\u2009>\u2009\u221215\u00b0C  or Aspergillus species . The stress biology, energy-generating capabilities and antimicrobial activities of these species undoubtedly contribute to their success . Several ecophysiological classification systems that are based on microbial growth-phenotype and/or substrate utilization (Table\u2009S2). Microbial generalists can occupy a wide range of ecological niches, and typically achieve this via the ability to utilize a wide range of nutrients and substrates (Table\u2009S2). Conversely microbial specialists, such as S.\u2009cerevisiae, H.\u2009werneckii and many basidiomycetes have specific nutritional and/or physicochemical requirements . By contrast P.\u2009putida appears to be an exceptional example of a microbial weed both in terms of its cellular biology and its ability to dominate diverse types of open habitat.Microorganisms have been previously categorized based on the way in which their phenotype impacts ecological behaviour: as autotrophs and heterotrophs; generalists and specialists; Saccharomyces cerevisiae supports global industries in fermented products, biofuel, biocides (ethanol is also an important disinfectant; McDonnell and Russell, P.\u2009anomala produces a substantial catalogue of biotechnologically useful substances and is employed in production of foodstuffs (see Walker, et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., P.\u2009putida is used for the commercial production of bulk and fine chemicals, industrial biocatalysis, and as the basis of many other industrial and environmental biotechnologies (Kruijt et\u2009al., et\u2009al., et\u2009al., et\u2009al., Aspergillus spp., P.\u2009putida and Clostridium spp. play primary roles in the treatment or decomposition of plant matter, oil and hydrocarbons, xenobiotics in polluted soils, sludge and slurry treatments, and other organic wastes (Tables\u2009S2 andAspergillus species are used for production of foods (Rose, et\u2009al., S.\u2009cerevisiae, Rhodotorula spp., P.\u2009anomala, P.\u2009putida, lactic acid bacteria and other weed species invaluable as agents of biological control, for preventing spoilage of drinks, foodstuffs and animal feeds (see Calvente et\u2009al., et\u2009al., et\u2009al., It is irrefutable that a small minority of microbial species recurrently appear as the dominant members of microbial communities; and we suggest here that these microbes have shared phenotypic traits. This implies that open-habitat ecology has impacted the evolutionary trajectories of these microbes, and that the activities of weeds determine microbial diversity in many localities within the biosphere. Whereas microbial weed species are not always useful to humankind see , they mads Rose, , fine chMicrobial weeds are also used as model systems for research, yet key aspects of their biology remain enigmatic. Many plant weeds have exceptional reproduction and dispersal systems  and it rCrop plants such as sunflowers, potatoes, wheat and barley are known to have weedy ancestors (Anderson,"}
+{"text": "However, in humans there is limited evidence of endocrine disruption caused by EDCs. EDCs are a large group of persistent organic pollutants (POPs), such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polybrominated ethers (PBDEs), chloronaphtalenes (PCNs), and bisphenol A (BPA), stable, lipophilic pollutants that affect fertility and cause serious reproductive problems. Xenoestrogens are synthetic compounds, but there are also numerous natural molecules in food that exhibit estrogen-mimetic activities. These natural molecules are mainly phytoestrogens isoflavones, and the most consumed are genistein and daidzein. Additionally, certain mushrooms or fungi can contain estrogen-like compounds called mycoestrogens.The potential effect of the so-called endocrine disruptors (EDCs) or xenoestrogens on human health and the proven effect on wildlife have got considerable attention in the scientific community. Endocrine disruption represents one of the most controversial environmental issues despite the fact that many substances, both natural and artificial, have been recognized to interfere with endocrine signaling pathways. Such interactions have been documented both in laboratory animal studies as well as Endocrine-disrupting chemicals: some actions of POPs on female reproduction.\u201dXenoestrogens activities in oocyte, ovary, placenta, and mammary gland and in the consequent serious reproductive problems, including ototoxic action, lack of ovulation, premature ovarian failure (POF), or polycystic ovarian syndrome (PCOS) are discussed in the review E. Gregoraszczuk and A. Ptak \u201cAssessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways\u201d discuss different molecular actions of some of the major xenoestrogens found in food or the environment and summarize the current models used to evaluate environmental estrogens. This paper is accompanied by clinical study of Caserta et al. \u201cCorrelation of endocrine disrupting chemicals serum levels and white blood cells gene expression of nuclear receptors in a population of infertile women\u201d compares the internal exposure to bisphenol A (BPA), perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), monoethylhexyl phthalate (MEHP), and di(2-ethylhexyl) phthalate (DEHP) in serum samples of 111 infertile women and 44 fertile women and analyses levels of gene expression of nuclear receptors  as biomarkers of effective dose.G. Kerdivel et al., in their paper \u201cTwo of the papers deal with aspects of alkylphenols action as endocrine disruptors. Association between endocrine disrupting phenols in colostrums and maternal and infant health\u201d showed that most neonates who are exposed to BPA rather than NP or OP via colostrum are recommended continuous biomonitoring of the phenols to clarify their suspected health risk on neonates and pregnant or gestation mothers. Furthermore, A. Hejmej in their paper \u201cPhotoperiod-dependent effects of 4-tert-octylphenol on adherens and gap junction proteins in bank vole seminiferous tubules\u201d evaluating in vivo and in vitro effects of 4-tert-octylphenol (OP) on the expression and distribution of adherens and gap junction proteins, N-cadherin, \u03b2-catenin, and connexin 43 (Cx43), in testes showed that long-term treatment with OP resulted in the reduction of junction proteins expressions independent of FSH indicating that OP acts directly on adherens and gap junction proteins in the testes.The paper by B. Yi et al. \u201cDiverse effects of phytoestrogens on the reproductive performance: cow as a model\u201d review how exposure of soybean-derived phytoestrogens can have adverse effects on reproductive performance in female adults. Authors suggest that these findings should be specially taken into consideration when recommendations are made regarding dietary or therapeutic phytoestrogen intake in humans. Particularly that they are commonly recognized as therapeutic compounds.I. Woc\u0142awek-Potocka et al. in their paper \u201cAction of halowax 1051 on enzymes of phase I (CYP1A1) and phase II (SULT1A and COMT) metabolism in the pig ovary\u201d describe local ovarian metabolism of PCNs in ovarian tissue and suggest that fast activation of phase I enzymes with simultaneous inhibition of phase II enzymes indicates that androgenic action of PCNs on follicular steroidogenesis may partially result from metabolite action occurring locally in ovarian follicles.Polychlorinated naphthalenes (PCNs) are new player as endocrine disruptors. Data concerning their potency and action on ovarian function are scarce. Dr J. Barc et al. in their paper \u201cTo complete the issue, B. Ayala-Garc\u00eda et al. revise current knowledge about the epigenetic mechanisms that underlie the effects of EDs on phenotypic variability and plasticity to stress the value of using the information derived from experiments with EDs to unveil the mechanisms that underlie phenotypic variability and speciation through epigenetic phenotypic plasticity.Taking into account that in this special issue have been published review articles, research articles and clinical studies, we hope that the information published in this special issue enriches the knowledge of our readers and scholars interested in the influence of xenobiotics on human health.Ewa L. GregoraszczukEwa L. GregoraszczukRadmila KovacevicRadmila Kovacevic"}
+{"text": "In heart failure (HF), exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac \u03b2-adrenergic receptor (\u03b2-AR) dysfunction. It has been demonstrated that exercise reverses \u03b2-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2) which is known to be involved in both \u03b21-AR and \u03b22-AR dysregulation in HF. Similar alterations of \u03b2-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/\u03b1-2AR/catecholamine (CA) production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores \u03b2-AR-dependent vasodilatation by increasing vascular \u03b2-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50% of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favorable effects of exercise on blood pressure control. It has been generally accepted that regular physical activity is associated with beneficial effects on the cardiovascular system  are associated with adverse outcome (Kaye et al., Since it has been demonstrated that myocardial GRK2 levels and activity mirror those measured in peripheral lymphocytes in HF patients (Iaccarino et al., Exercise training in patients with stable HF, can relieve symptoms, improve exercise capacity and quality of life, and reduce disability, hospitalization, and mortality (Piepoli et al., The crucial role of \u03b2-AR dysregulation in the pathophysiology of HF is well established. GRK2, which plays a key role in the regulation of \u03b2-AR, is significantly elevated in human and experimental HF (Ungerer et al., As mentioned above, exercise training appears to reduce autonomic derangement and neurohumoral excitation at rest in HF. The effects of exercise training on adrenergic hyperactivation in HF patients have not been completely clarified. Recently, an important molecular mechanism has been identified that contributes to the sympathetic overdrive of the failing heart. This mechanism involves the upregulation of GRK2 in adrenal medulla of HF animals, which leads to downregulation and G protein uncoupling of the \u03b12-ARs present in the chromaffin cell membranes of the adrenal gland that normally exert negative feedback control on CA turnover (Lymperopoulos et al., Noteworthy, alterations of \u03b2-AR system, similar to those observed in HF, have been described also in the senescent heart (Davies et al., Exercise has been shown to modulate GRK2 levels/activity by reducing levels of this kinase in the heart and, consequently, inducing \u03b2-AR \u201cresensitization.\u201d It has been previously demonstrated in rats that both exercise and \u03b2-blockers reverse \u03b2-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation (Leosco et al., At vascular level, studies conducted in the aorta and carotid arteries of old rats have shown a reduced \u03b2-AR-dependent vasorelaxation (Chapman et al., In old healthy subjects, it has been demonstrated that physical training ameliorates age-related deterioration of cardiac function in terms of enhanced LV inotropic response to CA (Ehsani et al., The most common form of hypertension is neurogenic hypertension that is associated with sympathetic overdrive, loss of parasympathetically mediated cardiac variability, and excessive angiotensin II activity Esler, . EvidencClinical interventions showing impressive blood pressure lowering effects by targeting reductions in SNS activation (Krum et al., Exercise training could elicit adaptations in the adrenergic system, since SNS is activated during each bout of exercise and repeated activation of SNS may result in an attenuation of sympathetic activity (Grassi et al., SNS overactivity is common in many cardiovascular disease states and is related to a higher incidence of morbidity and mortality. It is widely accepted that exercise training is associated with reductions in SNS activity, whether at rest or during conditions that produced sympathoexcitation, and this effect may represent an important mechanism by which exercise may contribute to long term cardiovascular health. Future studies are needed to further identify the molecular mechanisms that are involved in physical activity dependent changes in the control of SNS activity.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The objective of this article was to review the effects of xenobiotics on total antioxidant capacity (TAC). Measurement of TAC is appropriate for evaluation of the total antioxidant defenses of blood, cells, and different kinds of tissues and organs. TAC is reduced by alcoholism, smoking, and exposure to radiation, herbicides, carbon monoxide, carbon tetrachloride, lead, arsenic, mercury, cadmium, aluminum, and other toxic elements. The test is also an important tool in evaluating environmental and occupational exposure. The involvement of unstable free radicals and reactive species from oxygen (ROS), nitrogen (RNS), and chlorine in cell and tissue damage is well established , hydroxyl radical (\u2022OH), nitric oxide (NO\u2022), peroxynitrite (ONOO\u2013), though others are not   is any molecule that has one or more incomplete orbitals. A FR can gain electrons, oxidizing another atom/molecule or lose them, thus reducing an element. Some reactive oxygen species (ROS) are FR [superoxide anion , proteins (protein peroxidation), nucleic acids (DNA or RNA oxidation), and carbohydrates (glycosilation) (Vladimirov & Proskurnina 2\u2022\u2013) by mitochondria. As a further step, SOD and GPx convert O2\u2022\u2013 into hydrogen peroxide (H2O2). However, as H2O2 is also a toxic reactive oxygen species, it should also be modified to inocuous water and atomic oxygen by the enzyme CAT.Since the 1960's, many research groups have been evaluating oxidative and nitrosative stress and the antioxidant defenses by measuring the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione redutase (GSH) and glutathione peroxidase (GPx). As a consequence of oxidative phosphorylation, 3\u20135% of oxygen in converted to the free radical superoxide anion  of a biological sample , food or vegetable extract or of living tissues and organs . Many xenobiotics can be toxic to cells, tissues and organs, constituting environemntal and occupational health problems.et al., et al., et al., et al., et al., In order to know if a therapeutic drug can preserve or consume the antioxidants of a patient, TAC determination is done in medicinal drugs. Thus the perioperative anesthetics dopamine (1080\u00b1162 mmolET/L), propofol (100\u00b118 mmolET/L), dobutamine (80\u00b116 mmol ET/L), and noradrenaline (62\u00b116 mmolET/L) were found to present higher TAC values , one of the most potent liver toxins, presents a toxicological dose-response effect characterized by oxidative stress and lipid peroxidation events that induce reduction of liver TAC, liver degeneration, necrosis and fibrosis  are important metal-scavenging proteins protecting cells against cadmium, mercury, zinc and copper cytotoxicity  can also reduce plasma TAC by 20%  and activating the nuclear antioxidant response element which is further responsible for the increase in TAC levels. This could explain why exposure to magnetic fields has been correlated to increased TAC levels in male workers (Sirmatel et al., et al., Exposure to eletromagnetic radiation of 900MHz from mobile phones induced lipid peroxidation in the hippocampus and brain cortex of rats as well as oxidative stress and histopathological changes in the rats\u2019 endometrium, effects which were reversed by antioxidants (K\u00f6yl\u00fc et al., et al., et al., (It should be noted that the tecniques for determination of TAC in blood and biological fluids are still very recent. Thus potential clinical correlations between TAC and disease are yet in progress. Similarly, in many pathophysiological conditions the relationship with TAC levels has yet to be established. In a study with different degrees of injury, there was no correlation between plasma TAC levels and severity of lesions in patients with burns (Farriol  et al.,  revealedAlcohol, smoking, heavy metals and toxic elements, some pesticides, some occupational exposures, and eletromagnetic and nuclear radiations can decrease TAC, rendering subjects less resistant to oxidative and nitrosative injuries and subsequent diseases. More research is needed to address the role of antioxidant supplementation in xenobiotic exposure and disease prevention."}
+{"text": "To the Editor: Anthrax is a global zoonotic disease, but human infections are rare in countries of Western Europe. During 2009\u20132010, a total of 119 (47 laboratory-confirmed) drug-abuse\u2013related cases of anthrax were reported in the United Kingdom and Germany  user; the disease was described in 1 person who died in Norway in 2000  plnthracis  (7). TheB. anthracis into Western Europe (This reemergence of drug-related anthrax in Europe strengthens the view that heroin may provide a continuing route of entry for"}
+{"text": "Since time immemorial, in search for rescue for their disease, people looked for drugs in nature. The traditional use of medicinal plants can lead to the discovery of new potent botanical agents in the treatment of several diseases. Some 7000 natural compounds are currently used in modern medicine; most of these had been used for centuries by traditional healers and the global market value of medicinal plant products exceeds $100 billion per annum. In spite of the development of pharmacological agents for the treatment of chronic diseases, the use of medicinal plants continues to flourish. Over the last century, the drastic changes of human life style and eating habits lead to the emergence of various chronic diseases. The decreasing efficacy of some synthetic drugs and the increasing contraindications of their usage make the usage of natural drugs topical again. Thus, the study of phytotherapy for chronic diseases treatment might yield an excellent return in potential sources of medicinal plants which play vital roles in disease prevention and their promotion and use fit into all existing prevention strategies. In this issue, we aim to present some recent advances in the use of medicinal plants for treating the chronic diseases such as diabetes, cancer, cardiovascular diseases, inflammation, and neurologic disorders. Hydrangea paniculata, slows down the progression of membranous glomerulonephritis by anti-inflammatory effects and inhibiting immune complex deposition,\u201d investigated the renoprotective activity of skimmin, one of the major pharmacologically active molecules present in Hydrangea paniculata. They studied also the underlying mechanisms of the observed renoprotective effects of skimmin in a rat model of membranous glomerulonephritis induced by cationic bovine serum albumin which may be the inhibition of IL1\u03b2 and IL-6 expression. In another study \u201cTraditional Chinese medicine Tang-Luo-Ning ameliorates sciatic nerve injuries in streptozotocin-induced diabetic rats,\u201d D.-W. Zou et al. describe the beneficial effect of Tang-Luo-Ning (TLN), an effective traditional Chinese medicine for the treatment of diabetic peripheral neuropathy (DPN). To illustrate the underlying neural protection mechanisms of TLN, the effect of TLN on electrophysiology and sciatic nerve morphology was investigated in a model of streptozotocin-induced DPN. G. Belcaro et al., \u201cGrape seed procyanidins in pre- and mild hypertension: a registry study,\u201d studied the efficacy of a standardized grape seed procyanidins extract in decreasing blood pressure when associated with nondrug intervention (diet and lifestyle modification) in a controlled registry study involving healthy prehypertensive and mildly hypertensive subjects. The authors supported that the effect on blood pressure adds to the beneficial effects of grape seed procyanidins on the cardiovascular disease phenotype associated with the oxidation of membrane lipids . A study titled  by C. C. Velusami et al. demonstrates that both methanol and successive water extracts of Nelumbo nucifera petals had an effect on inhibition of lipid storage in adipocytes and increasing lipolysis. In addition, methanol extract exhibited the concentration dependent inhibitory effect on lipase activity. Furthermore, Nelumbo nucifera petal extracts showed evident agonist and antagonist activity towards serotonin and cannabinoid receptors, respectively, while it showed no effects towards melanocyte concentrating hormone and melanocortin receptors. Another clinical study performed by G. Belcaro et al. \u201cGreenselect Phytosome for borderline metabolic syndrome\u201d demonstrates that Greenselect Phytosome, a proprietary lecithin formulation of a caffeine-free green tea catechin extract, was especially effective for weight/waist changes in a controlled registry study on asymptomatic subjects borderline for metabolic syndrome factors and with increased plasma oxidative stress. A. Hunyadi et al., \u201cMetabolic effects of mulberry leaves: exploring potential benefits in type 2 diabetes and hyperuricemia,\u201d report a series of relevant in vitro and in vivo studies on the bioactivity of an extract of mulberry leaves and its fractions. In vivo antihyperglycemic and antihyperuricemic activity, plasma antioxidant status, in vitro glucose consumption by adipocytes in the presence or absence of insulin, xanthine oxidase inhibition, free radical scavenging activity, and inhibition of lipid peroxidation were analyzed.In a clinical study, \u201cEffect of eucalyptus oil inhalation on pain and inflammatory responses after total knee replacement: a randomized clinical trial,\u201d Y. S. Jun et al. demonstrate the beneficial effects of eucalyptus oil inhalation on pain and inflammatory responses after total knee replacement surgery. S. Zhang et al., \u201cSkimmin, a coumarin from Andrographis paniculata nees for treating lung adenocarcinomas,\u201d Y.-T. Tung et al. have studied the antipulmonary cancer effects of andrographolide in a lung tumor mouse model induced by human vascular endothelial growth factor A165 (hVEGF-A165). The antiangiogenesis and chemotherapeutic potential of andrographolide may provide a cure for pulmonary tumors in the future. Z.-Z. Meng et al., \u201cEffect of Xiaoyaosan decoction on learning and memory deficit in rats induced by chronic immobilization stress,\u201d observed the effect of Xiaoyaosan (XYS) decoction on chronic immobilization stress- (CIS-) induced learning and memory deficit in rats from behaviors and changes of proteins in hippocampus. The findings suggested that XYS decoction may be helpful in reversing CIS-induced learning and memory deficit by increasing the levels of postsynaptic density protein 95 and synaptophysin on the hippocampal nerve synapses and improving synaptic plasticity.In addition, known bioactive constituents of mulberry were identified and quantified. A study performed by H.-M. Zhao et al., \u201cSi Shen Wan inhibits mRNA expression of apoptosis-related molecules in p38 MAPK signal pathway in mice with colitis,\u201d demonstrated that Si Shen Wan, a formula of traditional Chinese medicine used to treat ulcerative colitis, allergic colitis, and chronic colitis, effectively inhibited mRNA expression of apoptosis-related molecules in p38 MAPK signal pathway to downregulate colonic epithelial cells apoptosis in colonic mucosa from mice with colitis. In another study \u201cTherapeutic potential of andrographolide isolated from the leaves of Garcinia origin (\u2013)-HCA,\u201d summarizes the update of chemical constituents, significance of in vivo/clinical antiobesity effects, and the importance of the current market potential of Garcinia/hydroxycitric acid especially as a potential supplement for weight management and as antiobesity agent. A study realized by Y. Liang et al., \u201cEffects of the Chinese traditional prescription Xiaoyaosan decoction on chronic immobilization stress-induced changes in behavior and ultrastructure in rat hippocampus,\u201d demonstrated the potential mechanism of Xiaoyaosan (XYS) decoction's antidepressant-like effect in \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors related to synaptic plasticity in the hippocampus rats induced by chronic immobilization stress. The study demonstrates that XYS decoction may produce an antidepressant-like effect, which appears to be involved with AMPA receptors related synaptic plasticity of hippocampus. In another study \u201cCitrus Bergamia Risso elevates intracellular Ca2+ intracellular stores in human umbilical vein endothelial cells,\u201d G. H. Seol et al. demonstrate that Citrus Bergamia Risso mobilizes Ca2+ from primary intracellular stores via Ca2+-induced and IP3-mediated Ca2+ release and affect promotion of Ca2+ influx, likely via an store-operated Ca2+ mechanism. This finding supports the potential roles of bergamottin in cardiovascular function. J. Hoscheid et al., \u201cInhibitory effect of the hexane fraction of the ethanolic extract of the fruits of Pterodon pubescens Benth in acute and chronic inflammation,\u201d confirm the anti-inflammatory activity of the hexane fraction of an ethanolic extract of Pterodon pubescens Benth. The anti-inflammatory activity was measured with increasing doses of the hexane fraction by using a carrageenan-induced rat model of pleurisy and a rat model of complete Freund's adjuvant-induced arthritis. The results of biochemical, hematological, and histological analyses indicated a significant decrease in glucose, cholesterol, and triglycerides levels and reduction in the number of total leukocytes and mononuclear cells. The study demonstrates also the absence of toxicity for the doses used. H. Park et al., \u201cAmpelopsis Radix protects dopaminergic neurons against 1-methyl-4-phenylpyridinium/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced toxicity in Parkinson's disease models in vitro and in vivo,\u201d have demonstrated that Ampelopsis Radix has neuroprotective effects with antioxidant mechanisms in Parkinson's disease models. The standardized extract of Ampelopsis Radix protected dopaminergic neurons by inhibiting reactive oxygen species generation in vitro, showed potent radical scavenging activities in vitro, and protected the dopaminergic neurons in the brain in the mouse Parkinson's disease model leading to motor improvements. Another paper by H. Ha et al., \u201cAntiatopic dermatitis effect of Artemisia iwayomogi in dust mice extract-sensitized Nc/Nga mice,\u201d demonstrates the anti-inflammatory and antiatopic dermatitis effects of Artemisia iwayomogi both in vitro and in vivo. Artemisia iwayomogi inhibited the nitric oxide and histamine productions in RAW264.7 and MC/9 cells. Furthermore, isochlorogenic acid A, chlorogenic acid, and scopoletin were demonstrated to be the major components of this plant. Additionally, in the mice, the topical application of Artemisia iwayomogi reduced the dermatitis scores in the dorsal skin and ears and reduced the plasma levels of IgE. E. Panzarini et al., \u201cAdministration dependent antioxidant effect of Carica papaya seeds water extract,\u201d demonstrate that Carica papaya seeds water extract is potentially useful for protection against oxidative stress. The authors have assessed the antioxidant activities of the Carica papaya seeds water extract against hydrogen peroxide oxidative stress in human skin Detroit 550 fibroblasts. An in vivo study by M.-H. Chen et al., \u201cAntidiabetic and antihyperlipidemic effects of Clitocybe nuda on glucose transporter 4 and AMP-activated protein kinase phosphorylation in high-fat-fed mice,\u201d demonstrates that amelioration of diabetic and dyslipidemic state by Clitocybe nuda extract in high-fat-fed mice occurred by regulation of GLUT4, glucose-6-phosphatase, and AMP-activated protein kinase phosphorylation. The plant extract decreased hepatic glucose production in the liver and enhanced glucose uptake in skeletal muscle. This study presents a deep analysis of mechanisms of action involved in the antidiabetic and antihyperlipidemic activities of Clitocybe nuda.A review conducted by L. O. Chuah et al., \u201cUpdates on antiobesity effect ofAfter the first volume of this special issue published in 2012, we hope that this issue will present valuable information for scientists and clinicians."}
+{"text": "These genes are thought to be functionally important for optimal viral replication and persistence in infected individuals. Primate lentiviruses can be classified by the composition of these accessory genes. While viruses of the HIV type1 (HIV-1) group have vpx gene derived from HIV-2 GL-AN clone (Kawamura et al., Although PPM consisting of seven consecutive prolines has been demonstrated to be required for efficient HIV-2 Vpx translation, thereby acquiring viral infectivity in macrophages, the effects of PPM mutations on the degradation of Vpx in cells was not formally analyzed as yet (Fujita et al., Various expression plasmids were transfected into human 293T cells (Lebkowski et al., Proteasomal degradation is generally triggered by the polyubiquitin modification of lysine residues in a protein. There are three lysines in the Vpx of HIV-2 GL-AN clone (Khamsri et al., In total, proteasomal or lysosomal degradation does not account for the extremely low expression level of Vpx exhibited by the PPM mutants. This is consistent with our previous conclusion that PPM is critical for efficient translation of Vpx (Miyake et al.,"}
+{"text": "Assessment of lymph node status is a critical issue in the surgical management of gallbladder cancer. The aim of this study was to compare the anatomical location of positive nodes, number of positive nodes, and lymph node ratio (LNR) as prognostic predictors in gallbladder cancer.\u03c72 scores calculated with the Cox proportional hazards regression model.We conducted a retrospective analysis of 135 patients with gallbladder cancer who underwent a radical resection with regional lymphadenectomy. A total of 2,245 regional lymph nodes were retrieved . The location of positive nodes was classified according to the AJCC staging manual (7th edition). \u2018Optimal\u2019 cutoff values were determined for the number of positive nodes and LNR based on maximal P\u2009<\u20090.001), number of positive nodes , and LNR  as significant prognostic factors. Multivariate analysis identified number of positive nodes as an independent prognostic factor ( P\u2009=\u20090.004); however, location of positive nodes and LNR failed to remain as an independent variable.Lymph node metastasis was found histologically in 59 (44%) patients. The \u2018optimal\u2019 cutoff values for the number of positive nodes and LNR were determined to be three nodes and 10%, respectively. Univariate analysis identified location of positive nodes  is valid for stratifying patients based on the prognosis after resection. Lymph node status  is an established prognostic factor in various gastrointestinal malignancies-7. Thereet al.[et al.[In the cases of gallbladder cancer, both the American Joint Committee on Cancer  and the et al. first reet al.) in patiet al.. Howeverl.[et al. were the\u03c72 scores calculated by the Cox proportional hazards regression model.The current study compared the prognostic power of positive node location , numberFrom May 1982 to January 2009, 148 consecutive patients underwent a radical resection for gallbladder cancer in the study department, defined as a resection of both the primary tumor and regional lymph nodes. Thirteen patients with an invasive primary malignant tumor in other organs were excluded, leaving 135 patients for this retrospective study. They included 94 women and 41 men with ages ranging from 37 to 85  years.en bloc regional lymph node dissection. Late-stage diseases often required more extensive resections such as major hepatectomy , pancreaticoduodenectomy (the Whipple procedure or pylorus-preserving procedure), or major hepatectomy combined with pancreaticoduodenectomy , duodenum (n\u2009=\u20094), portal vein (n\u2009=\u20093), stomach (n\u2009=\u20091), and inferior vena cava (n\u2009=\u20091). Among the total of 135 patients, 111 underwent an initial radical resection and 24 underwent a radical second resection after a prior simple cholecystectomy for presumed benign disease.en bloc. In the patients who underwent a pancreaticoduodenectomy, the right portion of the superior mesenteric node group was also dissected together with the above node groups. In some patients with early-stage disease, advanced age, or comorbid diseases, a less aggressive regional lymphadenectomy was performed at the discretion of the individual surgeons. In this series, 48 patients with suspected (or confirmed) regional nodal disease also underwent a dissection of the paraaortic lymph nodes [The regional lymph nodes of the gallbladder included the cystic duct, pericholedochal, posterior superior (posterosuperior) pancreaticoduodenal, retroportal, right celiac, and hepatic artery node groups,14,17. I artery),14,17.All pathological findings were documented by using the AJCC cancer staging manual (7th edition). The priImmediately after resection, the surgeon(s) retrieved lymph nodes from the node-bearing adipose tissues of the fresh surgical specimen, and grouped them according to location. A total of 2,829 lymph nodes  were retrieved from the 135 patients. A representative section, 3-\u03bcm thick, was cut from each lymph node retrieved, and the nodes examined for metastases on routine histological examination using hematoxylin and eosin.The number of positive lymph nodes as well as the total lymph node count (TLNC) was recorded for each patient. Paraaortic lymph nodes (if any) were not included in the TLNC, and any metastases detected in these lymph nodes were categorized as distant metastases and designated as pM1. Thus, iThree parameters were used to assess the nodal status in individual patients: the location of positive lymph nodes, the number of positive lymph nodes, and LNR. The location of positive nodes was classified into three categories: pN0, pN1, pN2, according to the AJCC cancer staging manual (7th edition). LNR wasThree patients died post-resection during a hospital stay, giving an in-hospital mortality rate of 2%. Adjuvant treatment after resection was administered at the discretion of the individual surgeons. Thirty-six patients received oral administration of 5-fluorouracil or its derivatives. Eight patients received intravenous administration of 5-fluorouracil alone or in combination with other agents. Six patients received intravenous administration of gemcitabine. No patients received adjuvant radiotherapy.Patients discharged home were followed regularly in outpatient clinics every one to six months for at least five years, with a median follow-up period of 146  months. At the time of disease status assessment, 53 patients had died of tumor recurrence and 19 patients had died of other causes with no evidence of tumor recurrence. One patient was alive with recurrent disease, and the remaining 62 patients were alive without the disease.Medical records and survival data were obtained for all patients. The survival time in each patient was defined as the interval between the date of the definitive resection and the date of the last follow-up or death. Only deaths from tumor recurrence were treated as failure cases in the analysis of disease-specific survival (DSS). The Kaplan-Meier method was used to estimate cumulative DSS rates, and the log rank test was used to evaluate differences between groups.\u03c72 scores, which were calculated using the Cox proportional hazards regression model. Eleven conventional variables  were found to be significant by univariate analysis  was used for all statistical evaluations. All tests were two-tailed, and A total of 2,245 regional lymph nodes were retrieved from the 135 patients, with TLNC per patient ranging from 3 to 55 . Of the study patients, 59 (44%) had a total of 252 positive lymph nodes; the number of positive nodes ranged from 1 to 26  per patient, and LNR ranged from 2.6% to 93% .\u03c72 score, the \u2018optimal\u2019 cutoff value was three nodes for the number of positive nodes , number of positive lymph nodes , LNR , pM classification, histological type, histological grade, lymphatic vessel invasion, venous invasion, perineural invasion, and residual tumor status as significant prognostic factors  and the 59 patients with TLNC\u2009>\u200916  P\u2009=\u20090.10; Table2P\u2009=\u20090.707).We then focused on a subgroup of 76 patients without nodal disease (pN0) for further survival analysis. Even in this subgroup of patients, no significant difference in DSS was noted between 51 with TLNC\u2009\u2264\u200916  and 25 with TLNC\u2009>\u200916   recommended \u2018analysis of a minimum of three lymph nodes\u2019 for accurate staging of gallbladder cancer. Howeveret al. and Mayo[et al. disclose[et al.. The abo[et al.-5,12,18.et al.[et al.[et al.[et al.[In contrast, Japanese hepatobiliary surgeons, including us, maintain an aggressive attitude toward regional lymphadenectomy for gallbladder cancer,13,14,23et al. and Mayo[et al. independ[et al. and Negi[et al. independ[et al.,18) is wet al.[et al.[et al.[et al.[In various gastrointestinal malignancies, evaluating a limited number of lymph nodes may result in an underestimated number of positive nodes, leading to \u2018stage migration\u2019 -5,12,18.et al., Lee et [et al., Sakata [et al., and Sie[et al. for pancet al.[\u03c72 scores calculated by the Cox proportional hazards regression model  and the et al. suggesteet al.), of poset al.). In addThe current study has several limitations: the retrospective nature of the analysis, the relatively small number of patients spanning a long period of time, some variability in the degree of nodal dissection, and the short follow-up time for some patients. We believe, however, that these limitations did not greatly affect the results of the study as the differences between groups were too marked to have resulted from bias. In addition, the role of the number of positive nodes in assessing the nodal status for gallbladder cancer is now more clearly defined than previously based on the current study. Our results thus provide useful information for accurately staging nodal disease, predicting prognosis after resection, and selecting candidates for adjuvant chemotherapy after resection. The current study also emphasizes the need to retrieve a larger number of lymph nodes than ever  in rThe number of positive lymph nodes better predicts the outcome after resection than either location of positive lymph nodes or LNR in gallbladder cancer, provided that lymph node evaluation is sufficient. Dividing the number of positive lymph nodes into three categories  is valid for stratifying patients based on the prognosis after resection.Written informed consent was obtained from the patients for publication of this report.AJCC, American Joint Committee on Cancer; DSS, Disease-specific survival; LNR, Lymph node ratio; TLNC, Total lymph node count.The authors declare that they have no competing interests.YS conceived the study and drafted the manuscript. JS helped to draft the manuscript and performed statistical analyses. TW performed chart review and follow-up of the study cohort. TO helped with chart review and patient follow-up. YA provided histological data. KH was responsible for the whole study and participated in its coordination. All authors read and approved the final manuscript."}
+{"text": "Synovial fluid is a viscous solution found in the cavities of synovial joints. The principal role of synovial fluid is to reduce friction between the articular cartilages of synovial joints during movement. The presence of high molar mass hyaluronan (HA) in this fluid gives it the required viscosity for its function as lubricant solution. Inflammation oxidation stress enhances normal degradation of hyaluronan causing several diseases related to joints.This review describes hyaluronan properties and distribution, applications and its function in synovial joints, with short review for using thiol compounds as antioxidants preventing HA degradations under inflammation conditions. The human skeleton consists of both fused and individual bones supported and supplemented by ligaments, tendons, and skeletal muscles. Articular ligaments and tendons are the main parts holding together the joint(s). In respect of movement, there are freely moveable, partially moveable, and immovable joints. Synovial joints , the free.g. those covering the bone ends in the knee joint \u2013 belong to mechanically highly stressed tissues in the human body. At walking, running, or sprinting the strokes frequency attain approximately 0.5, 2.5 or up to 10 Hz.In a healthy synovial joint, heads of the bones are encased in a smooth  cartilage layer. These tough slippery layers \u2013 et al.,in vivo.Cartilage functions also as a shock absorber. This property is derived from its high water entrapping capacity as well as from the structure and intermolecular interactions among polymeric components that constitute the cartilage tissue  are localized/embedded. Their primary function is to continuously extrude high-molar-mass hyaluronans (HAs) into synovial fluid.The synovial fluid (SF) of natural joints normally functions as a biological lubricant as well as a biochemical pool through which nutrients and regulatory cytokines traverse. SF contains molecules that provide low-friction and low-wear properties to articulating cartilage surfaces.et al.,et al., 2001), hyaluronan (HA)   comprised of tissue macrophage A cells, fibroblast-like B cells ,  it has b2\u2022\u2013, H2O2, \u2022OH) are generated in abundance by synovial neutrophils from RA patients, as compared with synovial neutrophils of osteoarthritis (OA) patients and peripheral neutrophils of both RA and OA patients   and/or catalase, which suggests the possibility that there is pathologic oxidative damage to synovial fluid components in RA patients. Dahl et al.  to be in sterically favorable equatorial positions while all of the small hydrogen atoms occupy the less sterically favorable axial positions. Thus, the structure of the disaccharide is energetically very stable. HA is also unique in its size, reaching up to several million Daltons and is synthesized at the plasma membrane rather than in the Golgi, where sulfated glycosaminoglycans are added to protein cores   in cosmetic surgery. It is reported that injection of such products into the dermis, can reduce facial lines and wrinkles in the long term with fewer side-effects and better tolerability compared with the use of collagen  initiated by the HO2.Propagation phase: formation of a peroxy-type C-macroradical of hyaluronan in a process of oxygenation after entrapping a molecule of OFormation of a hyaluronan-derived hydroperoxide via the reaction with another hyaluronan macromolecule.Formation of highly unstable alkoxy-type C-macroradical of hyaluronan on undergoing a redox reaction with a transition metal ion in a reduced state.et al.,et al.,et al.,et al.,et al.,Termination phase: quick formation of alkoxy-type C-fragments and the fragments with a terminal C=O group due to the glycosidic bond scission of hyaluronan. Alkoxy-type C fragments may continue the propagation phase of the free-radical hyaluronan degradation reaction. Both fragments are represented by reduced molar masses  preserving the redox status of cells and protecting tissues against damage caused by the elevated reactive oxygen/nitrogen species (ROS/RNS) levels, by which oxidative stress might be indicated.In vitro. High molecular weight hyaluronan samples were exposed to free-radical chain degradation reactions induced by ascorbate in the presence of Cu(II) ions, the so called Weissberger's oxidative system. The concentrations of both reactants  were comparable to those that may occur during an early stage of the acute phase of joint inflammation  balance and regulates signaling pathways during oxidative stress/conditions. GSH is mainly cytosolic in the concentration range of ca. 1\u201310 mM; however, in the plasma as well as in SF, the range is only 1\u20133 \u00b5M , another significant precursor of the GSH biosynthesis, has broadly been used as effective antioxidant in a form of nutritional supplement  ions to Cu(I), forming N-acetyl-l-cysteinyl radical that may subsequently react with molecular O2 to give O2\u2022\u2013 , when added at the beginning of the reaction, exhibited a clear antioxidative effect within ca. 60 and 80 min, respectively  is a cystine-depleting compound with antioxidative and anti-inflammatory properties; it is used for treatment of cystinosis \u2013 a metabolic disorder caused by deficiency of the lysosomal cystine carrier. CAM is widely distributed in organisms and considered to be a key regulator of essential metabolic pathways , when added before the onset of the reaction, exhibited an antioxidative effect very similar to that of GSH . Moreove"}
+{"text": "Recently, the Notch system has been shown to be an important bridge between APCs and T cell communication circuits. In the present review, we discuss recent findings that explore the mechanisms in the linkage of innate and adaptive immunity, including granulomatous formation though TLRs and Notch activation.Granulomas represent a spectrum of inflammatory sequestration responses that may be initiated by a variety of agents, including non-infectious environmental factors and infectious microbial pathogens. Although this reaction is designed to be protective, the associated tissue injury is often responsible for a profound degree of pathology. While many of the mechanisms that sustain the development of the granuloma are enigmatic, it is accepted that the maintenance of this inflammatory process is dependent upon dynamic interactions between an inciting agent, inflammatory mediators, various immune and inflammatory cells, and structural cells of the involved tissue. The best studied of the host-dependent processes during granuloma development is the innate and adaptive immune response. The innate immune response by antigen-presenting cells  is initiated quickly to protect from overwhelming pathogens, but with time, can also activate the adaptive immune response. APCs, essential regulators of the innate immune response, can respond to microbial ligands through Toll-like receptors (TLRs), which function in the recognition of microbial components and play an important role to link the innate and adaptive immune responses. CD4 The granulomatous response is a complex host defense mechanism that has evolved to provide containment of infectious and/or environmental agents Warren, . The maiThe initial response to infection is the engagement of the host's innate immune system that triggers a rapid, multifaceted anti-infectious response involving the release of proinflammatory cytokines and eventually leads to the activation of the adaptive immune response -\u03b3, Interleukin (IL)-12, and tumor necrosis factor (TNF) were necessary for lung lesion progression , were shown to be maintained by IL-4, IL-5, and IL-13, hallmarks of a type 2 response  or Schistosoma mansoni antigen followed by a pulmonary challenge with sized Sepharose beads coated with a known amount of tuberculin purified protein derivative (PPD) , that promote a dominant Th2 response  (Herbert et al., +, 15\u201330% are CD8+ T cells, and there are also about 2%\u03b3\u03b4 T cells (Tsai et al., + T cells in the control of mycobacterial infection has been highlighted by many studies in knockout mice, and also in HIV patients (Ladel et al., The typical granuloma contains mostly macrophages and DCs, surrounded by T lymphocytes, while myeloid DCs also have been found in the granulomas of tuberculosis patients and mouse tuberculin models (Ulrichs and Kaufmann, Innate immunity is the first line of host defense directed against invading pathogens and is designed to maintain host integrity (Si-Tahar et al., M. tuberculosis infection in vivo (Bafica et al., Mycobacterium tuberculosis (Bafica et al., Microbial products, including mycobacterium antigen, activate specific TLRs, which in turn induce specific gene transcription resulting in the up-regulation and secretion of select chemokines and cytokines (Krutzik and Modlin, + Th cells (Kumar et al., Pathogens such as bacteria, helminths, fungi, and viruses are recognized by and activate APCs, which in turn activate CD4in vitro data will require a number of in vivo studies using diverse granulomatous models, including bacterial, parasitic, and fungal, as well as autoimmune models.In addition, it has been shown that Notch proteins are also important in the induction of Th responses (Amsen et al., \u2212/\u2212 mice when compared to wild-type mice, Th2 cytokine levels of IL-4, IL-5, and IL-13 were increased in these knockout mice (Ito et al., \u2212/\u2212 mice and defined a role for TLR9 in the induction of both Notch ligand Dll4 and Th17 expression using both in vivo and in vitro approaches (Ito et al., \u2212/\u2212 mice exhibited significantly larger granuloma formation, following an impaired Th17-like response with decreased expression of Dll4 on DCs from TLR9\u2212/\u2212 mice compared with WT mice. Dll4 was the primary Notch ligand upregulated by mycobacterial infection of DCs in WT mice. When Dll4 was specifically blocked in vivo using anti-Dll4 Ab during mycobacteria-induced pulmonary granuloma formation, Th17 cellular responses were significantly inhibited and larger granulomas were observed. Moreover, in in vitro experiments, anti-dll4 antibody specifically blocked IL-17 production by CD4+ T cells, while overexpression of Dll4 augmented IL-17 production by CD4+ T cells, suggesting that Dll4 plays an important role in promoting Th17 activity during a mycobacterial challenge. In contrast, the observed histologic alterations in lung granuloma development in TLR9\u2212/\u2212 mice also coincided with a significant decrease in lung myeloid DCs, which are crucial to the differentiation of Th17 cells, as well as decreased levels of dll4 on DCs when compared with wild-type mice. This impaired migration of lung myeloid DCs in granuloma was attributed to decreased production of chemokine CCL20. Chemokines constitute a family of structurally related chemotactic cytokines that direct the migration of leukocytes throughout the body under both physiological and inflammatory conditions (Matsushima, in vivo in normal mice via homeostatic proliferation express CCR6 as well as CCL20 (Hirota et al., \u2212/\u2212 mice and in lungs with anti-dll4 Ab is correlated with not only impaired DC migration but also reduced numbers of Th17 cells in lungs during mycobacteria induced pulmonary granuloma formation (Ito et al., While the mechanism of granuloma formation is unclear, this distinct cellular response is considered a histologic hallmark for a protective immune response, involving both innate and adaptive immunity. TLR9 is known to play a role in the regulation of Th1 responses (Bafica et al., Schistosoma mansoni eggs to the lungs (Schaller et al., Our data suggest that an understanding of Dll4 regulation of Th17 responses through Notch may provide mechanistic approaches for modifying and controlling the immune response induced by the Th17 phenotype. Moreover, a number of studies have demonstrated that Notch proteins are important in the induction of Th1 responses. In the presence of functional MyD88, PAMP binding to TLR up-regulates Dll4, which causes the differentiation of na\u00efve Th cells to a Th1 phenotype. In addition, when Dll ligands are overexpressed on APCs or are cross-linked as fusion proteins, they also promote Th1 cell differentiation (Maekawa et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "DING proteins constitute a recently discovered protein family that is ubiquitous in eukaryotes. The structural insights and the physiological involvements of these intriguing proteins are hereby deciphered. ab initio the complete and exact sequence of this 38\u2005kDa protein by utilizing mass spectrometry and X-ray data in tandem. Taking advantage of this first complete eukaryotic DING sequence, a immunohistochemistry study was undertaken to check the presence of DING proteins in various mice tissues, revealing that these proteins are widely expressed. Finally, the structure of a bacterial representative from Pseudomonas fluorescens was solved at sub-angstrom resolution, allowing the molecular mechanism of the phosphate binding in these high-affinity proteins to be elucidated.DING proteins constitute an intriguing family of phosphate-binding proteins that was identified in a wide range of organisms, from prokaryotes and archae to eukaryotes. Despite their seemingly ubiquitous occurrence in eukaryotes, their encoding genes are missing from sequenced genomes. Such a lack has considerably hampered functional studies. In humans, these proteins have been related to several diseases, like atherosclerosis, kidney stones, inflammation processes and HIV inhibition. The human phosphate binding protein is a human representative of the DING family that was serendipitously discovered from human plasma. An original approach was developed to determine  MS experiments, including ESI-MS on intact HPBP, were used to correct errors from crystallographic sequencing, including those for the few peptides that could not be sequenced. Finally, this technique allowed, ab\u00a0initio and without ambiguities, the 38\u2005kDa HPBP to be sequenced  fragmentation in LC-MS/MS and MALDI-MS/MS experiments to be obtained. The primary sequence obtained by X-ray crystallography was used like an \u2018Ariane wire\u2019, useful to align peptide sequences subsequently obtained by mass spectrometry, without the need of having overlapping peptides. It can be noted that X-ray crystallography techniques provided important information that can barely be obtained using MS, such as the exact number of amino acids and the presence of the disulfide bridges, and the discrimination of residues that possess the same mass (Leu, Ile, 3.et al., 2008Taking advantage of obtaining the HPBP sequence (Diemer et al., 2010Leishmania major genome and western blot studies on plant tissues (Perera et al., 2008et al., 2010et al., 2007DING proteins were observed in all tested tissues, namely brain, skin, heart, aorta, lung and liver, suggesting that these proteins are widely expressed within the organism (Collombet SJ suppresses expression of HIV-1 genome (Darbinian et al., 2008SJ with human C/EBP\u03b2 transcription factor and viral Tat transactivator. Moreover, p27SJ possesses a phosphatase activity inducing a dysregulation at S and G2/M phases in cell cycles related to alteration of the Erk1/2 phosphorylation state (Darbinian et al., 2009et al., 2005The immunohistochemistry study also reveals that the DING protein cellular localization is tissue-dependent, being exclusively nuclear in neurons, and nuclear and cytoplasmic in the heart muscle. The nuclear localization of DING proteins fits well with previous observations concerning biological activities of DING proteins, showing a clear involvement of these proteins in complex processes within the nucleus. For example, p274.et al., 2006Pseudomonas fluorescens called PfluDING (Ahn et al., 2007et al., 2007a            et al., 1999Escherichia coli phosphate-binding protein. Interestingly, the unique feature of DING proteins compared with pstS is the presence of four protruding loops at the protein surface (Fig. 2b            Two structures of DING representatives are available: the structure of HPBP (Morales 5.K            D of approximately 1\u2005\u00b5M (Ahn et al., 2007et al., 2009Although their phosphate-binding ability has not been clearly related to their biological functions until now, DING proteins are able to bind phosphate with high affinity. Indeed, it has been shown that HPBP and PfluDING bind phosphate with a a            K            a values of the phosphate moiety, PfluDING binds only dibasic phosphate both at acidic and basic pH. The structures show that the phosphate ion is bound via 11 normal hydrogen bonds plus a highly energetic hydrogen bond, between a phosphate oxygen and the carboxylate side chain of Asp62 (Fig. 3b            K            a of atoms in the binding site. Indeed, the fact that PfluDING binds only dibasic phosphate both at acidic and basic pH can be explained by the finding of a very positively charged binding site, capable of altering dramatically the phosphate pK            a.The quality of the obtained data allows most of the H atoms in the protein structure to be located precisely (Fig. 36.ab initio HPBP using mass spectrometry and X-ray data in tandem. Taking advantage of the very high diffracting power of DING protein crystals, we elucidated the molecular mechanism of phosphate binding in high-affinity proteins. These studies illustrate that DING proteins are widely expressed in eukaryotic tissues, and their cellular localization is tissue-dependent, albeit being mostly nuclear. This nuclear localization partly explains some observed biological activities, such as the role in the cell cycle and the inhibition of the HIV replication by interacting with the viral protein Tat and the human transcription factor CEBP/\u03b2. The involvement of DING proteins in several important human diseases, together with their genetic mystery and our findings of unknown HMW-DING in eukaryotes, enhance the emerging scientific interest on this protein family.The DING proteins family is an intriguing protein family that seems ubiquitous in eukaryotes, albeit their coding genes are missing. This unconventional protein family requires, for its investigation, some methodological developments. For example, an original approach was developed in order to sequence"}
+{"text": "Cytokinins (CKs) are a large group of plant hormones which play a crucial role in many physiological processes in plants. One of the interesting functions of CKs is the control of programmed cell death (PCD). It seems that all CKs-dependent phenomena including PCD are accompanied by special multi-step phosphorelay signaling pathway. This pathway consists of three elements: histidine kinase receptors (HKs), histidine phosphotransfer proteins (HPs) and response regulators (RRs). This review shows the r\u00e9sum\u00e9 of the latest knowledge about CKs signaling pathways in many physiological processes in plants with special attention paid to PCD process. Programmed cell death (PCD) is a process that normally occurs during seed germination, development and senescence. This process is crucial for proper functioning of all multicellular organisms, both plants and animals \u2014kinetin and benzylaminopurine \u2014at high concentrations are able to induce PCD in plants  of roots which seems to be crucial for this synthesis. In cells, CKs are present in chloroplasts or as complexes bound with tRNA  or aromatic compounds  and their derivates. Derivates of zeatin and iP as well as their sugar conjugates are most popular, but their occurrence depends on plant species, stage of development and tissue , a purine-derived CK, discovered as a degradation product of DNA, plays a crucial role in plant cell division. It was isolated by Professor Scoog in 1955 and now it seems that it is the best-known CK  Fig.\u00a0. Active A. thaliana  and organismal response to stress, pathogens, senescence  which are responsible for reception of the CK signals  that mediate phosphoryl group transfer between AHKs and ARRs were also characterized  were observed. In rice, only two of HPs (OHP3 and OHP4) are involved in the CK signaling multi-step phosphorelay system. The RRs present in rice are also divided into two groups: OsRRs and ORRs. The former is similar to type-A ARRs  were described as negative regulators of CK signaling, whereas type-B  seems also to play a positive role in transcription factors engaged in CK signaling . They were closely related to AHK4, AHK3, and AHK2 receptors, respectively  and A. thaliana (L.) Heynh. In both carrot and Arabidopsis, PCD was induced by accelerating senescence or senescence-like process both in vitro (in cell cultures) and in vivo  is engaged in CK-stimulated induction of PCD (Vescovi et al. Zea mays and Arabidopsis (Caesar et al. The question arises V. faba ssp. minor after kinetin treatment (Kunikowska et al. Subcellular AHK localization sheds a new light on hormone functioning (Caesar et al."}
+{"text": "Bian Zheng) is a traditional diagnostic method to categorize patients' syndromes based on their presented conditions. Currently, combination of Zheng classification and biomedical diagnosis becomes a common model in TCM diagnostics in clinical practice. Clinical treatments of a patient rely on the classification of a specific TCM Zheng. This special issue collects articles describing the clinical trials with TCM Zheng classification, Zheng classification methodology from clinical data, systematic reviews on clinical studies using Zheng classification, and the clinical pharmacological evaluation on TCM interventions using the omics platforms as well as bioinformatics.According to the traditional Chinese medicine (TCM) theory, TCM Zheng  is an analysis on disease presentation by TCM practitioners. Zheng classification  for mild-to-moderate systematic lupus erythematosus: a pilot prospective, single-blinded, randomized controlled study\u201d by Zhong et al. showed that Zi Shen Qing is safe and effective for decreasing severity of systemic lupus erythematosus activity and withdrawal dosage of corticosteroids in the mild-to-moderate patients with \u201cDeficiency of Qi and Yin\u201d Pattern. \u201cTherapeutic efficacy of Fuzheng-Huayu tablet based traditional Chinese medicine syndrome differentiation on hepatitis-B-caused cirrhosis: a multicenter double-blind randomized controlled trail\u201d by Song et al. revealed that Fuzheng-Huayu decreases TCM syndrome scores and improves the quality of life of hepatitis-B-caused cirrhosis patients. The only longitudinal study included in this issue, \u201cIncreases in Xu Zheng and Yu Zheng among patients with breast cancer receiving different anticancer drug therapies\u201d by Huang et al. assessed Zheng using the TCM Constitutional Scale. It is significant that more and more clinical trials pay attention to the Zheng classification and put it as a criterion for participants selection and outcome assessment, and such changes not only provide the change to demonstrate the characteristics of TCM therapy, but also provide the more comprehensive assessment of an intervention compared with conventional biomarker-oriented assessment.Among included randomized controlled trials, \u201cPrescription of Chinese herbal medicine and selection of acupoints in pattern-based traditional Chinese medicine treatment for insomnia: a systematic review\u201d by Yeung et al. included 227 studies, 17,916 subjects, and 87 TCM patterns. They highlighted high-quality studies to examine the additional benefits of pattern differentiation and pattern-based TCM treatment. \u201cModified Dachengqi decoction combined with conventional treatment for treating acute exacerbation of chronic obstructive pulmonary disease: a systematic review based on randomized controlled trials\u201d by Wu et al. analyzed 16 studies involving 1,112 patients and showed that Dachengqi decoction combined with routine treatment enhances the effectiveness. \u201cTianma Gouteng Yin as adjunctive treatment for essential hypertension: a systematic review of randomized controlled trials\u201d by Wang et al. reveals no confirmed conclusion about the effectiveness and safety of Tianma Gouteng Yin for essential hypertension. \u201cZHENG-omics application in ZHENG classification and treatment: Chinese personalized medicine\u201d by Dai et al. gives the brief introduction and preliminary validation and discusses strategies and system-oriented technology. \u201cClinical applications of omics technologies on ZHENG differentiation research in traditional Chinese medicine\u201d by Song summarized the typical omics application in common studied diseases and TCM Zhengs and discussed the main problems and countermeasure of Zheng classification researches. \u201cSyndrome differentiation in Chinese herbal medicine for irritable bowel syndrome: a literature review of randomized trials\u201d by Li et al. involved 735 RCTs and 67,784 patients and indicated that 30.5% studies applied Zheng classification. Reviews and evidences, \u201cMetabonomics-based study of clinical urine samples in suboptimal health with different syndromes\u201d by Cui et al. identified the specific metabolic products of the syndrome of stagnation of liver Qi. \u201cSimilar connotation in chronic hepatitis B and nonalcoholic fatty liver patients with dampness-heat syndrome\u201d by Dai et al. discussed the molecular mechanism of similar connotation that exists in chronic hepatitis B and nonalcoholic fatty liver by metabonomics to give the modern understanding of dampness-heat syndrome. \u201cDifferences of excess and deficiency Zheng in patients with chronic hepatitis B by urinary metabonomics\u201d by Sun et al. suggested that chronic hepatitis B patients could be categorized into two groups with diverse pathogenesis. \u201cDifferences in metabolites of different tongue coatings in patients with chronic hepatitis B\u201d by Zhao demonstrated that tongue coatings have objective material basis. \u201cMetabonomics study of essential hypertension and its Chinese medicine subtypes by using gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy\u201d by Li et al. distinctly classified Yin deficiency, Yang-hyperactivity syndrome, and Yin-Yang deficiency syndrome by principal components analysis and partial least squares discriminant analysis. \u201cVisual agreement analyses of traditional Chinese medicine: a multiple-dimensional scaling approach\u201d by Lo et al. developed a novel visual agreement analysis for TCM via multiple-dimensional scaling. \u201cThe pattern element scale: a brief tool of traditional medical subtyping for dementia\u201d by Shi et al. evaluated the utility of the new pattern element scale in dementia patients. \u201cValidity of a diagnostic scale for acupuncture: application of the item response theory to the five viscera score\u201d by Tomura first applied the item response theory model to the five viscera score to test its validity by evaluating the ability of the questionnaire items to identify an individual's latent traits. \u201cInterrater reliability of Chinese medicine diagnosis in people with prediabetes\u201d by Grant et al. provides initial evidence of variation in the biomarkers of people with prediabetes according to the different TCM Zhengs. \u201cValidation of the constitution in Chinese medicine questionnaire: does the traditional Chinese medicine concept of body constitution exist?\u201d by Wong et al. adapted and validated the constitution in Chinese medicine questionnaire in Hong Kong Chinese people. \u201cClassification and progression based on CFS-GA and C5.0 boost decision tree of TCM Zheng in chronic hepatitis B\u201d by Chen et al. applied correlation-based feature selection, genetic algorithm, and decision tree for Zheng classification and progression in the TCM treatment of chronic hepatitis B (CHB). \u201cUnderstanding the molecular mechanism of interventions in treating rheumatoid arthritis patients with corresponding traditional Chinese medicine patterns based on bioinformatics approach\u201d by Jiang et al. indicates that molecular network analysis could provide insight into the full understanding of the underlying mechanism of how TCM pattern impacts the efficacy. \u201cThe correlation between high-sensitivity C-reactive protein, matrix metallopeptidase 9, and traditional Chinese medicine syndrome in patients with hypertension\u201d by Wu et al. investigated the relationships between Zheng and the two inflammatory biomarkers in patients with essential hypertension. \u201cResearch on Zheng classification fusing pulse parameters in coronary heart disease\u201d by Guo et al. illustrated that the nonlinear dynamic variables of TCM pulse can improve the performances of Zheng classification models. \u201cA two-level model for the analysis of syndrome of acute ischemic stroke: from diagnostic model to molecular mechanism\u201d by Dai et al. analyzed that collateral obstruction syndrome, the integration of diagnostic model and molecular mechanism analysis creates an interesting perspective to better understand Zheng. \u201cProgression from excessive to deficient syndromes in chronic hepatitis B: a dynamical network analysis of miRNA array data\u201d by Chen et al. suggested that miRNAs are important mediators for TCM Zheng classification and could be potential diagnosis and therapeutic molecular markers. \u201cCirculating miR-583 and miR-663 refer to ZHENG differentiation in chronic hepatitis B\u201d by Zhang et al. indicated that 354 putative targets for miR-583 and 68 putative targets for miR-663 were mainly involved in Axon guidance, Neurotrophin, and MAPK signaling pathway; miR-583 and miR-663 may be potential markers for Zheng differentiation in CHB. Besides, \u201cAutophagy inhibition enhances apoptosis induced by dioscin in Huh7 cells\u201d by Hsieh et al. showed that dioscin, a new water-soluble steroidal saponin from Dioscorea nipponica Makino, causes autophagy in Huh7 cells and suggested that dioscin has a cytoprotective effect.Zheng diagnosis for patients is sometimes inconsistent among different practitioners. This is in part due to the paucity of evidence-based diagnostic methods in TCM. To solve this problem, establishment of validated diagnostic tool is inevitable. \u201cClinical trial on the characteristics of Zheng classification of pulmonary diseases based on infrared thermal imaging technology\u201d by Ni et al. showed that the infrared thermal images characteristics of a different Zheng of pulmonary disease were distinctly different. These studies provide the potential of how to improve the quality of Zheng diagnosis. Further studiese are needed to systematically improve the quality of Zheng diagnosis and the integrate this method with modern medicine.Furthermore, Recently, a great progress has been made in the clinical studies focusing on the exploration of the effect of TCM interventions in the patients with clarified TCM Zheng in some diseases. The randomized controlled trials and systematic reviews provide strong evidence for Zheng classification. This special issue presents, even though partially, the efficacy of TCM practice with integration of TCM Zheng classification, biomedical disease diagnosis, and the biological basis of Zheng. We hope that our readers could share these works and further contribute to this important field."}
+{"text": "Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse, and hNK cells significantly differ in their subpopulations, functions, and receptor repertoires. Thus, there is a need for a model that is more closely related to humans and yet allows experimental manipulations. Non-human primate models offer numerous opportunities for the study of NK cells, including the study of the role of NK cells after solid organ and stem cell transplantation, as well as in acute viral infection. Macaque NK cells can be depleted in vivo or adoptively transferred in an autologous system. All of these studies are either difficult or unethical to carry out in humans. Here we highlight recent advances in rhesus NK cell research and their parallels in humans. Using high-throughput transcriptional profiling, we demonstrate that the human CD56bright and CD56dim NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of non-human primate models offers the potential to substantially advance hNK cell research.Human NK (hNK) cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on hNK cells has been generated using peripheral blood lymphocytes. In contrast, our knowledge of NK cells in human tissues is limited, and not much is known about developmental pathways of hNK cell subpopulations  NK cells are lymphocytes that have evolved to provide a first line of immune protection against viruses and malignancies before adaptive immune responses emerge Lanier, . IncreasThe study of murine NK (mNK) cells has clearly elucidated a number of fundamental principles, some of which seem to universally apply to all NK cells, such as the activation of NK cells by absent or altered MHC class I molecule expression, also known as the \u201cmissing self hypothesis\u201d , and CD16+ NK cells  on highly purified CD56+, CD16+, and DN rmNK cells. We either utilized rhesus-specific ABI TaqMan assays, when available, (Life Technologies), or custom-designed primers and probes based on rhesus mRNA sequences. A complete list of real-time PCR assays employed in our study is available upon request. All assays were subjected to a rigorous selection process to ensure that targeted rhesus macaque genes were orthologous to human genes.A previous transcriptome analysis study revealed a number of differentially expressed genes in CD56+, CD16+, and DN rmNK cell subsets  revealed a segregation of NK cells into groups corresponding to the CD56s Figure . Similars Figure . Converss Figure  as expecs Figure . In addis Figure . FinallyF Figure .+ and CD16+ NK cells, both in the PCA analysis as well as for most of the gene expression data presented in Figure bright NK cells represent a less mature developmental stage of NK differentiation, whereas CD56dim cells exhibit a more differentiated effector profile  in rhesus macaques with an acquired and transmissible immunodeficiency (Daniel et al., \u2212CD8+CD16+ cells (De Boer et al., + and DN rmNK cell subpopulations, and may have limited the authors' ability to accurately assess the effects of SIV infection on the full repertoire of rmNK cells.Multiple phenotypic and functional changes within the NK cell compartment have been documented in HIV infection (Fauci et al., dim NK cells and an increase of the CD56\u2212CD16+ NK cell subset (Alter et al., + NK cells (Reeves et al., bright and CD56+ cells, respectively, without affecting the frequencies of cells expressing CD62L (Reeves et al., Although NK cells from chronically HIV- or SIV-infected donors display a hyper-activated state, their capacity to respond to PMA and ionomycin is diminished (Azzoni et al., Whereas most hNK studies have focused on NK cell subsets from peripheral blood, much less is known about NK cells in tissues. The complexity and heterogeneity of hNK cells residing in various organs, such as uterus, brain, spleen, liver, pancreas, and skin, as well as various mucosal tissues, including the gut, is an area of research that is garnering increasing interest (Shi et al., + hNK cell subset was recently discovered in human and mouse mucosal-associated lymphoid tissues (Cella et al., + NK cells (Reeves et al., + NK cells displayed an altered functional profile with increasing resemblance to conventional NK cells. These alterations were linked to gut inflammation and the up-regulation of indoleamine 2,3-dioxygenase 1 (Reeves et al., A novel IL-22- and IL-17-producing NKp44+ NK cell subsets in treated HIV-patients with incomplete or suboptimal CD4+ T cell recovery (Sips et al., + NK cells could play a compensatory role in patients with ongoing compromised immunity. However, to our knowledge, the impact of HIV infection on IL-22-producing NKp44+ hNK cells has not yet been addressed.A recent study described an expansion of intraepithelial and lamina propria NKp46in vivo effects of cytokines on lymphocyte homeostasis and disease can be addressed in rhesus macaques (Kuramoto et al., + T cells (Mueller et al., In addition to improved access to tissue samples, a number of experimental procedures that have the potential to significantly advance our understanding of NK cells can be carried out in non-human primates. For instance, the in vivo setting.To evaluate the antiviral contributions of NK cells in control of SIV infection, mouse monoclonal antibodies against CD16 have been administered to rhesus macaques (Choi et al., ex vivo expanded cells. This approach could generate novel insights into NK cell turnover, differentiation, migratory behavior, in vivo killing of target cells, and other areas. Moreover, induced pluripotent stem cells have been used to generate hNK cells with antiviral activity against HIV (Knorr and Kaufman, in vivo NK cell development and differentiation. These and many other experimental manipulations of the immune system in non-human primates open a number of new avenues to address basic immunological questions and highlight the potential of these animal models.Furthermore, non-human primates could also be used in autologous transfer studies using fluorescently labeled cells and Here we present two arguments as to why NK cell research in non-human primate models has the potential to yield significant insights into hNK biology. First, as a consequence of the phylogenetic relatedness of humans and non-human primates, there are many shared properties between hNK and non-human primate NK cells. Second, as an animal model, non-human primates offer access to tissues and allow a variety of manipulations, which the \u201chuman model\u201d cannot offer due to ethical constraints. The work in non-human primates is challenging, as animals and their housing are relatively cost-intensive and require dedicated facilities and staff. Nonetheless, we believe that their significance as a disease model and the potential clinical applicability of immunological findings derived from these animals continue to make research in non-human primates highly rewarding.Non-human primate models not only bear relevance for humans as outstanding disease models but also as a valuable resource to address basic immunological questions. The exciting answers to these questions and the lessons non-human primates can teach us certainly deserve a greater consideration by the scientific community.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cryptococcus neoformans, chitin-like molecules associate with capsular glucuronoxylomannan (GXM) to form functionally distinct glycan complexes. Such interactions between glycans that result in the formation of structures with different functions strongly suggest that additional molecular complexes with unknown properties may exist in fungal pathogens. Moreover, the identification of these novel complexes has stimulated the search of new immunogens with potential to protect human and animal hosts against systemic mycoses.The biological properties of fungal immunogens have historically utilized testing of isolated molecules. Recent findings, however, indicate that fungal glycans differing in structure and function can interact to form hybrid complexes with unique properties. In the pathogenic yeast  The surface of fungal cells is rich in polysaccharides and protein- or lipid-bound oligosaccharides  chitooligomers promoted enlargement of GXM fibrils, and (3) exposure of C. neoformans cells to an inhibitor of N-acetylglucosamine synthesis caused a decrease in capsular dimensions (Fonseca et al., C. neoformans to form glycan complexes composed of chitin-derived structures and GXM, their production during infection, impact on the host's immune system, and structural determinants regulating this glycan-glycan interaction were unknown until very recently.The supposition that GXM and chitin-derived structures interact has been confirmed by a number of approaches (Rodrigues et al., N-acetyl amino group of chitin, but not on carboxyl and O-acetyl groups of GXM. Importantly, this study shows that glycan complexes formed by GXM and chitin-derived molecules also arise during macrophage infection. Injection of either isolated molecules or the glycan complexes into mice induced distinctly different cytokine responses. In fact, the glycan complexes were efficient in inducing the production of lung IL-10, IL-17, and TNF\u03b1, while the cytokine profiles of mice challenged with either GXM or chitin oligomers alone were similar to cytokine levels in control animals. The fact that glycan complex structures produce enhanced immunosuppressive and pro-inflammatory cytokine responses while chitin oligomers and GXM alone did not suggested that cell-associated C. neoformans glycans form hybrid structures with unique functions.A recent study (Ramos et al., C. neoformans model (Ramos et al., The discovery of the formation of functionally distinct glycan complexes raises a number of puzzling questions. For instance, the surface of fungal pathogens is decorated with many different glycans that coexist in several microenvironments (Nimrichter et al., C. neoformans is in fact increased in the lungs of infected rats (Fonseca et al., in vivo observations demonstrating that chitooligomer detection and capsule enlargement are more evident in host tissues manifesting higher activity of this enzyme (Fonseca et al., Chitooligomers are the products of enzymatic hydrolysis of chitin. Chitinase expression is induced during pulmonary cryptococcosis in rodents (Vicencio et al., C. neoformans. Microscopic examinations of C. neoformans yeast cells, in fact, support this possibility. Co-staining of cryptococci with antibodies raised to GXM and to \u03b11,3 glucan reveal that \u03b11,3 glucan is widely distributed in the capsule (Cordero et al., C. neoformans GXM (Reese and Doering, C. neoformans, the presence of the capsule is well-known to slow down the molecular traffic across the cell surface (Nosanchuk et al., GXM has the potential to associate with a number of hydrophilic components, mainly because of its high efficiency in the formation of hydrogen bonds. Thus, GXM-chitin interactions probably have other counterparts in Surface molecules do not exist in their isolated form in cellular systems and approaches investigating interacting molecules can provide a deeper understanding of complex biological processes than the study of individual purified molecules. The discovery of hybrid glycans with previously unknown functions suggests new venues of investigation on the roles of polysaccharides and glycoconjugates in fungal infections. In addition, the connections between glycan association and functional variation strongly indicate that molecular complexes with still unknown properties may exist in fungal pathogens. This conclusion encourages new perspectives on models aiming at the discovery of protective immunogens.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Distal expression quantitative trait loci  are genetic mutations that affect the expression of genes genomically far away. However, the mechanisms that cause a distal eQTL to modulate gene expression are not yet clear. Recent high-resolution chromosome conformation capture experiments along with a growing database of eQTLs provide an opportunity to understand the spatial mechanisms influencing distal eQTL associations on a genome-wide scale. We test the hypothesis that spatial proximity contributes to eQTL-gene regulation in the context of the higher-order domain structure of chromatin as determined from recent Hi-C chromosome conformation experiments. This analysis suggests that the large-scale topology of chromatin is coupled with eQTL associations by providing evidence that eQTLs are in general spatially close to their target genes, occur often around topological domain boundaries and preferentially associate with genes across domains. We also find that within-domain eQTLs that overlap with regulatory elements such as promoters and enhancers are spatially more close than the overall set of within-domain eQTLs, suggesting that spatial proximity derived from the domain structure in chromatin plays an important role in the regulation of gene expression. Expression quantitative trait loci (eQTL) experiments map mutations in a genome to variation in gene expression . They haWe determine whether spatial proximity plays a role in eQTLs regulating their target genes as illustrated in et al. submitted for publication)  spanning 10 publications and six cell types (L. Mangravite ication) . Of theset al.  observed for an edge E with read pairs mapping within the fragments u and v. The total frequency of a fragment v is then defined as et al. afford the use of an error-correction method by Yaffe and Tanay .For each chromosome, Hi-C data in its raw form can be represented as a weighted graph nd Tanay , and we et al. Domain boundaries for the Hi-C assays described earlier in the text were identified using a hidden Markov model  and published in the same location as the Hi-C data. Each domain in this sequence of topological domains n is the number of fragments in et al., yet still enriched for similar chromatin marks. The domain-finding method of Dixon et al. uses a Hidden Markov Model with a local \u2018directionality index\u2019 statistic, whereas the method for the alternative definition explicitly encodes the quality score of a domain in a dynamic program. Dixon et al.\u2019s method results in domains at a particular scale of genomic length , whereas the alternative definition identifies domains that persist across multiple length scales.We obtained topological domains for each chromosome from Dixon  domains  that havet al. submitted for publication) (Q of eQTLs.eQTLs were obtained from the eQTL browser (eqtl.uchicago.edu), which compiles genome-wide eQTL data from 10 publications ; National Institutes of Health (NIH) [1R21AI085376 and 1R21HG006913]; Alfred P. Sloan Research Fellow (to C.K.). Funding for open access charge: NIH [IR21HG006913].Conflict of interest statement. None declared."}
+{"text": "In this issue Mandl and colleagues replicated the findings of a previous study , observed as an increase in the gray matter (GM) magnetic resonance signal , White matter fraction (wmf = 1 \u2212 fgm), TE (78 ms) and b-value (1000 s/mm2) (Mandl et al., To test this hypothesis we simulated the effect which a partial-volume of gray matter would have on parallel and transverse diffusivity using published parameters. Relaxation rates Figure 3 resolution, it is likely that several WM voxels could be contaminated with volumes of GM, even after using standardized white matter templates. Noise in MRI acquisitions is thought to cause an overestimation of FA in both isotropic and anisotropic structures (Pierpaoli and Basser, A more technical consideration is the possible effect of image noise and partial volumes on FA quantification (Basser and Jones, +, K\u2212-ATPase utilization to recover post-activation transmembrane ion gradients, which in turn might translate into changes in vascular oxygenation levels. However, the extant evidence from BOLD fMRI and PET studies does not support a metabolic explanation for the observed effects. In vitro studies in the rat brain\u2014which are free from confounding vascular effects - show that massive depolarization and increases in metabolism have a minimal effect upon WM ADC quantification (Anderson et al., A final possibility is that FA increases may reflect activity-evoked glial swelling associated with increases in extracellular potassium levels (Ransom et al., R2 are excluded, requires 18 separate parameters (Basser and Jones, In order to advance the use of functional DTI, a more detailed exploration of the origin of the observed changes is vital. To describe the basic WM, GM, and CSF model, even when contributions from blood and The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Paxillin encodes a focal adhesion-associated protein and is involved in the progression and aggressive phenotypes of malignancies through its interactions with the actin cytoskeleton and key signal transduction oncogenes. The present study aimed to investigate the clinicopathological and prognostic significance of paxillin in gastric cancer. The expression of paxillin was evaluated using tissue microarrays of gastric adjacent non-cancerous mucosa, adenoma and carcinoma specimens by immunohistochemistry. Paxillin expression was compared against clinicopathological parameters and the survival time of the patients. Paxillin was highly expressed in gastric adenoma compared with that in non-neoplastic mucosa and carcinoma (P<0.05). Paxillin expression was lower in the younger carcinoma patients compared with that in the elder carcinoma patients (P<0.05). Paxillin expression was negatively correlated with tumor size, depth of invasion and lymph node metastasis, but not with patient gender, lymphatic or venous invasion, or TNM staging (P>0.05). Higher paxillin expression was observed in intestinal-type compared with diffuse-type carcinoma (P<0.05). Kaplan-Meier analysis indicated a positive association between paxillin expression and cumulative survival rate in all, advanced and intestinal-type carcinoma patients (P<0.05). Multivariate analysis using the Cox proportional hazards model indicated that patient age, depth of invasion, lymphatic invasion, lymph node metastasis, TNM staging and Lauren classification were independent prognostic factors for all gastric carcinomas (P<0.05). Aberrant paxillin expression may be involved in the growth, invasion, metastasis and differentiation of gastric carcinoma. Altered paxillin expression may, therefore, be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinomas. Despite a global decline in the incidence and mortality of gastric cancer in the last 60 years, it remains the fourth most common and second most frequent cause of cancer-related mortality. Gastric cancer continues to be a major health concern due to the slow decrease in incidence in Asia and high mortality from diagnosed gastric carcinomas in the West, despite the advanced diagnostic and operative techniques that are commonly used in clinical practice ,2. An inet al and adjacent non-neoplastic mucosa (n=197) collected at Toyama University Hospital  from 1993 to 2006. The adenoma samples were resected from endoscopic biopsy at Toyama University Hospital from 1997 to 2008. The patients with gastric carcinomas were 120 males and 272 females . Archival materials were obtained from the Department of Pathology of Toyama University Hospital. In 151 cases, tumor development was accompanied by lymph node metastasis. None of the patients underwent chemotherapy, radiotherapy and adjuvant treatment prior to surgery. All patients were followed up by consulting their case documents and by telephone.All tissues were fixed in 10% neutralized formalin, embedded in paraffin, cut into 4-\u03bcm sections and stained with hematoxylin and eosin (H&E) in order to confirm the histological diagnosis and microscopic characteristics of the specimens. The staging for each gastric carcinoma was evaluated according to the Union for International Cancer Control system, which indicates the extent of tumor spread . HistoloFrom H&E-stained sections of the tumor cases, representative areas of solid tumor were selected for sampling and 2-mm diameter tissue cores per donor block were punched out and transferred to a recipient block with a maximum of 48 cores using a tissue microarrayer . Sections (4-\u03bcm) were consecutively cut from the microarrays and transferred to poly-lysine-coated glass slides.Serial sections of TMA were deparaffinized with xylene, rehydrated with alcohol, and subjected to immunohistochemical staining with intermittent microwave radiation, as previously described . Rabbit Immunoreactivity for paxillin showed a cytoplasmic pattern . One hunStatistical evaluation was performed using Spearman\u2019s rank correlation test. Kaplan-Meier survival plots were generated and comparisons between survival curves were made with the log-rank test. Cox proportional hazards model was employed for multivariate analysis. SPSS 17.0 software  was applied to analyze all data, and P<0.05 was considered to indicate a statistically significant difference.As indicated in Follow-up information was available on 392 of the gastric carcinoma patients for periods ranging from 0.2 months to 121 months . de novo carcinogenesis is well understood, particularly in diffuse-type gastric carcinomas (Paxillin is a cytoskeletal protein that was recently identified as a component of focal adhesions and links between F-actin and integrin . In the rcinomas . These fet al(et al(et al(Cai et al found thet al. Li et a al(et al document al(et al found th al(et al. HoweverAlthough all types of gastric cancer are malignant tumors that originate from the same gastric epithelium, the morphological features of the cancers vary substantially in individual patients. According to Lauren classification, gastric intestinal-type carcinoma is characterized by cohesive carcinoma cells that form gland-like tubular structures, such as well- and moderately differentiated carcinoma; while cell cohesion is less apparent or absent in diffuse-type carcinoma, such as poorly differentiated or signet ring cell carcinoma ,17. Our et al(et al(To date, there have been several studies describing the prognostic significance of paxillin expression in malignancies ,12,14,26et al found thIn conclusion, aberrant paxillin expression may be important in the malignant transformation of gastric epithelial cells. Its reduced expression was closely correlated with growth, invasion, metastasis and a worse prognosis of gastric carcinomas. Its expression may be employed to differentiate between the intestinal- and diffuse-type carcinomas. It was considered as a promising marker to indicate the pathobiological behaviors and prognosis of gastric carcinomas."}
+{"text": "Historically there has been a distinction between basal ganglia dependent and hippocampus dependent memory systems (e.g., Squire, A newly published study by Foerde et al.  also supThe failure to learn from delayed feedback in patients with hippocampal lesions could be related to the loss of function of area CA1, since CA1 receives afferents from areas known to respond phasically to reinforcing stimulation (Gasbarri et al., Overall, the results described by Foerde et al.  provide"}
+{"text": "To the Editor: We challenge the conclusions of Feingold et al. that \u201cregional density of livestock is a notable risk factor for nasal carriage of LA-MRSA for persons with and without direct contact with livestock\u201d (Staphylococcus aureus (MRSA), but they retrospectively analyzed 87 culture-confirmed MRSA cases reported to a reference laboratory. These were a mixture of clinical disease isolates and screening  isolates that were unevenly distributed between the groups  was >180 times higher in 352 occupationally exposed persons than in 2,094 rural residents without farm exposure (0.24%) (Finally, the contention of Feingold et al. that pig production in the Netherlands is \u201cgreatly overshadowed by the density of pig-farming operations in the United States\u201d is mistaken . Pig den"}
+{"text": "An elevated resting heart rate is one of the strongest predictors of cardiovascular mortality and is independently associated with sudden cardiac death (SCD). Agents capable of reducing heart rate without significant side effects are therefore of particular interest for the prevention of SCD. Recent human and animal studies have shown that omega-3 fatty acids can reduce heart rate. Our work has shown that omega-3 fatty acids significantly reduce membrane electrical excitability of the cardiac myocyte by lowering its resting membrane potential and the duration of the refractory period through inhibition of ion channels. We propose that these actions may be the underlying mechanisms for the omega-3 fatty acid-induced reduction of heart rate observed in both humans and animals. The heart rate-lowering capability of omega-3 fatty acids may contribute to their preventive effect against SCD. The cardioprotective effects of omega-3 fatty acids have become widely recognized. One of the most significant effects is the prevention of sudden cardiac death (SCD)  is independently associated with SCD. Multiple prospective studies have shown that even after adjusting for common cardiovascular health-related variables, such as age, weight, smoking, alcohol consumption, diabetes, blood pressure, physical activity, blood cholesterol, medications, and socioeconomic status, elevated heart rate remains a risk factor for SCD and a predictor of time to cardiac death (Shaper et al., Given these consistent and robust findings, drugs or supplements that reduce heart rate are of particular interest for preventing SCD. In fact, studies that have examined outcomes for patients with chronic heart failure have revealed that pharmacotherapy to reduce heart rate is associated with better outcomes for at least 5 years (Franke et al., in vitro work provide a likely mechanism by which omega-3 fatty acids act on cardiac myocytes to reduce heart rate.The relationship between omega-3 fatty acids and cardiovascular disease is well studied, and has appeared inconsistent at times (Harris et al., The effect of omega-3 fatty acids on heart rate has been observed in many different populations, both with and without cardiovascular disease. A meta-analysis of 30 randomized, double-blind, placebo-controlled trials concluded that fish oil consumption can significantly reduce heart rate (Mozaffarian et al., In addition, several large-scale, population-based studies showed that increased dietary fish and omega-3 fatty acid intake was associated with a significant reduction in heart rate. Dallongeville et al.  analyzedFish oil also effectively reduces heart rate during times of increased cardiac demand such as exercise. A study of 25 Australian football players revealed that 6g/day of fish oil reduced heart rate during submaximal exercise over a period of 5 weeks (Buckley et al., Another set of interesting findings comes from a population perhaps the least likely to experience cardiovascular illness: infants. Term infants treated with varying amounts of DHA in their formulas for 12 months show that DHA supplementation reduces heart rate compared to infants whose formula does not contain DHA, with no evidence of a dose response (Pivik et al., Finally, Harris and colleagues performed a small prospective study that provides a valuable indication of which mechanisms are likely to underlie the omega-3 fatty acid-driven reduction in heart rate. The group enrolled heart transplant patients, ensuring that their transplants had occurred more than three months prior and there had been no transplant-related hospitalizations (Harris et al., Similar reductions in heart rate due to omega-3 fatty acids have been observed in animals. In a rat model, animals fed a DHA-enriched diet had lower heart rates than animals fed a control diet, a pattern that was achieved by 2 months and maintained until the end of the 32-week study (Ayalew-Pervanchon et al., Overall, it is apparent that a wide range of human and animal subjects, with or without cardiac disease, all respond to omega-3 fatty acid supplementation with reductions in resting and stress-induced heart rates. These findings suggest a highly consistent and robust effect of omega-3 fatty acids on heart rate.Although omega-3 fatty acids may reduce heart rate through several different mechanisms, our early studies demonstrated a direct effect of omega-3 fatty acids on cardiac cell membrane electrical excitability that contributes to reduced heart rate. We used isolated, neonatal rat cardiac myocytes that retain spontaneous beating behavior, allowing us to assess the effect of EPA and DHA on contraction as well as electrophysiological activity without neural or hormonal input. We found that EPA and DHA promptly reduced the contraction rate of the cardiac myocytes by 50\u201380% without a significant change in the amplitude of the contractions. This effect of omega-3 fatty acids on the excitability of the cells was similar to that produced by the class I antiarrhythmic drug lidocaine Figure , top Ka. In addiThe reduction of electrical excitability of cardiac myocytes by omega-3 fatty acids can be demonstrated directly by their response to electrical pacing (Kang and Leaf, To better elucidate the mechanism of action of omega-3 fatty acids on heart rate, we employed a patch-clamp technique to examine the electrophysiological activity in isolated neonatal rat cardiac myocytes. First, we induced the action potential in the myocytes exposed to EPA or DHA and measured the strength of the current required to elicit an action potential (Kang et al., At this point in our research, the manner by which omega-3 fatty acids reduce membrane excitability was still unclear. Therefore, we tested the effects of omega-3 fatty acids on single ion channel activity in neonatal rat cardiac myocytes. The results demonstrated a prompt inhibitory action of omega-3 fatty acids on the Na+ currents through fast sodium channels responsible for the phase 0 of the action potential in isolated neonatal rat cardiac myocytes. The inhibition of this ion channel was dose, time, and voltage dependent, but not use dependent Figure  Xiao et. SubsequRegulation of heart rate in humans is highly complex. Sympathetic output, vagal tone, and systolic and diastolic left ventricular function are only a few of the factors that contribute to the regulation of heart rate. While omega-3 fatty acids could potentially affect any or all of these factors, our studies strongly suggest a direct impact of omega-3 fatty acids (Leaf et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Post-translational modification of lysine residues of specific proteins by ubiquitin modulates the degradation, localization, and activity of these target proteins. Here, we identified gains of ubiquitylation sites in highly conserved regions of human proteins that occurred during human evolution.We analyzed human ubiquitylation site data and multiple alignments of orthologous mammalian proteins including those from humans, primates, other placental mammals, opossum, and platypus. In our analysis, we identified 281 ubiquitylation sites in 252 proteins that first appeared along the human lineage during primate evolution: one protein had four novel sites; four proteins had three sites each; 18 proteins had two sites each; and the remaining 229 proteins had one site each. PML, which is involved in neurodevelopment and neurodegeneration, acquired three sites, two of which have been reported to be involved in the degradation of PML. Thirteen human proteins, including ERCC2  and NBR1, gained human-specific ubiquitylated lysines after the human-chimpanzee divergence. ERCC2 has a Lys/Gln polymorphism, the derived (major) allele of which confers enhanced DNA repair capacity and reduced cancer risk compared with the ancestral (minor) allele. NBR1 and eight other proteins that are involved in the human autophagy protein interaction network gained a novel ubiquitylation site.The gain of novel ubiquitylation sites could be involved in the evolution of protein degradation and other regulatory networks. Although gains of ubiquitylation sites do not necessarily equate to adaptive evolution, they are useful candidates for molecular functional analyses to identify novel advantageous genetic modifications and innovative phenotypes acquired during human evolution. Ubiquitin is a 76-residue polypeptide that is highly conserved among eukaryotes. Ubiquitylation of the lysine residues of substrate proteins targets the ubiquitylated proteins for degradation by the proteasome . The ubiA large number of genetic modifications have occurred in the human lineage during primate evolution that might be responsible for the emergence of human phenotypes ,7. TheseN-acetylglucosamine modification sites [To assess the impact of PTMs on human proteome evolution and to identify candidates for evolutionarily innovative PTM sites, a large amount of PTM data from human cells is needed. Recent progress in high-throughput screening by mass spectrometric analysis has enabled the large-scale characterization of PTM sites in the human proteome, including phosphorylation sites ,18, O-lion sites , lysine on sites , and ubion sites -25.et al.[et al.[et al. and Wagner et al.\u2019s datasets include lysines modified not only by ubiquitin, but also by ubiquitin-like proteins such as SUMO, ISG15, and NEDD8. In this report, we therefore use the term \u201cubiquitylation\u201d to indicate both ubiquitin and ubiquitin-like protein modifications.We hypothesize that appearance of novel ubiquitylation sites in proteins along the human lineage during primate evolution may have modified protein regulatory networks, potentially resulting in the acquisition of novel phenotypic traits. To address this possibility, we developed a bioinformatics method to systematically identify gains of novel ubiquitylation sites in the human lineage during primate evolution. As a pilot study, we used ubiquitylation data for human proteins reported by Kim et al. and Wagnl.[et al. as inputhttp://www.uniprot.org) and PhosphoSitePlus (http://www.phosphosite.org) [et al.[et al.[We aimed to identify human ubiquitylated lysines located in highly conserved regions of mammalian proteins that first appeared along the human lineage during primate evolution. To do this, a large amount of ubiquitylation site data and multiple sequence alignments of orthologous mammalian proteins are required. To assess ubiquitylation sites, one can use databases containing PTM data, such as UniProt (ite.org) , or largite.org) -23,25. I) [et al. and Wagnl.[et al., as welll.[et al.. The oveThe timing of the gain of a ubiquitylated lysine was determined by finding the branch that enclosed the earliest shared lysine between humans and other primates on the mammalian phylogenetic tree. For example, the human PML residue Lys 394  protein, which is also known as XPD, is involved in transcription-coupled nucleotide excision repair and is implicated in cancer-prone xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome . In the The neighbor of BRCA1 gene 1 (NBR1) protein has been identified as one of the principle cargo receptors for selective autophagy of ubiquitylated targets ,32. AbnoPML gene is often fused with the retinoic acid receptor \u03b1 (RARA) gene, which is associated with acute promyelocytic leukemia [Of the 281 ubiquitylation sites, 269 sites in 243 human proteins were acquired along the human lineage during primate evolution, and are shared with chimpanzees and other primates  has a ubiquitylated Lys 33 that is shared with chimpanzees and gorillas, while other early-diverged primates (including orangutans) and all other mammals examined have a glutamine (Q) residue at this position Figure . NGDN fuThe scavenger receptor class B member 1 (SCARB1) protein is a plasma membrane receptor for high-density lipoprotein cholesterol (HDL). It mediates cholesterol transfer to and from HDL  and is iWe found that 56 novel ubiquitylation sites in 54 proteins first appeared in the common ancestor of catarrhine primates. One representative case is WD repeat-containing protein 35 (WDR35) Lys 684, at which position most other mammals have a glutamic acid (E) Figure . WDR35 hATXN2 gene causes spinocerebellar ataxia type 2 [Of the 281 novel human ubiquitylated lysines, 116 in 107 proteins are shared with simians. One example is ataxin 2 (ATXN2) Lys 349, at which position all the other mammals examined have an arginine (R)  Lys 211 first appeared in primates after their divergence from the common ancestor of Euarchontoglires and is shared in all primates examined  glutamine allele is designated as the mutant, which shows reduced DNA repair capacity; carriers of this minor allele therefore have an increased cancer risk . The gaiInterestingly, among the 252 proteins, nine proteins  have been found in human autophagy protein interaction networks . NBR1 haet al.[Hagai et al. showed tet al.. To explWe developed a bioinformatics method to identify novel ubiquitylation sites that evolved along the human lineage, resulting in the identification of 281 novel ubiquitylation sites. The gain of novel ubiquitylation sites could result in novel ubiquitin-associated protein regulatory interactions. Proteins with a novel ubiquitylation site are useful candidates in the search for genetic modifications implicated in the emergence of novel phenotypes during human evolution.et al.[et al.[To identify ubiquitylation sites in human proteins, we used the large-scale analysis datasets of Kim et al. and Wagnl.[et al.. These rl.[et al.. Peptidehttp://genome.ucsc.edu). The \u2018CDS FASTA alignment from multiple alignment\u2019 data, which are derived from the \u2018multiz46way\u2019 alignment data [Multiple sequence alignments of the human proteins and orthologous proteins from other mammalian species were obtained from the University of California Santa Cruz (UCSC) Genome Browser Database  was used to collect protein sequences for some species. The multiple sequence alignments were generated using MUSCLE (http://www.drive5.com/muscle).The National Center for Biotechnology Information (NCBI) Protein database  and may differ from those of the UniProt or NCBI Protein databases.Finally, 281 sites in 252 proteins were collected. We examined the multiple alignments to estimate the timing of the gain of the ubiquitylated lysine residue. Possible functional consequences of the gain of the ubiquitylation site were assessed by a literature survey. The positions of the residues noted in this manuscript are derived from the datasets of Kim et al. and Wagnl.[et al., which aThe authors declare that they have no competing interests.YH conceived of this study, conducted the programming work, and prepared the manuscript. DSK participated in the sequence analysis. Both authors read and approved the final manuscript.List of proteins with novel ubiquitylation sites.Click here for fileDetailed alignments of surrounding regions of novel ubiquitylation sites.Click here for filePhylogenetic tree of the 37 mammals used in this study.Click here for file"}
+{"text": "Our laboratory has been evaluating the potential contribution of environmentally bioavailable neurotoxic metals to the onset, development and progression of AD for about 30 years  is perhaps in vitro and in vivo aluminum promotes inflammatory signaling via the pro-inflammatory transcription factor NF-kB, another prominent feature characteristic of AD brain 2\u00b712H2O, or alum, as a clarification and \u201cfinishing\u201d agent  that at physiologically realistic concentrations, aluminum strongly promotes amyloid aggregation and accumulation, a key feature of AD neuropathology Exley, ; (ii) thn Bondy, ; (iii) tn Bondy, ; (v) than Bondy, ; (vi) th Flaten, ], and . A commonly used Tg2576 mouse model overexpresses a mutant form of beta amyloid precursor protein (\u03b2 APP), APPK670/671L, linked to early-onset familial AD, and develops amyloid plaques and progressive cognitive deficits as the mice age. Tg2576 mice exposed to dietary aluminum have been shown to develop oxidative stress and robust amyloidogenesis, key features of AD neuropathology (Pratic\u00f2 et al., in vitro and in vivo models for AD with AD itself. Indeed, the abundance of specific miRNAs are highly selective, and potential indicators and predictors of human health and disease, including progressive neurological disorders such as AD (Alexandrov et al., We would like here to briefly include some recent genetic data on aluminum and its effects on miRNA abundance in a highly relevant transgenic animal model for AD that shows strong parallels to miRNA profiles which are found in AD brain Figure . There ain vitro studies (Kruck et al., Lastly, more research into the potential contribution of aluminum to the AD process is clearly warranted. There are currently no treatments for AD that effectively prevent or cure AD's insidious onset or propagation. We think it important to emphasize that the most effective clinical treatment yet devised for moderate- to late-stage AD patients was the implementation of the first generation anti-oxidant and trivalent iron/aluminum chelator desferrioxamine to attempt to remove aluminum from the brains of AD patients (Crapper McLachlan et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The tumor necrosis factor superfamily (TNFSF) members play pivotal roles in embryonic development of lymphoid tissue and their homeostasis. RANKL  is recognized as an important player in bone homeostasis and lymphoid tissue formation. In its absence bone mass control is deregulated and lymph nodes fail to develop. While its function in bone is well described, there is still little functional insight into the action of RANKL in lymphoid tissue development and homeostasis. Here we provide an overview of the known functions of RANKL, its signaling receptor RANK and its decoy receptor OPG from the perspective of lymphoid tissue development and immune activation in the mouse. Expressed by the hematopoietic lymphoid tissue inducing (LTi) cells and the mesenchymal lymphoid tissue organizer (LTo) cells, RANKL was shown to stimulate Lymphotoxin (LT) expression and to be implicated in LTi cell accumulation. Our recent finding that RANKL also triggers proliferation of adult lymph node stroma suggests that RANKL may furthermore directly activate LTo cells. Beyond bone, the RANKL-RANK-OPG triad plays important roles in immunobiology that are waiting to be unraveled. There is now an emerging consensus to refer to the receptor as RANK and, as a consequence and for simplicity, its ligand is called RANKL. The acronym OPG has remained in use.Tumor necrosis factor (TNF) and Lymphotoxin (LT) were identified as the first members of a large family, now called the TNF-superfamily (SF). Not surprisingly, the receptors for these proteins also constitute a SF with sequence homology, named TNF Receptor (TNFR) SF. A hallmark of these ligand-receptor pairs lies in a threefold symmetry, where by the oligomeric binding arrangement amplifies their avidity and introduces flexibility. Further complexity arises through different partner affinities and generation of soluble ligand and receptor forms  cells and V\u03b35+ thymocytes as well as later arising CD4+CD8\u2212 single positive thymocytes and \u0393\u03b4T cells are equipped with RANKL  and cryptopatches (CPs) and abnormalities of the spleen (Dougall et al., Rankl\u2212/\u2212 and Lt\u03b1\u2212/\u2212 mice have lower number of LTi cells in mesenteric LNs of newborn mice (Kim et al., \u2212/\u2212 mice display fewer LTi cells in mesenteric LNs at E 17.5 but not at E15.5 (Yoshida et al., In view of the finding that LTi cell recruitment is LT independent (Eberl et al., Rankl\u2212/\u2212 mice. Second, mucosal LNs develop in LT\u03b2\u2212/\u2212 mice but not in Rankl/\u2212\u2212 mice (Alimzhanov et al., Rankl\u2212/\u2212 embryos cannot rescue LN genesis (Kim et al., In the current model of LN development a positive feedback loop takes place between LTi and LTo cells Figure . RANK siLT\u03b2R signaling in mTECs induces RANK expression (Mouri et al., Rankl\u2212/\u2212 mice (Knoop et al., A number of observations support a role of RANKL in SLO growth. The LNs that developed after neutralization of RANK signaling in embryos were smaller (Eberl et al., \u2212/\u2212 mice: it was noted that in these LNs B cells and FDCs were absent (Yoshida et al., \u2212/\u2212Rankl\u2009 mice and observed that most stromal cells in the B cell compartment lacked VCAM-1 and CXCL13 expression. Finally, postnatal RANKL overexpression resulted in an increase in small but clearly defined B cell follicles, which all comprised FDCs (Hess et al., B cell recruitment and organization into follicles occur in a CXCL13-dependent manner at later stages of SLO formation (Ansel et al., in vitro generated DCs and in combination with other TNFSF members (Wong et al., in vivo (Dougall et al., Activated CD4 and CD8 T cells express surface and soluble RANKL (Josien et al., Porphyromonas gingivalis (Kajiya et al., P. gingivalis-induced periodontitis and therefore reduce alveolar bone loss (Arizon et al., Th17 T cells represent an important osteoclastogenic T cell type by robust RANKL production and activation of RANKL release by mesenchymal cells (Sato et al., The RANK-RANKL-OPG axis plays a recognized role in bone homeostasis through the regulation of osteoclastogenesis. It is also implicated in SLO development and regulation of the immune response. There are many incentives to answer remaining questions. In addition to a restless curiosity of the researcher, tertiary lymphoid tissues that arise in inflamed tissue rely on similar if not identical cellular dialogs as those found in SLO development. Defining RANKL function in lymphoid tissue development will open new therapeutic avenues to treat inflammatory diseases and provide new strategies for vaccine development.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Burkholderia cepacia, Pseudomonas aeruginosa or Stenotrophomonas maltophilia, which cause diseases only in patients with predisposition or in hospital (Berg et al., Just like humans, plants have recently been recognized as meta-organisms, possessing a distinct microbiome and revealing close symbiotic relationships with their associated microorganisms (Berg et al., Microbiomes of humans and plants are currently intensively studied using the same methods and addressing similar scientific questions (Ram\u00edrez-Puebla et al., Despite the fact that the majority of our lifetime is spent in indoor environments such as home, work place, or public buildings, our knowledge of microbial diversity inside buildings is limited. We are not alone in these indoor environments: they provide new habitats and residence to numerous microbial communities comprising possibly hundreds of individual bacterial, archaeal and fungal species including diverse viruses. Recent studies analyzed potentially pathogenic and allergenic indoor microorganisms with mainly cultivation-based methods (T\u00e4ubel et al., 6 bacteria per person-hour as measured via 16S rRNA gene quantification from aerosols (Qian et al., Indoor microbial communities are an important component of everyday human health (Arundel et al., Indoor microbiomes originate primarily from human skin, pets, or the outside air (Flores et al., Empirically the positive effects of houseplants and flowers are well-known, but there is also evidence for psychological effects such as stress reduction and creative task performance (Fjeld et al., Plant DNA as frequently detected as chloroplast 16S rRNA gene sequences in amplicon surveys is a substantial part of all indoor microbiomes, but mainly filtered out for the presentation of data (Oberauner et al., Typical and often dominant plant-associated bacteria are members of the indoor microbiome. A relationship of bacteria genera occurring on plants and indoors is given in Figure Burkholderia cepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia (Ryan et al., At species level, no differentiation was possible for clinical and plant-associated isolates. This was studied for Interestingly, Thaumarchaeota, originally described to be associated with ammonia-oxidation in soil and the rhizosphere of plants, have been found on human skin (Probst et al., Comparing indoor with plant microbiomes, it is our opinion that both outside and inside plants are of importance for our indoor microbiome. Plants provide beneficial bacteria for indoor rooms and therefore can positively influence human health. The following facts support our opinion about the importance of plants as source for a beneficial microbial biodiversity:Based on these facts, we speculate the following:Enclosed environments and their microbiomes\u2014like private/public buildings, hospitals, and clean rooms, which are more or less separated from outside, are especially shaped by human influence and human associated microbes (Hospodsky et al., Microbes, which live in close vicinity to human beings, are adapted to us as symbionts, commensals, or pathogens, whereas these life-styles are changeable dependent on the host-microbe balance. Indoors we share these microbes, which might get deposited on various surfaces by one person and afterwards get collected by another. Human-associated microbes e.g., skin associated, are confronted with totally new biotic and abiotic factors in the built environment. Here they have to adapt to new surface materials, compete with others for scarce nutrients and withstand stresses associated to cleaning reagents etc. However, in the case of houseplants we allow them to proliferate in a protected environment. Plant associated microbes stay on the leave or stem surface, where they have adapted to and are sheltered from cleaning procedures. Although these phyllosphere communities are confronted with an absence of direct sun light and rain as well as other changed meteorological parameters like air/dust turbulences, their rhizosphere and surrounding soil communities stay in their natural habitat. Hence, these well balanced plant communities, which we bring inside, have the potential to balance an indoor microbiome, by increasing its diversity and filter airborne microbes.Members of the plant microbiome are an important source for indoor microbiomes. Both, plants from inside and outside can contribute to the micro-flora. Plant-associated bacteria could act as counterparts against pathogens within the microbial ecosystems. They stabilize the ecosystem, enhance biodiversity and avoid outbreaks of pathogens. However, more research is necessary to understand the microbiology of indoor environments. Currently used cleaning and hygiene strategies in built environments especially in hospitals and ICUs often promote multi-resistant pathogens instead of supporting beneficials. In future, it is important to re-think our understanding of necessary sterility and our relationship to our surrounding microbiomes. This \u201cparadigm shift in ecology\u201d is not only required for plants, humans Jones,  but also"}
+{"text": "Spruyt et al.  report aHow can an alcohol-avoidance bias be a predictor of relapse, while alcohol-avoidance training has positive effects in alcohol-dependent patients? Consider two recent clinical alcohol-avoidance training studies. In our first study in 214 alcohol-dependent patients  interventions, such as pharmacological treatment for alcohol craving: perhaps those patients with higher risk relapse had undergone different treatments that affected their approach/avoidance associations with alcohol. These particular third-variable explanations may or may not be true for the results of Spruyt et al.; they only serve to illustrate that a correlation between avoidance associations and relapse does not imply that the relapse risk was caused by the avoidance associations; and even less that inducing an avoidance association via training would cause an increased relapse risk.r\u2009=\u2009\u22120.05, p\u2009=\u20090.37, Field, personal communication). In our own first re-training study, we also used the relevant-feature approach-avoid Implicit Association Test . Hence, measuring an approach-bias with a relevant-feature task appears to be unrelated to measuring, and perhaps changing, an approach-bias with an irrelevant-feature task. It could at least theoretically be the case that the kind of avoidance associations as measured by a relevant-feature SRC cause an increased chance of relapse, while alcohol-avoidance associations retrained and assessed by an irrelevant-feature AAT decrease the chance of relapse.Second, different tasks were used in our studies and the study by Spruyt et al. In their prediction study, Spruyt et al. used the relevant-feature R-SRC, while we used an irrelevant-feature alcohol Approach Avoidance Task to measure the approach bias (alcohol AAT; Wiers et al., In conclusion, the evidence does not support the idea that the induction of an avoidance bias is likely to be harmful in alcoholic patients: the study of Spruyt et al. does not allow conclusions regarding causality, and a recent training study in fact showed that a relative increase in avoidance mediated the beneficial effects of avoidance training. We do, however, concur with Spruyt et al. that more research is needed regarding the assessment and modification of biases in action tendencies (Watson et al.,"}
+{"text": "Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation . To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Cachexia can occur as part of many chronic or end-stage diseases such as infections, cancer, AIDS, congestive heart failure, chronic renal failure, rheumatoid arthritis, tuberculosis, and chronic obstructive pulmonary disease. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention). Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption, and hyperthyroidism, and is associated with increased morbidity. CachexiaThe best management of cancer cachexia is to cure the cancer as this will completely reverse the cachexia syndrome. Unfortunately, this remains an infrequent achievement in adults with advanced solid tumors. A second option could be to counteract weight loss by increasing nutritional intake, but since in the majority of cachectic patients, anorexia in only a part of the problem, nutrition as a unimodal therapy was not completely able to reverse the wasting associated to cachexia. Indeed, a large number of randomized controlled trials of nutritional intervention did not show a significant benefit with regard to weight change or quality of life. These results have led to attempts to manipulate the process of cachexia with a variety of pharmacological agents, with the main purpose of providing symptomatic improvement. To date, however, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome.Progestagens, that is, Medroxyprogesterone Acetate (MPA) and Megestrol Acetate (MA) are currently considered the best available treatment option for CACS, and they are approved in Europe for treatment of cancer- and AIDS-related cachexia. However, progestational agents are nonetheless limited in their ability to treat cancer cachexia. Fewer than 30% of patients treated with MA experience short-term appetite stimulation, and alth5in vitro study,[et al., carried out a randomized placebo-controlled study[et al.,[In a subsequent ro study, they shoro study, Simons eled study to invesled study undertooy[et al., carried Among orexigenic agents, corticosteroids are widely used. In randomized controlled studies, they have been shown to improve appetite and quality of life compared with placebo.14 MA andet al.,[et al.,[et al.,[et al.,[Drugs able to inhibit the synthesis and/or release of cytokines (i.e. eicosapentaenoic acid (EPA), melatonin, etc.), the cytokine action -12, and IL- 15), and drugs able to inhibit the proteasome activity (i.e. bortezomib) have been tested in experimental models of cachexia, with some positive results. Unfortunately, most clinical trials in humans have provided limited or disappointing results. N-3 fatty acids, especially EPA, may have anticachectic properties. The first study by Fearon[et al., comparinet al., comparedet al., conclude,[et al., and Stra,[et al., have fai,[et al., showed n,[et al., showed tet al.,[Thalidomide has multiple immunomodulatory and antiinflammatory properties; its inhibitory effect on TNF-\u03b1 and IL-6 production may be responsible for its apparent anticachectic activity. Thus, thalidomide has been used for treatment of cachexia associated with acquired immunodeficiency syndrome, tuberculosis, and cancer. In the current literature, there are few studies that have assessed the anabolic effects of thalidomide in gastrointestinal cancer cachexia. Gordon et al., undertooet al.,[Research on experimental animal models has shown that non-steroidal anti-inflammatory drugs, including cyclooxygenase-2 (COX-2) inhibitors, may palliate cachexia through the suppression of systemic inflammation. Lai et al., carried Recently, much research interest has focused on ghrelin, a 28 amino acid peptide produced by the P/D1 cells of the stomach. Not only does ghrelin stimulate GH secretion (via the GH secretagogue-1a (GHS-1a) receptor) but it also promotes food intake (via the orexigenic NPY system) and decreases sympathetic nerve activity. Synthetic human ghrelin has been shown to improve muscle wasting and functional capacity in patients with cardiopulmonary-associated cachexia and to improve energy intake in anorexic cancer patients. Based on the animal studies and short-term human trials, there appears to be much promise for further studies to investigate the use of ghrelin and GHS-R agonists for the treatment of cachexia caused by multiple underlying conditions. Significant questions remain to be answered, however, before its widespread use, most prominently whether the gains produced by GHS R agonists maintain safety and efficacy with long-term use in human diseases. Clearly, more long-term research is needed.et al.,[of ghrelin to humans with cachexia has shown no univocal efficacy in increasing food intake with single dose intravenous administration.26 In a set al., 21 adultet al.,[et al.,[Neary et al., carried ,[et al., carried et al.,[Lundholm et al., carried Branched-chain amino acids are neutral amino acids with interesting and clinically relevant metabolic effects: They interfere with brain serotonergic activity and inhibit the overexpression of critical muscular proteolytic pathways. The potential role of branched-chain amino acids as antianorexia and anticachexia agents was proposed many years ago, but only recent experimental studies and clinical trials have tested their ability to stimulate food intake and counteract muscle wasting in anorectic, weight-losing patients. In experRecently, a prospective, randomized, phase III trial comparing the effects of oxandrolone (10 mg bid) and MA (800 mg q.d.) on weight, body composition, and quality of life (QOL) in 155 adult patients with solid tumors and weight loss receiving chemotherapy demonstrated that patients treated with oxandrolone experienced an increase in LBM, a reduction in fat mass, and reduced self-reported anorectic symptoms.et al.,[Olanzapine, an atypical neuroleptic with safe therapeutic window for several psychotic diseases, induces significant weight gain and positive metabolic effects. Preliminary data from a phase I pilot study by Braiteh et al., suggest et al.,[et al.,[n=12) or fish oil, 2 g tid, plus celecoxib 200 mg bid (n=10). All patients in both groups received oral food supplementation. After 6 weeks of treatment, patients receiving fish oil+placebo or fish oil + celecoxib showed significantly more appetite, less fatigue, and lower C reactive protein (C-RP) values than their respective baselines values . Additionally, patients in the fish oil+celecoxib group also improved their body weight and muscle strength compared to baseline values . Comparing both groups, patients receiving fish oil + celecoxib showed significantly lower C-RP levels  and higher muscle strength , and body weight  than patients receiving fish oil+placebo. The addition of celecoxib improved the control of the acute-phase protein response, total body weight, and muscle strength. In the context of combined approaches, one of the most intriguing ones was our open phase II trial.[L-carnitine 6 (4 g/day), (4) thalidomide (200 mg/day), or (5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 months. The sample size was 475 patients. The different single agents were selected on the basis of the following rationale. The antioxidant agents were shown to be effective in our previous studies.[4et al.,[From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. Cerchietet al., carried ,[et al., aimed toII trial.38 The ai studies.\u201344 The p studies. Synthetistudies.4\u201349 The \u03c9studies.4\u201352 Barbe[4et al., demonstr[4et al., in 200 p[4et al.,54 Patien[4et al., and the in vitro and slow muscle wasting in rats with cancer cachexia.[Current new trends include anti-IL-6 humanized monoclonal antibody which in murine models appear to inhibit cancer cachexia; IL-15, acachexia. Formotercachexia. Recentlyet al.,[A new class of nonsteroidal SARMs is being developed for use in cancer cachexia. SARMs are designed to have predominantly anabolic activity in muscle and bone with minimal androgenic effects in most other tissues. Evans et al., carried et al., Recent eet al., Predictiet al., Key defiet al.,In summary, based on current views on the cachexia syndrome in cancer patients, we put forward the following recommendations:Wasting is a predictable event in many cancer patients, readily diagnosed by assessment of weight, change in appetite, and food intake. Often these patients will also have anemia and low albumin, with a concomitant increase in C-reactive protein. The above simple assessments should form a consistent part of the record of all advanced cancer patients.Use a systematic formal guide to rule out treatable secondary causes of wasting.At the onset and throughout the course of illness, offer patients nutritional counseling , encourage them to take part in a rehabilitation program tailor made for their needs and abilities, and consider the use of specific nutraceutical and pharmacologic interventions. Follow-up visits should not only note careful evaluation of antitumor therapy and tumor volume, but also regular assessment of symptom control, weight, appetite, and function.Take careful note of the full medication profile of patients who are wasting. These might include drugs that could have a favorable effect on cachexia  and other agents that may be deleterious .Testosterone status should be established in cancer patients with the cachexia syndrome. If clearly reduced, physiologic testosterone supplementation should be considered after discussion with the patient.Patients must be assured of a reasonable intake of amino acids. Protein-containing foods are indicated and rich sources of both essential and nonessential amino acids will support any anabolic potential.Clinical researchers should be more cognizant of the work of their colleagues in sports medicine, AIDS, and geriatrics. Learning from their enterprises, further studies on creatine and supraphysiologic amounts of amino acids with a particular role in protein synthesis should be conducted. Similarly, the role of supraphysiologic doses of anabolic agents, in combination with nutrients and compounds that control muscle proteolysis, should receive high priority.There are few, if any, negative exercise trials. Patients should be encouraged to keep active or take part in tailored exercise programs, and studies on nutritional and pharmacologic agents should incorporate the potential additive effects of exercise."}
+{"text": "Studies over the past decade have helped to decipher molecular networks dependent on Toll-like receptor (TLR) signaling, in mycobacteria-infected macrophages. Stimulation of TLRs by mycobacteria and their antigenic components rapidly induces intracellular signaling cascades involved in the activation of nuclear factor-\u03baB and mitogen-activated protein kinase pathways, which play important roles in orchestrating proinflammatory responses and innate defense through generation of a variety of antimicrobial effector molecules. Recent studies have provided evidence that mycobacterial TLR-signaling cross talks with other intracellular antimicrobial innate pathways, the autophagy process and functional vitamin D receptor (VDR) signaling. In this article we describe recent advances in the recognition, responses, and regulation of mycobacterial signaling through TLRs. Mycobacterium tuberculosis (Mtb). In this state, healthy immune-competent individuals are able to combat infection by mounting of an effective immune response  for recognition of various molecular patterns of mycobacteria  occurs as early as 24 h post-infection. It is obvious that Mtb elicits inflammation-dampening signals in macrophages which would favor its survival.Numerous studies have revealed that TLR2 is involved in the innate recognition and responses in innate immune cells such as macrophages and dendritic cells of a variety of mycobacterial cell wall antigens including 19-kDa mycobacterial lipoprotein, glycolipids like lipoarabinomannan (LAM), LM, 38-kDa antigen, LprG lipoprotein, phosphatidylinositol mannoside (PIM), triacylated (TLR2/TLR1), or diacylated (TLR2/TLR6) lipoproteins [reviewed in Jo et al. ; KleinniMany previous studies have reported that mycobacterial components are involved in innate recognition and responses through TLR signaling , Rv0315, and Rv0577  induce dendritic cell maturation and activation leading to increased expression of costimulatory molecules  and proinflammatory cytokines , and potentiate the Th1 immune response . TDM has been reported to be tethered to several receptors, including TLR2, the class A scavenger receptor MARCO, Fc receptor-\u03b3 (FcR\u03b3), and macrophage-inducible C-type lectin (Mincle) , TLR2 signaling activates Wnt-\u03b2-catenin signaling. The authors suggest that TLR2 integrates Wnt-\u03b2-catenin signaling to modulate a battery of genes associated with T(Reg) cell lineage commitment. At low MOIs, Mtb-triggered macrophage apoptosis depends on a TLR2 signaling cascade associated with ASK1/p38 MAPK- and c-Abl-dependent phosphorylation of c-FLIP and its degradation, leading to caspase 8 activation (Kundu et al., Recent work by Bansal et al.  suggestsTLR-dependent NF-\u03baB signaling and MAPK pathways contribute to antimycobacterial innate immunity through secretion of antibacterial effector molecules, cytokines, and chemokines, thus recruiting various immune cells to the site of infection (Jo et al., M. bovis BCG, are linked with the increased production of Th1-type T cell cytokines through regulation of monocyte IL-10 production (Randhawa et al., M. bovis BCG infection (Davila et al., Human genetic polymorphisms of TLRs have a role in regulating innate recognition of microbes and in determining susceptibility to mycobacterial infection. The relationship between TLR polymorphisms, disease susceptibility, and innate immune activities against mycobacteria has been described in several reviews (Texereau et al., Previously, it was shown that human TLR1 deficiency is linked with impaired mycobacterial innate immune signaling and susceptibility to leprosy (Misch et al., Several other innate immune pathways are closely linked with the TLR signaling pathway, thus cooperatively defining the innate immune response which enables clearance of mycobacteria inside cells. Activation of autophagy has a critical effector role in innate immune responses such as enhancement of phagosomal maturation and coordination of the innate and adaptive immune systems Deretic, , 2012. IRecent studies have uncovered the interplay of vitamin D-dependent antimicrobial responses and autophagy pathways in the activation of host defense against mycobacterial infection (Yuk et al., in vivo and in vitro (Kim et al., The impact of host autophagy on phagosome maturation and Mtb killing gives rise to the idea that compounds that activate or modulate the autophagy pathway, could potentially enhance antimicrobial activities against Mtb infection (Gutierrez et al., Developing vaccines and chemotherapeutic agents is the cornerstone of the successful management of tuberculosis. Understanding the molecular mechanisms of specific interactions of Mtb with its host should augment efforts in both these areas. Immune modulation as a strategy to combat mycobacterial infection remains underexplored. This review brings to light how mycobacterial modulins signaling through TLRs, contribute either to an effective host immune response or to immune evasion by the pathogen. Targeting those modulins that facilitate immune evasion, or exploiting those that facilitate a robust innate and adaptive immune response, could offer new avenues for controlling infection. The review also brings forth the attractive possibility of developing therapeutics designed to augment autophagy as a means of restricting mycobacterial survival and combating infection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Spatial and bodily representations are multisensory processes that imply the integration of several afferent signals into a coherent internal model of our egocentric space. Crucially, this model involves also the vestibular information from the balance organs in the inner ear (Ventre et al., CVS has been used to modulate a wide range of cognitive and sensory functions in brain-damaged patients and in healthy participants (Utz et al., specificity of these effects. Does CVS directly affect the somatosensory processing? Are the observed effects mediated by non-specific factors, such as ocular movements, spatial attention or general arousal?Various hypotheses have been suggested to explain the CVS-induced modulation on tactile perception. In particular, one of the most controversial issues in the classical and current literature concerns the Since Rubens , most ofConversely, the role of non-specific effects such as spatial attention is still a matter of debate. This hypothesis argues that CVS may induce a reorientation of spatial attention toward the hemispace ipsilateral to the stimulated ear. Strong evidence against this hypothesis derives from a recent study on brain-damaged patients (Bottini et al., More recent behavioral and electrophysiological studies, in healthy participants, have strengthened this suggestion. There are at least three main crucial observations ruling out interpretation in terms of non-specific attentional effects. First, left-cold CVS affects the perception of distinct somatosensory sub-modalities, i.e., touch and pain, for both the ipsilateral and contralateral hand (Ferr\u00e8 et al., Previous studies exploring more widely CVS effects also support the idea that spatial attention does not have a pivotal role. Rorden et al.  did not specific and related to the activation of cortico-subcortical networks (Lopez et al., To conclude, this evidence suggests that in healthy volunteers the effects of CVS are"}
+{"text": "Biological Psychiatry, Levy-Gigi et al. found that a 12 weekly 90-mins cognitive behavioral therapy (CBT) treatment in individuals with posttraumatic stress disorder (PTSD) is associated with an increase in hippocampal volume and expression of glucocorticoid receptor genes, known as FKBP5 (Levy-Gigi et al., In a recent study in Interestingly, Levy-Gigi et al. found that CBT ameliorates all aspects of PTSD, including avoidance, re-experiencing, and hyperarousal symptoms. However, it is not clear from the Levy-Gigi et al. study whether changes to the hippocampal volume are associated with amelioration to which PTSD symptoms. Prior studies show that there is a trend for a negative correlation between higher re-experiencing symptoms and hippocampal volume (Shucard et al., At the neural level, several studies show that PTSD is associated with abnormalities to various brain areas, including reduced activity and volume of the hippocampus (Gilbertson et al., How can hippocampal dysfunction be related to PTSD symptoms? As noted by Levy-Gigi et al., the ventral hippocampus-amygdala pathway has been shown to be related to increased stress and anxiety (Fanselow and Dong, The Levy-Gigi et al. study also showed that CBT alters the expression of genes, including the FKBP5 gene. FKBP5 regulates glucocorticoid receptor sensitivity, and reduce the efficacy of cortisol in the brain (Mahon et al., Along these lines, Felmingham et al.  found thFuture computational modeling work is needed to explain how changes to the hippocampal volume and gene expression can ameliorate PTSD symptoms [see for example Krasne et al. ; Li et aIn summary, Levy-Gigi et al.  have ext"}
+{"text": "Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies. Current Opinion in Pharmacology 2013, 13:497\u2013503CancerThis review comes from a themed issue on Massimo Santoro and Francesca CarlomagnoEdited by Issue and the EditorialFor a complete overview see the Available online 7th May 20131471-4892/$ \u2013 see front matter, \u00a9 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.coph.2013.04.006The existence of distinct subpopulations of cancer cells within a tumour harbouring different behavioural phenotypes, including tumourigenicity, ability to metastasise and evolve resistance to treatment, has been recognised for many years . Recent In this article we review the clinical implications of ITH for the genetic stratification of tumours, the emerging evidence that suggests the need to investigate the changing nature of tumour subclonal architecture through therapy and the potential impact of such diversity on anti-tumour immunity. We argue that an in-depth understanding of tumour evolution over time, the mechanisms driving tumour diversity and its impact on immunity may lead to the improved management of cancer patients .Phenotypic heterogeneity observed in tumours results from both genetic and non-genetic causes of heterogeneity. Spontaneous tumours are known to arise through Darwinian-like somatic clonal evolution involving the acquisition of \u2018driver\u2019 events, such as genetic mutations or copy number variations, believed to affect cancer cell proliferation or survival, along with \u2018passenger\u2019 events, assumed to be phenotypically silent without a selective fitness advantage . Non-genRecent advances in massively parallel sequencing technologies have enabled the analysis of the complex clonal architecture of both primary and metastatic tumours . PatternHER2 predicts response to trastuzumab but its distribution can be heterogeneous in primary tumours and associated with shorter disease-free survival times compared to patients with homogenous HER2 amplification [et al. [HER2 amplification in oesophageal adenocarcinoma independently predicted worse disease-specific survival and overall survival compared to non-heterogeneous HER2 amplified tumours.The validation of predictive biomarkers may be simpler and less subject to tumour sampling bias when present in all regions of a tumour and sustained during disease progression. However, ITH for the expression of genetic and phenotypic biomarkers has been shown in several tumour types. In breast cancer, the amplification of fication . Yoon et [et al.  showed tEGFR predict response to gefitinib, but discordance for the EGFR mutation has been shown between primary and metastatic tumours [HER2 amplification and HER2 protein overexpression has been shown within the same tumour, and between diagnostic biopsies and resected tumours [HER2 amplification between primary and metastatic tumours has also been shown in breast cancer [et al. [KRAS, NRAS, BRAF, PIK3CA and TP53 genes. However, in patients with a history of more than one colorectal primary tumour and interval treatment, there was evidence for discordance in TP53. These examples demonstrate that relying on a single tumour biopsy may lead to sampling bias in some cases and risk missing potentially therapeutically relevant lesions or contribute to the allocation of a mutation as actionable without establishing clonal dominance [Primary and metastatic tumours can evolve independently and acquire different phenotypes leading to significant genetic divergence, and therefore discordance, between primary and metastatic tumours in terms of biomarkers detected in the diagnostic biopsy . In non- tumours . In prim tumours . Discordt cancer . In colo [et al.  found muominance . Furtherominance . This maT790M mutation known to confer insensitivity to gefitinib [et al. [EGFR mutations treated with EGFR TKIs, the presence of low frequency subclones harbouring T790M mutations before the onset of treatment was associated with shorter progression-free survival, and Turke et al. [MET amplification was associated with EGFR TKI resistance. In colorectal cancer, wild-type KRAS predicts sensitivity to anti-EGFR antibody therapies such as panitumumab. Diaz et al. [KRAS wild-type tumours, the emergence of mutations in KRAS could be detected during the course of therapy resulting in acquired resistance. They concluded that subclonal populations harbouring KRAS mutations existed before commencing treatment, and that under the selective pressure of anti-EGFR blockade, resistant subclones rapidly expand and repopulate the tumour. In chronic myeloid leukaemia and gastrointestinal tumours, resistance to imatinib due to mutations in the BCR-ABL fusion protein [Most advanced cancers still remain incurable despite significant progress in the fields of cancer research and therapy. Response to therapy is generally of limited duration. This may be due to the inevitable evolution and proliferation of resistant subclonal populations, which may exist before the onset of treatment, under the selective pressure of therapies \u2022\u2022. In NSefitinib \u2022\u2022. Su et [et al.  demonstre et al. \u2022 showed z et al. \u2022\u2022 showed protein  and KIT  protein  respecti protein . These eet al. [EGFR mutant NSCLC with an EGFR TKI and EGFR-specific antibody could prevent resistance associated with the expansion of a subclone harbouring a T790M mutation. Approaches like this would require the development of biomarkers predicting likely resistance mechanisms in different patients, and such mechanisms could be targeted either in combination, or alternating, with standard treatment regimens [In light of increasing evidence in support of ITH and its role in treatment resistance, there is a need for alternative therapeutic approaches. Gillies et al.  argue thet al. \u2022\u2022, and tregimens . Treatmeregimens  and melaregimens . Other aregimens .post hoc analyses of data originally generated by Sjoblom et al. [in vivo \u2018vaccine\u2019 or priming effect which could be further enhanced by interference with immune-modulatory pathways. Whilst the neo-antigenic repertoire generated by ITH could be seen as non-self by the immune system, the type of tumour cell death and inflammatory environment within the tumour will define their immunogenicity and the final outcome of the immune response (i.e. tumour progression versus regression). Importantly, immunity to tumour-associated antigens can be potentiated given proper identification and manipulation of immune-regulatory checkpoints restricting T cell function [Whilst emerging evidence supports the notion that ITH limits the efficacy of conventional and targeted therapeutics, its overall effect on the immune response to cancer may still be of potential benefit for the patient since intratumoural mutational diversity can provide neo-antigens that may be perceived by the immune system as non-self, producing unique opportunities for the generation of anti-tumour immunity. The wealth of data now being generated through whole genome sequencing of tumour samples provides further support for this concept. In silico-based computer algorithms combined with high-throughput m et al.  revealedm et al. . Furtherm et al. . MSI is m et al. . One potm et al. . Based ofunction . This hafunction . In addifunction \u2022).Although ITH may complicate diagnostic and treatment decisions, it can be clinically useful in predicting clinical outcome. In Barrett's oesophagus \u2022 and breWith the development of improved technologies allowing the interrogation of ITH, our understanding of tumours and their evolutionary trajectories may lead to better design of clinical trials in search of improved therapeutic interventions to anticipate the emergence of drug resistance mechanisms and generate improved predictive and prognostic biomarkers . Whilst None declared.None.\u2022 of special interest\u2022\u2022 of outstanding interestPapers of particular interest, published within the period of review, have been highlighted as:"}
+{"text": "A recent study found that mosquito-transmitted (MT) lines of rodent malaria parasites elicit a more effective immune response than non-transmitted lines maintained by serial blood passage (non-MT), thereby causing lower parasite densities in the blood and less pathology to the host. The authors attribute these changes to higher diversity in expression of antigen-encoding genes in MT cf. non-MT lines. Alternative explanations that are equally parsimonious with these new data, and results from previous studies, suggest that this conclusion may be premature. Plasmodium chabaudi or other malaria species are transmitted through mosquitoes, their virulence and asexual replication rate in the blood is reduced [et al.[Many studies have shown that when parasite lines of the rodent malaria  reduced -6. This  reduced ,6-13. Spet al. [et al.\u2019s [The family of genes that Spence et al.  found toet al.\u2019s  observatet al. (Plasmodium chabaudi in C57/Bl6 laboratory mice) parasite lines were evolved by SBP through either immunized or na\u00efve mice and, at the end, virulence of the evolved lines was measured, both in immunized and na\u00efve mice, and both before and after mosquito transmission [Does this resetting render MT parasites more controllable by the immune system, or is it just that MT parasites are less intrinsically virulent? In previous experiments studying the evolution of parasite virulence in the same experimental model used by Spence smission . Before et al.[et al.[et al.\u2019s [However, when the I-lines were compared to the N-lines in pre-immunized mice, the differences disappeared. In the light of new data from Spence et al., it is hl.[et al., these ret al.\u2019s  interpreet al.[However, several alternative explanations that invoke changes to the parasite\u2019s intrinsic virulence, as opposed to the immunity it provokes, are similarly parsimonious with the data of Spence et al. and fromet al.,2. Severet al. and expeet al., bottlenet al. virulencet al.[Plasmodium falciparum, the most deadly of the human malaria parasites, that certain subsets of the variable surface antigens are highly pathogenic [Although virulence attenuation in laboratory models of malaria -6 is higthogenic -20 thus The author declares that she has no competing interests."}
+{"text": "Plants imperatively have to cope with adverse conditions owing to their lack of mobility and to the high amounts of reactive oxygen species (ROS) generated from both respiration and photosynthetic metabolism. Although thiol redox homeostasis in plants is mainly preserved by the cellular glutathione pool, specific strategies have been adopted by the plant kingdom during evolution to manage these \u201cextra\u201d pro-oxidative conditions. Unlike human or yeast, plants generally possess a higher number of genes coding for antioxidant proteins, including protein families responsible of dithiol/disulfide exchange reactions. During the last decades, redox-dependent post-translational modifications of proteins proved to be pivotal to many cellular functions. In particular, this is critically important under some situations of environmental constraints taking into account the alterations and fine adjustment of the cellular redox status occurring during and after any biotic or abiotic stresses.Indeed, thiol groups of cysteinyl residues are highly sensitive to oxidation which might critically perturb cellular homeostasis. Members of the thioredoxin superfamily are key proteins involved in the regulation of cysteine/protein redox state. They share two common and well-known features: (i) the presence of an active center containing at least one catalytic cysteine residue, and (ii) a highly conserved 3D-structure, the so-called thioredoxin fold, which consists of a four-stranded anti-parallel \u03b2-sheet surrounded by three \u03b1-helices. Key members of this super family are thioredoxins (TRX) and glutaredoxins (GRX). Representatives of both subgroups are distributed in most cellular compartments and contain at least one TRX motif in their structures. While TRXs are generally reduced by thioredoxin reductases (TR), the reduction of GRXs depends on reduced glutathione (GSH).The 19 reports of this Research Topic provide timely overviews and new insights into redox regulation, focusing on both TR/TRX and GSH/GRX reduction systems in plants. The biochemical characteristics of these systems as well as their target proteins and functions in metabolic and signaling pathways are discussed. Several contributions to this Research Topic deal with the role of TRX systems in plastid metabolism. Michelet et al.  summarizArabidopsis, and on the discovery of trans-thylakoid redox pathways controlling disulfide bond formation and reduction.Within the photosynthetic context, Karamoko et al.  propose in vivo approach showing the positive effect of NTRC overexpression in plant performance.In addition, the importance of NADPH thioredoxin reductase C (NTRC) in plastid redox regulation is also reported in four articles. The paper by Puerto-Gal\u00e1n et al.  discusseThe importance of redox regulation in plant mitochondria is also highlighted in this Research Topic by L\u00e1zaro et al. . These ah with selected target proteins using surface plasmon resonance. The presented data reveal a stronger preference of TRX h for an oxidized target, thus explaining the selective association of TRX with oxidized proteins. Zaffagnini et al. (Some aspects of the cytosolic redox regulation pathways have also been developed in this Research Topic. Hara and Hisabori  analyzedi et al.  review hgrx mutants, that GRXs are essential for stress adaptation in cyanobacteria. Finally, Knaff and Sutton (GRXs are oxidoreductases of the TRX family which display a particularly rich diversity in higher plants. Beyond classification in three main subgroups based on sequence and structural features, Couturier et al.  indicated Sutton  describeArabidopsis. The data demonstrate that cellular glutathione homeostasis influences the root architecture and the leaf area under optimal and stress conditions. Another aspect where glutathione and homoglutathione are crucial molecules is nodule development and in the context of legume-rhizobium mutualistic interactions. Indeed, these organs are peculiar due to the formation of a bacteroid in which the oxygen-sensitive nitrogenase reduces di-nitrogen to ammonia. However, the importance of other redox systems in this unique organ has been poorly documented. Frendo et al. (Glutathione is a key component in regulation and maintenance of cellular thiol redox homeostasis. It also plays key roles in different aspects of plant development. Here, Rahantaniaina et al.  provide o et al.  review to et al.  summarizThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "N-acetyl-beta-d-glucosaminidase), markers of inflammation  and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice.Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein,  Chronic kidney disease (CKD) is an important public health problem and the prevalence is estimated to be 8%\u201316% worldwide . DiabeteAccording to the above mentioned, it is clear that new biomarkers are needed to predict patients who will develop diabetic nephropathy or are at risk of progressing to ESRD. Some of the promising new biomarkers in serum and urine will be presented in this paper.Tubulointerstitial damage is an important feature of diabetic nephropathy and is, in addition to glomerular damage, an important predictor of renal dysfunction ,5,6,7. INeutrophil gelatinase-associated lipocalin (NGAL) is small (25-kDa) protein that is released from injured renal tubular cells in acute kidney injury into the blood and urine, long before a decrease in the glomerular filtration rate can be detected ,9,10. Seet al., included 96 patients with CKD stages 2\u20134, among them 20% with diabetic nephropathy [et al., 74 type 2 diabetic patients were included [et al., 158 patients with CKD stage 3 and 4 were included, and 6% were patients with diabetic nephropathy [2) over one year. Adding urine NGAL-to-creatinine ratio demonstrated the greatest benefit in identifying patients with CKD progression only in group of patients with relatively low proteinuria. In the study by Nauta et al., 94 diabetic  and 45 non-diabetic control subjects were included [et al., in 63 type 1 diabetic patients with diabetic nephropathy who were followed for three years [et al., serum and urine NGAL were used in addition to albuminuria to predict the GFR decline rate in type 2 diabetic patients, but only urine albumin excretion rate was significantly associated with eGFR and the eGFR decline rate [In one of the first large studies, Bolignano hropathy . Patientincluded . They wehropathy . The basee years . Accordiine rate .According to conflicting results of previously mentioned studies, and due to the strong link with proteinuria in most of the studies, serum and urine NGAL do not offer additional prognostic information compared to already established biomarkers.Kidney injury molecule 1 (KIM-1) is a transmembrane tubular protein with unknown function, not detectable in the normal kidney, but elevated in experimental and clinical kidney damage . It is aet al., in biopsies from various renal diseases  and controls, renal KIM-1 was significantly increased in all diseases versus controls, except minimal change [versus controls and correlated positively with tissue KIM-1 and negatively with renal function, but again not with proteinuria [et al., 145 renal transplant recipients were included and were followed for four years for graft loss [In the study by von Timmeren l change . KIM-1 wl change . Renal Kl change . At the l change . Urinaryteinuria . In the aft loss . At baseaft loss . In multaft loss . Urinaryaft loss ,27,28,29Liver-fatty acid-binding protein (L-FABP) is an intracellular carrier protein that is expressed in proximal tubules of the kidney and liver. Although its precise function is unknown, it is believed to be endowed with protective functions . L-FABP et al., including 165 normoalbuminuric type 1 diabetic patients urinary L-FABP predicted the development of micro- and macro-albuminuria independent of recognized biomarkers [et al., including over 100 type 2 diabetic patients, high urinary L-FABP levels were associated with the increase in albuminuria, progression of diabetic nephropathy to ESRD or induction of haemodialysis [et al., only urine albumin excretion rate was significantly associated with eGFR and eGFR decline rate in type 2 diabetic patients and not L-FABP [In the large prospective study by Nielsen omarkers . In anotdialysis . In the t L-FABP .et al., including type 2 diabetic patients, heart fatty acid-binding protein (H-FABP), a marker of distal tubular damage, was the only tubular marker associated with eGFR after adjustment for other risk markers of progressive diabetic nephropathy [In the study by Nauta hropathy .According to published studies, members of the FABP family are emerging as the tubular markers with the greatest chance of offering added predictive value for progressive diabetic nephropathy over and above that offered by established risk markers .N-acetyl-beta-d-glucosaminidase (NAG) is a lysosomal enzyme that is constitutively expressed by the proximal tubule and a well-studied urinary marker of established proximal tubule cell injury [Urinary l injury . NAG is l injury .et al., lower urinary NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus [et al., including type 1 diabetic patients who participated in the Diabetes Control and Complications Trial (DCCT), baseline levels of urinary NAG independently predicted the development of micro- and macro-albuminuria during the follow up period of nine years [In the study by Vaidya mellitus . In the ne years . The lacne years . FurtherSeveral factors are involved in the development and progression of diabetic nephropathy. Growing evidence indicates that pathogenesis and progression of diabetic nephropathy is associated with the presence of a chronic subclinical low-grade inflammatory state and oxidative stress ,43. IncrCytokines are low molecular weight polypeptides and their most important function is regulation of the inflammatory process. They contribute in accelerating and maintaining chronic inflammation. The first studies suggesting the role of inflammatory cytokines in the development of diabetic nephropathy were published more than 20 years ago ,45.et al., 194 type 1 diabetic patients from multi-centre Finnish Diabetic Nephropathy Study (FinnDiane) were included [et al., including 29% of patients with diabetic nephropathy baseline IL-6 levels gradual increase from control subjects to CKD stage 3 and 4 and to CKD stage 5 patients [et al., five inflammatory markers\u2014IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), interferon \u03b3-inducible protein (IP-10), and macrophage inflammatory protein 1d\u2014were measured in urine samples collected from individuals with type 1 diabetes [Interleukin-6 (IL-6) is a proinflammatory cytokine, which is produced by many cells  and is also associated with visceral obesity and insulin resistance . In the included . They weincluded . In thisincluded . In the patients . In the diabetes . Baselindiabetes . By multdiabetes .et al., 151 type 2 diabetic patients with various degrees of nephropathy, as well as 80 healthy volunteers, were included [In the study by Moriwaki included . Signifiincluded . In addiincluded .et al., serum and urinary IL-18 and serum IL-6 levels were also significantly elevated in patients with type 2 diabetes compared to control subjects [In the another study by Nakamura subjects . In uni-subjects .et al., reported in two studies direct and significant association between serum TNF-\u03b1 and urinary protein excretion in diabetic patients with normal renal function and microalbuminuria, as well as in subjects with overt nephropathy and renal insufficiency [et al., where significant differences in serum levels of TNF-\u03b1 were observed between the type 2 diabetic patients and control subjects [The primary source of tumour necrosis factor-\u03b1 (TNF-\u03b1) are monocytes and macrophages, although intrinsic renal cells are also able to synthesize this cytokine . It was ficiency ,56. Urinficiency ,56. Multficiency ,56. Simisubjects . In patisubjects .et al., only levels of soluble forms of receptors 1 and 2 for TNF-\u03b1, and not TNF-\u03b1, were found to be associated with GFR in a multivariate analysis [et al., 410 patients with type 2 diabetes were included and were followed for 12 years [et al., 628 patients with type 1 diabetes, normal renal function and no proteinuria were included and followed for 12 years; in the follow up period, 69 patients developed eGFR less than 60 mL/min per 1.73 m2 [Interestingly, in the study by Niewczas analysis . In anot12 years . In foll12 years . In the  1.73 m2 . In this 1.73 m2 . SimilarInfiltration of leukocytes into inflammatory lesions is mediated by adhesion to endothelial cells and transmigration from vascular lumen to inflammatory sites . Adhesioet al., type 1 diabetic patients and healthy subjects were included [et al., baseline levels of ICAM-1 and VCAM-1 were measured from stored blood samples from the 1441 participants of the DCCT [et al., 30 hypertensive type 2 diabetic patients and 30 non-diabetic normotensive subjects were included; their VCAM-1, ICAM-1 and selectin levels were measured [In the study by Clausen included . In thisincluded . In the the DCCT . Only anthe DCCT . In the measured . The diameasured . Due to Growing evidence suggests that recruitment of inflammatory cells from the circulation into renal tissue plays a pivotal role in the progression of various renal diseases, including diabetic nephropathy. Infiltration of activated T cells and monocytes initiate renal damage and lead to a progressive loss of renal function ,67. Chemet al., 45 type 2 diabetic patients and 20 healthy subjects were included [et al., levels of urinary MCP-1 in type 2 diabetic patients with normal renal function were significantly higher than those in healthy adults, and urinary MCP-1 levels increased gradually from normo-, micro- to macro-albuminuria [et al., urinary levels of MCP-1 in patients with macroalbuminuria were significantly elevated compared to the levels in patients with normo- and micro-albuminuria [et al., in type 1 diabetic patients, baseline urinary MCP-1 was significantly higher in those with an early progressive kidney function decline compared with those who displayed stable kidney function [In the study by Wada included . Urinaryuminuria . Similaruminuria . In thisuminuria . In prevfunction .et al., showed that blockade of the renin\u2013angiotensin system in patients with type 2 diabetes was associated with a reduction in urinary MCP-1 levels as well as an improvement in renal function [et al., found that aldosterone blockade by spironolactone may offer beneficial renoprotective effects through anti-inflammatory mechanisms via the modulation of MCP-1 [Two interesting studies demonstrating the effect of treatment with ACE inhibitors and spironolactone on MCP-1 in type 2 diabetic patients have been published. In the first, Amann function . In the of MCP-1 .etc., and reduced levels of antioxidant agents and enzymes, such as bilirubin, superoxide dismutase and antioxidant vitamins, thus promoting oxidative stress [Under normal physiological conditions, there is a balance in the generation of oxygen-free radicals and the antioxidant defence mechanisms used to deactivate free radical toxicity . Experime stress ,76. Mease stress ,78. 8-OHe stress ,78. Urine stress ,78.et al., 396 Japanese type 2 diabetic patients with normoalbuminuria or microalbuminuria were included and followed for five years [In the large study by Hinokio ve years . Authorset al., 52 patients with type 2 diabetes mellitus (32 with nephropathy and 20 without) and 20 healthy control subjects were included [The multivariate logistic regression analysis suggested that the urinary 8-OHdG was the strongest predictor of nephropathy among several known risk factors. In the another study by Serdar included . The conAccording to conflicting results of clinical studies, it is questionable if markers of oxidative stress add additional prognostic information in relation to the development or progression of diabetic nephropathy compared to established risk markers.etc. [Today, in clinical practice, most commonly used markers of renal disease and progression of CKD and also diabetic nephropathy are serum creatinine, eGFR and proteinuria/albuminuria but unfortunately they are all insensitive. Some new biomarkers reviewed in this paper are promising but further large, multicenter prospective studies are needed before they can be used in everyday clinical practice. The main problem is that most of the biomarkers are still at an intermediate phenotype level, which is too distant from the gene level and most of these biomarkers are deeply influenced by environment, genetics, sex differences, etc. . It is aDespite that the purpose of this paper is to present the biomarkers of renal disease and progression in patients with diabetes, it is also important and should be mentioned that, in patients with diabetic nephropathy, there is also a concomitant increase in cardiovascular morbidity and mortality . Some of"}
+{"text": "Recently, Christoph Thiel and colleagues from Aachen University published an improved physiologically based pharmacokinetik modeling (PBPK) technique for mouse to human extrapolation . This pThe translation of preclinical knowledge often generated in mice to first-in-human studies represents a critical step . More tspecies-specific physiology, such as differences in organ size, perfusion, etc. the species-specific non-protein bound fraction of the test compound, max and KM for the primary route of excretion, and kinetic parameters, such as Vtissue-specific gene expression of the metabolizing key enzymes and transporters.The authors start with a na\u00efve extrapolation where humans are considered as 'large mice' where the same dose per body weight was administered . This nInterspecies differences represent a major problem in toxicology (Dohnal et al., 2014; BernauePBPK modeling has been used since long to predict absorption, distribution, metabolism and excretion (Sterner et al., 2013; Lee et"}
+{"text": "G-nitro-L-arginine methyl ester  was performed throughout fructose intake. L-NAME treatment itself induces increase in blood pressure and relative heart weight as well as impairment in arterial relaxation and contractility. However, in these rats, fructose administration did not cause further elevation of blood pressure and other abnormalities observed in rats receiving fructose without L-NAME. Our results showed that in the state of NO deficiency (induced by L-NAME administration) fructose does not induce cardiovascular and metabolic alterations which develop in rats with a functional NO system. This indicates that impairment of the NO system may participate in many of the adverse effects induced by high-fructose intake.The aim of this study was to evaluate the involvement of nitric oxide (NO) system damage in the deleterious effects of high-fructose intake in rats. Fructose was administered as 10% solution in drinking water to twelve-week-old male Wistar rats for the period of 8 weeks. Blood pressure was measured by tail-cuff plethysmography. After sacrificing the rats at the end of the treatment, relative weights of heart and liver and biochemical parameters in blood plasma were determined. Reactivity of isolated conduit arteries was measured using a force-displacement transducer for recording isometric tension. Fructose drinking rats had increased blood pressure and impaired acetylcholine-induced relaxation of the thoracic aorta in comparison with control rats drinking just tap water. Relative liver weight and plasma concentrations of glucose and triglycerides were also elevated after fructose administration. In a further group of Wistar rats, inhibition of NO production by administration of N NG-nitro-L-arginine methyl ester \u2013 L-NAME) causes NO deficiency and impaired vascular relaxation leading to sustained blood pressure increase  plays a critical role as a molecular mediator in a variety of biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. In spite of its pleiotropic effects in organisms, its role has been most extensively studied in physiology and pathology of the cardiovascular system. It is its prominent role in endothelium-dependent relaxation of vessels thanks to which the function of NO in the cardiovascular system was discovered and identified , fructose drinking rats (receiving 10% solution of fructose for 8 weeks), L-NAME treated rats (receiving 40 mg/kg/day of L-NAME in drinking water for 8 weeks), L-NAME treated fructose drinking rats (receiving 40 mg/kg/day of L-NAME in 10% solution of fructose for 8 weeks). The animal protocols used in this study were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, and approved by the Animal Health and Welfare Division of the State Veterinary and Food Administration of the Slovak Republic.Twelve-week-old male Wistar rats were housed at 22\u201324\u00b0C on a 12:12-h dark-light cycle (06.00\u201318.00 h lights on) and maintained on a standard laboratory rat chow th week of life), all rats were fasted overnight  and then they were sacrificed under CO2 anesthesia. Samples of their blood were collected immediately and used for measurement of plasma glucose, cholesterol and triglyceride concentration. Wet weight of the left heart ventricle and of the liver and the length of the tibia were determined for calculation of the ratio of left heart ventricle weight to tibia length and of liver weight to tibia length. The thoracic aorta and superior mesenteric artery were carefully removed and prepared for functional studies performed by isometric tension recording.Systolic blood pressure and heart rate were measured in conscious rats by the non-invasive tail-cuff method. At the end of the experiment (in the 202 + 5% CO2) modified Krebs solution maintained at 37\u00b0C. The Krebs solution had the following composition (in mmol/l): NaCl 118, KCl 5, CaCl2 2.5, MgSO4 1.2, NaHCO3 25, KH2PO4 1.2, glucose 11, CaNa2.EDTA 0.03. The arterial rings were set up for isometric tension recording using a force-displacement transducer Sanborn FT 10 . The preparations were equilibrated under a resting tension of 10mN for 60\u201390 min and the solution was changed every 15 min.The arteries were cut into rings (3.0\u20133.5 mm in width) and suspended in 20 ml organ baths filled with oxygenated (95% O\u20136 mol/l). When the contraction reached a plateau, increasing concentrations of acetylcholine were applied in a cumulative manner (10\u20139\u201310\u20135 mol/l).To examine the endothelium-dependent vasorelaxation, the preparations of the aorta were first precontracted by phenylephrine (10\u201310\u20133\u00d710\u20135 mol/l).Adrenergic contractions were determined in endothelium-intact thoracic aortas and mesenteric arteries as the responses to cumulatively applied exogenous noradrenaline . Frequency-response curves to electrical stimuli were obtained using square pulses of 0.5 ms in duration, at supramaximal voltage (>30 V), applied at 1\u201332Hz, for a period of 20 s. In our preliminary observations we found that the contractions of rat mesenteric arteries elicited by electrical stimulation (using the described parameters of stimulation) were blocked by phentolamine or tetrodotoxin, indicating that they were induced by nerve-released (endogenous) noradrenaline.N\u03c9-Nitro-L-arginine methyl ester hydrochloride (L-NAME) were purchased from Sigma-Aldrich (Germany); other chemicals were purchased from local commercial sources.Acetylcholine chloride, L-Noradrenaline hydrochloride and The results are presented as means \u00b1 S.E.M. The arterial responses to particular pharmacological and electrical stimuli are expressed as absolute values in mN and normalized to the cross sectional area of the respective ring preparation.p<0.05.Statistical evaluation was carried out by using one-way analysis of variance (ANOVA). The results were considered to be significant when After eight weeks of treatment with fructose, the Wistar rats had significantly elevated blood pressure without change in heart rate, when compared to control untreated rats. Body weight and relative weight of the left heart ventricle did not differ between control and fructose drinking rats. However, the relative liver weight, as well as plasma glucose and triglyceride concentrations were increased due to fructose treatment .In the thoracic aorta, endothelium-dependent relaxations in response to acetylcholine were significantly decreased after fructose administration . ContracEight-week L-NAME administration to control Wistar rats caused significant increase in blood pressure, relative weight of left heart ventricle, and in plasma cholesterol level . It alsoIn this study we found that eight-week-lasting fructose administration to adult Wistar rats induced metabolic changes associated with increase in plasma glucose and lipids, enlargement of liver, mild but significant blood pressure elevation, and reduction in acetylcholine-induced arterial relaxation. We also showed that in rats made NO deficient by L-NAME treatment, the high-fructose intake did not evoke such alterations. These observations indicate that impairment of the NO system might represent an important mechanism of high-fructose induced damage.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., It was shown by other investigators that production of NO decreased after feeding normal rats with excess of fructose and that this effect may induce hypertension development in such treated individuals  which exhibit similar severity of hypertension as L-NAME-treated rats and their arteries have also diminished endothelium-dependent relaxation. However, in conduit arteries of adult SHR the NO synthase activity is markedly elevated and their resting relaxant capacity is still sufficiently NO dependent (Puzserova et al., et al., 1996; Yoneyama et al., The presented observations show that fructose administration had no effect on the magnitude of arterial contractions induced by exogenous or endogenous noradrenaline. On the other hand, treatment of rats with L-NAME alone led to diminution of arterial contractile responses. This paradoxical effect of inhibiting NO synthase was demonstrated by many authors (Dowell et al. (et al., Inhibition of NO production eliminated also the high-fructose evoked increase in liver mass and in plasma glucose and lipids. It is known that NO is implicated in a myriad of mechanisms regulating liver metabolism and its higher amount may have the potential for both protecting the liver as well as exacerbating its injury. Spruss et al.  demonstr et al.,  or in ra et al., , variousIn conclusion, in this study we demonstrated that NO deficiency abolished the abnormalities observed during fructose administration in normal rats. It may thus be supposed that impairment of the NO system may participate in many of the adverse effects induced by high-fructose intake since a functional NO system is necessary for their manifestation."}
+{"text": "The endothelium is the orchestral conductor of blood vessel function. Pathological blood vessel formation  or the inability of endothelial cells (ECs) to perform their physiological function (a condition known as EC dysfunction) are defining features of various diseases. Therapeutic intervention to inhibit aberrant angiogenesis or ameliorate EC dysfunction could be beneficial in diseases such as cancer and cardiovascular disease, respectively, but current strategies have limited efficacy. Based on recent findings that pathological angiogenesis and EC dysfunction are accompanied by EC-specific metabolic alterations, targeting EC metabolism is emerging as a novel therapeutic strategy. Here, we review recent progress in our understanding of how EC metabolism is altered in disease and discuss potential metabolic targets and strategies to reverse EC dysfunction and inhibit pathological angiogenesis. Partialet al, et al, et al, et al, The hexosamine biosynthesis pathway starts with the conversion of the glycolytic intermediate fructose-6-phosphate (F6P) into glucosamine-6-phosphate (GlucN6P) Fig . GlucN6Pet al, et al, et al, et al, Other metabolic pathways are less well characterized in ECs. Fatty acid (FA) oxidation (FAO) and glutamine oxidation have been implicated in replenishing the TCA cycle to produce ATP via oxidative phosphorylation Fig   in ECs. Arginine is a metabolite in the ornithine cycle and converted into citruline and nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) Fig  , which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1)  in the rate-limiting step of glycolysis. EC-specific PFKFB3 deletion diminishes retinal and hindbrain vascularization in mice, showing that increased glycolytic flux is required for growth factor-induced angiogenesis  is metabolically demanding and mediated by adaptations in EC metabolism Fig A. While in vivo -1-(4-pyridinyl)-2-propen-1-one (3PO) or EC-specific genetic silencing of PFKFB3 inhibits tumor growth et al, et al, et al, et al, et al, in vivo and that pharmacological blockade of MCT1 inhibits angiogenesis and reduces tumor growth in mice  Fig A  is characterized by heightened pressure in pulmonary arteries caused by excessive EC proliferation and vascular dysfunction  levels are another hallmark of PAH ECs  are partly reminiscent of the metabolic profile of angiogenic ECs. It would be thus interesting to determine if reducing glycolysis by pharmacological blockade of PFKFB3 can reduce the hyperproliferative rate in PAH ECs. Alternatively, the beneficial effects of PDK inhibition in PAH to induce oxidative metabolism could also be beneficial to block angiogenesis by preventing the glycolytic switch in ECs. Indeed, PDK blockade with dichloroacetate inhibits angiogenesis in glioblastoma patients  and reactive nitrogen species (RNS), which might be mediators of EC dysfunction Fig  Blake &. High glet al, et al, et al, et al, et al, et al, et al, et al, et al, et al, Accumulation of F6P increases the flux through the hexosamine biosynthesis pathway (HBP), which produces UDP-GlcNac, an important precursor of glycosylation reactions Fig A Brownl. While get al, et al, et al, et al, et al, et al, et al, et al, in vitro and transgenic overexpression of glyoxalase-I in rats reduces vascular AGE formation and improves vasoreactivity  at the expense of NADPH, increasing ROS. Sorbitol is subsequently converted into fructose and the highly reactive 3-deoxyglucosone (3DG), which promotes the formation of AGEs  and by a salvage pathway from dihydrobiopterin (BH2) via dihydrofolate reductase (DHFR)  Fig B  metabolism centers around the ability of folate-derived co-enzymes to carry activated 1C units Fig  Tibbett. DHFR caEC metabolism is best characterized in the diseases discussed above. However, these represent only a minor fraction of the disorders in which pathological EC responses are presumably involved. Indeed, it is highly likely that EC metabolic alterations are also involved in the pathogenesis of other diseases such as ischemia, pre-eclampsia, vasculitis, vascular neoplasms and others although this has hardly been studied.et al, et al, et al, et al, in vitro, and in vivo levels of serum nitrites (an indicator of NO production) are inversely proportional to serum uric acid concentrations  is common in patients with hypertension and may even be a root cause of EC dysfunction leading to cardiovascular disease (Feig et al, et al, A broader characterization of EC metabolism in the future might reveal novel therapeutic targets in metabolic pathways that are generally not considered to be important in pathological EC function. Recent findings that endothelial cholesterol efflux to high-density lipoprotein regulates angiogenesis (Fang The findings in this review suggest that blood vessel pathology is mediated, or at least characterized, by disease-specific alterations. However, at present, there are no studies that incorporate state-of-the-art metabolomics tools to characterize EC metabolism in disease. Metabolic profiling using isotope incorporation studies and metabolic flux analysis could greatly increase our understanding of the metabolic alterations that underlie EC pathology.In vivo studies to characterize EC metabolism in animal models of human disease could provide highly relevant insight in disease-specific metabolic alterations. However, this requires isolation of ECs from diseased tissue, which at present poses technical and interpretational challenges for proper analysis of metabolism using advanced metabolomics methods.in or ex vivo models. The recent development of new protocols to isolate ECs from patient tissue offers the possibility to study metabolism in clinically relevant systems. Accordingly, such studies could greatly advance the identification of novel biomarkers and therapeutic targets in EC metabolism.Another pressing issue is the lack of studies characterizing metabolism in patient-derived tissue using either et al, et al, et al, et al, Overall, it is clear that pathological blood vessel responses are associated with metabolic alterations in ECs. These metabolic adaptations are not just innocent bystanders, but in many cases mediate important aspects of disease. Increased EC glucose metabolism is emerging as a key feature of angiogenic and hyper-proliferative ECs. Targeting EC glucose metabolism has recently been shown as a viable strategy to curb pathological angiogenesis, but is still in its infancy (Schoors"}
+{"text": "Cryptococcus species, with neoformans strains mostly isolated from individuals with impaired immunity  strain that lacks the sterylglucosidase enzyme and administered to mice preceding fungal infection confers complete protection in animals challenged with lethal doses of either C. neoformans or C. gattii , a class of immunomodulatory glycolipids, in a genetically engineered non-pathogenic C. neoformans pulmonary infection and reduced phagocytosis, which can be restored by administration of IgM (Subramaniam et al., C. neoformans infected rodents produce fungal binding IgM and depletion of these cells resulted in impaired macrophage function facilitating cryptococcal dissemination to the brain (Rohatgi and Pirofski, B cells play a critical role in protection against experimental cryptococcosis (Subramaniam et al., C. neoformans. For instance, NKT cells are increased in the lungs of mice infected with C. neoformans, associating the chemokine MCP-1 in their recruitment and accumulation (Kawakami et al., sgl1 strain (Kawakami et al., C. neoformans in the lungs correlates with macrophage polarization (Davis et al., C. neoformans.SGs have been shown to modulate cytokine production (Lee et al., sgl1 strain might provide a potential vaccination strategy against cryptococcosis. Rella et al., provide a proof of concept study that opens a novel area of research and a potential therapeutic strategy to prevent and reduce the devastating consequences of cryptococcosis.Further studies focusing on the immune responses generated by SGs and safety issues associated with delivering live-attenuated cryptococci, heat-killed fungi, or vesicle formulations containing SGs preparations are necessary. However, these findings are significant in the setting of HIV/AIDS immune deficiency suggesting that the \u0394The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ischemia-reperfusion injury represents a pathological condition characterized by an initial undersupply of blood to an area or organ followed by a restoration of perfusion and concomitant reoxygenation (= reperfusion). Ischemia typically occurs in the presence of embolism or thrombosis but can also be triggered by surgery and transplantation. Anyway, the disturbance in perfusion results in a severe imbalance between metabolic supply and demand, subsequently causing tissue hypoxia . NotablyInterestingly, restoration of blood flow and reoxygenation is commonly associated with an exacerbation of tissue injury and a profound inflammatory response (\u201creperfusion injury\u201d) , 2. IschFor example, myocardial ischemia followed by reperfusion typically manifests in microvascular dysfunction, death of myocytes, and myocardial stunning or dysfunction.Ischemia-reperfusion injury (IRI) of the lung, for example, following transplantation, is characterized by nonspecific alveolar damage, edema formation, and hypoxemia. The clinical spectrum of pulmonary IRI may range from mild hypoxemia to acute respiratory distress syndrome.In contrast to other organs, the brain is particularly susceptible to ischemia and irreversible neuronal damage already occurs after only 5 minutes of complete ischemia . For braIRI of the kidney may occur in the setting of transplantation and cardiac arrest and during cardiac surgery. Here it is important to note that renal injury is usually associated with a high morbidity and mortality. The cortical-medullary region is the most susceptible region to tubular injury, inflammation, and vascular alterations.Generally, IRI of a single organ causes the release of different proinflammatory mediators, which may subsequently induce inflammation in other organs, thereby potentially contributing to multiple organ dysfunction or even failure .\u03baB (NF-\u03baB) [Different pathological processes contribute to tissue injury secondary to ischemia-reperfusion. During ischemia, limited oxygen availability leads to an impaired endothelial cell barrier function with a concomitant increase in vascular permeability and leakage due to decreases of intracellular cAMP levels caused by a reduced adenylate cyclase activity . Further (NF-\u03baB) .Reperfusion of ischemic tissue activates a complex inflammatory response without the involvement of pathogenic triggers, a phenomenon also referred to as sterile inflammation. During the initiation of this inflammatory response, endogenous molecules act as alarmins or danger-associated molecular patterns (DAMPs) . The inf \u201cThe effects of remote ischemic preconditioning and N-acetylcysteine with remote ischemic preconditioning in rat hepatic ischemia-reperfusion injury model\u201d by B. U. Togrul et al., \u201cThe effects of spinal, inhalation, and total intravenous anesthetic techniques on ischemia-reperfusion injury in arthroscopic knee surgery\u201d by S. C. Karahan et al., \u201cEfficacy and safety of hepatectomy performed with intermittent portal triad clamping with low central venous pressure\" by D. Dohman et al., \u201cAdalimumab ameliorates abdominal aorta cross clamping induced liver injury in rats\u201d by Y. Demirci et al., \u201cEvidence for the use of isoflurane as a replacement for chloral hydrate anesthesia in experimental stroke: an ethical issue\u201d by B. Mich\u00e8le et al., \u201cThe effect of dexmedetomidine on oxidative stress during pneumoperitoneum\u201d by S. C. Karahan et al., \u201cThe comparison of the effects of sevoflurane inhalation anesthesia and intravenous propofol anesthesia on oxidative stress in one lung ventilation\u201d by D. Dohman et al., and \u201cRole of ethyl pyruvate on systemic inflammatory response and lung injury in an experimental model of ruptured abdominal aortic aneurysm\u201d by G. Altun et al.This special issue is devoted to the modulation of ischemia-reperfusion injury by different measures and contains eight original papers addressing this clinically relevant topic. These papers are accompanied by two review articles dealing with the effects of anesthetics on ischemia-reperfusion injury. Papers from B. U. Togrul et al., D. Dohman et al., and Y. Demirci et al. are focusing on ischemia-reperfusion injury of the liver. In two of these three papers, different therapeutic interventions on hepatic ischemia-reperfusion injury are evaluated, whereas the third paper is a retrospective study in which the authors investigated the efficacy and safety of intermittent portal triad clamping with low central venous pressure during liver resection. In this context, it has been reported that remote ischemic preconditioning and therapeutic interventions can reduce liver damage after inducing ischemia-reperfusion injury. The studies by S. C. Karahan et al., B. Mich\u00e8le et al., S. C. Karahan et al., D. Dohman et al., and G. Altun et al. elucidate the effects of different anesthetic techniques and drugs on ischemia-reperfusion injury. These eight papers are entitled as follows:Alexander ZarbockAhmet ErogluEngin ErturkCan InceMartin Westphal"}
+{"text": "Advances in medical science and technology allow people live longer lives, which results in age-related problems. Humans cannot avoid the various aged-related alterations of aging; in other words, humans cannot remain young at molecular and cellular levels. In 1956, Harman proposed the \u201cfree radical theory of aging\u201d to explain the molecular mechanisms of aging. Telomere length, and accumulation of DNA or mitochondrial damage are also considered to be mechanisms of aging. On the other hand, stem cells are essential for maintaining tissue homeostasis by replacing parenchymal cells; therefore, the stem cell theory of aging is also used to explain the progress of aging. Importantly, the stem cell theory of aging is likely related to other theories. In addition, recent studies have started to reveal the essential roles of tissue-resident mesenchymal progenitors/stem cells/stromal cells in maintaining tissue homeostasis, and some evidence of their fundamental roles in the progression of aging has been presented. In this review, we discuss how stem cell and other theories connect to explain the progress of aging. In addition, we consider the mesenchymal progenitor theory of aging to describing the process of aging. Several theories to explain the aging-related alterations in our bodies have been proposed and accepted. The free radical theory of aging was first proposed by Harman in 1956 as one factor of aging Harman, . The numAll adult stem cells exist in a unique microenvironment, which is known as a niche. The niche is consistent with heterogeneous types of cells and extracellular matrix proteins. The blood vessel has been proposed as a niche in common. Using expression patterns of cell surface receptors of the SLAM  family in hematopoietic stem cells, Kiel et al. showed that many hematopoietic stem cells are associated with sinusoidal endothelium in the spleen and bone marrow  differentiation and self-renewal potentials. They are indispensable for renewal and regeneration of parenchymal cells after damage. In adult mammals, many but not all tissues have functional resident tissue-specific stem cells that satisfy the criteria, including hematopoietic, skeletal muscle, pigment, epithelial, sperm, adipose, intestinal, and neural stem cells. Although a subset of adult stem cells is maintained in a quiescent state  in the homeostasis of skeletal muscle and hematopoiesis , some of the reactive oxygen species (ROS), and their reactive products. ROS consist of superoxide anions (O\u22122), hydrogen peroxide (H202), and hydroxyl radicals (OH.), which are mainly generated in cells by the mitochondrial respiratory chain  is another molecule that regulates the ROS pathway in hematopoietic stem cells. The FOXO subfamily  is known as the downstream target of the PI3K-AKT signaling pathway. Mice conditionally depleted of C. elegans. Two genes were identified as responsible for longevity in C. elegans. One is the daf-2 gene, an equal homolog to both the mammalian insulin and IGF-1 receptors, and the other is age-1, a homolog to the worm PI3K-kinase catalytic subunit  and SKN-1 (homolog of NRF2) , which is a truncated and farnesylated form of LAMIN A. HGPS affects mesenchymal linages. Zhang et al. produced iPS cells from HGPS dermal fibroblasts and differentiated them into neural progenitors, endothelial cells, fibroblasts, vascular smooth muscle, and mesenchymal stem cells  and an increase of mitochondrial MnSOD-dependent ROS  is an inherited disorder that causes premature aging and shortens the life span. The causative gene of HGPS is s Figure . Lentiviin vivo importance of telomere length, mice with the telomerase RNA component Terc knocked out (\u2212/\u2212Terc) were generated by Blasco et al.  \u2212/\u2212Terc mice exhibited failures in highly proliferative organs including the hematopoietic and reproductive systems  knockout (\u2212/\u2212Atm) mice, and the offspring showed increased telomere erosion and genomic instability . Compared with mdx mice, mdx/mTR mice showed severe dystrophic phenotypes and decreased proliferative potential of muscle stem cells  is a well-known inherited X-linked disorder occurring in one in 3500 boys. The causative gene is \u2212/\u2212Terc and +/\u2212Terc littermates (CD45.2). First, they observed impaired B cell lymphopoiesis and increased myeloid proliferation in \u2212/\u2212Terc recipient mice. Twelve-month-old \u2212/\u2212Terc mice showed a more severe defect of B cell lymphogenesis and accelerated myelopoiesis compared with 2-month-old \u2212/\u2212Terc mice. The environment of \u2212/\u2212Terc mice limited the engraftment of even wild-type hematopoietic stem cells. They also showed a shortened telomere length in mesenchymal progenitors  in \u2212/\u2212Terc mice and a decrease in their number. Taken together, these results suggest that the shortening of telomere length in both stem cells and mesenchymal progenitors are factors of the telomere theory aging in various tissues  is known to cause a photosensitive form of the brittle hair disorder trichothiodystrophy. A study of de Boer at al. showed that mice with mutated Xpd genes (TTDXpd) exhibit many aged-related symptoms including osteoporosis, kyphosis, osteosclerosis, early graying, cachexia, infertility, and a reduced life span although the mice are born with developmentally normal phenotypes , Nijnik found that impairment of the NHEJ pathway causes a progressive loss of hematopoietic stem cells during aging -deficient mice  pathway is a well known mechanism to repair DNA double-strand breaks. One of its components is DNA ligase IV. Using ice Lig4Y88C mice,Accumulating studies also demonstrated that a component of serum is altered during aging. By utilizing parabiotic pairings, Conboy et al. showed that the age-related decline of muscle stem cell activity can be modulated by systemic factors that change with age  (Janzen et al., p16INK4a expression induced senescence, and a knockdown of p16INK4a prevented the senescence of human mesenchymal stem cells (Shibata et al., Cellular senescence is a unique state generally defined as irreversible cell cycle arrest. Recent studies have shown that senescent cells exhibit a robust increase in mRNA expression and secretion of numerous proinflammatory cytokines, which work in a paracrine manner (Campisi et al., Fibroblasts can be observed in all tissues. Fibroblasts and mesenchymal progenitors show similar morphologies, but their differentiative potentials distinguish them. Sudo et al. investigated the differentiation potential of human fibroblasts derived from various tissues and found that cells originally considered fibroblasts have potential to differentiate into the mesenchymal lineage, which includes osteoblasts, chondrocytes, and adipocytes (Sudo et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To better understand the type and range of health issues initiated by patients and providers in \u2018high-quality\u2019 primary-care for adults with diabetes and low socio-economic status (SES).Although quality of care guidelines are straightforward, diabetes visits in primary care are often more complex than adhering to guidelines, especially in adults with low SES who experience many financial and environmental barriers to good care.We conducted a qualitative study using direct observation of primary-care diabetes visits at an exemplar safety net practice in 2009\u20132010.In a mainly African American (93%) low-income population with fair cardiovascular control , visits addressed a variety of bio-psychosocial health issues [median: 25 problems/visit (range 13\u201332)]. Physicians most frequently initiated discussions about chronic diseases, prevention, and health behavior. Patients most frequently initiated discussions about social environment and acute symptoms followed by prevention and health behavior.Primary-care visits by diabetes patients with low SES address a surprising number and diversity of problems. Emerging new models of primary-care delivery and quality measurement should allow adequate time and resources to address the range of tasks necessary for integrating biomedical and psychosocial concerns to improve the health of socio-economically disadvantaged patients. Africanet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Previous research has shown patient, provider, or system factors associated with improved diabetes outcomes, such as better medication adherence, greater medication intensification, fewer competing demands at the office visit, greater access to care, greater patient motivation, and better continuity of care  from a county hospital in Northeast Ohio, performing in the top quartile on their biomedical quality of care scores for their patients with diabetes in 2009\u20132010 after obtaining institutional review board approval. The biomedical quality of care scores are locally adapted National Council of Quality Assurance measures for adults with diabetes, and included the percent of diabetes patients with blood pressure (BP) <140/90 mmHg, hemoglobin A1c<7%, and low-density lipoprotein cholesterol (LDL-c) <100 mg/dL. We purposively selected adult patients with diabetes who were scheduled for routine follow-up visits with their primary-care provider at the practice site.We used participant/direct observation for data collection, as we were interested in the observed number, range, and types of health issues brought up at the primary-care visit for adults with diabetes and as the primary author was a provider at the practice site. For each of the practices\u2019 four primary-care physicians, we audio taped, observed, and transcribed three to four routine follow-up visits with diabetes patients after obtaining informed consent from patients and physicians. We excluded the primary-care provider who authored this paper due to potential biases; however, all the other providers participated in the study. Providers were told that we were observing the visit to evaluate current primary-care practice. We continued the enrollment of patients until we reached saturation of themes . The research assistant and internal medicine physician developed and piloted an observation form, environmental checklist, performed key informant interviews of providers and patients, wrote daily field notes, and composed reflective memos. For this analysis, we focused on analyzing the transcribed office visits, as these were felt to be most pertinent to our objective of evaluating the range and types of health issues that arose at the visit. The research assistant (a PhD sociology candidate) audio-recorded and observed most of the patient visits, whereas a primary-care provider/health services researcher audio-recorded and observed the remaining patient visits.et al., et al., A multidisciplinary team used a purposeful, constant comparative approach to count and categorize health issues, raised by the patient or the physician at the primary-care visit (Bradley n=5) were more likely to be men but were otherwise similar to participants in terms of age and race. The providers were all family practice physicians, Caucasian, and married. Three providers were women and one provider was a man.The safety net clinic serves a mainly low-income African American population . Out of the 20 patients asked to enroll, 15 patients consented to participate. The 15 patients were mainly African American (93%) with fair cardiovascular risk factor control . The patients had a mixture of insurance categories: private (33%), private plus medicare (20%), medicare alone (7%), medicaid (7%), and uninsured (33%). These numbers were similar to the numbers of the overall clinic population outlined above. Patients who refused to participate , prevention , changes in sexual partners, her spiritual beliefs as they relate to her health, and two acute issues.In-depth study reveals a rich subtext of the attitudes, beliefs, knowledge, and behaviors, as well as the role of popular culture underpinning patients\u2019 attempts to manage their diabetes. It is instructive for \u2018Dr Smith\u2019 to know that \u2018Ms Jones\u2019 \u2018ate at Subway for a whole month\u2019 (because Jared lost weight doing so) and decided that because the contestants on the Biggest Losers maintained their weight loss \u2018at home, after the show,\u2019 she could do so as well. Ms Jones acknowledges that she allows herself \u2018wiggle room\u2019 in trying to manage her diabetes: \u2018I ate only half the foot long for lunch and the other half for dinner.\u2019 Ms Jones\u2019 expression of the belief that \u2018my body feels better when my sugar is higher\u2019 initiated a lengthy discussion about how to manage low as well as high blood sugar.Her physician resourcefully integrates both the physician-directed health priorities such as chronic disease management of her diabetes and the patient-directed priorities such as her social environment into the overall plan of care. For instance, the physician incorporates the patient\u2019s concerns about potential job loss and concern for medication costs when writing prescriptions, and the provider and patient work together with the social worker to derive the most appropriate regimen that will minimize costs while maximizing adherence. In the end, the provider prescribes some expensive medications such as insulin, which will be obtained through the help of the social worker via a free pharmaceutical company program that will mail the patient her medications. Other generic medications were prescribed that cost four dollars a month, such as her cholesterol medicine. Furthermore, the physician incorporates the patient-directed comments about her social environment regarding diet into the plan for weight loss by encouraging recent weight loss while modifying the \u2018subway\u2019 diet to have less bread.Patients and providers discussed a wide range of issues at these primary-care visits . Importaet al., et al., Although we expected the primary-care visit for adults with diabetes and low SES to be diverse in the range of health issues, the surprisingly large number of health issues (median 25) and the inter-relationship with the social environment of patients\u2019 lives was remarkable. Similar to our study, one previous observational study reported that primary-care physicians deal with an average of 17 topics, questions, and symptoms at the primary-care diabetic visit (Parchman et al., Quantitative studies often fail to capture other issues such as the social environment (Samuels et al., et al., et al., These findings show what is possible in dedicated primary care \u2013 possibilities that provide hope for overcoming the chasms of fragmentation and poor quality that characterize much of the US healthcare system IOM, . Study fSeveral limitations to our study deserve mention. As this was a qualitative study that was carried out at one clinic, the conclusions may not be generalizable to the overall population. However, we were not trying to generalize findings but explore the range of health issues discussed in a primary-care visit to inform future potential interventions to improve care. Second, although we tried to combat bias in our analysis by including sociologists and primary-care physicians along with third-party physician review to confirm or refute findings, we recognize that some biases are hard to fully address. For instance, providers are more likely to conclude that they need more time with patients as we have suggested in this study. However, we also note that patients are more likely to bring up psychosocial issues than providers during an office visit; therefore, not all of our findings are biased toward positive provider performance.et al., et al., et al., et al., This study also has several important implications. First, the study raises questions about how \u2018productivity\u2019 is assessed in primary care. From bio-psychosocial and patient-centered points of view, the observed visits were highly productive. However, most of the present productivity measures and financial incentives emphasize \u2018throughput\u2019 (Morrison and Smith, Systems that incentivize quality and care integration over quantity may have the benefit of allowing scheduling of complex patients at more appropriate intervals and allow for more adequate resources for caring for biomedical and psychosocial aspects of patient health. In this time of tumultuous change in care organization and payment, we should support models of primary-care delivery and quality measurement, which allow adequate time and resources to address the range and complexity of tasks that are necessary for improving the health of socio-economically disadvantaged patients."}
+{"text": "In 2014, Schlichting and co-workers  have opened up new opportunities to collect damage-free diffraction data from randomly oriented sub-micron-sized crystals using serial femtosecond crystallography (SFX) (Chapman  al. 2015 demonstrIUCrJ, Schlichting and co-workers (Nass et al., 2016et al., 2014In this issue of They then applied the same methodology to a thaumatin data set collected at the LCLS using the native sulfur as a source of anomalous scatterering Fig. 1. A photoet al., 2015de novo phasing of SFX data, particularly with only native crystals, is still far from trivial. Millions of crystals and many hours of beamtime are usually required to collect a sufficient amount of data for structure determination. Nass et al.\u2019s study has demonstrated that with optimized data processing technology, single-wavelength anomalous diffraction data from the native sulfur atoms can allow protein structures to be solved ab initio. Improvements in XFEL instrumentation and processing software should further reduce the number of images required to phase SFX data.X-ray free-electron lasers have provided a new way to obtain SFX data that is advantageous over traditional synchrotron sources in terms of better data resolution, smaller sample size and minimal radiation damage (Kang"}
+{"text": "Pseudomonas aeruginosa biofilm (Costerton et al., Bacillus subtilis can choose between a variety of lifestyles such as sporulation, motility as an explorative lifestyle, biofilm formation, and the acquisition of genetic competence for the uptake of foreign DNA (L\u00f3pez and Kolter, In their endless struggle to survive in harsh and rapidly changing environments, many bacteria depend on their ability to live together as multicellular communities, also known as biofilms. In these communities cells are embedded within a self-produced slimy matrix that is mainly composed out of extracellular polysaccharides and proteins (Hall-Stoodley et al., B. subtilis biofilm communities, different groups of cells fulfill distinct functions, which are important for the well-being of the whole community of clonal identical bacteria. Some bacteria produce extracellular polysaccharides and proteins and thereby provide the matrix for the community. Other cells secrete exoproteases for degradation of protein as an alternative energy source (Marlow et al., In the B. subtilis suggest that tyrosine phosphorylation plays an important role in the regulation of biofilm formation and cell differentiation, in addition to the known mechanisms of transcriptional regulation and protein-protein interactions (for review see Vlamakis et al., B. subtilis encodes two protein tyrosine kinase/ modulator couples, PtkA/ TkmA, and EpsB/ EpsA. Interestingly, the simultaneous deletion of either both kinase or modulator genes totally abolished extracellular polysaccharide production causing a biofilm defect. The single mutants did not phenocopy the kinase or modulator double mutant and were still able to produce exopolysaccharides. However, colony structure and pellicle formation was affected in the single mutants (Gerwig et al., B. subtilis at different levels: EpsB acts downstream of the central regulator of cell differentiation, Spo0A, whereas PtkA is likely to act upstream of Spo0A (see Figure Recent studies in In principle, the stochastic phosphorylation state of the Spo0A protein determines to which promoters the protein binds and consequently if cells differentiate into a spore or become a matrix producer. High levels of phosphorylated Spo0A induce spore development, whereas medium levels lead to matrix production (Fujita and Losick, In order to influence sporulation efficiency as shown by Kiley and Stanley-Wall , PtkA moptkA mutant, Kiley and Stanley-Wall (In order to explain altered biofilm formation and the sporulation defect of the ley-Wall  conducteley-Wall  were notley-Wall , except ley-Wall . ClearlyA more obvious problem for the identification of tyrosine phosphorylated proteins with the potential to control biofilm formation and sporulation is that most published data relates to cells harvested from exponentially growing cultures rather than from biofilms. Moreover, the studies were performed with strains derived from a domesticated strain that does not produce robust bofilms. Thus, it is reasonable to assume that not all of the proteins that might be relevant for biofilm formation and sporulation are expressed under these conditions. Furthermore, regulatory phosphorylation is a rapid method for adapting cellular processes to environmental changes. Thus, it seems safe to assume that not all phosphorylations are present permanently. Interestingly, all currently identified tyrosine phosphorylation reactions with functional relevance have been found by attempts other than large-scale phosphoproteomics analyses. Examples include the regulator of unsaturated fatty acid synthesis FatR (Derouiche et al., eps operon for exopolysaccharide production. Hence, the regulation of the two corresponding genes is similar. The eps operon is only strongly expressed if the SinR anti-activator protein is inhibited by either of its antagonists SinI and SlrR under biofilm forming conditions (Kearns et al., epsB gene only affects exopolysaccharide production but leaves sporulation unaffected (Gerwig et al., The second level of regulatory tyrosine phosphorylation is provided by the EpsB kinase that phosphorylates the glycosyltransferase EpsE (Elsholz et al., Straight signal transduction is an important issue for many conserved multi-component signal transduction system families and has been extensively studied for two-component regulatory systems and phosphotransferase system-controlled RNA-binding antitermination proteins. These systems have evolved to avoid non-cognate interactions either by restricting the interactions with non-cognate proteins partners, ligands, and target molecules. Moreover, differential gene expression of the non-cognate components has been observed to prevent non-productive cross-talk (Schilling et al., Staphylococcus aureus that also contains two similar tyrosine kinase/ modulator couples. In this case, the Cap5A1 modulator protein of one couple and the Cap5B2 protein tyrosine kinase of the other couple show functional cross-talk suggesting that interplay between different tyrosine/ modulator couples might not be limited to B. subtilis (Soulat et al., However, this might be different for regulatory tyrosine phosphorylation, as suggested for the interplay between EpsB and PtkA. In yeast (Shi et al., B. subtilis is one of the most exciting results of recent studies. This is underlined by the observation of extensive links between the different signal transduction systems that involve post-translational modifications (van Noort et al., ptkA deletion mutant. Furthermore, large-scale phosphoproteomics under biofilm-promoting conditions could help to identify potential tyrosine phosphorylated targets. Additional tasks are the identification of substances that can be sensed by the PtkA modulator protein TkmA and to further dissect the potential cross-talk between the two known tyrosine kinase/ modulator couples EpsB/ EpsA and PtkA/ TkmA in B. subtilis.The detection of a regulatory interplay between protein tyrosine phosphorylation and classical sensing via the phosphorelay in the control of cell differentiation in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Microarray technologies facilitate high-throughput gene expression analysis. However, the diversity of platforms for rice gene expression analysis hinders efficient analysis. Tools to broadly integrate microarray data from different platforms are needed.http://www.ricearray.org) to explore gene expression across 1,867 publicly available rice microarray hybridizations. The ROAD\u2019s user-friendly web interface and variety of visualization tools facilitate the extraction of gene expression profiles using gene and microarray element identifications. The ROAD supports meta-analysis of genes expressed in different tissues and at developmental stages. Co-expression analysis tool provides information on co-regulation between genes under general, abiotic and biotic stress conditions. Additionally, functional analysis tools, such as Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) Orthology, are embedded in the ROAD. These tools facilitate the identification of meaningful biological patterns in a list of query genes.In this study, we developed the Rice Oligonucleotide Array Database  contains supplementary material, which is available to authorized users. Oryza sativa) is a staple food for more than 50% of the human population. Because of the high level of genomic colinearity and conservation of gene function among grass species, rice serves as a useful research model in other grass studies . The co and Gale), has br and Gale; Itoh et and Gale; Tanaka  and Gale). Despit and Gale).japonica and indica) have been reported and their characteristics are summarized in Table\u2009japonica and indica cultivars, respectively. Agilent has constructed a 22K Rice Oligo Microarray Kit based on rice FLcDNAs and recently announced a 44K version  was designed by the Beijing Genomics Institute and Yale University  and based on the draft indica and japonica sequences. The University of California, Davis, led a National Science Foundation (NSF) supported effort to design, print and validate 22K and 45K oligonucleotide arrays based on gene model predictions from TIGR\u2019s osa1 version 3.0 release.Microarray technologies are an important strategy for genome-wide expression pattern analysis and is becoming increasingly important for gene functional analysis . Severano et al.). The Orhttp://ricexpro.dna.affrc.go.jp/), which is based on the Agilent 44K microarray, provides an overview of the spatiotemporal gene expression profiles of various organs and tissues  provides a meta-analysis toolbox to explore gene expressions across a wide variety of biological contexts for rice and other species, but it is commercial and not completely publicly available , which integrates the most comprehensive public microarray datasets and provides several functional analysis tools. With a user-friendly web interface, the ROAD is a useful reference for elucidating rice gene expression and function.These rice microarray platforms have been successfully used in characterizing gene expression profiles from different tissues and organs , differto et al.). Geneveuz et al.). Other uz et al.), RicePLuz et al.), Bio-Aruz et al.) and Yaluz et al.) are usend Fobert). This sWe collected information from six rice microarray platforms, including the Affymetrix, Agilent 22K and 44K, BGI/Yale, and the NSF 20K and 45K, to construct the ROAD. Probe sequences from each platform were extracted and mapped onto cDNAs to match the probes to the expressed genes; the cDNAs were drawn from the Rice Genome Annotation Project  V6 , Rice A2(Cy3/Cy5)) were used and the color-swap hybridizations were manually corrected to make them comparable among other samples. Normalized data were integrated into the ROAD, thus simplifying the retrieval process of their gene expression profiles. After entering a list of genes or microarray element IDs into the ROAD, the user can then select the microarray platform and specific experiment to search against  to assemble microarray data from different experiments into context-related profiles (meta-profiles). This large-scale combination and analysis of expression data from a single organism using a single platform allows the identification of biologically meaningful expression patterns of individual genes . One drSimilarity of gene expression profiles (co-expression) can provide powerful information to identify new genes functionally related. The rapid accumulation of microarray data in past decade allows the creation of co-expression networks by examining the co-expression patterns of genes over a large number of experimental conditions. Several online co-expression analysis tools have been developed for rice, including OryzaExpress , RiceArp value is calculated for each GO/KO term, whose value is based on comparisons of the observed number from the queried gene list and the expected number from the genome scale.Gene Ontologies (GO) provide controlled vocabulary to describe the biological process, molecular function, and component of the cell to which a gene product putatively contributes , R package marray in Bioconductor was used to do the normalization with within-array Lowess and between-array MAD scale normalization methods  were collected from NCBI GEO , EBI ArCleveland; Wang etCleveland). The coad et al.). The sead et al.). Regardhttp://www.ricearray.org. Heatmap and classic line plots were generated by the PHP library JpGraph (http://jpgraph.net/).The ROAD database was constructed with PHP (Hypertext Preprocessor) and MySQL, run on a Windows 2003 server. The http address isAfter MAS normalization of all Affymetrix microarray samples, outliers were detected using the arrayQualityMetricsBioconductor package, which uses three different statistical tests to identify outliers     and KO sa et al.). The RAka et al.). Then hTable S1. Detailed information of rice microarray experiments available in ROAD. (XLS 204 KB)Additional file 1: Figure S1. Screenshots of meta-analysis in ROAD queried with 19 root-preferential genes for anatomy (a) and developmental stages (b) of Affymetrix array platform, and anatomy (c) and developmental stages  of Agilent 44K array platform. (JPEG 5 MB)Additional file 2: Authors\u2019 original file for figure 1Authors\u2019 original file for figure 2Below are the links to the authors\u2019 original submitted files for images."}
+{"text": "This Research Topic aims to cover recent progress in research studying how genetic make-up and environmental factors can contribute to the development of mental disorders such as anxiety, depression, schizophrenia, and psychoactive substances abuse. It has brought together leading experts in the field to address these questions from different angles in eleven reviews, seven original research articles and two theoretic/opinion papers.1A receptor KO mice compared to WT animals. Then, by performing loose-seal cell-attached electrophysiological recordings in 5-HT transporter knockout (Sert\u2212/\u2212) and tryptophan hydroxylase-2 knockout (Tph2\u2212/\u2212) mice, Araragi et al.  in the pathophysiology and the treatment of psychiatric disorders. First, Prof. Gardier  nicely si et al.  demonstret al.'s  results The following eleven articles provide excellent insights into the interaction between gene and environment in mental disorders as well as the role of several transmitters/neuropeptides and the different therapeutic strategies. El-Hage et al.  elegantlin vivo. They present novel methods using [11C]-(+)-PHNO and PET which could provide insights into the function of D3 receptors in addiction.The last five articles cover neuroscience research on drug of abuse. In order to better understand the processes by which peer influences take effect in prairie voles, Anacker and Ryabinin  measure In summary, these studies illustrate how mental disorders can arise from multiple sources. It even seems that the entire body can impact on mental state and psychiatric health (Renoir et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Most individuals experience these threats at least once during their lives, and some individuals experience them daily  and other forms of interpersonal rejection threaten individuals' physical and psychological well-being  because these behaviors are more likely to achieve re-inclusion; anti-social behaviors should be more likely to fortify power/provocation needs (control and meaningful existence) because these behaviors will likely provoke acknowledgement from the ostracizers . Thus, participants who give a small amount could be interpreted as either being less aggressive or potentially more pro-social because they are obeying the experimenter nominally but also not subjecting the target to unnecessary discomfort. Further, how do researchers categorize participants who actively choose not to allocate any hot sauce at all? Is this simply lack of aggression or also an independent pro-social behavior toward the target?Future research needs to address directly these two conflicting behavioral responses. Often, researchers only give participants one behavioral option. Because of this, it is hard to rule out the possibility that ostracized participants are simply responding more extremely than included participants using whatever option they are given because it is the only option they have to fortify some of their basic needs. Some behavioral measures can be interpreted as pro- or anti-social depending on how participants respond  and devaluate the same target  simultaneously (Sommer and Bernieri, Other threat-focused models [e.g., rejection-based threats, Smart Richman and Leary , or threResearchers could also measure theoretically meaningful individual difference variables to test potential moderation of the anti-social/pro-social paradox. For example, ostracized participants who have a higher dispositional need to belong (Leary et al., future expectations argument. Wesselmann et al. (Some individual differences should moderate anti-social responses. Individuals higher in rejection sensitivity (i.e., the tendency to expect and easily perceive rejection; Ayduk et al., n et al.  offer ann et al. , but theflight response (compared with fight responses, i.e., pro- and anti-social behaviors; Williams, freeze response (Williams, flight and freeze responses.Williams  developemeaning/significance (also Jonas et al., control (Kruglanski, Chronically ostracized individuals may also be susceptible to recruitment by predatory/extreme groups because these groups may offer a last bastion of inclusion (Wesselmann and Williams, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Epichlo\u00eb, Bacon et al., Balansia, Porter et al., Claviceps purpurea where the alkaloids, typically ergotamine and ergocristine, are responsible for the resultant ergotism associated with C. purpurea. The presence of these toxins can compound livestock issues with the concomitant consumption of ergovaline produced by the endophyte. In terms of livestock production systems, associated ergot alkaloid toxicities are not limited to pasture or feeding pasture products. While Claviceps Africana is widespread throughout Africa and Asia, the first reported case of toxicity was in Australian sorghum in 1996 (Ryley et al., C. Africana-infested sorghum has been demonstrated to be detrimental to steer performance in Australian feedlots that utilize this feedstuff (Blaney et al., Ergot alkaloids have been associated with endophyte-infected grasses (e.g., the While ergot alkaloid incidences are rare in humans resulting from increased regulation of grain processing (Flieger et al., If fungi that synthesize ergot alkaloids pre-date the human race, and knowledge of ergot properties has been recorded as far back as 1100 BC Schiff, , why havA multi-disciplinary approach will be needed to solve most ergot alkaloid related issues. This research topic, Recent Investigations of Ergot Alkaloids Incorporated into Plant and/or Animal Systems, epitomizes that reality through diverse scientific approaches addressing the core issue of ergot alkaloids in agriculture. Innovative research articles highlight the numerous effects that ergot alkaloids can have on livestock (Aiken and Flythe, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Chandelier cells  are a specialized GABAergic interneuron subtype that selectively innervates pyramidal neurons at the axon initial segment (AIS), the site of action potential generation. ChC connectivity allows for powerful yet precise modulation of large populations of pyramidal cells, suggesting ChCs have a critical role in brain functions. Dysfunctions in ChC connectivity are associated with brain disorders such as epilepsy and schizophrenia; however, whether this is causative, contributory or compensatory is not known. A likely stumbling block toward mechanistic discoveries and uncovering potential therapeutic targets is the apparent lack of rudimentary understanding of ChCs. For example, whether cortical ChCs are inhibitory or excitatory remains unresolved, and thus whether altered ChC activity results in altered inhibition or excitation is not clear. Recent studies have shed some light onto this excitation-inhibition controversy. In addition, new findings have identified preferential cell-type connectivities established by cortical ChCs, greatly expanding our understanding of the role of ChCs in the cortical microcircuit. Here we aim to bring more attention to ChC connectivity to better understand its role in neural circuits, address whether ChCs are inhibitory or excitatory in light of recent findings and discuss ChC dysfunctions in brain disorders. Discovered in the 1970s, ChCs quickly gained intrigue as a unique and potentially powerful subtype of GABAergic interneurons that selectively innervates pyramidal neurons at the axon initial segment (AIS), directly regulating the site of action potential generation , L3, L5a and L5b , ChC axons can vary in their complexity and localization in different cortical areas and layers, and depends on the type and age of the animal  mice (Kirmse et al., Whether ChCs are inhibitory or excitatory is not currently agreed upon. ChCs activate GABAd Kaila, . However\u2212 regulation at the postsynaptic AIS (Szabadics et al., \u2212 concentrations, Szabadics et al. used the gramicidin perforated patch technique (Szabadics et al., in vivo. Nevertheless, a possibility for ChC excitation is hypothesized to occur during \u201cdown\u201d states, when pyramidal neurons are hyperpolarized and sodium channels are deinactivated (Szabadics et al., ChCs in L2/3, on the other hand, have been shown to be capable of mediating excitatory activity in brain slices from animals well past the developmental period when GABA-mediated excitation is thought to occur (Szabadics et al., in vivo conditions indicated that L2/3 ChCs were predominately inhibitory (Woodruff et al.,  In vivo studies that clearly demonstrate whether ChCs are inhibitory or excitatory are lacking, but some results suggest that ChCs are not excitatory (Klausberger et al., Because the perforated patch technique may still alter GABAergic activity, concerns with this technique and the results obtained were raised (Glickfeld et al., in vivo data, suggest that ChCs are inhibitory, as originally assumed (Somogyi, ChC-mediated excitation is an enigmatic issue. This is largely due to the complications when recording GABAergic responses. Nevertheless, currently those experiments using the least invasive techniques, along with Somogyi,  and demoSomogyi, .A receptor \u03b12 subunit is increased in pyramidal neurons in schizophrenia (Volk et al., ChC dysfunctions are well associated with schizophrenia (Lewis et al., Schizophrenia is associated with significant changes in neural activity. These changes are shown with both structural and functional alterations and result in abnormal neural network oscillations and synchrony (Meyer-Lindenberg et al., in vivo recordings show that ChCs fire more robustly than other types of cortical neurons when overall cortical excitation increases (Zhu et al., ChC dysfunction is also implicated in epilepsy (DeFelipe, A significant impediment that prevents elucidating the link between ChC dysfunctions and brain disorders is the uncertainties in the role of ChCs in the cortical microcircuit, including whether ChCs are inhibitory or excitatory. Ideally, the ability to specifically target ChCs with the identification of specific markers will greatly aid in resolving the role of ChCs in brain functions. One such undertaking is the creation of the Nkx2.1CreERT2 mouse line that can label a portion of interneurons, the majority of which are ChCs (Taniguchi et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GGB and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
+{"text": "Autism spectrum disorder (ASD) is an umbrella term for a heterogeneous group of developmental disorders that present with persistent deficits in social communication/interaction and repetitive/restricted patterns of behavior, interests, or activities that cannot be better explained by intellectual disability or global developmental delay   could directly affect the enteric nervous system (ENS), a nervous tissue within the gut wall often called \u201cthe second brain\u201d due to its size, structure, complexity, and autonomic regulation of gut functions, such as bowel motility, secretion/absorption and local blood flow Furness, , 2012. FS-nitrosoglutathione (GSNO) , traditionally considered as only supportive cells of the ENS, are emerging as local GI regulators. They are strategically located at the interface between the neurons and other non-neuronal cells in the gut, such as enterocytes or immune cells, and participate in the regulation of gut motility, intestinal epithelial barrier, and inflammatory processes  in Rett Syndrome (Yasui et al., Recent study showed the role of EGCs' Cx43 hemichannels in the regulation of the GI motility (McClain et al., Concurrently, Cx43 on EGCs is taking part in the inflammatory process. Neuronal loss is one of the characteristics of intestinal inflammation and is driven by the activation of neuronal purinergic receptor (Gulbransen et al., 2+oscillations that can consequently regulate gene transcription (Dolmetsch et al., Animals with ablated Cx43 in EGCs also exhibited an increased fluid content in stools, indicating disabled water reabsorption/secretion (McClain et al., EGCs are also in proximity of capillaries within the gut wall (Fu et al., In summary, we presented a hypothetical link between the Cx43 of EGCs and GI related symptoms in patients with autism Figure . EGCs inThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Literature indicates that racism, sexism, homophobia and HIV-related stigma have adverse impacts on health, well-being, and quality of life among HIV-positive women of African descent (African/Black diaspora). However, limited evidence exists on the effectiveness of interventions aimed at reducing stigma tailored for these women. This study systematically reviewed randomized controlled trials (RCTs), non-randomized observational and quasi-experimental studies evaluating the effectiveness of interventions aimed at reducing stigma experienced by this population.The Cochrane methodology was used to develop a search strategy in consultation with a librarian scientist. Databases searched included the Cochrane Library, Ovid EMBASE, PsycInfo, and 10 others. Two reviewers independently assessed the studies for potential relevance and conducted the Cochrane grading of RCTs to assess risk of bias and the Newcastle\u2013Ottawa scale to assess the quality of non-randomized studies. Eligible papers were selected if they employed an intervention design with African/Black diasporic women living with HIV as the target population and had a primary outcome of stigma reduction.Of the five studies that met all of the eligibility criteria, four demonstrated the effectiveness of interventions in reducing HIV-related stigma. Only two of the five studies were designed specifically for HIV-positive African/Black diasporic women. Limitations included the absence of interventions addressing other forms of stigma and discrimination .Our findings suggest that there are limited interventions designed to address multiple forms of stigma, including gender and racial discrimination, experienced by HIV-positive African/Black diasporic women. Both in the global South and the global North, the HIV epidemic has disproportionately impacted people of African descent. Disproportionate rates of HIV in women of African descent have been reported in Western countries including Canada, the United States and the United Kingdom ,2. For tThe demographic profile in Canada signifies that a high proportion of HIV-positive women were born outside of Canada, particularly in Africa and the Caribbean . CurrentA preponderance of research has documented negative associations between singular forms of marginalization \u2013 HIV-related stigma, racism, sexism \u2013 and the health and well-being of people with HIV . For HIVThe term intersectional stigma was coined to describe the co-occurrence of stigma based on multiple identities of women living with HIV, including ethnoracial identity, gender and gender identity, national identity, sexual orientation and HIV serostatus . InterseAs recent HIV research recommends interventions that address stigma/discrimination at the micro, mesa and macro levels, there is limited evidence of interventions that address intersecting forms of marginalization ,43. Neveet al. [et al. [While evidence syntheses have been conducted evaluating the effectiveness of interventions designed to reduce HIV-related stigma ,54, theret al.  evaluate [et al.  examinedTo identify interventions designed for African/Black diasporic women with HIV and to examine their effectiveness at reducing stigma, we reviewed randomized controlled trials (RCTs), non-randomized quasi-experimental and observational studies that reported on the efficacy of stigma reducing interventions compared to treatment as usual in reducing the multiple forms of stigma and discrimination experienced by HIV-positive African/Black diasporic women. For the purposes of this review, we define African/Black diaspora as people of African ancestry who are living outside of the African continent  with a sFor our systematic review of stigma reducing interventions for African/Black diasporic women, we identified intervention research that targeted any level  or form  of stigma and discrimination experienced by this population. As applicable, we also evaluated the effectiveness of stigma reducing interventions at addressing well-being and self-efficacy among African/Black diasporic women living with HIV.This project was not prospectively registered. A protocol was developed during the planning process (Grant# CIHR No. 97106 U of T Fund No. 487453 sub-grant 11).This systematic review adheres to guidelines outlined by the Cochrane Collaboration . The PRIIn June 2013 (current end date of electronic search), we conducted a search of 13 electronic databases that covered national and international literature in medical/health sciences, psychology, and social sciences. The search strategy was applied to Ovid MEDLINE (1946\u2013current) and Ovid EMBASE (1980\u2013current), then adapted for AgeLine Database (1978 \u2013 current), ASSIA: Applied Social Sciences Index and Abstract database (1987 \u2013 current), CINAHL (1980 \u2013 current), Clinicaltrials.gov (1999 \u2013 current), the Cochrane Library, a collection of six databases including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) Database, and NHS Economic Evaluation Database (NHS EED) (1898 \u2013 current), Dissertation Abstract International (1637 \u2013 Current), PsycINFO (1806 \u2013 present), Social Services Abstracts database (1979 \u2013 current), Social Science Abstracts (1972 \u2013 current), Sociological Abstracts (1952 \u2013 current), Social Sciences Citation Index (1900 \u2013 current). Keywords searched included: (1) HIV/AIDS keywords ; (2) stigma/discrimination keywords  intervention search terms ). We also undertook a hand search of 19 journals (Supplementary Appendix) from 1995 to August 2013 to identify articles missed by our search, and conducted a citation search of the reference list of included studies. As only published manuscripts were included, authors were contacted by email to ascertain if a complete manuscript or publication was available. If any additional information or clarification were required, authors were also contacted.Two reviewers  divided and screened all titles from the literature search for obvious exclusions. The remaining abstracts were independently assessed by two reviewers , with disagreements resolved by a third reviewer (LAC). We included published intervention studies if: (1) study population included HIV-positive women of African ancestry ; (2) the intervention aimed to reduce stigma and discrimination; (3) the study provided quantitative outcome data for: (a) stigma and discrimination , and (b) well-being , or (4) self-efficacy . Only RCTs and observational study designs were included.Three reviewers  designed and independently piloted a data extraction form. The following items were extracted: (1) study information ; (2) participant information ; (3) intervention information ; (4) outcomes and measures used. Two investigators  independently extracted data from relevant research. The definition of stigma reduction intervention is any intervention for which the reduction of stigma or discrimination was considered an outcome of the intervention. Our definition of stigma included HIV-related stigma as well as other forms of stigmatization or discrimination identified . The datasets were compared for each study, and a third party settled disagreements (LAC). Our review did not have any jurisdiction restrictions; though we were only able to extract data from papers published in English.The risk of bias of each eligible study was assessed by two investigators  using the eight-item Newcastle\u2013Ottawa Scale for non-random and observational studies  and the An a priori decision was made to conduct a meta-analysis; however, due to the heterogeneity of the study findings, including type and measurement of health outcomes, it prevented us from pooling the results using meta-analysis. Instead, we reported on study findings and conducted a descriptive analysis based on reported outcomes.Our study selection process is described in Supplementary Fig. 2 using an adapted version of the PRISMA flow diagram . After rThe details of the study characteristics of the included studies are reported in Supplementary Table 1. Of the five studies that met criteria for inclusion, three reported findings from RCTs ,62,64, aThe review sample totalled 238 participants of which 188 participants (79%) identified as African\u2013American women with HIV. Sample size ranged from 11 to 109 per study. Although all of the included studies focused on HIV-positive populations and considered cultural differences such as gender and ethnoracial identity in their analysis, only two of the five studies designed their interventions specifically for African\u2013American women ,65. The et al. [et al. [et al. [et al. [All five of the included studies reported on the effectiveness of interventions where stigma reduction was an expected outcome. Abel et al.  and Abelet al.  evaluate [et al.  evaluate [et al.  evaluate [et al.  evaluateet al. [et al. [The results of the risk of bias assessments are reported in Supplementary Table 2 for the included RCTs and Supplementary Table 3 for observational studies. Overall, the three RCTs had a moderate risk of bias. Of the two prospective cohort studies Hosek et al.  had a lo [et al.  had an uWe conducted a descriptive synthesis of findings based on stigma reduction outcomes and reported on the effectiveness of the interventions for reducing stigma and discrimination. We also summarized findings on physical and mental well-being as reported in each study. The resulting data from each included study are presented in Supplementary Table 4.All five included studies reported stigma outcomes. Four studies measured perceived HIV stigma  \u201364. One et al.\u2019s [et al. [Findings from four of the included studies indicated that the specified interventions demonstrated promise in reducing stigma. Both of the studies with an exclusively African/Black diasporic female sample reported reductions in stigma post-intervention. Rao et al.\u2019s  evaluati [et al.  reportedet al. [The two studies with a mixed ethnoracial female sample also demonstrated reductions in stigma post-intervention. Findings from Abel et al.  and Abelet al.  indicateet al. , and 12 et al. .et al. [The one study with a gender and ethnoracially diverse sample demonstrated mixed results in regards to stigma reduction. The Project ACCEPT intervention evaluated by Hosek et al.  reportedet al. .et al. [et al. [et al. [Findings on physical and mental well-being post-intervention were mixed. Abel et al.  reported [et al.  reported [et al.  noted siWe performed a comprehensive systematic review of the literature to evaluate the efficacy of current HIV-interventions in reducing stigma and discrimination experienced by African/Black diasporic women with HIV. We identified five studies that met our inclusion criteria, of which four studies demonstrated that their interventions had a positive effect on reducing HIV-related stigma in women living with HIV. These findings indicate that stigma reducing interventions can be of benefit for African/Black diasporic women with HIV. These findings could be useful for practitioners wishing to identify interventions that are effective in addressing HIV-related stigma in this population and the subsequent health benefits of such interventions.et al. [et al. [Of these studies, two exclusively sampled African/Black diasporic women with HIV and developed interventions that were culturally appropriate for this population. Rao et al.  adapted  [et al.  develope [et al. ; oral an [et al. ), peer fet al. [et al. [The included studies identified interventions that showed promise in reducing the effects of stigma on African/Black diasporic women with HIV; however, only two studies were designed specifically for this population. While Abel et al.  and Abelet al.  conducteet al. . Althoug [et al.  revealedet al.\u2019s [et al. [et al. [Furthermore, only one of these interventions was specifically designed to address both internal and perceived experiences of stigma. Rao et al.\u2019s  interven [et al. , the aim [et al.  addresse [et al. ,61. Over [et al.  integratThis review also shows limited evidence of the long-term effectiveness of stigma reducing interventions for African/Black diasporic women with HIV. The follow-up duration ranged from four weeks to six months, with only two studies having a follow-up period of three months or longer ,64. WhilAdditionally, while all of these studies reported HIV-related stigma outcomes using similar measures, there is a lack of data demonstrating the effectiveness of stigma reducing interventions addressing other forms of stigma experienced by HIV-positive African/Black diasporic women including sexism and racism. These interventions were also focused on addressing stigma at the interpersonal or intrapersonal level; there is little evidence of interventions addressing stigma and discrimination at community, institutional or structural levels, which has been identified in the literature as essential to combating stigma . MoreoveSeveral limitations in our review merit discussion. First, although our study did not exclude based on language, in our analysis we were unable to include studies published in languages other than English. Our search strategy did not include an electronic database search for grey literature, though we did conduct manual searches that could capture non-peer reviewed or unpublished literature. Our study definitions of stigma/discrimination and health derived from Westernized concepts and may not have captured non-Westernized conceptualizations of these terms. Lastly, we were unable to pool the data for meta-analysis because of the significant heterogeneity in many study features.In summary, our systematic review contributes to the emerging body of literature on stigma reducing interventions for people with HIV ,53,54. NClick here for additional data file.Click here for additional data file."}
+{"text": "Increasing distress about climate change consequences is noticeable in daily press releases and science news articles. In the last 5 years more than 3 hundred thousand scientific articles included the terms \u201cclimate change,\u201d \u201cdrought stress\u201d and/or \u201cclimate adaptation\u201d as a main topic. This build-up of energy devoted to understand climate change significance parallels the fact that any living organism must be able to cope with environmental changes to survive. Plant's sessile condition reinforces even more the need of an efficient adaptive response to counteract a suboptimal environment. Such adaptive strategies synchronize growth and development adjustments, as well as cellular and molecular activities, aimed at an efficient use of scarce resources, e.g., water.Arabidopsis HD-Zip I transcription factors, named ATHB7 and ATHB12, down-regulating a number of genes encoding ABA-receptor proteins, in addition to up-regulating protein phosphatases type 2C. Both ABA receptors and protein phosphatases 2C are well established components of the ABA signaling pathway  accumulation upon drought perception serves as an initial signal for long-term acclimation reactions, which eventually involve the differential expression of genes leading to changes in transcript and protein patterns (Vald\u00e9s et al., As previously mentioned, developmental changes and morphological alterations are part of the plant adaptation and, besides controlling stress responses, HD-Zip I genes have additional roles in controlling development (Ariel et al., in silico interactions between genes early regulated in the shade-avoidance response and, ATHB7 and ATHB12 that highlight their potential participation also in light signaling pathways (Ciolfi et al., Besides water availability, the plant environmental context is defined by additional, simultaneous external factors, e.g., light and temperature, and should these factors influence the transcript levels of HD-Zip proteins the dynamic behavior of the ABA-driven stress response becomes automatically dependent on such factors. This implies that cross-communication between different signaling systems should be mediated by the same HD-Zip proteins. In this sense, available genomic and proteomic data have predicted The intricate network established within this superfamily of transcription factors suggest that the plant-specific and evolutionary highly conserved HD-Zip proteins are crucial players modulating stress responses and may be linking patterning and adaptation by acting to adjust developmental programs to specific environmental situations.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The exponential growth in generation of large amounts of genomic data from biological samples has driven the emerging field of systems medicine. This field is promising because it improves our understanding of disease processes at the systems level. However, the field is still in its young stage. There exists a great need for novel computational methods and approaches to effectively utilize and integrate various -omics data.Systems medicine has been growing rapidly in part due to the emerging technologies to gather high-volume measurements from biological samples. One of the first such technologies, the mRNA microarray, is being replaced by next generation sequencing (NGS), which provides a much higher resolution  of genetic information . Array and NGS-based methods to characterize genetic variation , DNA methylation changes, microRNAs (miRNAs) differential expression, and other types of biological information have dramatically expanded the generation of biological data. Other sources of data from mass spectrometry-based proteomics and metabolomics to high-throughput determination of protein-protein interactions and regulatory relationships provide further information for a systems-level understanding of disease. Finally, collection of clinical data and electronic medical records (EMRs) has made modern biomedical research possible on the full scale of data integration, that is, an integration scenario of using genomic, transcriptomic, proteomic, metabolomic, and phenotypic data.The rationale of discovery-based high-throughput investigation of disease is that there are molecular signatures  that can be identified for better diagnosis, prognosis, and/or treatment of disease. However, challenges arise in the analysis of high-throughput data because of the large number of possible variables raising the very real potential for false-positive predictions and overfitting of data, as well as many other potential problems . To ameliorate these problems, computational approaches have been developed that utilize existing knowledge, such as overlaying high-throughput observations on regulatory or protein-protein interaction networks or canonical biological pathways.For this special issue we solicited manuscripts in several different subject areas including data integration from multiple high-throughput sources, NGS data analysis and applications, personalized medicine and translational bioinformatics, modeling of pathways and networks, and data mining and pattern recognition in biomedical applications. We briefly describe the accepted papers in this special issue in the remainder of this editorial.MultiRankSeq: multi-perspective approach for RNAseq differential expression analysis and quality control\u201d by Y. Guo et al. and \u201cQPLOT: a quality assessment tool for next generation sequencing data\u201d by B. Li et al., describe algorithms for analysis of NGS data. Y. Guo et al. introduce a novel tool, namely, MultiRankSeq, which combines the output of three independent programs to determine differential expression from RNAseq data to provide a single improved output. QPLOT is a tool for assessing the quality of NGS runs by providing both summary quality metrics and graphical representations of these metrics. In another paper, entitled \u201cComparative study of exome copy number variation estimation tools using array comparative genomic hybridization as control,\u201d Y. Guo et al. systematically compare four different tools for detecting copy number variations (CNVs) from whole exome sequencing (WES) against a standard array-based method for CNV evaluation.Two papers, \u201cComputational analysis of transcriptional circuitries in human embryonic stem cells reveals multiple and independent networks,\u201d X. Wang and C. Guda assess the role of core transcription factors in the pluripotency of embryonic stem (ES) cells. Their computational analyses identified several additional transcriptional regulatory networks that might be involved in this complex regulatory process, providing interesting hypotheses about mechanisms of fate determination in ES cells. The paper \u201cNetwork-assisted prediction of potential drugs for addiction\u201d by J. Sun et al. describes computational analyses of drug-target networks for addictive and nonaddictive drugs. The authors analyzed the topology of these networks and found that drugs with similar effects could cluster together and identified a set of nonaddictive drugs that might have therapeutic benefits for treatment of addiction. This paper was called out in the recent \u201cTranslational Bioinformatics Year-in-Review\u201d in 2014 Joint Summits on Translational Science (http://www.amia.org/jointsummits2014). In \u201cDeGNServer: deciphering genome-scale gene networks through high performance reverse engineering analysis,\u201d J. Li et al. describe their webserver to infer transcriptional regulatory networks from large-scale datasets. The server makes use of a computer cluster to run a number of network inference algorithms and return the results to the user very quickly, thus facilitating genome-scale network reconstruction.In \u201cDevelopment of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking\u201d and \u201cNovel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations,\u201d deal with molecular docking simulations to determine small-molecule inhibitors targeting Alzheimer's disease. In the first paper, M. Goyal et al. used a fragment-based quantitative structure activity relationship (QSAR) analysis to identify lead compounds that might inhibit interaction of proteins that drive Alzheimer's disease pathogenesis. In the second paper, the authors describe large-scale docking simulations to screen for inhibitors of the conformational change of apolipoprotein E4 (ApoE4) that is thought to drive Alzheimer's pathogenesis. They further show the value of molecular dynamics simulations to screen candidates to eliminate molecules that do not have stable binding properties with targets. In \u201cHGF accelerates wound healing by promoting the dedifferentiation of epidermal cells through \u03b21-integrin/ILK pathway,\u201d J.-F. Li et al. experimentally investigate the contribution of hepatocyte growth factor (HGF) to wound healing. They showed that treatment of diabetic mice promoted proliferation and migration of epithelial cells and that this effect could be blocked by silencing the \u03b21-integrin signaling pathway.Two papers from M. Goyal et al., \u201cIntegrative analysis of miRNA-mRNA and miRNA-miRNA interactions,\u201d the authors first generated RNAseq data for normal and tumor cell lines and then identified aberrantly expressed mRNAs and miRNAs. Groups of similarly expressed miRNAs and mRNAs were analyzed to highlight examples of flexible and selective regulatory networks underlying these interactions. In \u201cA diverse stochastic search algorithm for combination therapeutics,\u201d M. U. Caglar and R. Pal show how the use of a stochastic search algorithm can be useful in identification of optimal combinations of drugs for therapy, the so-called drug cocktails. Their novel method greatly reduces the number of experimental steps needed to assess the optimal combination of drugs for a particular therapy. In \u201cEvaluating word representation features in biomedical named entity recognition tasks\u201d by B. Tang et al., the authors present a comparative analysis of three different methods for word representation in recognition of named entities from biomedical literature. Their findings indicate that a combination of the complementary approaches can improve results on benchmark recognition tasks.In the paper \u201cMultiple biomarker panels for early detection of breast cancer in peripheral blood,\u201d the authors describe the use of machine-learning approaches to identify a five-gene panel that can identify breast cancer from peripheral blood samples. In the paper by Jiang et al., \u201cNew aQTL SNPs for the CYP2D6 identified by a novel mediation analysis of genome-wide SNP arrays, gene expression arrays, and CYP2D6 activity,\u201d the authors develop a novel approach for the detection of transexpression quantitative trait loci (eQTLs) from genome-wide association studies by considering indirect effects introduced by a mediator gene. They apply their method to analyze indirect regulatory effects on the important liver enzyme, CYP2D6. Finally, in \u201cExpression sensitivity analysis of human disease related genes,\u201d L.-X. Ma et al. examine the expression of genes implicated in a range of diseases. They report that genes that are robustly expressed under different perturbations are more likely to be associated with lethal diseases, whereas less robustly expressed genes are associated with nonlethal diseases.In the paper by F. Zhang et al., \u201c"}
+{"text": "Although 3D cell cultures better mimic in vivo microenvironments of human tissues and provide an in-depth understanding of the morphological and functional features of tissues, they are also limited by having relatively low throughput and thus are not amenable to high-throughput screening (HTS). One attempt of making 3D cell culture amenable for HTS is to utilize miniaturized cell culture platforms. This review aims to highlight miniaturized 3D cell culture platforms compatible with current HCI technology.High content imaging (HCI) is a multiplexed cell staining assay developed for better understanding of complex biological functions and mechanisms of drug action, and it has become an important tool for toxicity and efficacy screening of drug candidates. Conventional HCI assays have been carried out on two-dimensional (2D) cell monolayer cultures, which in turn limit predictability of drug toxicity/efficacy  To address this issue, high content imaging (HCI) or high content screening (HCS) technology\u2014which refers to a high-throughput, automated microscope-based assay that provides information on multiple properties or features of individual cells simultaneously with several fluorescent dyes\u2014has been adapted to a more systematic and accurate evaluation of drug candidates ,9998,99]G2 cells . Similarll lines . Apart fll lines . Cheong  [et al. . Additio [et al. ,105,106  [et al. . One of  [et al. ,109. High-throughput HCI on miniaturized 3D cell culture has a potential to decipher toxicodynamic and toxicokinetic traits of drugs and helps us to understand complicated toxicology pathways and related adverse responses in early stages of drug discovery. Simplifying steps for miniaturized 3D cell culture and integrating the cell culture platforms with automation systems for liquid handling and image acquisition/analysis are critical to implement 3D HCI. Microwell and cellular microarray platforms are more compatible with automated liquid dispensing robots such as microarray spotters than microfluidic devices, resulting in increased throughput of HCI, whereas microfluidic devices are inherently low throughput in HCI due to the sample loading processes and large pumping units . In addi"}
+{"text": "Studies over the last decade have provided insights on the molecular and structural determinants of Gag-membrane binding. The human immunodeficiency virus type-1 (HIV-1) Gag polyprotein adopts a compact \u201cfolded over\u201d conformation and exists in the monomeric or low-order oligomeric states prior to targeting to the PM  in the pericentriolar region of the infected cell and therefore. Structural details of M-PMV MA binding to single phospholipids are discussed. Dick et al. describe the principles that govern Gag interactions with membranes, focusing on RSV and HIV-1 Gag , a channel mediating release of Ca2+ from ER stores, as a cellular factor differentially associated with HIV-1 Gag that might facilitate ESCRT function in virus budding. In a research article, Ehrlich et al. show that Gag modulates ER store gating and refilling  and how various membrane components facilitate these events. It is well established that assembly of most of retroviral Gag proteins occurs on the plasma membrane (PM) (Ono et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Streptomyces, which includes several hundred species, many of which produce biotechnologically useful secondary metabolites. The last 2 years have seen numerous publications describing Streptomyces genome sequences . Our blastn searches (using these two cluster sequences as queries) failed to detect a complete streptomycin gene cluster in the S. gancidicus genome, but there were some regions of sequence similarity on a 111 kb contig (GenBank: AOHP01000057). An antiSMASH 2.0 search failed to find any aminoglycoside biosynthetic cluster in this genome. We are not aware of any experimental evidence that this strain produces the aminoglycoside streptomycin and conclude that these seven genes highlighted by the authors  and relatively high error rates associated with these platforms can lead to rather fragmented and/or incomplete genome assemblies. The situation is not helped by the biased sequence composition (approximately 70% G + C) of Streptomyces DNA. Furthermore, non-ribosomal peptide synthases (NRPS) and polyketide synthetases (PK) are long, modular proteins made up of many repeated domain units. This means that the genes encoding these key enzymes can be particularly difficult to assemble accurately from short sequence reads. To overcome this issue, the authors of the Mg1 genome project  and which is notable for its production of the antibiotic moenomycin A , which has an 11.14 Mbp genome. Rather, strains SPC6 and DSM 40736 are closely related and fall within a clade with several other strains for which draft genomes are available and with Streptomyces venezuelae for which a complete finished genome sequence is available (Pullan et al., S. venezuelae reference sequence. Evidently, genome reduction has also occurred in S. albus strain J1074 (Zaburannyi et al., S. somaliensis (Kirby et al., Among bacteria, streptomycetes have some of the largest genomes, typically within the range of 8.7 Mbp to 11.9 Mbp (Zhou Streptomyces and related species [e.g. (Liu et al., Streptomyces sp. strain OH-4156, revealing an unusual class of post-translationally modified ribosomally synthesized peptides (Claesen and Bibb, et al., Streptomyces genome comes from strain PRh5, an endophyte of wild rice that produces nigericin, an antibiotic effective against mycobacteria (Yang et al., The availability of cheap sequencing has led to the generation of numerous genome sequences for"}
+{"text": "Escherichia coli is a heterogeneous species that can be part of the normal flora of humans but also include strains of medical importance. Among pathogenic members, Shiga-toxin producing E. coli (STEC) are some of the more prominent pathogenic E. coli within the public sphere. STEC disease outbreaks are typically associated with contaminated beef, contaminated drinking water, and contaminated fresh produce. These water- and food-borne pathogens usually colonize cattle asymptomatically; cows will shed STEC in their feces and the subsequent fecal contamination of the environment and processing plants is a major concern for food and public safety. This is especially important because STEC can survive for prolonged periods of time outside its host in environments such as water, produce, and farm soil. Biofilms are hypothesized to be important for survival in the environment especially on produce, in rivers, and in processing plants. Several factors involved in biofilm formation such as curli, cellulose, poly-N-acetyl glucosamine, and colanic acid are involved in plant colonization and adherence to different surfaces often found in meat processing plants. In food processing plants, contamination of beef carcasses occurs at different stages of processing and this is often caused by the formation of STEC biofilms on the surface of several pieces of equipment associated with slaughtering and processing. Biofilms protect bacteria against several challenges, including biocides used in industrial processes. STEC biofilms are less sensitive than planktonic cells to several chemical sanitizers such as quaternary ammonium compounds, peroxyacetic acid, and chlorine compounds. Increased resistance to sanitizers by STEC growing in a biofilm is likely to be a source of contamination in the processing plant. This review focuses on the role of biofilm formation by STEC as a means of persistence outside their animal host and factors associated with biofilm formation. Escherichia coli is a diverse species of bacterium that includes members of the normal commensal flora of humans and animals but also pathogenic strains of veterinary and medical importance. Pathogenic members are usually classified in two major groups: intestinal E. coli (InPEC) and extraintestinal E. coli (ExPEC). The latter group is typically responsible for urinary tract infections [uropathogenic E. coli (UPEC)], neonatal sepsis, and meningitis in humans and various infectious diseases in animals including mastitis  associated with Crohn's disease, diffusely adherent E. coli (DAEC), enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), Shiga-toxin producing E. coli (STEC) that includes enterohemorrhagic E. coli (EHEC), and enteroinvasive E. coli (including Shigella) (EIEC)  strain will not be covered in this review because it does not fit within the classic STEC pathotype.The predominant STEC serotype associated with outbreaks is O157:H7. Since it was one of the first serotypes identified as causing hemolytic uremic syndrome (HUS) and the most severe illness, EHEC O157:H7 is the most commonly reported STEC serotype in the media , but in complex communities called biofilms. Biofilms are aggregates of microorganisms  enclosed in a self-produced extracellular polymeric matrix that are attached to a biotic or abiotic surface , several of which encode fimbrial adhesins  for the matrix architecture  among 51 STEC strains found that the presence of autotransporter genes within the genome was variable among STEC serotypes , colanic acid, and/or cellulose. The genes encoding proteins that are involved in the synthesis of these polysaccharides are present in the genomes of STEC strains EDL933 and Sakai  and capsules, which are surface structures, have been implicated in biofilm formation by E. coli group 4 capsule, which is composed of the same sugar repeats as the LPS O-antigen and acetamido sugars in their repeat-unit structures  and the export machinery (CsgE-G) , the signal molecule for AI-1, secreted by others bacterial species. In Sharma et al.  systems  in EPEC and aggregative adherence fimbriae (AAFs) in EAEC, results in the detachment of bacteria from the biofilm and surface  are also significantly up-regulated when E. coli O157:H7 interacts with lettuce roots , expel vesicles containing viable E. coli O157:H7, whereas Colpoda steinii and Acanthamoeba palestinensis (flagellates) do not . The persistence of STEC in the presence of disinfectants gives rise to the probability that STEC survive and grow within a biofilm in processing plants  and 4\u00b0C (production hours temperature) (Dourou et al., E. coli O157:H7 attachment increased at 4\u00b0C over time in the presence of a fat-lean tissue homogenate (Dourou et al., E. coli O157:H7 EDL933 is able to adhere and produce a dense biofilm on surfaces that are not favorable for its attachment when collagen I is present, which is a muscle fibrous extracellular matrix protein (Chagnot et al., E. coli O157:H7 is also able to form biofilms on stainless steel when grown in spinach leaf lysates (Carter et al., E. coli O157:H7 biofilms produce large amounts of AI-2 when cultured in pork, beef or spinach broth (Silagyi et al., In the processing plant environment, temperatures are normally controlled and maintained between 4 and 15\u00b0C. Many studies have shown that STEC are able to grow in a biofilm within this temperature range (Dourou et al., E. coli O157:H7 biofilms were more resistant to sanitizers than at lower RH (Bae et al., E. coli O157:H7 that were able to regrow as a biofilm on polyurethane (Marouani-Gadri et al., Fouladkhah et al. showed that the use of quaternary ammonium compound-based and peroxyacetic-based chemical sanitizers on biofilms that had matured for 1 week were more effective at 4\u00b0C than 25\u00b0C. However, these commercial sanitizers used at concentrations recommended to kill planktonic STEC were not able to kill or remove STEC biofilms from stainless steel surfaces (Fouladkhah et al., Comamonas testosterone, Acinetobacter calcoaceticus, Burkholderia caryphylli, and Ralstonia insidiosa, can initiate biofilm formation and may allow E. coli O157:H7 to integrate within a pre-formed biofilm, resulting in a mixed biofilm (Marouani-Gadri et al., C. testosteroni can enhance the ability of E. coli O157:H7 to form biofilms (Marouani-Gadri et al., C. testosteroni within the biofilm did, however, decrease the number of colony forming units of E. coli O157:H7 following chemical treatment when compared to chemical treatment of a single species E. coli O157:H7 biofilm (Marouani-Gadri et al., Interestingly, non-pathogenic bacteria isolated from processing plants, such as E. coli O157:H7 (Ryu et al., E. coli O157:H7 from sanitizer treatments (Ryu et al., E. coli O157:H7 could colonize a mature biofilm formed by EPS-producing bacteria (Castonguay et al., The ability to secrete EPS is related to biofilm formation on stainless steel surfaces, but it was shown that overproduction of the EPS inhibits the initial attachment of E. coli in general, a slow-growing and dormant subpopulations are highly tolerant to antibacterial treatments (Lewis, In addition to the protection offered by the biofilm matrix against sanitizers, it is well established that for s Lewis, . Cells fs Lewis, . The emes Lewis, . This noIt is known that STEC biofilms are more resistant to sanitizers than their planktonic counterparts (Wang et al., E. coli O157:H7 inside a biofilm. However, the biofilm matrix remains attached to the surface (Perez-Conesa et al., E. coli O157:H7 biofilms from processing plants. Others strategies such as bacteriophage treatments of E. coli O157:H7 biofilms have also been investigated. The KH1 bacteriophage reduces the population of O157:H7 cells attached to stainless steel, but not those incased within a biofilm matrix (Sharma et al., E. coli O157:H7 within the biofilm and remove the biofilm matrix from the contaminated surface. For example, a combination of steam and lactic acid were able to kill E. coli O157:H7 and remove the biofilm matrix from stainless steel surfaces (Ban et al., Many essential oils have been shown to have good antibiofilm activity against food-borne pathogens (Giaouris et al., Contamination of the environment and processing plants with cow feces containing STEC is a major concern for food and public safety, especially since STEC can survive for prolonged periods of time outside its host. Biofilm formation appears to contribute significantly to STEC survival on produce, in rivers, and in processing plants. Several factors involved in biofilm formation such as curli, cellulose, PGA, and colanic acid are involved in plant colonization and attachment to different surfaces often found in meat processing plants. However, the factors involved in STEC survival within biofilms in rivers remain unknown. Furthermore, STEC biofilm formation on farms, in manure, and in soil has not been thoroughly explored despite the presence and persistence of STEC in these environments. The Stx toxin, which is a key factor in human host pathology, also appears to be an important factor for STEC survival against protozoan predation. In the food industry, resistance to sanitizers improves the ability of STEC to persist in the processing plant. Despite the development of new strategies to eradicate biofilms formed by food-borne pathogens, no effective solutions to remove STEC biofilms from surfaces have been identified. Therefore, future research should focus on the identification of factors promoting STEC survival, especially non-O157 STEC, and the persistence of STEC in environmental biofilms on the farm.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "N = 106)  , a recently developed therapy for resistant hypertension, is generally regarded as a safe procedure  renal artery stenosis causes recurrent hypertension in denervated patients (Kaltenbach et al., Long-term randomized trials are needed. Two major randomized trials on RDN, i.e., the Symplicity HTN-2 and HTN-3 trials (Esler et al., Imaging methods monitoring renal artery stenosis need to be standardized. Symplicity HTN trials did not standardize renal artery imaging methods during follow ups. Ultrasonography, magnetic resonance angiography, and computerized tomographic angiography were used (Krum et al., It is likely that improved catheters for RDN using lower power radiofrequency over a shorter time will reduce the local tissue injury at the ablation site compared with that caused by the first generation RDN systems (Versaci et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We appreciate Lioy et al.\u2019s interest in our recent article  documentn-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) is encouraging, but the rising trend in other phthalates, such as diisobutyl phthalate (DiBP) and diisononyl phthalate (DiNP), is worrisome. Lioy et al. note that DiNP is less potent as an antiandrogen than the other phthalates. However, its increasing presence in the U.S. general population warrants public health concern: The U.S. Environmental Protection Agency (EPA) has expressed concern about DiNP\u2019s use [Phthalates Action Plan  and other large environmental health studies to evaluate the presence of potential \u201csubstitute\u201d chemicals not only of phthalates but also of other environmental chemicals to provide the best human exposure information. In fact, for the most recent NHANES survey (2011\u20132012), scientists at the Centers for Disease Control and Prevention are beginning to release population-level data for the urinary metabolite of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), a nonphthalate plasticizer that is used as a replacement for some of the high-molecular-weight phthalates . Indeed,"}
+{"text": "Growth factors such as transforming growth factor-\u03b2 (TGF-\u03b2), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) have been associated with the tendon healing process  as a novel method for treating tendon and ligament injuries is also discussed.Human tendon healing process is classified into five phases as follows: immediate post injury phase, inflammatory phase, proliferation phase, reparative phase, and remodeling phase  consist of MSCs and HSCs, which can further differentiate into various cell types that secrete growth factors  is impeded by the lack of soft tissue around it. However, partially ruptured ACL can regenerate with growth factor administration and after cell transplantation. Intra-articular transplantation therapies using MSCs have been used for treating torn ACLs (Agung et al., Recently, we showed that partially transected rodent ACL can be repaired by injection of BMCs or cultured MSCs into the articular cavity at 1 week after transection (Oe et al., Stem cell therapies use several stem cell sources such as human embryonic stem cells, MSCs, BMCs, and bone marrow mononucleated cells have been reported (Chen et al., Few clinical trials have been performed using stem cells transplantations for treating tendon and ligament injuries in humans. Ahmad et al have reviewed 5 clinical studies that used stem cell therapy for treating tendon injuries and concluded that stem cells can have positive effect on tendon healing (Ahmad et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Our earlier studies showed that lactational exposure to lead (Pb) caused irreversible neurochemical alterations in rats. The present study was carried out to examine whether gestational exposure to Pb can cause long-term changes in the brain cholinergic system and behavior of rats. The protective effect of calcium (Ca) supplementation against Pb toxicity was also examined. Pregnant rats were exposed to 0.2% Pb (Pb acetate in drinking water) from gestational day (GD) 6 to GD 21. The results showed decrease in body weight gain (GD 6\u201321) of dams, whereas no changes were observed in offspring body weight at different postnatal days following Pb exposure. Male offspring treated with Pb showed marginal alterations in developmental landmarks such as unfolding of pinnae, lower and upper incisor eruption, fur development, eye slit formation and eye opening on postnatal day (PND) 1, whereas significant alterations were found in the righting reflex (PNDs 4\u20137), slant board behavior (PNDs 8\u201310) and forelimb hang performance (PNDs 12\u201316). Biochemical analysis showed decrease in synaptosomal acetylcholinesterase (AChE) activity and an increase in acetylcholine (ACh) levels in the cortex, cerebellum and hippocampus on PND 14, PND 21, PND 28 and in the four-month age group of rats following Pb exposure. Significant deficits were also observed in total locomotor activity, exploratory behavior and open field behavior in selected age groups of Pb-exposed rats. These alterations were found to be maximal on PND 28, corresponding with the greater blood lead levels observed on PND 28. Addition of 0.02% Ca to Pb reversed the Pb-induced impairments in the cholinergic system as well as in behavioral parameters of rats. In conclusion, these data suggest that gestational exposure to Pb is able to induce long-term changes in neurological functions of offspring. Maternal Ca administration reversed these neurological effects of Pb later in life, suggesting a protective effect of calcium in Pb-exposed animals. Developmental exposure to Pb has become an important public health concern because of the possible toxic impact on sensitive development and programing of organ functions  is an essential mineral for the newborn infant and alteration in Ca signaling may have life-long consequences in brain functions (Bass Lead acetate (99.99% purity) was purchased from Sigma Chemicals  and all other chemicals from Merck, India.et al.,et al.,et al.,et al.,Female and male albino rats (Wistar) were acclimatized for one week before mating. Two females and one male were placed overnight in a cage and the presence of a vaginal sperm plug was recorded. Pregnancies determined by the presence of sperm in the vaginal smear were considered gestational day (GD) 1. On GD 6, the dams were randomly assigned to three experimental groups  exposed rats and Group III \u2013 animals exposed to 0.02% calcium supplement together with Pb. The animals were housed individually. Pregnant animals were exposed to low level Pb (0.2%) by intake of Pb-acetate dissolved in deionized water from gestational day 6 (GD 6) until the birth of pups (GD 21) . Calciumet al.,et al.,Starting with PND 1, the number of pups  was counted and gender differences were recorded. The male pups were weighed and observed for developmental signs, such as fur development (the appearance of fur sufficient to cover skin), incisor teeth eruption (the first appearance of the upper and lower incisors), pinnae detachment (both ears completely unfolded from the head), eye slit formation, eye opening (both eyes fully open) and crown rump length  stretched between two wooden blocks was then permitted to grasp the string with its forepaws, where the point was released, so that it was suspended from the string by its forepaws. The latency to fall from the string (maximum 60 s) was measured and each pup was tested for a single trial on each of the five test days  at the designated time periods (PNDs) for a period of two hours in the morning (08.00\u201310.00AM). The activity was presented as counts/min.Open field behavior: The open field behavior was measured in a chamber measuring 90\u00d790\u00d790 cm. The floor of the arena was divided into 36 equal squares. The number of squares crossed with all paws (crossing), standing on the hind legs (rearing), standing on the hind legs and placing the forelimbs on the wall , placing the nose against the wall or floor (sniffing), and wiping, licking or combing of any part of the body (grooming) were recorded. The sum of all tasks in open field was considered the total behavior  containing three equally spaced holes (3 cm in diameter) in the floor. Each rat was placed in the center of the arena for 5 min., the time during which the number of head dips and head-dipping duration (in seconds) were recorded. A head dip was scored if both eyes disappeared into the hole.et al.,For the determination of Pb levels, 5.0 ml of whole blood was taken by heart puncture. After digestion with concentrated nitric acid using a microwave digestion system followed by addition of 30% hydrogen peroxide, the samples were brought to a constant volume. Blood Pb levels were determined with an atomic absorption spectrophotometer (AAS-Shimadzu-AA 6300) with graphite furnace (GFA-EX7i)  followed by Student-Newman-Keuls (SNK) post hoc test using statistical package for social sciences (SPSS 16) to compare the effects among various groups. The 0.05 level of probability was used as the criterion for significance. All the data in this study were analyzed using the dam or litter as the experimental unit. For some behavioral measures, two pups from each litter were tested, but the values were averaged and only one value from each litter was considered for statistical analysis. The variation within the litter was less than 5%.p<0.05), while the body weight of male offspring from Pb-exposed mothers showed no significant changes on PND 7, PND 14, PND 21, PND 28 and in 4-month-old rats compared to controls (p<0.01) was observed in the latency to turn in the righting reflex and slant board behavior of Pb-exposed offspring (p<0.01) recorded from PND 12 to PND 16  and levels of acetylcholine (ACh) were determined in the cortex, cerebellum and hippocampus on PND 14, PND 21, PND 28 and in the 4-month age groups of control and Pb exposed rats  and 7. Ap<0.001) increased the Pb levels  in all selected age groups of rats  levels at any age induce neuro-degeneration that leads to impairment of neurobehavioral functions (Schwartz et al.,  observed et al., also obset al.,et al., (et al.,et al.,et al.,et al.,et al.,et al.,et al.,Dietary Ca intake can support normal fetal growth and development during pregnancy in animals and humans (Han et al.,  have sugConsistent with the published work and results from our laboratory, it is clear that gestational exposure to Pb is sufficient to induce late life alterations in neurobehavioral functions in rats. These neurobehavioral changes continue even long after the Pb exposure was stopped. Although Ca supplement reversed the Pb-induced neurotoxicity, longterm protection by Ca is partial, suggesting that adequate calcium intake would be beneficial in treating Pb-induced toxicity during pregnancy in rats."}
+{"text": "Recent advances in modern molecular technology and next-generation sequencing platform have brought in enormous insights into evolution. Although challenges remain, evolutionary research now enters a new era and becomes a hybrid discipline encompassing the fields of molecular biology, genetics and genomics, metabolomics, neuroscience, structural and chemical biology, bioinformatics, proteomics, pharmacology, statistics, and computational biology. The common bond or theme that unifies the various fields is the need to reveal complex genotype-phenotype relationships and their mechanistic regulations, attempting to understand the diversifying functionality in life and ultimately find the underlying causes and effective means of treating disease.Articles in this special issue cover a broad range of topics related to the evolution of genomes, transcriptomes, proteomes, and interactomes in diverse organisms, including humans.Signal transduction networks are dynamic and constantly under environmental selection in evolution. This topic is covered in the long review article \u201cMulti-OMICs and Genome Editing Perspectives on Liver Cancer Signaling Networks\u201d by S. Lin et al. This review covers multiple advances in the multi-OMICs and genome editing technologies, now available for use in biomedical and cancer research, and provides new perspectives in targeted therapy and precision medicine. Proteome and interactome networks are also investigated in an accompanying research paper \u201cPositive Selection and Centrality in the Yeast and Fly Protein-Protein Interaction Networks.\u201d S. Chakraborty and D. Alvarez-Ponce study the selective pressures of yeast and fly proteome and show that long-term positive selection has preferentially targeted the periphery of the yeast interactome, while interestingly in flies genes under positive selection encode significantly more connected and central proteins.Transcriptional and functional regulation and conservation during evolution are touched upon in two other reviews in this special issue. In \u201cCircadian Control of Global Transcription,\u201d S. Li and L. Zhang discuss circadian rhythms through investigating expression of clock-controlled genes (CCGs). They summarize the circadian control of CCG transcription in five model organisms, including cyanobacterium, fungus, plant, fruit fly, and mouse, providing an overview to the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. In \u201cRoles of Hsp70s in Stress Responses of Microorganisms, Plants, and Animals,\u201d A. Yu et al. review the heat shock protein 70s family members, a class of molecular chaperones that are highly conserved and ubiquitous in organisms ranging from microorganisms to plants and humans. This review provides an overview of the specific roles of Hsp70s in response to stress, particularly abiotic stress, in diverse taxa. Mycobacterium tuberculosis and Lung Cancer: Implications into Host-Pathogen Interaction and Coevolution,\u201d Y. Tian et al. study the cross-link between pathogens and cancer. They examined the association between the Mycobacterium tuberculosis (MTB) and lung cancer and found that 62% of the lung cancer samples are MTB-L positive, suggesting a link between MTB infection and lung cancer development. In another paper \u201cLost Polarization of Aquaporin4 and Dystroglycan in the Core Lesion after Traumatic Brain Injury Suggests Functional Divergence in Evolution,\u201d H. Liu et al. study the roles of aquaporin4 and dystroglycan in brain edema formation after traumatic brain injury. They found that at an early stage of traumatic brain injury aquaporin4 and dystroglycan maintained the polarized distribution, which were subsequently lost from perivascular end-feet and induced cytotoxic brain edema. In addition, in the study entitled \u201cIdentification and Evolutionary Analysis of Potential Candidate Genes in a Human Eating Disorder,\u201d U. Sabbagh et al. set out to find genes linked with eating disorders and associated with both metabolic and neural systems . Through a text-based analysis, they identified a number of potential candidate genes including VGF. VGF human polymorphism studies contribute to eating disorders and obesity, suggesting a new approach to connect eGWAS and GWAS in NES patients.Evolutionary principles and adaptation lessons learned from research have been successfully applied to human disease studies, revealing important insights into potential targets for therapy. In the paper \u201cClinical End-Points Associated with flfl Triggers JNK-Dependent Cell Death in Drosophila,\u201d J. Huang and L. Xue study a gene, falafel (flfl), that encodes a fruit fly Drosophila homolog of human SMEK. They performed both gain-of-function and loss-of-function analysis in Drosophila and identified flfl as a negative regulator of JNK pathway-mediated cell death. In another study \u201cNeurotrophin, p75, and Trk Signaling Module in the Developing Nervous System of the Marine Annelid Platynereis dumerilii,\u201d A. Lauri et al. study the evolution of neurotrophic signaling in neuronal development, neural circuit formation, and neuronal plasticity using the worm Platynereis system. They discovered and validated nucleotide sequences encoding putative neurotrophic ligands and receptors in two annelids, suggesting roles of these molecules in nervous system and circuit development, as well as their involvement in shaping neural networks during protostome-deuterostome evolution.Model systems have been instrumental in elucidating signaling mechanisms underlying biological function, providing interesting cues in evolutionary research areas. In the article \u201cLoss ofThe great leap in evolutionary research would not be possible without the development of modern molecular technologies. CRISPR/Cas9 system is a powerful technology to perform genome editing in a variety of cell types. In the paper \u201cA CRISPR-Based Toolbox for Studying T Cell Signal Transduction,\u201d S. Chi et al. adapted CRISPR/Cas9-based tools to study human Jurkat cells. They showed that distinct Cas9 variants, including wild-type Cas9, dCas9-KRAB, and sunCas9 function as expected in different Jurkat cell lines.With the advent of next-generation sequencing platforms, a large number of genomewide sequencing data become available, which greatly facilitate the evolution research field to promote to a new height. In the paper \u201cComputational Analysis of the Binding Specificities of PH Domains,\u201d Z. Jiang et al. study Pleckstrin homology domain proteins with significant insights into binding specificity and abnormal regulation in disease. In addition, in another report \u201cSimFuse: A Novel Fusion Simulator for RNA Sequencing (RNA-Seq) Data,\u201d Y. Tan et al. developed the SimFuse pipeline to accelerate fusion discovery from RNAseq data. SimFuse utilizes real sequencing data as the fusions' background to closely approximate the distribution of reads from a real sequencing library and uses a reference genome as the template from which to simulate fusions' supporting reads, improving the performance metrics, rigor, and control.The future evolution researchers will need to be well versed in interdisciplinary fields and have the appropriate background to leverage the biological, clinical, and computational resources necessary to understand their data and track dynamic evolution. The communication among these specialty disciplines, acting in unison, will be critical as we strive to uncover answers underlying the complex and often puzzling molecular events in evolution.We hope that this special issue would shed light on major advances in the broad area of signal transduction with evolutionary insights and engender novel hypotheses and research innovations to investigate deeper mechanisms and further to engineer signaling circuits for personalized therapeutics in human disease."}
+{"text": "Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes.Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico-pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371\u2013373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down-regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371\u2013373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor  In addition to considering genomic and protein-coding transcriptomic changes, we will emphasize findings from expression profiling studies of short non-protein-coding RNAs, termed microRNAs, in GCTs. Our improving knowledge of the molecular mechanisms underlying the pathogenesis of GCTs is contributing to the identification of new biomarkers and therapeutic targets, and the development of clinico-biological algorithms for disease segmentation and risk stratification. Combined with the developing collaborations between international clinical trial groups, we can be cautiously optimistic that these approaches will, in the foreseeable future, improve the clinical management of the children, adolescents and young adults affected by this disease , regardless of patient age, tumour site and histological subtype Teilum, . Despiteet\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., 1996bet\u00a0al., et\u00a0al., Malignant GCTs rapidly became a highly curable disease, even when diagnosed at advanced clinical stages, with the advent of cisplatin-based chemotherapy in the 1970s  located at the common region of 12p gain (12p13.31), suggesting that they are likely to be important in tumorigenesis. However, other non-seminomatous tumours, for example YSTs, which also have 12p gain, do not over-express these genes, suggesting other mechanisms must be important.As the only consistent structural chromosomal abnormality in malignant GCTs of adult patients, 12p gain is implicated in invasive malignant GCT development. The observation that the pre-invasive testicular lesion intratubular germ cell neoplasia unclassified demonstrates a similar pattern of overall genomic changes to those seen in invasive TGCTs, except for 12p gain, supports this theory  and novel  cancer genes in TGCT pathogenesis. Gene expression patterns in malignant GCTs characteristic of embryonic stem cells (ESCs) were confirmed and a distinctive transcriptomic programme was identified for individual histological subtypes , TFAP2C and UTF] and paediatric YSTs were associated with genes such as AFP, those involved in differentiation , lipid metabolism  and proliferation pathways  are not only involved in normal PGC development, resulting in oogenesis and spermatogenesis, but are also implicated in GCT development  are associated with the development of bilateral GCTs  in seminomas, resulting in phosphorylation of KIT and PI3K and therefore constitutive activation of the PI3K pathway, even in the absence of KITLG . Although MAPK1 is globally expressed in adult GCTs, mutations of KRAS and BRAF are rare events, pointing to the involvement of KIT as an upstream protein in activation of RAS/RAF signalling  of target mRNAs, and whose expression profiles are dysregulated in cancer  reported data from 48 paediatric samples, including gonadal and extragonadal  malignant GCTs . Consistent with these observations, the miR-29 family is under-expressed in YSTs, when compared with seminomas  and human choriogonadotrophin (HCG) assist malignant GCT diagnosis, they have limitations in sensitivity and specificity  family of microRNAs, which regulate cell proliferation  is not a feature of malignant GCTs (Palmer et\u00a0al., LIN28 over-expression (Murray et\u00a0al., LIN28/let-7 axis represent promising targets for novel therapies in malignant GCTs. As well as depleting LIN28, an alternative strategy is direct replacement of let-7 family members (Murray et\u00a0al., et\u00a0al., In addition, low LIN28/let-7 axis in all malignant GCTs also suggests a pathway that may be a target for the development of novel therapeutic agents.Our increasing knowledge of the biology of malignant GCTs needs to be harnessed to improve outcomes for both adult and paediatric patients. In particular, genomic and protein-coding transcriptomic data confirm that malignant GCTs of childhood are biologically distinct from those of adulthood and provide evidence supporting the different management approaches employed in patients of different ages. In contrast, all malignant GCTs over-express the miR-371\u2013373 and miR-302/367 clusters regardless of patient age, histological subtype or anatomical tumour site. The detection of elevated serum levels of these microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment, highlights the universal diagnostic potential of this finding. In addition, the dysregulation of the Further studies are now required, integrating genomic changes using high-resolution methods with combined analysis of mRNA and microRNA expression profiles in malignant GCTs from both adult and paediatric patients with good and adverse clinical outcomes. These approaches are likely to identify regulatory pathways and networks associated with treatment sensitivity and resistance. In particular, such studies should aim to define further the clinical relevance of age-specific biological characteristics of malignant GCTs. These insights may assist the optimal management of affected patients and identify biological targets suitable for the development of novel therapeutic agents. The ultimate aim of this approach will be to improve clinical outcomes for this under-investigated patient group, both through improved survival of patients with poor-risk disease and reduced late-effects of treatment for those with low-risk disease."}
+{"text": "Diabetes is a progressive metabolic disorder that can ultimately lead to serious chronic vascular complications including renal failure, vision loss, and cardiac dysfunction , a novel class of non-coding RNAs of 22~24 nucleotides in length, act as post-transcriptional regulators of gene expression by binding to the 3\u2032-untranslated region (3\u2032-UTR) of target mRNA that induces mRNA degradation and/or translational repression (Lim et al., Cardiomyocyte hypertrophy, myocardial fibrosis, and cardiomyocyte apoptosis are important features of diabetic cardiomyopathy (Ruiz and Chakrabarti, in vitro, indicating that overexpression of miR-223 might be a compensatory response to restore glucose metabolism in diabetic heart (Lu et al., Hyperglycemia, oxidative stress and mitochondrial damage are involved in the etiology of diabetes-induced cardiac dysfunction and diabetic cardiomyopathy (Shantikumar et al., Accumulating evidence has indicated that circulating miRNAs can be used as sensitive biomarkers for certain diseases such as cardiovascular diseases and cancers Fabbri, . DespiteTaken together, desregulated miRNAs are potentially involved in the etiology and pathogenetic processes of diabetic cardiomyopathy. An in-depth understanding of their functional roles and molecular mechanisms in the development of diabetic cardiomyopathy will provide better prospects to identify sensitive clinical biomarkers and novel therapeutic targets for diabetic cardiomyopathy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Production of fuels and chemicals through a fermentation-based manufacturing process that uses renewable feedstock such as lignocellulosic biomass is a desirable alternative to petrochemicals. Although it is still in its infancy, synthetic biology offers great potential to overcome the challenges associated with lignocellulose conversion. In this review, we will summarize the identification and optimization of synthetic biological parts used to enhance the utilization of lignocellulose-derived sugars and to increase the biocatalyst tolerance for lignocellulose-derived fermentation inhibitors. We will also discuss the ongoing efforts and future applications of synthetic integrated biological systems used to improve lignocellulose conversion. One of the daunting challenges faced by the modern world is our unsustainable dependence on petroleum as the primary source for transportation fuels and many chemical products including solvents, fertilizers, pesticides, and plastics Service, . To fulfd-glucose linked by \u03b2-1,4 glycosidic bonds while a mixture of pentoses, especially d-xylose, and hexoses comprises the main component of hemicellulose (20\u201340% of biomass dry weight)  represents arguably the most important renewable feedstock on the planet. Lignocellulose is a complex matrix of various polysaccharides, phenolic polymers, and proteins that are present in the cell walls of woody plants Saha, . Converst) Saha, . Lignin t) Saha, . Chemicat) Saha, . After pt) Saha,  and therse Saha, . Althougse Saha, . Third, se Saha, . For exase Saha, , 2011. Ise Saha, . The conse Saha, . OverlimDespite government incentives and mandates, these grand challenges have prohibited the commercialization of lignocellulose conversion into fuels and chemicals at low cost  , yield , and productivity (4\u2009g/L/h) in a complex medium  and then converts pyruvate into ethanol and CO2  after extensive metabolic engineering and adaptive laboratory evolution  and yield (0.48\u2009g/g xylose) using mineral salts medium  in 16\u2009h  to release catabolite repression; (2) overexpression of a glucose transporter from Z. mobilis to restore glucose transport and metabolism; (3) overexpression of genes rpiA, tktA, rpe, and talB to increase pentose phosphate pathway. Recently, a completely different approach to decrease glucose repression has been developed , organic acids, and phenolic compounds Saha, . FurfuraE. coli and S. cerevisiae  conferred the tolerance to furan aldehydes including furfural and 5-HMF in E. coli (Miller et al., E. coli biocatalysts (Wang et al., A significant amount of effort has been contributed to the identification and optimization of biological components to increase the resistance to furan aldehydes, especially furfural Table . The toxS. cerevisiae gene disruption library was screened for mutants with growth deficiencies in the presence of furfural and ZWF1 was found to relate to furfural tolerance (Gorsich et al., ZWF1 increased furfural tolerance (Gorsich et al., ZWF1 encodes glucose-6-phosphate dehydrogenase, which catalyzes the first step of the pentose phosphate pathway, the major pathway providing NADPH when utilizing glucose as the carbon source. A similar approach using genome-wide RNAi screen showed that inactivation of the SIZ1 gene increased furfural tolerance (Xiao and Zhao, SIZ1 encodes E3 SUMO-protein ligase and inactivation of SIZ1 increases the tolerance to oxidative stress besides furfural (Xiao and Zhao, S. cerevisiae cells and to cause damage to mitochondria, vacuole membranes, and cytoskeletons (Allen et al., YAP1 or its target genes CTA1 and CTT1encoding catalases increased tolerance to furan aldehydes (Kim and Hahn, E. coli. The expression of the genes in major oxidative regulons such as OxyR and SoxRS regulons is not activated by the presence of furfural (Miller et al., E. coli, an oxidoreductase UcpA with an undefined function was found to be associated with furfural tolerance by a transcriptomic analysis and its overexpression increased furan aldehyde tolerance (Wang et al., E. coli on plates. Beneficial plasmids containing the thyA gene were recovered from all three genomic libraries. The thyA gene encodes thymidylate synthase, important for dTMP biosynthesis, suggesting furfural toxicity is possibly related to DNA damage (Zheng et al., E. coli mutants led to the discovery of some polyamine transporters including PotE, PuuP, PlaP, and PotABCD with a beneficial role for furfural tolerance (Geddes et al., E. coli (Glebes et al., lpcA, groESL, ahpC, yhiH, rna, and dicA genes are associated with furfural tolerance although the overexpression of these genes individually only showed limited positive effect (Glebes et al., E. coli the tolerance to furan aldehydes (Wang et al., A variety of genomic and transcriptomic approaches have yielded many beneficial genetic traits related to furan aldehydes tolerance Table . S. cerepntAB and the deletion of the yqhD gene together, made cells less tolerance to furfural than the cells with either one of these two beneficial genetic traits alone (Wang et al., There are at least two major challenges for designing such an integrated detoxification system. First, most epistatic interactions between beneficial genetic traits are not predictable and the experimental search for the optimal combination of multiple effector genes is time-consuming and labor-intensive (Sandoval et al., Efficient xylose metabolism and tolerance to furan aldehydes are desired features of microbial catalysts used in lignocellulose conversion. Past efforts of synthetic biology focused on identification and optimization of individual biological parts needed for a successful lignocellulose conversion. We have gradually accumulated much knowledge about xylose metabolism and transport, glucose repression, and furan aldehyde toxicity. Limited success of lignocellulose conversion has been achieved using these individual optimized parts (Sandoval et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Diabetes is a risk factor for Alzheimer disease (AD). Apolipoprotein E (ApoE) and several genes related to AD have recently been identified by genome-wide association studies (GWAS) as being closely linked to lipid metabolism. Lipid metabolism and glucose-energy metabolism are closely related. Here, we review the emerging evidence regarding the roles of lipid and glucose metabolism in the modulation of \u03b2-amyloid, tau, and neurodegeneration during the pathogenesis of AD. Disruption of homeostasis of lipid and glucose metabolism affects production and clearance of \u03b2-amyloid and tau phosphorylation, and induces neurodegeneration. A more integrated understanding of the interactions among lipid, glucose, and protein metabolism is required to elucidate the pathogenesis of AD and to develop next-generation therapeutic options. Familial AD is caused by mutations in the amyloid precursor protein (Goate et al., ApoE is an essential regulator of cholesterol metabolism and is the strongest genetic risk factor for AD Ashford, . The Apoin vitro experiment in which transient membrane cholesterol loading increased A\u03b242 secretion (Marquer et al., Moreover, independently of ApoE\u03b54, high levels of low-density lipoprotein cholesterol and low levels of high-density lipoprotein cholesterol are associated with higher amyloid-PET indices (Reed et al., In addition to the ApoE gene, recent GWAS studies have identified novel risk genes for AD (Hollingworth et al., in vivo and in vitro, statins reduced the A\u03b2 level in the brain (Fassbender et al., Although clinical studies have indicated that statins have no beneficial effect on cognitive function (McGuinness et al., Normal tau promotes the assembly and stabilization of microtubules. However, hyperphosphorylated tau sequesters normal tau and disrupts microtubules, forming NFT (Iqbal et al., As the largest pool of cholesterol resides in neuronal myelin membranes, disorders that impair sterol synthesis or intracellular trafficking of lipids in neurons cause hypomyelination and neurodegeneration (Saher and Stumpf, +-ob/ob mice, generated by crossing diabetic ob/ob mice, display increased A\u03b2 deposition in the cerebral vasculature (Takeda et al., Diabetes in midlife is associated with mild cognitive impairment (MCI; Roberts et al., db/db mice (Kim et al., in vitro and in animal models (Kickstein et al., Several neuropathological studies suggest that the magnitude of NFTs in the brain at autopsy is not different between AD patients with and without diabetes Kalaria, . HoweverDiabetes causes structural deficits in the brain (Sato and Morishita, Recent large, long-term, randomized controlled trials suggest that a multidisciplinary intervention, including exercise and diet, could improve or maintain cognitive function in at-risk elderly people (Ngandu et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Stem cell (SC) research holds the promise of controlling and/or curing a variety of diseases. SC applications include cell therapy, disease modeling, and developmental biology. This commentary focuses on an important study that examined Notch signaling in murine satellite muscle SCs  in which Notch signaling is specifically blocked in the satellite SC using the dominant negative pan-Notch inhibitor, dnMaml1. The Pax7-Cre+/dnMaml1+ mutant mice showed myopathy manifested as muscle damage and weakness as early as 6 months of age and a shortened life span of about 8 months. The satellite SC pool was totally depleted in the mutant mice due to skewing of the balance between self-renewal and differentiation to differentiation rather than self-renewal. Further, the progeny of myoblasts showed reduced proliferation compared to controls. These experiments and others post cardiotoxin (CTX)-induced injury provided evidence that Notch pathway blockade leads to loss of quiescence and depletion of the satellite SC pool. These results are concordant with reports of other studies that blocked murine Notch pathway signaling by selectively inhibiting the recombining binding protein-Jj (RBP-Jj), a nuclear factor involved in the canonical Notch signaling pathway (Bjornson et al., To add further complexity, NOTCH family members have been shown to carry out different and sometimes opposing functions in the same tissue and/or cell type (Yin et al., NOTCH gene mutations have been found in approximately 15% of HNSCC (Gaykalova et al., NOTCH1 may act as a tumor suppressor gene in HNSCC (Pickering et al., In addition to its important role in muscle development, regeneration and repair, the NOTCH pathway is dysfunctional commonly in several developmental, vascular and cardiac diseases, including leukoencephalopathy and pulmonary arterial hypertension (Fouillade et al., Notch1 knockout mice (Nicolas et al., The Lin et al.  paper isTargeted therapies against stemness regulatory pathways like NOTCH are promising in a variety of disorders. Owing to the high possibility of muscle side effects after long-term administration, we recommend following patients by physical exam for muscle wasting and avoiding concomitant use of steroids, which can lead to myopathies. The study by Lin and colleagues  highlighThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Selective motor neuron degeneration is a hallmark of amyotrophic lateral sclerosis (ALS). Around 10% of all cases present as familial ALS (FALS), while sporadic ALS (SALS) accounts for the remaining 90%. Diverse genetic mutations leading to FALS have been identified, but the underlying causes of SALS remain largely unknown. Despite the heterogeneous and incompletely understood etiology, different types of ALS exhibit overlapping pathology and common phenotypes, including protein aggregation and mitochondrial deficiencies. Here, we review the current understanding of mechanisms leading to motor neuron degeneration in ALS as they pertain to disrupted cellular clearance pathways, ATP biogenesis, calcium buffering and mitochondrial dynamics. Through focusing on impaired autophagic and mitochondrial functions, we highlight how the convergence of diverse cellular processes and pathways contributes to common pathology in motor neuron degeneration. SOD1; Rosen, Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of large motor neurons in the brain and spinal cord, resulting in progressive voluntary muscle wasting and respiratory failure. Patient death typically ensues 3\u20135 years following symptom onset . AMPK, activated by a drop in cellular energy, phosphorylates ULK1 on Serine 317 and Serine 777 , a well-established autophagosomal marker  have emerged as the most common cause of both sporadic and familial ALS  and Parkin. Mutations in The downstream events that link the targeting of depolarized mitochondria by PINK1-Parkin to the canonical autophagy core machinery are not yet entirely clear. Direct interaction of Parkin with Beclin1 represents one possible explanation  to glycolysis and induction of mitophagy without compromising membrane polarization. Importantly, PINK1 stabilization is not required for this process; iron chelation-induced mitophagy is efficiently activated in fibroblasts deficient in Parkin  mutations have been linked with ALS and other degenerative diseases, including dementia . In this process, electrons pass along a sequence of protein complexes (I-IV) located in the inner mitochondrial membrane  Polymerase 1 (PARP1), thereby increasing its activity and potentiating PARP1-induced cell death (Joshi et al., Further evidence concerning additional roles for constituents of the autophagy machinery in traditional caspase-dependent pathways implicates even broader contributions to cell death. For example, cleavage of the autophagy-related gene Motor neuron cell death in both familial and sporadic forms of ALS is attributable to necroptosis (Re et al., SOD1 or VCP-associated inclusion body myopathy mutant models did not suggest a similar beneficial effect (Zhang et al., SOD1 mutant mice lacking mature lymphocytes, a modest survival increase was noted following rapamycin treatment (Staats et al., SOD1 mutant model (Castillo et al., ATG genes through an mTOR-independent pathway.That protein aggregates are characteristic of ALS and other neurodegenerative diseases suggests that the autophagy pathway may be an attractive therapeutic target for the prevention and treatment of neurodegeneration (Vidal et al., G2019SLRRK2 mutation implicates autophagic induction as an early event. Accordingly, RNAi-mediated knockdown of autophagy factors LC3 or ATG7 is sufficient to rescue neurite length (Plowey et al., Atg7-deficient mice that negatively regulating autophagy is sufficient to promote cell survival of hippocampal pyramidal neurons following ischemic insult (Koike et al., Although direct defects in autophagy genes may not be the causal link in all cases of ALS, dysfunction of autophagy exacerbates disease phenotypes (Bruijn et al., As increasing evidence suggests a prominent role for mitochondrial dysfunction and oxidative stress in motor neuron degeneration, enhancing mitochondrial health represents a promising strategy for treating ALS and related diseases. In line with this, long-term users of the antioxidant vitamin E show a decreased risk for ALS (Wang et al., Atg genes is sufficient to cause neurodegeneration in mice, suggesting a prominent role for autophagic clearance pathways in neurodegenerative disease (Hara et al., Protein aggregates are chief characteristics of many neurodegenerative diseases, including ALS (Blokhuis et al., BME, NM, and YCM conceived of, drafted, edited, and approved the corresponding review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The consequence is impaired utilisation of glucose in brain cells. Where are published papers denying the results of Edge et al. and Nyenwe et al.?The authors write \u201cEvidence that significant harmful effects are derived from metabolic acidosis by itself has not been provided in human beings and therefore the successful management of metabolic acidosis require the therapy of the underlying causative disorder.\u201d According to Edge et al.  and NyenThe authors write \u201cBoth retrospective and prospective studies have consistently documented that sodium bicarbonate therapy does not improve metabolic responses, biochemical parameters, acid-base balance normalisation, or clinical outcomes among patients with DKA, either children or adults.\u201d In diabetic ketoacidosis, life-threatening is only its most severe stage, coma. If the facts presented in paragraph 1 are correct, thus increase of the very low blood-pH in the comatose patient after infusion of alkalising solution (such as sodium bicarbonate) should result in recovery to normal state of consciousness. And this has been reported in reality: lethality of coma in diabetic ketoacidosis is zero with treatment which includes infusions of alkalising solutions, for example, Umpierrez et al. . WithoutIn the paper of Adeva-Andany et al.  there ar"}
+{"text": "RNA-induced silencing complex (RISC), whose core component is one of the Argonaute family proteins. MiRNAs then direct RISCs to target mRNAs, which are recognized through partial sequence complementarity. Bioinformatic prediction and experimental target gene identification have shown that a miRNA binds mRNAs of hundreds of protein coding genes, which often span a broad spectrum of functional categories  are endogenously encoded single-stranded RNAs of about 22 nucleotides (nts) in length that play essential roles in a large variety of physiological processes in animals and plants Ambros, . Mature  Bartel, . The fun Bartel, . Subsequ5 copies of mature miRNAs in a cell (Calabrese et al., 4 copies per cell (Neilson et al., 4 copies per cell in hepatocytes (Chang et al., 4\u20131.7 \u00d7 105; Janas et al., in vivo mechanism of action of mammalian miRNAs remains to be a central question in the field of miRNA research.However, the model miRNA used in the aforementioned zebrafish study, miR-430, is unique in that its expression is rapidly induced and reaches millions of copies per cell in a few hours after fertilization. This expression level of miR-430 is at least 10 times more than all mature miRNAs combined in a mammalian cell, and serves the single purpose of degrading its target genes, maternal mRNAs, at the maternal-zygotic transition (Giraldez et al., In contrast to these desperate efforts to search for a unified model of miRNA mechanism of action, studies of individual functional targets in primary cells or tissues from miRNA mutant mice are painting a rather different picture. Depending on miRNAs, target genes, and cellular contexts, the outcome of miRNA-target mRNA interactions could be predominantly translation repression or mRNA degradation, or a mixture of both. This heterogeneity in miRNA mechanisms of action has been increasingly recognized as more and more miRNA mutant mice are generated and analyzed (Olive et al., cis-elements in mature miRNAs and target mRNAs determine the mechanism of miRNA action. Future investigation is warranted to identify these cis-elements, if they exist at all.Here we sought to summarize the relative contribution of translation repression and mRNA degradation to miRNA regulation of functional targets in miRNA mutant mice. We focused on miRNA target genes whose protein and mRNA levels were measured concurrently in primary cells or tissues from mutant mice with genetic ablation or transgenic expression of individual miRNA genes. This includes a total of 159 target genes from 77 miRNA mutant mice Table . Our anaFrom a practical standpoint, measuring target gene protein levels is preferred to mRNA levels for the purpose of studying the effect of a miRNA on its target genes. Even for target genes predominantly regulated by mRNA degradation, the miRNA effect can still be captured by measuring their protein abundance. In the same vein, translatome analysis is more appropriate for measuring the global effect of a miRNA on its target genes, while transcriptome analysis often failed to identify any significant effect of miRNA deletion on its target genes, despite the obvious functional consequences in mutant mice (Matkovich et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Citation: Cowie, S. M., P. Knippertz, and J. H. Marsham (2013), Are vegetation-related roughness changes the cause of the recent decrease in dust emission from the Sahel?, Geophys. Res. Lett., 40, 1868\u20131872, doi:10.1002/grl.50273[1] Since the 1980s, a dramatic downward trend in North African dustiness and transport to the tropical Atlantic Ocean has been observed by different data sets and methods. The precise causes of this trend have previously been difficult to understand, partly due to the sparse observational record. Here we show that a decrease in surface wind speeds associated with increased roughness due to more vegetation in the Sahel is the most likely cause of the observed drop in dust emission. Associated changes in turbulence and evapotranspiration, and changes in large-scale circulation, are secondary contributors. Past work has tried to explain negative correlations between North African dust and precipitation through impacts on emission thresholds due to changes in soil moisture and vegetation cover. The use of novel diagnostic tools applied here to long-term surface observations suggests that this is not the dominating effect. Our results are consistent with a recently observed global decrease in surface wind speed, known as \u201cstilling\u201d, and demonstrate the importance of representing vegetation-related roughness changes in models. They also offer a new mechanism of how land-use change and agriculture can impact the Sahelian climate.  Goudie and Middleton, Engelstaedter and Washington, Zender and Kwon, Moulin and Chiapello, Prospero and Lamb, Evan et al., Olsson et al., Fensholt et al., Mahowald et al., Evan and Mukhopadhyay, Chiapello et al., Mahowald et al., [2] North Africa is the world's largest dust source  A general challenge in investigating the causes of this dust trend is the sparse observational record from source regions. Satellite-based data sets are short and mainly provide aerosol optical thickness but not emission directly [Ackerman and Cox [FDE) as the fraction of all reports containing these ww codes. We purposely omitted the frequently reported ww code 6  to exclude transport events. The seven stations were selected on the basis of a minimum of 1000 dust observations overall during the time period 1984\u20132010 and at least 500 observations per year for each of the 27 years.[4] We use the seven Sahelian stations of Nouakchott , Nema (61497), Tombouctou (61223), Gao (61226), Niamey (61052), Agadez (61024), and Gour\u00e9 (61045) see . Wind sp and Cox ). We defu and v wind vectors from the European Centre for Medium-Range Weather Forecasts ERA-Interim reanalysis at a horizontal resolution of 80 km were used for the area inside the blue box shown in DUP) diagnostic parameter  In addition, 6-hourly 10 m Klink [[6] An analysis of the possibility of artificial trends due to instrument changes (as in Klink ) suggestV) decrease from 4.6 ms\u20131 in the mid-1980s to 3.3 ms\u20131 in recent years , and FDE and DUP (0.93) reflect the strong control of wind speed on the occurrence of dust emission. Surprisingly, corresponding trends in regionally averaged mean wind and DUP computed from ERA-Interim reanalysis are substantially smaller (dashed lines in \u20131) and \u221214%, respectively.[7] e et al. , shows a[8] We have also analyzed the trends for: (a) day/night-time time data, (b) data at each major SYNOP hour , and (c) data in each season. In each case the results are robust , supporting the hypothesis that the observed trends are real and not an artefact of a change in sampling through the period.Helgren and Prospero, Foltz and McPhaden, Fensholt et al., v25 and v75, at which the probability of dust emission is 25% and 75%, respectively  are in boreal winter , while no clear trends are found at higher latitudes (15\u00b0N\u201330\u00b0N), which are probably more strongly influenced by the very sparsely vegetated Sahara [Decadal Sahel dust trends analyzed with surface observations and new diagnosticsWind-speed changes dominate over soil changes in recent dust emission decreaseVegetation-induced roughness changes are the main control on wind-speed trends"}
+{"text": "The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS. Within this family, segregation is observed between the translocation event and a spectrum of psychiatric disorders, including major depression, schizophrenia, and bipolar disease  development in both humans and rodents, and gradually decreases during life  fractions, and has been also shown to be present in dendritic spines by the use of ultrastructural methods  reagents. A recent methodological approach that has been exploited successfully in studies of DISC1 biology is et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., DISC1 knockdown by in utero delivery of short hairpin RNA . The most prevalent observations involve modifications to neurogenesis, neuronal migration, and integration of neurons into the neuronal parenchyma of their final destination. The last of these results in subpopulations of slightly misplaced neurons and alterations in mature neuronal morphology, such as changes in process branching  increases both the number of spines and their size, whereas continuing inhibition of DISC1 expression up to 6 days results in fewer and smaller spines  is injected into the medial prefrontal cortex of young rats , and LTP was also small in both genotypes, probably because the experiments were not performed with GABA receptor antagonists, which is the normal methodology employed for studying perforant pathway LTP in brain slices.Comparatively high levels of DISC1 are expressed both in the dentate gyrus and in its major output region, the hippocampal CA3 subfield. Manipulation of DISC1 is known to produce effects on adult neurogenesis and wiring in this brain area  enhancement of mossy fiber paired-pulse facilitation at all interstimulus intervals examined, but no change in 1-Hz frequency facilitation studied with 20 consecutive stimuli . Kvajo et al. , is probably the most widely studied single pathway in the mammalian brain. Synaptic transmission in this pathway was investigated in mice engineered to express a C-terminal fragment of DISC1 in the forebrain in an inducible and reversible fashion. These animals, which showed a number of behavioral changes when expression of the DISC1 fragment was induced, also had a depressed input\u2013output relationship in the SCCP at the age of 3\u20134 months. However, no changes in either short-term plasticity or LTP were found . In the DISC1tr cohort, neither pathway showed changes in input\u2013output relationships or short-term synaptic dynamics. Also, the ratio of N-methyl-d-aspartate (NMDA) receptor-mediated and AMPA receptor-mediated components of the synaptic response was not genotype-dependent. Interestingly, however, we found a clear enhancement of theta burst-induced LTP in the SCCP of DISC1tr mice, but a complete loss of LTP in the temporoamonic pathway. The mechanisms underpinning these pathway-specific effects of the truncated form of DISC1 on long-term synaptic plasticity require further investigation. Our article also describes our single-cell recordings used to compare a broad range of intrinsic excitability properties in CA1 pyramidal cells from 4-month-old DISC1tr mice and wild-type littermates. These identified no substantial dependence on genotype.The SCCP has also been studied in DISC1et al., DISC1. These experiments suggested that reducing the level of DISC1 by \u02dc60% may serve to increase the duration of action potential bursts, although whether this reflects an intrinsic or synaptic change is not apparent from this type of data.One report concerning DISC1 function in hippocampal neurons describes the use of mixed hippocampal cultures prepared from embryonic day 17.5 mouse embryos and grown on multielectrode arrays  by \u02dc30%, probably reflecting the increased number of spines present under these conditions. Cortical cultures have also been employed to demonstrate that knockdown of DISC1 with siRNA increases NMDA receptor-mediated currents in response to exogenous agonist application .Other neurophysiological studies in the cortex have also employed brain slices. One study examined slices from two different mouse models \u2013 the first was the DISC1, et al. . In this et al., , spontanin utero knockdown of DISC1 (Niwa et al., in utero electroporation, have unaltered membrane resistance or membrane potential. However, dopamine D2ergic modulation of electrically evoked excitatory postsynaptic potentials in these deep layer neurons is strongly attenuated when DISC1 is knocked down. This observation is thought to be related to the disturbed dopaminergic innervation of this cortical area produced by the knockdown of DISC1 (Niwa et al., Acutely prepared slices of mouse prefrontal cortex have also been used to study the neurophysiological consequences of et al., et al., et al., et al., et al., et al., et al., et al., DISC1 levels are unquestionably high in postsynaptic elements. Additionally, a number of DISC1 binding partners also show prominent postsynaptic localisation and possess known postsynaptic roles. Consequently, investigations of DISC1 neurophysiology at synapses have tended to concentrate on postsynaptic functionality. However, DISC1 expression appears also to be a feature of some axons and presynaptic terminals (Kirkpatrick in utero electroporation to introduce Cre-dependent inducible expression vectors for full-length DISC1 or a C-terminal truncation of DISC1 or DISC1 RNAi reagents, in addition to channelrhodopsin2. This permitted both expression of both DISC1-related contructs and light-mediated activation to be confined entirely to presynaptic elements. Recording from layer 2/3 cells, the authors found that spontaneous EPSC frequencies were enhanced by a truncated form of DISC1 (Maher & LoTurco, et al. (DISC1 knockdown lowers the probability of release. In future, it will be interesting to determine which proteins DISC1 is interacting with to produce these actions in presynaptic elements. Possibly related to these functional observations of altered presynaptic function is the observation that full-length DISC1 promotes, and C-terminally truncated DISC1 retards, transport along neuronal processes of vesicles containing a synaptic vesicle protein target (Flores et al., A recent elegant study using optogenetic methodologies has provided more direct evidence for presynaptic functions of DISC1 in the neocortex of Wistar rats (Maher & LoTurco, , et al.  in transin vivo studies in appropriate models. Such work is currently ongoing in our group and presumably elsewhere as well, so we should expect to see data on in vivo DISC1-related neurophysiology in the near future.In conclusion, neurophysiological investigation of the neurobiological functions of DISC1 is still in its infancy. We believe that further analyses using neurophysiological measures will provide important insights into the biology of this protein and, consequently, pathways with important roles in psychiatric disease. The data produced to date indicate that alterations to DISC1, such as those that elicit psychiatric disease, can affect multiple processes. As described above, there is evidence for activities on both the presynaptic and postsynaptic sides of the fast chemical synapse, and for interactions with processes controlling long-term synaptic plasticity. The first hints of how these might impact on the behavior of intact complex networks are appearing, although there is a clear need for suitable"}
+{"text": "Drosophila and vertebrate systems has implicated a family of proteins, the Teneurins, as a new transsynaptic signal in both the peripheral and central nervous systems. The Teneurins have established roles in neuronal wiring, but studies now show their involvement in regulating synaptic connections between neurons and bridging the synaptic membrane and the cytoskeleton. This review will examine the Teneurins as synaptic cell adhesion molecules, explore how they regulate synaptic organization, and consider how some consequences of human Teneurin mutations may have synaptopathic origins.To achieve proper synaptic development and function, coordinated signals must pass between the pre- and postsynaptic membranes. Such transsynaptic signals can be comprised of receptors and secreted ligands, membrane associated receptors, and also pairs of synaptic cell adhesion molecules. A critical open question bridging neuroscience, developmental biology, and cell biology involves identifying those signals and elucidating how they function. Recent work in  The developing neuron has a myriad of tasks to complete along its path to become part of a functioning brain network. The final goal is to form a reliable synaptic connection with its defined partner. While synapse formation has been intensively studied  because of its expression in specific stripes of the fly embryo  has been the most frequently studied synapse in Drosophila, Teneurins have two distinct expression levels. They are highly expressed at connections between select pairs of pre- and postsynaptic partners (Hong et al., all neuromuscular and olfactory connections, a lower, basal level of expression exists, suggesting a more general role. Here, the interaction is heterophilic between presynaptic Ten-a and postsynaptic Ten-m. Perturbation of either component of this basal level at the NMJ causes a myriad of phenotypes including fewer synaptic boutons, failed active zone apposition, disorganization of synaptic proteins, failed pre- and postsynaptic differentiation, and reduced function (Mosca et al., In Drosophila use Teneurins to ensure proper partner matching (Hong et al., Both the olfactory system and the NMJ in These findings revealed a number of facets about Teneurin biology, synaptic regulation, and the logic underlying neuronal development. First, it identified the Teneurins as novel, critical components of the transsynaptic cadre of signals. Ten-a and Ten-m regulate cytoskeletal organization and cooperate with known transsynaptic signals like Neurexin/Neuroligin (Mosca et al., 2+ signaling (Silva et al., Recent evidence further suggests synaptic roles for Teneurins in diverse vertebrate systems. An unbiased proteomics screen (Silva et al., in vivo (O\u2019Sullivan et al., teneurin-3 knockdown impairs the morphology and connectivity of retinal ganglion cells (Antinucci et al., teneurin-3 knockdown, the role of Teneurins at vertebrate synapses remains an exciting question of great importance for future work.Latrophilins regulate excitatory synapse development and strength The Teneurins are one of a critical suite of cell surface molecules for synapse formation, organization, and function. These include cell adhesion molecules, ligand-receptor complexes, and secreted factors (Johnson-Venkatesh and Umemori, The Teneurins are synaptic cell surface molecules with such diverse functions. They are synaptic organizers (Scheiffele et al., Drosophila has compared Teneurin and Neuroligin1 perturbations (Mosca et al., Beyond synaptic induction, the Teneurins also ensure an ordered cytoskeleton, a role which may be more unique to this family. While Nectins can organize actin (Mori et al., Drosophila, only two Teneurins exist, but regulate all of these events (Baumgartner et al., Drosophila NMJ, where Teneurins have been most mechanistically studied, but further consider translation. While the more complex vertebrate nervous systems may have evolved additional mechanisms for controlling synaptic organization absent in the fly, it is important to note the CNS and PNS conservation of Teneurins in the Drosophila (Mosca et al., A critical question is how the Teneurins regulate such diverse processes as neuronal wiring, synapse organization, morphogenesis, and patterning. In At the NMJ, the Teneurins function to organize the cytoskeleton and ensure properly apposed active zones. Muscle Ten-m interacts in a complex with \u03b1-spectrin (Mosca et al., While spectrin is also presynaptic, the microtubule cytoskeleton instead is the predominant player in ensuring proper NMJ morphology and function (Hummel et al., neuroligin and ten-a mutants synergize, suggesting an alternative mechanism. Indeed, ultrastructural defects like detached and misshapen active zones following Teneurin perturbation (Mosca et al., Beyond the cytoskeleton, the Teneurins have an independent role in regulating active zone apposition and structure. Teneurin perturbation causes failures (Mosca et al., C. elegans, the Teneurin ten-1 interacts with the Integrin and Dystroglycan homologs ina-1 and dgn-1 and the prolyl 4-hydroxylase phy-1 to regulate collagen IV and maintain basement membranes during embryonic development (Trzebiatowska et al., ten-1 phy-1 double mutants, embryos display gross defects in epidermal development, body wall musculature, and enhanced lethality. These phenotypes also synergize with mutations in collagen IV, leading to a model whereby epidermal TEN-1 binds collagen IV in the basement membrane. In the absence of phy-1, collagen IV is improperly processed and fails to be secreted into the basement membrane to bind TEN-1, weakening the muscle structure. Similar defects and interactions also occur with Integrin and Dystroglycan mutations (Trzebiatowska et al., Teneurins can interact heterophilically with other Teneurins (Oohashi et al., Drosophila, synaptic Integrins and Dystroglycan regulate NMJ development (Hoang and Chiba, pgant3 and pgant35A, two protein alpha-N-acetylgalactosaminyltransferases that regulate integrins. Mutations in these genes control the levels of the synaptic integrin receptor \u03b1PS2 and Ten-m (Dani et al., pgant. Further supporting this interplay is evidence that Ten-m and \u03b1PS2 directly interact (Graner et al., trans (Graner et al., In Drosophila, Teneurins mediate partner matching and synaptic organization at the same synapses (Hong et al., In in vivo will be able to offer important clarity on these differences are achieved.An intriguing possibility may lie in the Teneurins themselves. If their intrinsic structural properties could distinguish homo- and heterophilic interactions, this would enable both signaling modes with the fewest restrictions Figure . BiophysIn recent years, the synaptic basis of neurological disorders has been more concretely appreciated (Thompson and Luscher, How may the Teneurins be synaptopathic? Teneurin mutations have been implicated in a number of intellectual disabilities. Large regions of the human X and 5th chromosomes containing Teneurins-1 and -2, respectively, are linked to mental retardation (Tucker and Chiquet-Ehrismann, A tantalizing link between Teneurins and synaptopathies rests with bipolar disorder. Genome-wide association studies linked Teneurin-4 mutations to enhanced susceptibility to bipolar disorder (Psychiatric GWAS Consortium Bipolar Disorder Working Group, Drosophila, they order the underlying synaptic cytoskeleton and ensure proper synaptic function, differentiation, and morphology. Understanding their complete synaptic role, however, is in its infancy, and remains an exciting area for future study. Further work is needed to decipher the mechanisms of synaptic Teneurin function, leading to how they affect human brain function. Indeed, while human nervous systems have more complex circuit regulatory requirements than invertebrates, the marked conservation in worm, fly, and mouse models for Teneurin function suggests that their diverse roles may rely on similar core mechanisms. It will be critical to determine how these synaptic roles differ from those of partner matching. Understanding their downstream effectors and how homo- and heterophilic Teneurin signals are distinguished in partner matching vs. synaptic organization will achieve this goal. Linking these mechanistic studies to those of patients with Teneurin mutations will further enhance our understanding of how these proteins function. As future work addresses these questions, the Teneurins may take their place alongside known synaptopathic and ASD genes like Neurexin and Neuroligin as critical synaptic determinants, highlighting their importance in producing a functioning, organized brain.The Teneurins have emerged as transsynaptic, cell surface molecules essential for synaptic organization. In The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The effective management of cardiac arrhythmias, either of atrial or of ventricular origin, remains a major challenge. Sudden cardiac death due to ventricular tachyarrhythmias remains the leading cause of death in industrialized countries  and a large capacity (mc) per unit area.\u201d This \u201ccable model\u201d considers that the intracellular and extracellular potentials vary along the longitudinal axis only, and that both the cytoplasm and the extracellular spaces can be approximated as ideal ohmic conductors (with ir and er respective resistances per unit length). Hence, propagating cardiac action potentials along a fiber can be described by the following second-order partial differential equation (PDE):ionicI is the nonlinear membrane ionic current density (\u03bcA/cm2), defined by the active/stochastic electrical properties of the cell. Alternatively, multiplying by mr, Equation (1) can be re-written asmcmr is the trans-membrane time-constant (e.g., Plonsey, Engelmann  was perhUsing this theoretical framework, Weidmann  demonstrMyocardial infarction and/or acute ischemia provoke profound changes in the passive electrical properties of cardiac muscle (De Groot and Coronel, in vivo. Therefore, del Rio et al. (The role that changes in intrinsic properties of pacemaker cells (Yaniv et al., o et al.  studied The authors hope that this monograph will provide a better appreciation of the crucial role that myocardial passive electrical properties play in not only the maintenance of a normal cardiac rhythm but also how changes in these parameters can trigger atrial and ventricular arrhythmias. The application of this knowledge should facilitate the development of more effective anti-arrhythmic therapies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Tests al., 2015). This tal., 2015). In thial., 2015). An intin vitro systems for hepatotoxicity, because they may improve the throughput and avoid difficulties due to interspecies extrapolation, because human cells can be used . Howeveeif, 2014; Ghallabeif, 2014, 2014; Cam; Camin val., 2015; Driesseal., 2015; Tolosa al., 2015; Grinberal., 2015). Other"}
+{"text": "The 13th International Conference on Bioinformatics (InCoB2014) was held for the first time in Australia, at Sydney, July 31-2 August, 2014. InCoB is the annual scientific gathering of the Asia-Pacific Bioinformatics Network (APBioNet), hosted since 2002 in the Asia-Pacific region. Of 106 full papers submitted to the BMC track of InCoB2014, 50 (47.2%) were accepted in BMC Bioinformatics, BMC Genomics and BMC Systems Biology supplements, with three papers in a new BMC Medical Genomics supplement. While the majority of presenters and authors were from Asia and Australia, the increasing number of US and European conference attendees augurs well for the international flavour of InCoB. Next year's InCoB will be held jointly with the Genome Informatics Workshop (GIW), September 9-11, 2015 in Tokyo, Japan, with a view to integrate bioinformatics communities in the region. The 13th InCoB , an official conference of the Asia-Pacific Bioinformatics Network (APBioNet) [We offered authors four tracks to submit manuscripts for potential publication in the supplement issues of BMC Bioinformatics, BMC Systems Biology or BMC Genomics (BMC track) and PeerJ . Of the BMC Medical Genomics [BMC Bioinformatics supplement [BMC Systems Biology supplement [The 20 articles in this supplement cover mainly \"genomic\" topics, with three medically-oriented papers going into Genomics  for the pplement  comprisepplement . Five mopplement .et al.[de novo assembly software for fungal genome data. Proteogenomics is increasingly used for the accurate annotation of protein coding regions using proteomic data. As currently available proteogenomic tools are tailored specifically for human and eukaryotic data, Uszkoreit et al.[With genome sequencing technologies becoming more and more accessible and affordable, the genetic origin of the Marwari horse was established by whole genome sequencing  while thet al. have assit et al. have devet al.[et al.[et al.[et al.[et al.[Seven papers are devoted to transcriptome analysis addressing a range of challenges from epigenetics ,14 to unet al. have idel.[et al. have pinl.[et al. have idel.[et al. have idel.[et al. have appet al.[Guanine-rich nucleotide sequences form four-stranded G-quadruplex structures. Yano and Kato  have useet al. have devet al. have devet al.[In the era of genomic medicine, it is possible that some approved drug molecules can be used for diseases other than those they were originally approved for. Yang and co-workers  propose et al. have optet al.[et al.[Taguchi and co-workers  have ideet al.. Xu et al.[et al. have devet al.[Papers specifically relating on genome-scale analysis with a disease focus are presented in a new supplement in BMC Medical Genomics and a brief overview of these articles is presented here. With pandemic viral infections spreading rapidly by jet travel, understanding cross-species transmissibility of vectors is addressed by Tan and co-workers  for inflet al. have anaWith the growth in regional bioinformatics meetings, including ISCB-Asia meetings and the 2013 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) in China , there iThe authors declare that they have no competing interests.SR wrote the introduction. CS and SR (Program Committee Co-chairs) managed the review and editorial processes, respectively. TWT supported the post-acceptance manuscript processing.List of Program Committee Members and Additional Reviewers in Alphabetical Order.Click here for file"}
+{"text": "Picornaviridae and genus Hepatovirus, which is a sole member of this family. HAV has radically different properties from those of other picornaviruses. First, HAV is extremely resistant to degradation caused by environmental conditions, which include thermal denaturation , acid treatment , 20% ether and chloroform, and detergent inactivation . Second, the HAV has a highly de-optimized codon usage and grows slowly in a tissue culture. Third, VP1-2A or PX, which is a 67-residue C-terminal extension of VP1, has been implicated in the particle assembly (Graff et al., Hepatitis A, which is a major global health problem (Nainan et al., Picornavirus family. VP4, which is a small viral protein, was first detected in HAV mature virions. The external surface of HAV exhibits fewer features than those observed in enteroviruses and cardioviruses (Wang et al., Recently, structures of a mature virion and an empty capsid assembly intermediate of HAV were determined by X-ray crystallography (Wang et al., Although the structure of HAV presents significantly different properties compared with other previously characterized viruses, reveals the phylogenic relationship between typical picornaviruses and insect viruses and also indicates a novel uncoating mechanism, several important biological parameters, such as the entry of HAV and release of an RNA genome, still need to be clarified."}
+{"text": "International Journal of Molecular Sciences [The author would like to insert the citation after the following sentence, \u201cThese RBPs are detected on laser trackswithin one minute after laser irradiation, and are excluded from the laser tracks shortly  [Sciences .et al. [R-loops), they presented several data supporting that the exclusion of these factors is part of a DDR Pi3K-like kinases-dependent mechanism operating at DNA damage sites to prevent R-loops accumulation.The author wants to stress that an important reference has been inadvertently omitted in the appended review. Britton et al.  recently"}
+{"text": "In a recent review paper on theoretical explanations of affective stimulus-response compatibility (aSRC) effects between positive/negative stimuli and approach/avoidance-related movements, Kozlik et al. ; KNL argKrieglmeyer et al.  report a2. We agree that smiling and frowning are linked to positive and negative affects, respectively, more rigidly than non-facial actions commonly are. We also agree that aSRC effects for facial responses are less affected by instructions of arbitrary action goals  result in greater left frontal activation, while other smiles do not  to AE.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The use of synthetic non-coding RNAs for post-transcriptional regulation of gene expression has not only become a standard laboratory tool for gene functional studies but it has also opened up new perspectives in the design of new and potentially promising therapeutic strategies. Bioinformatics has provided researchers with a variety of tools for the design, the analysis, and the evaluation of RNAi agents such as small-interfering RNA (siRNA), short-hairpin RNA (shRNA), artificial microRNA (a-miR), and microRNA sponges. More recently, a new system for genome engineering based on the bacterial CRISPR-Cas9 system , was shown to have the potential to also regulate gene expression at both transcriptional and post-transcriptional level in a more specific way. In this mini review, we present RNAi and CRISPRi design principles and discuss the advantages and limitations of the current design approaches. Natural regulatory RNAs are a heterogenous group of endogenous non-coding RNAs that modulate biological processes at many levels through different mechanisms. They have inspired the design of synthetic RNA molecules, such as riboswitches, sensors, and controllers, as key elements for programing cellular behaviors, as well as antisense-based approaches for specific gene expression regulation, which is the focus of this mini-review  was discovered in 1998, when Andrew Fire and Craig C. Mello reported the capability of exogenous double-stranded RNAs (dsRNA) to silence genes in a specific manner in miRNAs are small endogenous non-coding RNAs, typically 18\u201322\u2009bp long, which derive from longer hairpin-shaped precursors called pre-miRNA Bartel, . A pre-msiRNAs are mostly exogenous dsRNA molecules derived from viral RNAs or artificially introduced into the cell  has been recently proposed . Sequence rules concern the position of the binding site in the target transcript and its nucleotide composition. The target region should be chosen preferably 50-100\u2009nt downstream of the start codon and should avoid the middle of the coding sequence , which possesses the highest affinity toward complementary RNA, Bifunctional oligodeoxynucleotide/antagomiR constructs, which ensure high transfection efficiency and prevention of unintended immune stimulation, and morpholino oligomers, which have been shown to be efficient inhibitors of both pri-miRNA and mature miRNA activity in zebrafish and Xenopus laevis  are efficient sponges with structurally accessible and indigestible miRNA binding sites Figure H Haragu, 2012. TAn exciting and promising advance in the field of artificial gene regulation comes from Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). CRISPR is a natural adaptive immune system used by archaea and bacteria against phage and plasmids  in order to perform genome editing in eukaryotes  mechanisms, thus this system can be used to either disrupt or edit a gene . Many tools are currently available online for the design of sgRNAs Table .Besides genome-editing applications, the CRISPR/Cas9 system can be employed for gene expression regulation. The system, known as CRISPR interference (CRISPRi), is based on a catalytically dead Cas9 (dCas9) lacking endonuclease activity co-expressed with a sgRNA (Gilbert et al., A \u201cseed\u201d region has been identified as the 12nt region adjacent to the PAM site. Mismatches in the seed region can dramatically reduce the repression, while mismatches in the non-seed area can cause a mild effect. Design guidelines recommend using a length of 20\u201325\u2009nt as the base-pairing region of the sgRNA (Larson et al., Gilbert et al. also introduced the sunCas9 CRISPRa system, in which expression of a single sgRNA with one binding site is sufficient to turn on genes that are poorly expressed or that increase the expression of well-expressed genes (Gilbert et al., in vivo by site-specific genome engineering (Bassett et al., CRISPRi can also be successfully employed to knock out miRNAs, by using a sgRNA/Cas9 complex targeting the pre-miRNA sequence (Zhao et al., Finally, although current tools for CRISPRi are based on the DNA targeting approach described above, the discovery of other Cas proteins targeting RNA molecules, such as Cmr, suggests an alternative post-transcriptional methodology similar to RNAi (Hale et al., Both RNAi and CRISPRi represent valid approaches for artificial gene regulation and both can suffer from significant side effects which may result from factors beyond sequence match. One clear advantage of CRISPRi over RNAi is that being an exogenous system it does not compete with the endogenous machinery of miRNA processing. Nevertheless, both techniques require more work in terms of enhancing targeting efficiency and reducing side effects.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.http://www.frontiersin.org/Journal/10.3389/fbioe.2014.00065/abstractThe Supplementary Material for this article can be found online at Click here for additional data file."}
+{"text": "PLOS Genetics, Head et al.  with caffeine; e.g., increases in citrate synthase and cytochrome c oxidase mRNA were observed 24 hours after caffeine exposure  during contractions and increased fatigue resistance [2+] and muscle weakness [From an evolutionary perspective, the SR Caweakness , in muscweakness , and in weakness . In thissistance  in non-sweakness .ACTN3 577xx allele promote increased energy expenditure and improved mitochondrial function without requiring an increase in physical activity? Perhaps treatments to induce a controlled SR Ca2+ leak provide such an opportunity, but then the risk of causing impaired muscle function due to excessive Ca2+ leakage has to be overcome.Human evolution and athletic performance are fascinating, but the findings of Head et al. provide additional avenues for future studies with important implications for human health, since the benefits of improved mitochondrial function span far beyond increased exercise capacity. Obesity and the metabolic syndrome are associated with impaired mitochondrial function, and of course, constitute a widespread and rapidly increasing health problem. Could strategies that phenocopy the effects of the"}
+{"text": "In response: We agree with Berry et al. (Bulinus snails, which can serve as intermediate hosts for Schistosoma haematobium, were found during a malacological survey in 2014 (As stated in our manuscript, we cannot exclude the possibility that our case definition generated false-positives; the potential limitations of our findings have already been discussed ("}
+{"text": "We discuss Wittmann et al.  \u201cEffectsThe brain integrates partial sensory input with internal representations to construct the elaborate story we know as time Hammond, . Our ord2A receptors in internal clock models (ICMs) in duration discrimination and temporal control of motor performance. The study revealed a decreased ability to accurately produce intervals longer than 3 s and synchronize finger-tapping to auditory beats separated by more than 2 s. This suggests that effects of psilocybin on temporal processing are specific to relatively long durations, attributable to memory, and decision-making components of the ICM (Gibbon et al., Serotonergic hallucinogens generally slow the perceived flow of time Shanon, . PharmacComparable results are observed in Wackermann et al. , assessiTemporal processing of longer durations is impaired in people with schizophrenia Fuchs, . However2A receptor agonists may induce clinical symptoms of schizophrenia such as hallucinations, delusion, psychomotor poverty, and distorted perception (Teixeira et al., 2AR activation have shown to assist NMDAR-dependent memory mechanisms (Zhang and Stackman, 2A R occupancy in the prefrontal cortex of schizophrenic patients (Zhang and Stackman, Psychopharmacological research suggests that drugs such as psilocybin may serve as useful tools for understanding temporal serotonergic signaling mechanisms underlying psychosis, due to their capacity to cause distorted perception in normal subjects (Rammsayer, 2A receptor antagonist ketanserin.Impairments in working memory, selective attention, and executive control, as seen in schizophrenia, lead to distorted sequencing and integration of past, present, and future into a personal narrative. Carter et al.  demonstr2A receptor activity is associated with time distortion in both psychiatric disorders and hallucinogenic experiences. Manipulating antagonists/agonists provides an approach to utilizing psychoactive drugs as tools in research for understanding time perception in the ordinary brain. It would be fruitful to compare healthy subjects under the influence of psilocybin with patients with acute schizophrenia, utilizing a common paradigm as in Wittmann et al. (5-HTn et al. . Howevern et al.  excludesn et al. . An fMRIn et al. . Negativn et al. .Neuroimaging techniques combined with psychophysical tests of time perception (for a review see Grondin, A2 receptor activities. Commonalities across pharmacological treatments and neurological disorders should be explored within a common experimental paradigm to better understand neurochemical processes mediating temporal processing in ordinary states.Slowing of perceived time is induced by psilocybin and schizophrenia; having a common basis in 5-HTKS obtained comprehensive research and drafted original article, with collaboration of JB's efforts. JB provided substantial advisory of research materials and writing processes. Both authors edited and revised the article, insured the integrity of the product, and agreed on the final version for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The design of biomaterials and the sourcing for appropriate cells are two integrated aspects of tissue engineering to construct a tissue implant for clinical applications. During the past decades, many innovative biomaterials with desirable biological and mechanical properties have emerged, while stem cells have been shown to be a promising cell source to differentiate into many cell types. However, the testing of these bioartificial tissue constructs in the clinical trials is far from satisfactory. How microenvironments in the biomaterials regulate cellular signaling pathways and functions, how stem cell-derived target cells respond to extracellular cues presented by the biomaterials, and how implanted tissue constructs interact with host tissues remain to be investigated. The information of the interplay between cell and biomaterials would be helpful to guide us in improving our current strategy to refine the tissue constructs for effective tissue repair in regenerative medicine. in vivo and in vitro studies. They suggest that well-designed randomized animal trials are needed before moving into clinical trials. Then we introduce three types of innovative biomaterials: (1) bionanocomposites based on bacterial cellulose and magnetic nanoparticles (magnetite) for efficient chronic wounds healing reported by B. Galateanu et al.; (2) the elastomeric poly(\u03b5-caprolatone urethane) (PCLU) scaffolds using a high internal phase emulsion for bone tissue regeneration developed by S. Changotade et al.; and (3) a novel gelatin-alginate-polyacrylamide 3D interpenetrating network with superior performance in promoting chondrogenesis using human adipose-derived stem cells designed by S. Dinescu et al. Most importantly, our special focus will be given to the insight studies on the cell-biomaterial interactions. C.-H. Wang et al. demonstrate that the migration ability of bone marrow stem cells can be regulated by varying the porous structure of the artificial ligaments and this regulation is related to the RhoA/ROCK signaling pathway. M. Deng et al. demonstrate the endothelial differentiation of human adipose-derived stem cells on the polyglycolic acid/polylactic acid (PGA/PLA) mesh and propose the synergistic effect of 3D environments and biochemical signals such as growth factors on the acquisition of mature characteristic endothelial phenotype. S. Fu et al. have investigated the protective effect of neuropeptide Substance P on bone marrow stromal cells against apoptosis induced by serum deprivation through Wnt signaling. J. Michel et al. have reviewed a wide range of hydroxyapatite containing scaffolds and their interactions with mesenchymal stem cells in in vitro and in vivo contexts.In this special issue, we first present a thorough review by M. Ramamoorthi et al. on the efficacy of dental stem cell therapy in bone regeneration in preclinical"}
+{"text": "Neovascular ocular disorders such as diabetic retinopathy and neovascular age-related macular degeneration (neovascular AMD) are an important cause of blindness in the world . In thesA flow cytometric analysis of vitreous inflammatory cells in patients with proliferative diabetic retinopathy.\u201d Histological and flow cytometric analyses have recently demonstrated the importance of histiocytes/macrophages and T lymphocytes in the development and activation of this disease, but no prediction on the visual prognosis was made. Moreover, higher CD4/CD8 ratio in the vitreous of patients with PDR compared to that in their blood was consistent with local inflammatory response in the disease.Inflammation has an important role in the development of proliferative diabetic retinopathy (PDR) as described in the paper by M. Urban\u010di\u010d et al., 2013, \u201c ex vivo cultured cells growing out of human fibrovascular epiretinal membranes (fvERMs) from PDR can give insight into their function in immunity, angiogenesis, and retinal detachment, as described in the paper by Z. Ver\u00e9b et al., 2013, \u201cFunctional and molecular characterization of ex vivo cultured epiretinal membrane cells from human proliferative diabetic retinopathy.\u201d Several surface markers such as hematopoietic  and mesenchymal stem cell markers  have recently been reported in fvERMs from patients with PDR. Additionally, secretion of different angiogenesis-related factors  was demonstrated in cells growing out of the fvERMs.Characterization of the cell surface marker phenotype of \u201cCandidate genes for proliferative diabetic retinopathy.\u201d Several pathogenetic mechanisms have been implicated in the development of PDR such as alteration in retinal blood flow, hemostatic abnormalities, metabolic changes, increased oxidative stress, increased polyol and hexosamine pathway flux, activation of protein kinase C isoforms, and increased advanced glycation end-product formation, growth factors, and so forth . The role of epigenetics in diabetic retinopathy is now an emerging area as described in \u201cEpigenetic modifications and diabetic retinopathy\u201d by R. A. Kowluru et al., 2013. It is well known that diabetic environment facilitates epigenetics modifications, which can alter the gene expression without permanent changes in DNA sequence. It has been shown recently that genes encoding mitochondrial superoxide dismutase and matrix metalloproteinase-9 are epigenetically modified, and, by activation of epigenetically modified enzymes, DNA methyltransferases are increased and micro-RNAs responsible for regulating nuclear transcriptional factor and growth factors are upregulated.Epigenetic mechanisms are expected to be involved in the pathogenesis of PDR as well. Gene polymorphisms and epigenetic mechanisms responsible for PDR are reviewed in this paper  in the angiogenic cascades to developing new therapies for retinal vascular diseases. Anti-VEGF agents such as ranibizumab and aflibercept have become increasingly well-established therapies as shown in the paper by M. Hanout et al., 2013,Does the adult human ciliary body epithelium contain \u201ctrue\u201d retinal stem cells?\u201d). However, until fully accepted as an important treatment modality in different eye disorders, their usefulness must be confirmed in well-designed clinical trials.Stem cell therapy is a promising approach in different diseases, including those causing blindness. Recent reports of retinal stem cells being present in several locations of the adult eye have sparked great hopes that they may be used to treat the millions of people worldwide who suffer from blindness as a result of retinal disease or injury . A populDaniel Petrovi\u010dQuan Dong NguyenBorut PeterlinGoran Petrovski"}
+{"text": "Cryptococcus neoformans (Cn) has become one of the leading causes of mortality in AIDS patients. Understanding the interactions between Cn and phagocytes is fundamental in exploring the pathogenicity of cryptococcal meningoencephalitis. Cn may be extracellular or contained in the monocytes, macrophages, neutrophils, dendritic cells and even endothelial cells. The internalized Cn may proliferate inside the host cells, or cause the lysis of host cells, or leave the host cells via non-lytic exocytosis, or even hijack the host cells (Trojan horse) for the brain dissemination, which are regulated by microbe factors and also immune molecules. Coexistence of protective and deleterious roles of phagocytes in the progression of cryptococcosis warrant further investigation.Meningoencephalitis caused by  Cn has been co-evolved with the phagocyte predators, e.g., amoebas  and proliferates in the brain parenchyma. As Cn is a facultative intracellular pathogen, it is speculated that the transmigrating Cn might be extracellular or within some phagocytes, thereby invading the central nervous system (CNS) via a trans-cellular pathway or Trojan horse pathway  promotes the inflammatory cytokines (Retini et al. The recruited neutrophils in the lung internalize Cn after intratracheal inoculation (Feldmesser et al. Candida albicans infection (Romani et al. Neutrophils are not only phagocytes but also the modulators of immune responses. Depletion of neutrophils results in a Th2 response and renders mice susceptible to high monocytes (Osterholzer et al. Upon Cn airway infection, CCR2 mediates the recruitment of Ly6G+ T cell responses against Cn (Bauman et al. In the lymphnodes, Langerhans cells and myeloid DC induce protective CD4Candida albicans also invades brain endothelial cells via endocytosis (Filler and Sheppard Different from monocytes/macrophages, neutrophils and dendritic cells, endothelial cells are not professional phagocytes. Yet, Cn is observed in the brain endothelial cells of infected mice (Chretien et al. Serological evidences suggest that people may have been infected with environmental Cn in early childhood (Goldman et al."}
+{"text": "This special issue on photorespiration focuses on recent advances in this topic. The majority of the papers summarizes and extends contributions given at the 2nd workshop, \u2018Photorespiration\u2013key to better crops\u2019, held in Warnemuende, Germany in June 2015. This was organized by the DFG (German Research Foundation)-supported research network, \u2018Photorespiration: origins and metabolic integration in interacting compartments\u2019 (FOR 1186\u2013Promics).2 uptake and CO2 release. It is closely associated with photosynthetic CO2 assimilation and represents one of the major highways of carbon metabolism in most plants. By mass flow, surpassed only by photosynthesis, PR actually constitutes the second most important process in the land-based biosphere. Plants using the most widespread C3 type of photosynthesis for CO2 assimilation display particularly massive photorespiratory CO2 production. PR is initiated by competition of O2 with CO2 at the active site of the universal carboxylating enzyme Ribulose 1,5-bisphosphate Carboxylase/Oxygenase (Rubisco) (2-containing atmosphere (The term photorespiration (PR) describes a light-induced biochemical process that converts 2-phosphoglycolate (2PG) into 3-phosphoglycerate (3PGA) and is accompanied by ORubisco) , which pmosphere . To conv2 and NH3. Quantitatively, PR can decrease photosynthesis by up to 30% under current atmospheric concentrations of CO2 and O2 and even more at elevated temperature , chlorophytes, C3 and C4 plants were not viable in ambient air and could only be rescued under artificially enhanced CO2/O2 ratios  highlight the important role of PR in the evolution of C4 photosynthesis via intermediary stages, in which the capacity for PR is lost from leaf mesophyll cells and relocated to the bundle sheath cells. As shown by D\u00f6ring et al. (this issue), in fully evolved C4 plants such as sorghum, the majority of genes encoding components of PR are also expressed preferentially in bundle sheath cells. Khoshravesh et al. (this issue) highlight the importance of organelle positioning in bundle sheath cells and the relocation of photorespiratory activity to this tissue during the evolution of C4 photosynthesis in grasses. Hagemann et al. (this issue) review the current position on the continuous coevolution of photosynthesis and PR. The evolution of all photorespiratory enzymes was elucidated and it was revealed that the present-day plant photorespiratory enzymes originated from archaeal, bacterial, and cyanobacterial sources, which served as eukaryotic host cell (Archaea), and mitochondrial (proteobacteria) or plastdial (cyanobacteria) endosymbionts, respectively. Moreover, calculating in terms of the geological era, ancient CO2/O2 ratios indicated that photorespiratory metabolism existed from the invention of oxygenic photosynthesis and remained necessary in cells evolving different types of carbon-concentrating mechanisms (CCM).The insight paper and three reviews discuss the current view on PR and its evolution. Sage (this issue) summarized the stepwise development of Cet al. (this issue), by using mutants that lack the activity of mitochondrial NADH dehydrogenase, analysed the role of the mitochondrial electron transport chain in photosynthesis. Using transcriptomic analysis of Lotus japonicus wild type and GS2 mutant plants on a range of different nitrogen concentrations and at ambient and elevated CO2, P\u00e9rez-Delgado et al. (this issue) show that primary nitrogen assimilation and PR are transcriptionally co-regulated. They also identify candidate transcription factors mediating this co-ordinated response. Betti et al. (this issue) summarize recent advances obtained in photorespiratory engineering and discuss the potential of realizing gains in crop productivity through manipulation of the photorespiratory pathway. Nunes-Nesi et al. (this issue) explore natural genetic variation in yield and photosynthetic capacity and point to the fact that photorespiratory capacity, in part, is genetically determined. Obata et al. (this issue) review the tight integration of PR with other metabolic pathways which reach beyond the recycling of carbon from the Calvin\u2013Benson cycle, a topic that is further extended by Hodges et al. (this issue). Timm et al. (this issue) focus on the still limited understanding of regulatory interactions between plant PR and photosynthesis and discuss its critical impact for successfully engineering photosynthesis. Montgomery et al. (this issue) also explore the regulatory effect of light reactions on PR in their opinion paper. They employ the framework of modularity in the cyanobacterium Fremyella diplosiphon and suggest a highly controlled interplay among light reactions, PR, and CCM. The opinion paper by Orf et al. (this issue) also centres on cyanobacteria. According to their comparative meta-analysis of cyanobacterial and plant metabolite profiles, the authors propose that cyanobacteria can serve as a much simpler surrogate to study the complex, highly compartmentalized, plant PR metabolism.Another set of contributions deals with the intertwining of the photorespiratory pathway with the central metabolism and its significance for engineering plant productivity. For example, Fromm et al. (this issue). Alonso-Cantabrana and von Caemmerer (this issue) report on using carbon isotope discrimination as a tool to quantify C4-like photosynthesis in C3\u2013C4 intermediate species. Labelling with the stable carbon isotope 13C also revealed a strong effect of reduced mitochondrial malate dehydrogenase activity on PR . Sharwood et al. (this issue) emphasize the importance of standardized and validated protocols for quantifying carbon fixation capacity in plants with differing carbon assimilation strategies, with particular emphasis on quantifying Rubisco activity.A deeper understanding of PR requires technology to determine rates of PR and photosynthesis accurately and this is reviewed by Hanson et al. (this issue). Dellero et al. report on the impact of reduced photorespiratory glycolate oxidase activity on leaf metabolism in Arabidopsis  and review recent advances in the understanding of glyoxylate metabolism in different plant organs . Knocking out glycolate oxidase of Cyanidioschyzon merolae resulted in the first mutant with a photorespiratory phenotype among red algae . This finding revealed that the plant-type photorespiratory cycle using a peroxisomal glycolate oxidase evolved before the split of red and green algae, and it represents a further example that organisms, though carrying a CCM, also depend on functional PR.Four papers deal with the specific role of the central enzyme, glycolate oxidase. The biochemistry of this peroxisomal enzyme converting glycolate into glyoxylate is reviewed by Hodges 4 plants. Not only is it essential to support photosynthetic carbon assimilation, it is also heavily intertwined with other metabolic pathways and is the driving force for the evolution of C4 photosynthesis  would be an important future aim. However, in the long-term, it is also envisaged that synthetic pathways for carbon assimilation (i.e. pathways not existing in nature), that are not affected by oxygen, might become a reality (The past decades of research on the process of PR have revealed that this pathway is an indispensable companion to oxygenic photosynthesis and includes photosynthetic organisms that feature highly efficient CCMs such as cyanobacteria, many algae, and C"}
+{"text": "Autism spectrum disorder (ASD) is a set of complex neurodevelopmental disorders. ASD is characterized by early-onset difficulties in social interaction, repetitive behavior, and verbal and non-verbal communication. Worldwide prevalence of ASD is about 1%  .There is both direct and indirect evidence for the role of prenatal testosterone and related androgens in the etiology of autistic traits and ASD. Recently, Baron-Cohen et al.  found dip\u2009<\u20090.05)   in mothers of autistic children compared to control subjects.Autistic-like traits are the first signs of ASD  is a disease that leading to overproduction of adrenal androgens due to an enzyme deficiency [usually of 21 hydroxylase (21-OH)]  and the fourth digit (the \u201cring\u201d finger) is an indicator of prenatal sex steroid levels Manning, . HoweverSeveral studies have investigated 2D:4D ratios among individuals with ASD, and the majorities of them reported lower 2D:4D ratios in autistic probands [reviewed in Teatero and Netley ]. For exAttention deficit hyperactivity disorder is a group of behavioral symptoms including hyperactivity, inattention, and impulsiveness. ADHD symptoms are often observed in individuals with ASD. Both disorders are more frequent in males than females ; in contrast, the sex ratio was significantly decreased in pregnant women with low levels of anti-Toxoplasma IgG antibodies . Moreover, infected women had significantly more facial hair (p\u2009=\u20090.001) and hair reduction (p\u2009=\u20090.002) than the control group.Ingudomnukul et al.  reportedSeveral complex neurodevelopmental disorders may be associated with higher levels of testosterone, including antisocial and aggressive behavior  that involved in the etiology of various neuropsychiatric disorders (Vyas et al., T. gondii infection (Miller et al., Different mechanisms have been shown to involve in the etiology of neuropsychiatric disorders and behavioral alterations during Several direct and indirect evidences support the role of increased prenatal testosterone in ASD and latent toxoplasmosis. Latent toxoplasmosis may also be involved in the etiology of various testosterone-related medical disorders and plays different roles in the etiology of neuropsychiatric disorders. Taken together with the high prevalence of latent toxoplasmosis in different nations (approximately 25\u201330% of the world\u2019s human population (Robert-Gangneux and Dard\u00e9, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Journal of the American Academy of Child and Adolescent Psychiatry . On page 169, two of the 95% CIs reported in An error appeared in the article \u201cCognitive Training for Attention-Deficit/Hyperactivity Disorder: Meta-Analysis of Clinical and Neuropsychological Outcomes From Randomized Controlled Trials\u201d by Samuele Cortese, Maite Ferrin, Daniel Brandeis, et\u00a0al., published in the March 2015 issue of the"}
+{"text": "Cell fate conversion is considered as the changing of one type of cells to another type including somatic cell reprogramming (de-differentiation), differentiation, and trans-differentiation. Epithelial and mesenchymal cells are two major types of cells and the transitions between these two cell states as epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) have been observed during multiple cell fate conversions including embryonic development, tumor progression and somatic cell reprogramming. In addition, MET and sequential EMT-MET during the generation of induced pluripotent stem cells (iPSC) from fibroblasts have been reported recently. Such observation is consistent with multiple rounds of sequential EMT-MET during embryonic development which could be considered as a reversed process of reprogramming at least partially. Therefore in current review, we briefly discussed the potential roles played by EMT, MET, or even sequential EMT-MET during different kinds of cell fate conversions. We also provided some preliminary hypotheses on the mechanisms that connect cell state transitions and cell fate conversions based on results collected from cell cycle, epigenetic regulation, and stemness acquisition. As two major types of cells in most animals, epithelial cells are known for their basement membrane, apical-basal axis of polarity, gap junction, immobility, and so on, while the characteristics of mesenchymal cells are almost just opposite, loosely associated, no polarity, and high mobility. Although the two types of cells are so different from each other, the transitions between epithelial and mesenchymal states, epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), have been observed clearly and studied extensively during a variety of biological processes including embryonic development, cancer progression, and somatic cell reprogramming.The first observation of EMT can be dated back to as early as 1890 when some ductal epithelial cells were described to acquire mesenchymal characteristics in breast tumors progression as reviewed previously Nieto, . It is sEMT has been observed in multiple biological processes, especially embryonic development. The generation of adult tissues and organs requires multiple rounds of sequential EMT-MET, which is used to refer an EMT followed with its reversed process, MET  into embryonic stem cells (ESC)-like cells with Oct4, Klf4, c-Myc, and Sox2. The generated cells were named induced pluripotent stem cells (iPSC). iPSC are able to generate tumors containing a variety of tissues from all three germ layers cells after being transplanted into nude mice and viable, fertile live-born progeny by tetraploid complementation (Takahashi and Yamanaka, During the generation of iPSC, multiple changes have been observed with the MEF, including those in gene expression profiles (Brambrink et al., Although MET is necessary for fibroblasts reprogramming, there are still several questions remaining unclear. Firstly, since the process from MEF to iPSC can be considered as a reversed process of embryonic development at least partially, the reversed process of sequential EMT-MET, which is also a sequential EMT-MET, might be observed during iPSC generation. Secondly, the different or even opposite regulatory roles of the four transcriptional factors, like on TGF\u03b21 and TGF\u03b2 receptor 2, make MET induction more complex (Li et al., Briefly, we determined reprogramming efficiencies with totally 74 different infection sequences. One particular infection sequence, Oct4 and Klf4 first, c-Myc next and Sox2 last, generated iPSC with the highest efficiency, about 600% of basal level (Liu et al., The reports on MET during iPSC generation in 2010 suggest this temporary EMT should generate more difficulties for later MET and decrease the reprogramming efficiency at the first glance (Li et al., To explain how short EMT was induced on MEF which are already in mesenchymal state and why sequential EMT-MET promotes iPSC generation, we proposed a new model in previous report (Liu et al., Another available hypothesis is that the optimal mesenchymal state may be more suitable for the cell fate conversions, which is partially supported by the connection between EMT and stem cell characteristics (Hayashida et al., in vitro differentiation of ESC or iPSC is also useful for EMT/MET research because of their similarity to embryonic development and relative simplicity of the system. As a membrane marker for epithelial cells, E-cadherin has also been used as one of the markers for undifferentiated ESC (Li et al., Multiple rounds of sequential EMT-MET make embryonic development an excellent model and hot topic for EMT/MET research Nieto, . HoweverTake the differentiation from iPSC to NSC as an example, immediate up-regulation of N-cadherin, a marker for mesenchymal cells, is essential for the efficient differentiation. However, E-cadherin expression is required to support the self-renewal of NSC (Karpowicz et al., The successful trans-differentiation of somatic cells into functional neurons (Sheng et al., The observations of EMT/MET during different kinds of cell fate conversions do not enable us to answer the question that EMT/EMT is a by-product or a significant cause for cell fate conversions. Take MET during iPSC generation from MEF for example, MEF and iPSC definitely have the characteristics of mesenchymal and epithelial cells respectively. Thus the successful conversion from MEF to iPSC must be accompanied by a MET process. MET is demonstrated to be required for MEF reprogramming, because reprogramming was greatly impaired when EMT was induced or MET was inhibited (Li et al., One way to answer the question above is to study the reprogramming of epithelial cells. Ciliary body epithelial cells have been reported to have higher reprogramming efficiency to iPSC than fibroblasts (Ni et al., Unfortunately, the studies on MET are fewer than those on EMT not only because MET is regarded as a reversed and following process of EMT during embryonic development but also because both MET and EMT employ same regulatory system and most method to inhibit EMT can induce MET (Li et al., 1 phase similar to ESC (Neganova and Lako, Cell cycle regulation is an old topic in cell biology and is observed during almost all kinds of cell fate conversions. iPSC have a high proliferation rate and short G1/S phase, where lies the major difference on cell cycle signatures between MEF and iPSC (Yang et al., On the other hand, EMT and cell cycle regulation are also inter-connected. TGF\u03b2 can lead to proliferation arrest and has extensive interaction with p53 (Adorno et al., 0 phase.To explain the positive correlation between proliferation rate and reprogramming efficiency, Dr. Jaenisch\u2019s laboratory has provided a model which suggested the early phase of MEF reprogramming was a stochastic process (Buganim et al., 1 phase, whereas cells are focused to DNA replication in S phase. Thus genes that specify the original cell fate would be silenced in S phase, as partially confirmed by the relative higher DNA methylation in S phase than G1 phase (Brown et al., 1 phase. Since genes specify original cell fate is in a hypo-methylated state in contrast to the hyper-methylated state of genes specify other cell fates, the cells would keep their original fate without outside stimulants. However, when the expression of genes specifying for other cell fates were increased significantly like during iPSC generation and trans-differentiation, the possibility for cells to switch cell fate will increase significantly. In addition, it is also reasonable to propose that decreasing the overall DNA methylation might facilitate cell fate conversion by reducing the methylation levels on the genes specifying for other cell fates. This hypothesis is supported by the study on Tet1 and lysine-specific demethylase 1 (Chen et al., The following question is what kind of events or markers during cell cycle promote reprogramming. One possibility is the DNA methylation regulation during cell cycle progression (Bou Kheir and Lund, As just discussed on DNA methylation, histone modifications are also required to be duplicated and inherited during cell cycle progression (Probst et al., The histone modifications affect cell fate conversions from a variety of aspects (Papp and Plath, +/CD24\u2212/low on cell surface (Al-Hajj et al., +/CD24\u2212/low population with properties associated with mammary epithelial stem cells like abilities to form mammosphere and to differentiate into myoepithelial or luminal epithelial cells (Mani et al., As mentioned above, EMT was first observed in breast cancer and plays critical roles during cancer progression (Thiery et al., However, the studies on ESC and iPSC are not fully consistent with the hypothesis above. ESC as isolated from inner cell mass are considered to be typical epithelial cells. The epithelial marker, E-cadherin, together with proteins like SSEA1, alkaline phosphatase, Oct4, Nanog, and others have been used to determine the undifferentiated state of ESC (Horie et al., We have provided a brief review on the connection between EMT/MET and cell cycle, epigenetic regulation, and stemness to provide possible mechanisms underlying the contributions of EMT/MET to cell fate conversions. Of course, EMT/MET also twists with other biological processes or factors including cell senescence with telomerase reverse transcriptase (Qiao et al., In our opinion, the well established connections between EMT/MET and large amount of biological processes is the major problem faced by researchers who intend to study the contributions of EMT/MET to cell fate conversions. Firstly, the complex interactions among different biological processes make it difficult to study one aspect at one time. For example, cell cycle, DNA methylation, and tumor progresses have been suggested to function together under certain circumstances (Robertson et al., To solve the problem above, one possibility is to put EMT and MET together and study sequential EMT-MET during cell fate conversions. Sequential EMT-MET has been observed during embryonic development and iPSC generation (Liu et al., To explain why temporary EMT before EMT promotes iPSC generation from MEF, we proposed a hypothesized model with optimal mesenchymal and optimal epithelial states as above. Considering the sequential EMT-MET, the preliminary hypothesis that an optimal mesenchymal may function as intermediate for efficient cell fate conversions might be more reasonable. This hypothesis is able to explain the beneficial effects of temporary EMT during iPSC generation and the opposite roles of EMT on stemness regulation. The hypothesis is supported by the chromosomal instability during EMT and in mesenchymal stem cells (Miura et al.,"}
+{"text": "Modifications aiming at improving their efficiency and their delivery to their target cells are studied. However, their use as drugs is not straightforward. The biological activities of these fragments are mediated by several receptor families. Several matricryptins may bind to the same matricellular receptor, and a single matricryptin may bind to two different receptors belonging or not to the same family such as integrins and growth factor receptors. Furthermore, some matricryptins interact with each other, integrins and growth factor receptors crosstalk and a signaling pathway may be regulated by several matricryptins. This forms an intricate 3D interaction network at the surface of tumor and endothelial cells, which is tightly associated with other cell-surface associated molecules such as heparan sulfate, caveolin, and nucleolin. Deciphering the molecular mechanisms underlying the behavior of this network is required in order to optimize the development of matricryptins as anti-cancer agents.The extracellular matrix (ECM) is a source of bioactive fragments called matricryptins or matrikines resulting from the proteolytic cleavage of extracellular proteins  and proteoglycans . Matrix metalloproteinases (MMPs), cathepsins, and bone-morphogenetic protein-1 release fragments, which regulate physiopathological processes including tumor growth, metastasis, and angiogenesis, a pre-requisite for tumor growth. A number of matricryptins, and/or synthetic peptides derived from them, are currently investigated as potential anti-cancer drugs both  Matricryptins are biologically active fragments released from extracellular matrix (ECM) proteins and glycosaminoglycans by proteases  collagen prolylyl hydroxylase  is composed of two membrane associated proteins (the protective protein/cathepsin A and neuraminidase-1) and of the elastin-binding protein, an inactive spliced variant of lysosomal \u03b2-galactosidase . These trials include phase I (Lin et al., Clinical trials of endostatin mostly focus on solid tumors in association with cytotoxic drugs (fundus oculi angiogenesis diseases (Zhang et al., in vivo and exerts anti-fibrotic activity (Nishimoto et al., Several matricryptins such as the propeptide of lysyl oxidase, which is a tumor suppressor (Min et al., SV drafted the Section Receptors and Co-receptors of Matricryptins and Table The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recently, two groups have reported that FMRP is important in the replication stress (RS) response and may play a role in meiosis  in response to RS, rather than double strand break (DSB), is suppressed when endogenous FMRP is down-regulated. This suppression can be rescued by exogenous expression of wild-type FMRP but not by its nucleosome-binding-deficient mutant T102A or Y103L. Similar phenomena were also observed by Zhang et al. in a Drosophila S2 cells, while Alpatov et al. demonstrated that Fmrp levels in total lysate of mouse embryonic fibroblasts (MEFs) reduces slightly upon aphidicolin (APH) treatment. Using fractionation and immunofluorescence (IF) data, they both conclude that FMRP is recruited to chromatin upon RS.Zhang et al. found that dFmr1 increases at both the mRNA and protein levels in replication-stressed Due to the nature of FMRP, such a fractionation strategy may not be suitable for researching the intracellular localization of the protein. It has been well-established that FMRP is tightly associated with the ribosome and the rough endoplasmic reticulum (RER)  to facilitate IF detection of nuclear FMRP. Zhang et al. demonstrated that dFmr1 accumulate in an S2 nucleus treated with combination of hydroxyurea (HU) and LPB, but not with HU or LPB alone, and that the dFmr1 signal concentrates in the Hoechst dull staining area. In MEFs, Fmrp staining is proximal to DAPI-condensed chromocenters, reminiscent of the centromere localization of PARP-1, which has been reported to interact with FMRP , indicating that FMRP chromatin function is independent of its canonical mGluR function. However, as reported by Reeve et al.  is necessary to clarify its locus on chromatin (if ChIP-grade anti-FMRP is available). The data will provide deeper insight into the chromatin function of FMRP and also provide supporting information about whether or what histone modification recruits FMRP st year since the property of FMRP protein was initially characterized. As a cytoplasmic protein also functioning in chromatin, FMRP opens a new chapter of its story (Fig.\u00a0This year marks the 21"}
+{"text": "Together these diverse perspectives spin an intricate web of ion channel regulation in the nervous system.Ion channels are complex hetero-oligomeric structures characterized by large, dynamic interaction networks, or \u201cinteractomes.\u201d In addition to directing channel localization, density and ion fluxes, these complexes facilitate downstream signaling events. Moreover, pathological modulation of these networks contributes to neurological dysfunction. Our contributors to this Research Topic, Described by Fan et al.  as a \u201cmuSeveral other contributions shed light on the new insights into the function and composition of interactomes of various voltage-gated channels, regulated leak channels, and so called large pore channels.+ channel regulatory proteins are growing in complexity in terms of function and type. Known to regulate activation and trafficking of muscarinic receptor-activated Kir3 channels, Zylbergold et al. , by the so-called auxiliary subunits, dipeptidyl peptidase-like proteins (DPLPs) and Kv4 channel interacting proteins (KChIPs). While these were amongst the first identified interactors  and low voltage-activated Ca2+ channels (Cav3) functionally interact with other conductances to regulate signal processing in the cerebellum.Traditionally viewed as auxiliary subunits, Kd et al.  provide d et al.  focus spd et al.  describes et al.  review hElusive until recently, understanding of this regulated leak channel whose loss in mice is lethal (Lu et al., Permeable to ions and small metabolites like ATP, Panx1 channels gained early notoriety as \u201cdeath pores\u201d in ischemic stroke and seizure (Thompson et al., 2+ entry. They describe foundational work implicating STIM1 as the Ca2+ sensor in this process critical for maintaining neurotransmission. Further they outline key physical interactions between STIM1 with Ca2+-release activated channels and voltage-gated Ca2+ channels that coordinate the activation and inhibition of these types of channels, respectively. Finally, two papers by Wilson et al. (2+ channels.A number of contributions underscore the capacity of \u201cpromiscuous\u201d intracellular proteins to modulate a variety of ion channels and receptors through physical interaction. Reviewed by Donnelier and Braun , cysteinn et al. ,b focus Adding further complexity to ion channel networks is consideration of lipid membrane composition and lipid second messengers. In the sole lipidome-oriented contribution, Raboune et al.  identifyWhile daunting, elucidating these macromolecular intricacies has a translational silver lining: while difficult to identify and unravel, the myriad interaction loci revealed by studying these interactions present unique opportunities for discrete, and potentially safer therapeutic intervention. For example, selective blockade at key interaction loci with cell-permeable peptides now provides an infinite number of ways in which interactomes can be discretely modulated to improve health outcomes.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Depression is a heterogeneous mood disorder that has been classified and treated in a variety of ways. Although, a number of synthetic drugs are being used as standard treatment for clinically depressed patients, but they have adverse effects that can compromise the therapeutic treatments and patient's compliance. Unlike, synthetic medications, herbal medicines are widely used across the globe due to their wide applicability and therapeutic efficacy associated with least side effects, which in turn has initiated the scientific research regarding the antidepressant activity. This review is mostly based on the literature of the last decade, aimed at exploring the preclinical profile of plant-based alkaloids (the abundant secondary metabolite) as an emerging therapy for depression. Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behavior, feelings and sense of well-being Sandra, . People The current antidepressant drugs are facing many challenges as mentioned by Alexander and Preskorn , in his Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral (McNaught and Wilkinson, Psychotria myriantha Mull. which exhibited antidepressant-like effect when studied on a 5-HT system in rat hippocampus (Farias et al., Annona cherimolia, including 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine. The results showed that repeated treatment with this plant produced an antidepressant-like action in mice (Mart\u00ednez-V\u00e1zqueza et al., Rhazya stricta. Acute administration of the lyophilized extract of R. stricta resulted in a significant antidepressant-like effect in experimental animals (Ali et al., Mitagyna spicosa. Mitagynine i.p injection significantly reduced the immobility time of mice in both forced swim test and tail suspension test without any significant effect on locomotor activity (Idayu et al., Ziziphus apetala which showed strong activity against 11-\u03b2-hydroxysteroid dehydrogenase inhibition in vitro (Han et al., Aconitum baicalens exhibited an antidepressant-like effect in an animal model of depression (Nesterova et al., Boerhaavia diffusa Linn. It showed significant antidepressant activity in unstressed and stressed mice in different models (Dhingra and Valecha, Evodia fructus and found that it could reverse the decreases of sucrose preference, a number of crossing, 5-HT, and Na level and also increase immobility time (Jiang et al., Sceletium tortuosum have antidepressant property in animal studies (Loria et al., Piper nigrum. Its antidepressant activity has been observed in mice exposed to both chronic and acute stress. It caused a significant change in both immobility and swimming times (Wattanathorn et al., Piper laetispicum. When tested in the forced swim test, it caused a significant dose-dependent decrease in mobility at various test doses and thus possessed antidepressant activity (Yao et al., Dactylicapnos scandens Hutch, had an antidepressant effect in mice. It dose-dependently reduced the immobility time in the tail suspension test and thus could be effective for the moderate state of depression (Xu et al., The antidepressant effect of various plant alkaloids has been reported in the literature Table . Braziliin vitro and, therefore, could be the possible mechanism for its antidepressant effect (Han et al., Aconitum baicalense, improved serotonergic system activity in an animal model of depression (Nesterova et al., in vitro assays (Xu et al., Strictosidinic acid probably exhibited antidepressant effect due to an inhibition of monoamine oxidase activity (Farias et al., Our review on the basis of available literature suggested that alkaloids could play a potential role as natural antidepressants. Keeping in mind their abundance in nature, the alkaloids could be an economical source of healing the depressive disorder. The available therapeutic agents fail to produced effect in all patients; approximately 30\u201340% failure has been reported to first-line antidepressant drugs accompanied by the very slow onset of action. Several alkaloids are in clinical practice and producing outstanding results in different therapeutic classes. These reported alkaloids though evoked antidepressant effects in various animal studies, but still deficient in clinical evidence. In conclusion, enough scientific evidence gathered in our review supported that the plant-based alkaloids can serve as leads for antidepressant drug discovery. It is key to subject these alkaloids to further clinical studies for efficacy, potency, and safety to ensure their clinical status.SP carried out all the literature survey and written an initial draft of the review and AK draw the structures of compounds and help in review-draft. HK supervised the overall project and finalized the final version of the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Brueelia-complex (Bush et al., 2015Brueelia-complex and 30 outgroup taxa selected from across the order Phthiraptera. Also included are phylogenetic reconstructions based on Bayesian inference analyses of combined COI and EF-1\u03b1 sequences for Brueelia-complex species and outgroup taxa.Data is presented in support of a phylogenetic reconstruction of one of the largest, and most poorly understood, groups of lice: the"}
+{"text": "International experience and evidence-based practices have shown that reduction in variability through use of protocolized perioperative care improves surgical outcomes and reduces costs to patients and healthcare systems. In this series of Expert Opinions, we provide consensus recommendations for the various components of perioperative care to aid with the development of enhanced recovery after surgery protocols. Early ambulation, early feeding, and early return of bowel function are linked with quicker recovery, earlier discharge, and improved satisfaction. Postoperative nausea and vomiting (PONV) is a common complication following abdominal surgical procedures with patient , anesthetic (use of opioids and volatile anesthetics), and surgical  factors contributing to its incidence and severity. Nausea and vomiting should be viewed as existing on a continuum, and sequelae and patient discomfort vary based on patient experience, surgical procedure, and recovery profile. Guidelines for its avoidance and treatment are based on evidence-based literature, expert opinion, and professional association recommendations [ASPAN\u2019S evidence-based clinical practice opinion for the prevention and/or management of PONV/PDNV. J Perianesth Nurs 2006 [Gan et al. 2007] Gan et al. 2014. Gan et al. 2003. Use of volatile anestheticsIntraoperative use of opioidsSurgical/anesthetic timeSmoking (tobacco use decreases PONV risk)Modifiable risk factorsFemale sexYoung age (<50)History of PONVSurgical location Surgical technique (laparoscopic)Non-modifiable risk factors Apfel et al. 2012a Prophylaxis of PONV is based on a number of risk factors\u00a0. Prophylaxis and treatment should rely on modification of anesthetic technique, if possible, and the use of medications that work at a variety of receptor sites allowing for full multimodal benefit. Non-pharmacologic techniques include ensuring appropriate analgesia and hydration, acupuncture/acupressure, and aromatherapy. Pharmacologic techniques include medications that work at different receptor sites:All patients should receive PONV prophylaxis during the perioperative period. The numbers of medications used for treatment and prophylaxis should be determined by the number of modifiable and non-modifiable risk factors. Medications used should represent different mechanisms of action in an attempt to achieve multimodal benefit Tram\u00e8r 2001."}
+{"text": "During the Oligo\u2010Miocene, major phases of phosphogenesis occurred in the Earth's oceans. However, most phosphate deposits represent condensed or allochthonous hemipelagic deposits, formed by complex physical and chemical enrichment processes, limiting their applicability for the study regarding the temporal pacing of Miocene phosphogenesis. The Oligo\u2010Miocene Decontra section located on the Maiella Platform  is a widely continuous carbonate succession deposited in a mostly middle to outer neritic setting. Of particular interest are the well\u2010winnowed grain to packstones of the middle Miocene Bryozoan Limestone, where occurrences of authigenic phosphate grains coincide with the prominent carbon isotope excursion of the Monterey event. This unique setting allows the analysis of orbital forcing on phosphogenesis, within a bio, chemo, and cyclostratigraphically constrained age\u2010model. LA\u2010ICP\u2010MS analyses revealed a significant enrichment of uranium in the studied authigenic phosphates compared to the surrounding carbonates, allowing natural gamma\u2010radiation (GR) to be used as a qualitative proxy for autochthonous phosphate content. Time series analyses indicate a strong 405 kyr eccentricity forcing of GR in the Bryozoan Limestone. These results link maxima in the GR record and thus phosphate content to orbitally paced increases in the burial of organic carbon, particularly during the carbon isotope maxima of the Monterey event. Thus, phosphogenesis during the middle Miocene in the Mediterranean was controlled by the 405 kyr eccentricity and its influence on large\u2010scale paleoproductivity patterns. Rare earth element data were used as a tool to reconstruct the formation conditions of the investigated phosphates, indicating generally oxic formation conditions, which are consistent with microbially mediated phosphogenesis. Phosphogenesis during the Monterey event forced by 405 kyr eccentricity controlled paleoproductivityGamma radiation is directly linked to phosphogenesis via U enrichment of authigenic phosphateTrace elements show the phosphates formed under microbially mediated and well\u2010oxygenated conditions This also presupposes the need for sections with well\u2010established correlations to both global chronostratigraphy as well as global climatic records. Furthermore, phosphogenesis needs to be studied with sufficiently high temporal resolution to estimate changes in the amount of phosphate formed over time, in order to accurately correlate them with established palaeoecological and paleoclimatological records. To that end the Decontra section, which is a well\u2010established shallow\u2010marine reference section, with a robust orbitally tuned stratigraphic framework [F\u00f6llmi, Mutti and Bernoulli, Hubert et al., Crosby and Bailey, F\u00f6llmi, Filippelli, Delaney, Schenau et al., Slomp et al., van der Zee et al., Paytan and McLaughlin, Slomp and Van Cappellen, Recent studies found that most occurrences of phosphogenesis in the present day and ancient oceans were directly mediated by microbial activity, irrespective of the marine setting in which they formed [The present work deals with three questions regarding phosphogenesis in the Decontra section during the MMCO and Monterey event: (1) Determine the phosphate contents on a sufficiently high\u2010resolution to correlate them with global climatic records; (2) Apply selected rare earth element (REE) proxies to reconstruct the formation history of the phosphates, in order to put them into relation to the already established paleoenvironmental history of the section; (3) Find the dominant uranium\u2010bearing phase using electron microprobe and LA\u2010ICP\u2010MS analyses and understand the proxy\u2010relationship between these phases and existing gamma log data.2Vecsei and Sanders, Crescenti et al., Mutti et al., Vecsei et al., Vecsei and Sanders, Carnevale et al., The late Oligocene to late Miocene Decontra section lies on the northern slope of the Orfento river valley  southeast of the village Decontra on the Maiella mountains in Central Italy  The Cerratina cherty Limestone\u2014a 35 m thick succession of hemipelagic wackestones to packstones dominated by planktic foraminifers containing chert nodules, phosphatized foraminiferal tests, and sponge spicules. The first occurrence of the planktic foraminifer Praeorbulina sp. in the upper part of this unit indicates an age of <16.2 Ma; (3) The 32 m thick Bryozoan Limestone dominated by winnowed bryozoan grainstones with abundant planktonic and benthic foraminifers; (4) The 3 m thick Orbulina Limestone with abundant Orbulina sp.; (5) The Lithothamnium Limestone characterized by abundant red algal fragments overlying the Orbulina Limestone with a sharp contact. The base of the Lithothamnium Limestone is a 1.5 m thick horizon containing abundant Heterostegina fragments [see Reuter et al., Vecsei and Sanders, Carnevale et al., Reuter et al., Auer et al., Vecsei and Sanders, Cornacchia et al., Reuter et al. [Within the section five lithostratigraphic units are described Figure : (1) Ther et al.  and the inifera;  The CerrMutti and Bernoulli, Reuter et al., Mutti and Bernoulli, Reuter et al., Reuter et al., Auer et al., Orbulina Limestone, is interpreted as the Ser4/Tor1 sequence boundary [Reuter et al., Orbulina Limestone to \u223c15.24\u2013\u223c11.92 Ma, indicating generally low but continuous sedimentation within this part of the section [Auer et al., The Decontra section is also well known for occurrences of authigenic phosphate, particularly within the middle Miocene Bryozoan Limestone, where a prominent phosphatic hardground occurs [3Reuter et al., Auer et al., 2O5 content and check for impurities in the limestone  as well as JLS\u20101  were measured as unknowns and reproduced within the reported errors for major components including P2O5.The gamma\u2010ray measurements were carried out in the field in 2012 using a portable \u201cGS\u2010512\u201d gamma\u2010ray spectrometer , and are reported in total counts (TC) [2O5 was subsequently correlated with the reported gamma\u2010ray values from the field measurements. Comparison was done by averaging the gamma\u2010ray measurements in the vicinity of the sampling spot. The results of this comparison together with the correlation coefficient were plotted in a standard cross plot  of the samples were prepared and documentation of phosphatic grains was performed by backscattered electron (BSE) imaging, using a Jeol Superprobe JXA\u20108200 electron microprobe (EMP) at the Eugen F. Stumpfl Electron Microprobe Laboratory, UZAG . Figure .Williams et al., [Fryer et al., Using the BSE images, suitable phosphates were selected for LA\u2010ICP\u2010MS analyses. LA\u2010ICP\u2010MS analyses were performed at the NAWI Graz Central Lab \u201cWater, Minerals and Rocks\u201d (University of Graz and Graz University of Technology), in order to obtain concentrations for U, Th, and selected rare earth element  610 of the National Institute of Standards and Technology, Gaithersburg, MD, USA. Values for the SRMs reported by m et al.  were appJochum et al., Evans and M\u00fcller, Caragnano et al., Williams et al., http://georem.mpch-mainz.gwdg.de) [Jochum et al., While the NIST SRM glasses are not matrix\u2010matched to the analyzed carbonate and phosphate material, they offer distinct benefits compared to various matrix\u2010matched standards . Several analytical studies using biogenic carbonates and authigenic apatite found that the analytical advantages offered by the NIST SRM glasses outweigh the disadvantages of standardization using an unmatched matrix, which is largely based on the much better known trace element concentration of the NIST reference glasses compared to other standards [Koenig et al., Electron microprobe (EMP) analyses were subsequently carried out in close proximity to the LA\u2010ICP\u2010MS craters, after repolishing the samples. Since the grains are complex and often highly porous mineral aggregates of calcium fluor apatite and calcium carbonate, EMP analysis did not yield results close to the theoretical value of fluor apatite and calcite. Thus, all calculations of analyzed phosphates as well as calcium carbonates utilize a consistent CaO concentration of 55 wt. % as the internal standard value [e.g., 3.1Prior to interpretation, the measurements were evaluated for mixed signals of phosphate grains and surrounding carbonate rock based on their major elements . This preevaluation excluded several spots from the subsequent data analyses .McLennan, Alibo and Nozaki, Shields and Stille, Haley et al., Garnit et al., REE concentrations for each spot were transformed into shale\u2010normalized REE concentrations using the Post Archean Australian Sedimentary Rocks (PAAS) standard [German and Elderfield, Bau and Dulski, Morad and Felitsyn, Shields and Stille, Garnit et al., German and Elderfield [De Baar et al. [PAAS normalized REE concentrations were then used to calculate the Ce anomaly, a useful tool for the characterization of paleoredox conditions [derfield  defined r et al. .  [Hammer et al., The REDFIT power spectrum for the Bryozoan Limestone shown in Figure r et al.  and used44.1Amphestigina, Elphidium, and miliolids) and corallinaceans are common [Reuter et al., Mutti and Bernoulli, Reuter et al., Thin section analysis of the 27 samples taken within the Bryozoan Limestone reveals well\u2010winnowed carbonatic grainstones, predominantly composed of bryozoan and echinoid derived skeletal fragments containing a variable amount of planktonic and benthic foraminifera. In the lowermost 2 m of the unit below, the microbially formed phosphatic hardground, notable occurrences of benthic foraminifera  , showing that potassium is not a major gamma\u2010ray source for the sediment .Results of the XRF analysis show that all samples are very pure carbonates, with only race amounts of SiO4.2LA\u2010ICP\u2010MS and EMP analyses reveal that most investigated phosphatic grains likely represent complex microcrystalline aggregates of phosphate and calcium carbonate, making accurate analysis of the mineral composition difficult. This was further corroborated by the performed electron microprobe analysis of the samples. Nevertheless, matrix standardized results reveal a significant U enrichment of phosphate containing grains in gamma\u2010ray sources compared to the surrounding purely carbonatic host material. Results of the LA\u2010ICP\u2010MS analyses show that the uranium content in the investigated phosphate grains is consistently elevated ranging between 13.5 and 131 ppm, with an average of 48.4 ppm and a median of 43.5 ppm. By comparison, the uranium concentration in the carbonate matrix ranges between 0.17 and 1 ppm, with an average of 0.44 ppm and a median of 0.39 ppm. The standard deviation of the U concentration in the biogenic carbonates is 0.25 ppm. These values result in an average enrichment of roughly 1:111 of uranium in the phosphatic grains compared to the carbonate matrix. Thorium content is comparably low in most analyzed grains, with only three grains showing significantly elevated Th content, in the range of \u223c30 ppm , indicating overall weak contribution of 40K to the total gamma ray counts. K2O is furthermore only weakly correlated with gamma\u2010ray intensity  and both large and small\u2010scale patterns occur within the gamma\u2010ray (GR) record of the Decontra section [2O5 and total gamma radiation counts . TOC is generally lost in the sedimentary record, as it is quickly dissolved and refracted by biological processes in most settings. This also explains the comparably low organic carbon content of the investigated grainstones Figure . TOC val5.2Auer et al., 2O5 content of the XRF measurements of discrete rock samples  is assumed to be the predominant U bearing mineral phase within the sediment [s Figure a.Compton et al., The fact that no other significant U sources occur within the sediment, and U concentrations of the carbonates remained relatively constant  in the marine realm [\u22121) [Auer et al., O'Brien et al., Mutti and Bernoulli, Reuter et al., Auer et al., The comparably low sedimentation rates for the Bryozoan Limestone , the main constituent of marine snow, acts as a transport mechanism for organically bound phosphate to the sediment.F\u00f6llmi, Mutti and Bernoulli, Arning et al., Filippelli, Crosby and Bailey, This setting led to a complex interplay of organic matter transport , authigenic/microbial phosphate formation, and uranium incorporation. Release of OM\u2010derived P in the sediment pore water occurred through degradation of both microbial mats and marine snow through microbial activity within the sediment. Microbes at the sediment water interface used POM as nutrient source, which in turn liberated P and U into a closed biochemically controlled micromilieu at the sediment water interface [Davey and O'toole, F\u00f6llmi, Schenau et al., van der Zee et al., Paytan and McLaughlin, Filippelli, Crosby and Bailey, Reuter et al., Auer et al., Thin section and geochemical evidence  within in the sediment, without significant mixing or enrichment from the overlying ocean water and in conjunction with the activity of magnetotactic bacteria [Bau and Dulski, German and Elderfield, German and Elderfield, Bau and Dulski, Alibo and Nozaki, Morad and Felitsyn, Haley et al., Shields and Stille, Garnit et al., Emsbo et al., REE signatures show a negative Ce anomaly in both the carbonate matrix and all investigated phosphatic grains using the Ce/Ce* versus Pr/Pr* plot [Reynard et al., Shields and Stille, Garnit et al., Reynard et al., A slight trend toward more negative La/Sm values as well as enriched La/Yb values occurs in our data. This suggests that both phosphates and carbonates in the Decontra section were affected by substitution processes as well as adsorption processes during early diagenesis [Auer et al., This creates a good explanation for the largely in\u2010phase variability of both the magnetic susceptibility and GR records of the Decontra section [5.4Filippelli, Mutti and Bernoulli, Reuter et al., Vincent and Berger, Jacobs et al., Abels et al., Mourik et al., Holbourn et al., J. C. Zachos et al., J. Zachos et al. Harzhauser et al., Economically viable phosphorites are generally deposited as lag deposits or hardgrounds formed during episodes of nondeposition or even active sediment removal. Thus, virtually all global phosphorite deposits are generally unrelated to primary P accumulation within the sediment and subsequent phosphogenesis [F\u00f6llmi, Filippelli, van der Zee et al., Filippelli, Holbourn et al., Our results indicate that the well\u2010known link between the carbon and phosphorous cycle [Compton et al., F\u00f6llmi, Jacobs et al., John et al., F\u00f6llmi et al., Holbourn et al., Diester\u2010Haass et al., Holbourn et al., Our results provide insights into the pacing and formation requirements of the widespread middle Miocene shallow marine phosphorite deposits [13C record during the Monterey event [Holbourn et al., Diester\u2010Haass et al., Holbourn et al., Diester\u2010Haass et al., Holbourn et al., Our model is thus in accordance with the hypothesis that variations in ocean circulation are the cause of the 405 kyr eccentricity\u2010forcing observed in the \u03b46Mutti and Bernoulli, Reuter et al., Auer et al., The present study uses LA\u2010ICP\u2010MS data of carbonate grainstone as well as authigenic phosphate to characterize microbially mediated phosphogenesis in the middle Miocene Bryozoan Limestone of the Decontra section in the Maiella mountain range . Our results show that: (1) primary microbially controlled phosphogenesis persisted throughout the Bryozoan Limestone in accordance with previous studies [Supporting Information S1Click here for additional data file.Table S1Click here for additional data file."}
+{"text": "Matricaria chamomilla L. essential oils and a potent pro-apoptotic molecule  and enhanced the production of tumor growth factor-beta 1 (TGF-\u03b21) on NCTC 2544 keratinocytes, although it did not change the activity of monocytes and dendritic cells , as the major mechanism of tumor immune escape, a crucial hurdle for tumor immunotherapy (Jacobs et al., in vitro cultured keratinocytes (Frikeche et al., +CD25+FoxP3+ regulatory T cells, through TGF-\u03b2 expression (Baumgartner et al., in situ.Darra et al., reported that the anti-neoplastic action exerted by \u03b1-bisabolol, derives fundamentally by its ability in inducing mitochondria-mediated apoptosis in cancer cells (Darra et al., In vitro research usually neglected this issue, as most of investigations based on cell lines obviously never consider the immune microenvironment existing in the in vivo situation. In this perspective, the recent article by Frikeche et al., raises some criticism about the actual role of \u03b1-bisabolol as a real, promising chemopreventive molecule.Despite its promising activity as an anti-tumor molecule, \u03b1-bisabolol does not possess so different features respect to the widest family of plant-derived anti-inflammatory and chemopreventive polyphenols (Chirumbolo, Alpha bisabolol might affect mitochondrial permeability transition also in non cancer cells (Leanza et al., in vitro cancer lines, such as MiaPaCa, should be considered with caution.As with other phytochemicals, the role of \u03b1-bisabolol on cancer therapy should be expanded in future debates, while any further proposals to investigate this organic compound on The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood\u2013brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-\u03b2, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-\u03b3, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-\u03b2. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction. As highlighted by recent expression profiling studies, the majority of the genes acutely modulated in the blood of stroke patients are implicated in the regulation of the innate immune system  and specialized cells, activated in the brain or recruited from the periphery, actively participate to the detrimental processes implicated in tissue damage, as well as to the repair and regeneration phases  and cytokine signaling pathways -\u03b3  proteins and other DAMPS, plays an important role in ischemic brain injury , represent promising therapeutic options, effective in reducing the inflammatory response to stroke injury  is a member of the immunoglobulin family of cell surface receptors and has been implicated in the development and progression of stroke. The full-length, membrane-bound RAGE isoform (fl-RAGE) is mainly expressed in neurons and in microglia/macrophages. Up-regulation of this receptor has been documented after both permanent and transient focal cerebral ischemia in rodents  has been reported in rats subjected to either transient or permanent focal brain ischemia -1\u03b1 have been correlated with favorable long-term outcome  and MIP-1\u03b1 have been shown to play an important role in promoting tissue damage via recruitment of inflammatory cells  deficiency exacerbates ischemic brain damage by upregulation of proinflammatory cytokines and this Zn finger-containing immunoregulatory protein also participates in LPS- and electroacupuncture-induced ischemic stroke tolerance  occurring in peri-ischemic regions 2\u20137 days after focal ischemia in mice is coincident with the delayed increase of MMP-9, suggesting its involvement in neurovascular remodeling (Zhu et al., 2+ homeostasis in neurons through activation of EP1 receptors (Kawano et al., After an ischemic insult, the expression of COX-2 is elevated in neurons, vascular cells and neutrophils, as demonstrated both in stroke patients and in animal models (Nogawa et al., in vitro (Kim et al., COX-2 has been implicated in hyperbaric oxygen preconditioning, since pharmacological inhibition of this enzyme abolishes the beneficial effects of the conditioning stimulus in a rat model of transient global cerebral ischemia (Cheng et al., de novo expression of inducible NOS contribute to ischemic tissue damage (Iadecola et al., While elevated expression of inducible NOS is associated with ischemic (Cho et al., NO plays a crucial role in cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats (Horiguchi et al., Although ischemic stroke is a major cause of mortality and long-term disability worldwide (Go et al., All the authors participated in the collection, review, and analysis of the relevant literature, as well as to drafting and revising of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sepsis is an infection-initiated systemic inflammatory syndrome with an estimated incidence of 18 million cases annually worldwide. Despite advances in intensive care and supportive technology, the mortality rate of sepsis still ranges from 15% to 80%, reminding scientists and clinicians that it remains to be a major clinical challenge. The key to winning the \u201ccampaign\u201d to combat sepsis is improved understanding of the epidemiology, pathogenesis, and biomarkers of sepsis and discovery of novel therapies. The present special issue shows several encouraging results and provides comprehensive reviews of the latest advances in this field. in vitro, in vivo, and genetic studies on the effects of defensins as well as the corresponding mechanisms within sepsis. Their review, \u201cDefensins and Sepsis,\u201d also points out that the function of defensins reflects both their immunomodulatory and broad-spectrum antimicrobial effects.The effector cells from the innate and adaptive immune systems play a crucial role in sepsis. Dendritic cells, in particular, serve as professional antigen presenting cells and are involved in the aberrant immune response to sepsis. In this special issue, X. Fan et al. discuss the effects of sepsis on the amount, surface molecule expression, cytokine secretion, and T-cell activating function of dendritic cells and the underlying mechanisms in their review \u201cAlterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis.\u201d Recent postmortem studies of patients who died of sepsis showed that depletion of CD4 and CD8 lymphocytes is an important characteristic. Thus, knowledge of these circulating lymphocyte abnormalities is relevant for the understanding of sepsis pathophysiology. R. de Pablo et al., who have previously reported on the alteration of B cells, natural killer cells, and T-cell function in septic patients, summarize their latest findings on the role of blood lymphocytes in sepsis and discuss the different kinetic patterns of lymphocyte subsets and their relationship to outcome in their review \u201cRole of Circulating Lymphocytes in Patients with Sepsis.\u201d Both the clinical and basic researches have shown that sepsis-associated immunosuppression is associated with adverse outcomes. A novel heterogeneous population of immature myeloid cells that possess immunosuppressive activities, termed myeloid-derivedsuppressorcells(MDSCs), has gainedmuchattention in recent sepsis studies. D. Lai et al. discuss the complex functions of MDSCs in the pathogenesis of sepsis. Their review \u201cMyeloid-Derived Suppressor Cells in Sepsis\u201d also proposes that the overall role of MDSCs involves much more than simply being an immunosuppressive cell population. These 3 review articles provide a comprehensive analysis of the major important immune cells in sepsis and highlight potential therapeutic targets. As a group who have investigated the function of the family of defensins in sepsis for nearly 10 years, G.-H. Xie et al. summarize the\u03baB-Mediated Inflammatory Response.\u201dAlthough the international Surviving Sepsis Campaign guidelines have been released for 10 years, sepsis remains a fatal syndrome due to the lack of efficient biomarkers and novel treatments. D. N. Nguyen et al. investigated plasma cortisol levels in septic patients with delirium and coma and found that cortisol is a potential biomarker of brain dysfunction in their article \u201cCortisol Is an Associated-Risk Factor of Brain Dysfunction in Patients with Severe Sepsis and Septic Shock.\u201d F. Song et al. and P. Madhusudan et al. discuss two important but controversial issues related to the Surviving Sepsis Campaign Guidelines. In a meta-analysis of 12 randomized trials involving 4100 septic patients, \u201cIntensive Insulin Therapy for Septic Patients: A Meta-Analysis of Randomized Controlled Trials,\u201d F. Song et al. reported no benefit and a higher incidence of hypoglycemia with intensive insulin therapy compared with conservative glucose management. P. Madhusudan et al. discuss the current debate on the choice, amount, and end points for fluid resuscitation in sepsis in their review \u201cFluid Resuscitation in Sepsis: Reexamining the Paradigm.\u201d K. Xie et al. investigated the therapeutic function of hydrogen gas in a septic animal model for several years, and, in their present review, \u201cHydrogen Gas Presents a Promising Therapeutic Strategy for Sepsis,\u201d they summarize the progress of hydrogen treatment in sepsis. J. Zhou et al. and X. Li et al. explore novel drugs for sepsis from the perspective of the neuroendocrine network in sepsis in their two studies, \u201cEpinephrine Enhances the Response of Macrophages under LPS Stimulation\u201d and \u201cAgmatine Protects against Zymosan-Induced Acute Lung Injury in Mice by Inhibiting NF-In this present special issue about the pathogenesis, biomarkers, and treatment of sepsis, the authors provide comprehensive reviews and attractive research perspectives on the mechanisms of sepsis which we hope will inspire researchers investigating novel biomarkers and therapeutic sepsis targets."}
+{"text": "Escherichia coli (STEC) are a group of diarrheagenic bacteria associated with foodborne outbreaks. Infection with these agents may result in grave sequelae that include fatality. A large number of STEC serotypes has been identified to date. E. coli serotype O104:H4 is an emerging pathogen responsible for a 2011 outbreak in Europe that resulted in over 4000 infections and 50 deaths. STEC pathogenicity is highly reliant on the production of one or more Shiga toxins that can inhibit protein synthesis in host cells resulting in a cytotoxicity that may affect various organ systems. Antimicrobials are usually avoided in the treatment of STEC infections since they are believed to induce bacterial cell lysis and the release of stored toxins. Some antimicrobials have also been reported to enhance toxin synthesis and production from these organisms. Various groups have attempted alternative treatment approaches including the administration of toxin-directed antibodies, toxin-adsorbing polymers, probiotic agents and natural remedies. The utility of antibiotics in treating STEC infections has also been reconsidered in recent years with certain modalities showing promise.Shiga toxin-producing  Escherichia coli (STEC) are a group of bacterial organisms that are capable of producing one or more types of Shiga toxin (Stx). STEC are associated with a disease spectrum ranging from diarrhea and hemorrhagic colitis (HC) to the potentially fatal hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). STEC infections are typically food-borne  that has acquired the ability to produce Stx2, typically produced by enterohemorrhagic E. coli (EHEC) rather than EAEC group members. This may have occurred via horizontal gene transfer resulting in a new E. coli virotype dubbed the Enteroaggregative Hemorrhagic E. coli or EAHEC (Bloch et al., E. coli O104:H4 and humans are believed to be the major reservoir for this organism (Wieler et al., E. coli O104:H4 was relatively similar to that caused by other STEC infections some pertinent differences existed. For instance, about a quarter of subjects affected developed HUS during the 2011 outbreak, which is 2\u20135 fold higher than the rate usually observed for an STEC infection (WHO, Perhaps highlighting the relevance of monitoring these non-O157 serotypes was the emergence of the rather notorious The lack of an effective treatment strategy for an STEC infection has made these agents a prominent public health threat and a burden to the medical community at large. The currently recommended management of an STEC infection mainly relies on supportive therapy and hydration Thorpe, . The useThe debatable use of antimicrobial agents for the treatment of an STEC infection has led to the rise of various alternative treatment approaches Table . These hin vitro and were demonstrated to protect challenged mice when administered intravenously (Nishikawa et al., in vitro and in animals (Kitov et al., in vitro and upon testing in animals (Paton et al., in vitro. This agent, however, was not effective in clinical trials (Trachtman et al., Various agents that mimic Stx receptors and bind them thus reducing their availability to cellular receptors have been developed. Carbosilane dendrimers harboring Gb3 at their termini neutralize Shiga toxins cycl, was shown to protect cells in culture against Stx (Noel et al., Cell permeable agents that can bind Stx2 and potentially interfere with its intracellular trafficking have been reported. These include Ac-PPP-tet (Watanabe-Takahashi et al., E. coli O104:H4 outbreak (Lapeyraque et al., E. coli O104:H4-induced HUS results in no additional benefits (Kielstein et al., Preparations of antibodies that can bind Shiga toxins and neutralize their effects have been reported. Anti-lipopolysaccharide antibodies have shown protective abilities upon laboratory assessment (Paton et al., in vitro or in experimental animal models; however, they have not been evaluated in clinical studies. Worth noting is a study that showed a synergistic effect between green tea extract and an antibiotic, levofloxacin, in the treatment of an STEC-infected mouse model (Isogai et al., Various natural products have been considered as potential therapeutic agents for STEC infections. These have included lactic acid (Pittman et al., The use of antimicrobial agents in treating STEC infections has been controversial and the subject of an ongoing debate. While some studies indicated that the use of particular agents may increase the risk of HUS, others have reported a decrease of this risk upon implementation of antimicrobials. While these observations may be particular to certain agents at some doses, the potential risk of antimicrobial treatment inducing HUS has led to a general contraindication of such agents (Qadri and Kayali, in vitro; these include the quinolones, trimethoprim, and furazolidone (Kimmitt et al., E. coli O104:H4 from the 2011 outbreak in Europe do not display an increase in toxin production upon treatment with meropenem, ciprofloxacin, chloramphenicol, or fosfomycin, unlike E. coli O157:H7 (Corogeanu et al., E. coli O157:H7 and in E. coli O104:H4. A sub-MIC concentration may, after all, be the concentration available locally at the site of infection. We noted that the response is variable depending on the isolate used and the concentration of antimicrobial implemented (Nassar et al., Several antimicrobial agents have been shown to enhance the release or the production of Shiga toxins from STEC cells E. coli O104:H4 during the 2011 outbreak (Geerdes-Fenge et al., E. coli O157:H7 cells remain viable, followed by treatment with gentamicin at a bactericidal concentration. This strategy was effective in decreasing toxin release compared to solely treating the cells with a bactericidal gentamicin concentration (Kanbar et al., E. coli O157:H7 infection mouse model resulted in an improved animal survival rate (Rahal et al., E. coli O104:H4 infected mice similarly resulted in an improved survival rate compared to untreated control mice that were infected with the organism; however, the highest survival rate observed was with mice treated with gentamicin alone, unlike our observations with E. coli O157:H7 (Fadlallah et al., Reconsideration of treating STEC infections with antimicrobial agents has nevertheless gained ground in recent years. Ciprofloxacin was recently reported to decrease the risk of HUS in subjects infected with in vitro beneficial effects of probiotics and that inoculation of animal models with a probiotic prior to an experimental STEC infection has preventative capabilities (Asahara et al., in vitro study showed that cultivation of STEC organisms in the presence of various Bifidobacterium, Pediococcus, and Lactobacillus strains results in a decreased production of Stx2. This was attributed to a decrease in pH due to the acids produced by these agents (Carey et al., Although probiotics may not have a therapeutic benefit in the management of an STEC infection, they may have a relevant preventative utility. Probiotics are probably capable of disrupting host-infectious agent/toxin interactions by occupying cellular receptors themselves, by producing decoy receptors that take up the toxins or by modifying the local milieu, hence making these interactions unfavorable (Corr et al., in vitro (Niu et al., Another preventative measure proposed as a means of controlling STEC is the application of lytic phages. Lytic phages have been shown to reduce STEC numbers Various vaccine approaches have also been attempted including the development of preparations that contain bacterial peptides and virulence factors (Wen et al., In conclusion, despite the passage of more than three decades since STEC organisms were first associated with human clinical illness CDC, , a generThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Schizosaccharomyces pombe undergoes a closed mitosis, it exhibits a short period during meiosis  when nuclear and cytoplasmic proteins are mixed in the presence of intact NE and nuclear pore complexes (NPC). This \u201cvirtual\u201d nuclear envelope breakdown (vNEBD) involves changes in the localization of RanGAP1, an activator of Ran-GTP hydrolysis. Recently, Nup132, a component of the structural core Nup107-160 subcomplex of the NPC, has been shown to be involved in the maintenance of the nuclear cytoplasmic barrier in yeast meiosis. In this review, we highlight the possible roles of RanGAP1 and Nup132 in vNEBD and discuss the biological significance of vNEBD in S. pombe meiosis.Ran, a small GTPase, is required for the spindle formation and nuclear envelope (NE) formation. After NE breakdown (NEBD) during mitosis in metazoan cells, the Ran-GTP gradient across the NE is lost and Ran-GTP becomes concentrated around chromatin, thus affecting the stability of microtubules and promoting the assembly of spindle microtubules and segregation of chromosomes. Mitosis in which chromosomes are segregated subsequent to NEBD is called \u201copen mitosis.\u201d In contrast, many fungi undergo a process termed \u201cclosed mitosis\u201d in which chromosome segregation and spindle formation occur without NEBD. Although the fission yeast  In eukaryotic cells, the nucleus is enclosed by a nuclear envelope (NE) in interphase. The NE is a double membrane structure which separates the nucleoplasm from the cytoplasm. Macromolecules are transported between the nucleus and the cytoplasm across the NE through nuclear pores which are formed by large protein complexes called nuclear pore complexes  occurs (open mitosis) , nuclear and cytoplasmic molecules are mixed similar to open mitosis. Interestingly, both the NE and NPCs are maintained in this phase and thus this phenomenon is called \u201cvirtual\u201d NEBD  that regulate its localization  unts Figure . NotablyS. pombe. Interestingly, the metazoan Nup107-160 subcomplex is known to re-localize to the kinetochores upon NEBD and functions in kinetochore-microtubule attachment (Lo\u00efodice et al., S. pombe meiosis I. In addition, Nup133, a human homolog of S. pombe Nup132, is required for proper localization of RanGAP1 at the kinetochore in human cells (Zuccolo et al., Our discovery raises the question of how Nup132 regulates both kinetochore assembly and NE permeability during meiosis I in nup132 mutant activates the spindle assembly checkpoint and delays meiosis I progression (Figure Inadequate kinetochore-microtubule attachment in the n Figure . The durn Figure . Alternan Figure . These rS. cerevisiae Nup133 results in Ran being uniformly localized in the cell rather than being enriched in the nucleus (Gao et al., S. pombe and S. cerevisiae, Nup132/Nup133 is required for the uniform distribution of NPCs along the NE (Doye et al., nup132 mutant will help determine whether changes in nuclear permeability during anaphase I involve NPC disassembly or NE rupture.As mentioned above, Nup132 depletion results in the loss of barrier function of the NE during anaphase I (Yang et al., S. pombe may be regulated by phosphorylation or other post-translational modifications of nucleoporins. Further studies are required to elucidate the role of post-translational modifications of Nup132 or other nucleoporins in the regulation of barrier function of NPCs and vNEBD during meiosis in S. pombe.Functional alterations in Nup132 or other nucleoporins may change the barrier function of the NE without inducing NPC disassembly. Post-translational modifications in nucleoporins may alter the barrier function of NPCs. In mammals, nucleoporin Nup50 is phosphorylated by ERK kinase, which in turn changes the affinity of importin \u03b2 to NPCs (Kosako et al., S. pombe cells produce spores, and a correlation of vNEBD with spore formation has been established (Arai et al., mes1 mutant, which is deficient in blocking the degradation of cyclin Cdc13 (Izawa et al., mes1 mutant shows no vNEBD (Arai et al., tws1 mutant, a meiosis-specific allelic mutant of Cdc2 (MacNeill et al., tws1 mutant, nuclear proteins diffuse to the cytoplasm and RanGAP1 localizes to the nucleus during meiosis I (Arai et al., S. japonicus (Aoki et al., The timing of vNEBD corresponds to meiosis II during which S. pombe produces spores under nutritionally starved conditions. These spores are metabolically inactive until they experience growth-favorable conditions (Shimoda and Nakamura, S. pombe (Nishijima et al., vNEBD occurs specifically during anaphase II and results in the diffusion of nuclear proteins into the cytoplasm and cytoplasmic proteins into the nucleus, which is similar to that observed during open mitosis. vNEBD may allow cytoplasmic proteins to function in the nucleus during or after anaphase II. Occurrence of vNEBD is correlated with spore formation (Arai et al., S. pombe. This provides an example in which the regulated barrier function of the NE plays an important role for regulating meiotic processes in eukaryotes.The phenomenon of vNEBD suggests the importance of \u201copening\u201d the gate between the nucleus and cytoplasm during meiosis. Nucleoporins and RanGAP1 may play key roles during open meiosis without physically breaking down the NE in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Gan-Cao, coming from extracts of dried roots of Glycyrrhiza uralensis, Glycyrrhiza glabra, and Glycyrrhiza inflata, of which chemical analyses were performed (Zhang and Ye, A recent paper by Glycyrrhiza species (Fiore et al., According to these authors, 18-\u03b2-glycyrrhetinic acid and glycyrrhizin possess an anti-viral potential, assessing previous evidence about the antiviral properties of Glycyrrhiza extracts contributes in hampering a full comprehension of their beneficial effects. Licocalchone A downregulates the inflammation-induced P450 1B1 while isoliquiritigenin exerts an opposite effect, then differentially influencing the role of estrogens in chronic inflammation and in carcinogenesis (Dunlap et al., Molecular interactions between 18-\u03b2-glycyrrhetinic acid and glycyrrhizin modulates the inhibition of several drug-metabolizing enzymes and efflux transporters (Feng et al., The authors did not address either clinical trial about licorice activity against microbes.Glycyrrhiza-derived purified substances, such as glabridin, are recently addressed as promising tools to prevent bacterial infections and against parasites (Cheema et al., Moreover, the role exerted by licorice in blood pressure may influence immunity and DCs functionality, as the equilibrium between the inflammatory response induced by T cell and T cell suppressor responses is critical for the regulation of blood pressure levels (Rodr\u00edguez-Iturbe et al., in vitro, yet surely clinical evidence is needed.This evidence supports the idea that the introduction of a whatsoever can be considered as a beneficial phytochemical from raw plants in the highly complex network of signaling interactions between cells and organs, even considering the different individual ability coming from genetics and phenotypic polymorphism or from epigenetics and lifestyle, cannot allow physicians, as well as researchers, to foresee the \u201creal\u201d effect of that substance in the whole organism. An interesting hypothesis is that phytochemicals, as toxic substances, produced by plants to protect themselves are beneficial only in a restricted range of doses. In this perspective, there is interesting evidence about the role of low doses of phytochemicals, particularly flavonoids, on stress response and immune reactions The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "CCDC151), which has been shown to be essential in motile cilia of many animals and other vertebrates but its effects in humans was not observed until currently. We observed a novel nonsense mutation in a homozygous state in the CCDC151 gene (NM_145045.4:c.925G>T:p.[E309*]) in a clinically diagnosed PCD patient from a consanguineous family of Arabic ancestry. The variant was absent in 238 randomly selected individuals indicating that the variant is rare and likely not to be a founder mutation. Our finding also shows that given prior knowledge from model organisms, even a single whole-exome sequence can be sufficient to discover a novel causal gene.Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder characterized by impaired ciliary function that leads to subsequent clinical phenotypes such as chronic sinopulmonary disease. PCD is also a genetically heterogeneous disorder with many single gene mutations leading to similar clinical phenotypes. Here, we present a novel PCD causal gene, coiled-coil domain containing 151 ( Primary ciliary dyskinesia  is a genetically heterogeneous ciliopathy inherited in an autosomal-recessive fashion [Bush et al., DNAI1, DNAH5, DNAH11, RPGR, and OFD1) had been identified and these accounted for just 40% of the cases [Zariwala et al., CCDC151 deficiency as a further cause of PCD.Understanding the genetic aetiology of PCD has been challenging. In 2007, only five genes , and a long history of wet cough with light-green colored sputum  and his unaffected brother were studied . The parents\u2019 blood samples were also collected for further analysis. Details on all methods used in this study can be found in the Supp. Materials and Methods. Summary statistics from WES of proband can be found in Supp. Results.CCDC151 gene and the other was a frameshifting insertion in the ZNF595 gene (p.N201fs). The stop gain was absent in dbSNP, Exome Variant Server (EVS), our internal database (which includes his unaffected sibling), and 1000 Genomes Project databases, whereas the insertion was present (in a homozygous state) in many of our previously whole-exome sequenced controls (of Arabic ancestry) and also had a total MAF of 8.6% in EVS. The filtering process is depicted in Figurehttp://databases.lovd.nl/shared/variants/0000040146#04563).Initially, all LRoH regions identified by Plink [Purcell et al., PCR was used to amplify a region 221 bp long (harboring the stop gain) in the proband, the unaffected brother, and the parents, which was then subsequently sequenced (using Sanger sequencing method) and digested with AvrII enzyme to confirm the variant status  is in the local population, a buccal swab sample from 238 randomly selected individuals of Saudi Arabian ancestry  were collected . The PCR amplicons produced (using primers in Supp. To deduce how common the c.925G>T:p.(E309*) variant in CCDC151 gene was first identified as a potential human ciliome gene by Ostrowski et al. (CCDC151 was among the 110 proteins (with Accession no: BAB01602) identified by one-dimensional polyacrylamide gel electrophoresis analysis of human ciliary axonemes . More recently, Jerber et al. -dependent cilia in Drosophila. In the same analysis, they reported that Ccdc151 was expressed in tissues with motile cilia in zebrafish, and morpholino-induced depletion of the gene product lead to, similar to human PCD phenotypes, left\u2013right asymmetry defects [Jerber et al., Ccdc151 is strongly expressed in (and was restricted to) motile-ciliated tissues, where it is required for dynein arm assembly and for the transport of the docking complex Ccdc114  [Jerber et al., Ccdc151 is important in the control of IFT-dependent dynein arm assembly in many animals [Jerber et al., Ccdc151 in IMCD3 mouse cells resulted in a deregulated ciliary length [Jerber et al., Chlamydomonas ODA10 gene that is the homolog of the mouse Ccdc151 gene  was calculated to be approximately 0.0009 . Additional evidence from the absence of mutation in EVS and internal database , GERP scores [Davydov et al., CCDC151 carried out by Jerber et al.  \u03a6 mutations in autosomes were quantified in three healthy individuals (two of Arabic and one of European ancestry); and this figure was found to be approximately 60 on average. However, a very large proportion of these were in a heterozygous state and in olfactory, taste- and hearing-related genes. The amount of \u03a6 mutations that fell in the entire ciliome database (i.e. list 1 and 2) was on average one. The ciliome database contains within it 2,004 genes related to all types of cilia , but a crude estimate on the number of \u201crespiratory cilia\u201d-related genes (not including the known PCD genes) was estimated to be approximately 100 . As aforementioned, known PCD genes explain around 70% of PCD, which leaves the other 30% to these 100 genes. Thus, the probability of one of these \u03a6 mutations falling in one of the second-tier candidate PCD genes in an autozygous region , certain combinations of ultrastructural defects and/or sterility (or subfertility) are far from being completely understood [Vincensini et al., CCDC151 to cilia [Jerber et al., CCDC151 were not observed (until now) to associate these findings to the human model. Here, we report a homozygous nonsense mutation  in CCDC151 in a patient who has been clinically diagnosed with PCD. The variant was screened in 238 unrelated individuals, and it was found to be absent in all of them indicating that the mutation is not a founder mutation and may have occurred relatively recently and/or is tribal specific. Nevertheless, CCDC151 adds to the already identified 25 genes  in which mutations are known to cause PCD and indicates the important role CCDC151 plays in human respiratory ciliary function. Our findings also show that given prior knowledge from an animal model, even a single WES (with high read depth) can be adequate when pinpointing a novel causal gene.To conclude, although animal models have strongly linked"}
+{"text": "C) to trigger intracellular signals appears central to neurodegeneration pathways, yet the physiological significance of such signals is rather puzzling. For instance, PrPC deregulation disrupts phenomena as diverse as synaptic transmission in mammals and cell adhesion in zebrafish. Although unrelated, the key proteins in these events -the NMDA receptor (NMDAR) and E-cadherin, respectively- are similarly modulated by the Src family kinase (SFK) Fyn. These observations highlight the importance of PrPC-mediated Fyn activation, a finding reported nearly two decades ago. Given their complex functions and regulation, SFKs may hold the key to intriguing aspects of PrP biology such as its seemingly promiscuous functions and the lack of strong phenotypes in knockout mice. Here we provide a mechanistic perspective on how SFKs might contribute to the uncertain molecular basis of neuronal PrP phenotypes affecting ion channel activity, axon myelination and olfactory function. In particular, we discuss SFK target proteins involved in these processes and the role of tyrosine phosphorylation in the regulation of their activity and cell surface expression.The ability of the cellular prion protein (PrP Yes, there are two paths you can go by but in the long run There's still time to change the road you're on(R. Plant and J. Page)C on neuronal cell surfaces is required for pathogenic prions and a\u03b2 oligomers to trigger cellular damage  within lipid rafts, thereby stimulating neurite outgrowth  anchor, PrP is unlikely to physically associate with cytosolic SFKs. Nevertheless, co-immunoprecipitation data indicate that, in epithelial cells, PrP and SFKs interact at least indirectly within a larger protein complex (Morel et al., C triggered Fyn activation and hyperphosphorylation of the NR2B subunit of the NMDAR at tyrosine residue 1472 (Um et al., C promotes embryonic cell adhesion by stabilizing E-cadherin at the cell-surface (M\u00e1laga-Trillo et al., C as a modulator of cell-cell adhesion in zebrafish and synaptic transmission in mammals converge at a common mechanism, namely the ability of SFKs to control the internalization of trans-membrane proteins by phosphorylating their endocytic signals and/or the corresponding binding molecules. Given the functional diversity of SFK target proteins, we reasoned that altered SFK activity may account for at least some of the distinct neuronal phenotypes observed in PrP knockout and transgenic mice (Figure At first glance, some of these findings have no apparent connection with each other, aside from the common involvement of SFKs. However, closer scrutiny reveals mechanistic similarities pertinent to our understanding of PrP function. This is particularly manifest in two of the aforementioned models, where the downstream targets of PrP turned out to be transmembrane proteins modulated by tyrosine phosphorylation. In the study by the Strittmatter lab, binding of a\u03b2 oligomers to PrPC clearly shows that the latter can influence the activity of ion channels (Um et al., C suppresses NMDAR activity and glutamate excitotoxicity via the inhibition of NR2D subunits (Khosravani et al., 2+-mediated excitotoxicity (Solomon et al., 2\u03b4-1 subunit and retain it at the ER, thus disrupting its delivery to the plasma membrane. Notably, while the molecular mechanisms of these two phenotypes seem unrelated, they are both consistent with the ability of SFKs to regulate the activity of ligand- and voltage-gated ion channels (Salter and Kalia, 2\u03b4-1 during biosynthesis is the most likely explanation for its reduced levels at the plasma membrane (Senatore et al., The NMDAR-mediated glutamate excitotoxicity induced by a\u03b2 oligomers and PrPv1.3 voltage-gated potassium channels are expressed along the dendrodendritic synapse and are negatively regulated by Src phosphorylation (Fadool and Levitan, v1.3 null mice have modified action potentials and deregulated potassium currents, resulting in structurally altered olfactory bulbs and a heightened sense of smell (Fadool et al., 2+ influx that triggers inhibitory GABA release (Chen et al., v1.3 channels, and NMDARs provides testable explanations for the olfactory defects of PrP knockout mice.Unique among mouse PrP knockout phenotypes was the finding of impaired olfactory behavior (Le Pichon et al., Re-examination of a mild, late-onset phenotype in PrP knockout mice led to the discovery of defects in the maintenance of peripheral myelin (Bremer et al., As with the olfactory phenotype of Le Pichon et al., copious evidence suggests a potential involvement of SFKs in the PrP-CDP phenotype. Comprehensive reviews on the role of Fyn during myelination are available elsewhere (Kramer-Albers and White, v1.5 and Kv2.1 potassium channels in Schwann cells is controlled by the interplay between Src, Fyn, PTP\u03b1, and PTP\u03b5 (Sobko et al., in vivo, this regulation might be relevant for re-myelination but not for OPC development (De Biase et al., Finally, voltage- and ligand-gated ion channels constitute further regulatory targets of SFKs during myelination. For instance, the phosphorylation state of KC in the proliferation and differentiation of various stem cell lineages (reviewed in Martin-Lanner\u00e9e et al., Altogether, the common regulation of ion channels, olfaction and myelination by PrP and SFKs suggests that this phenomenon may extend to some of the other subtle PrP phenotypes mentioned above. For instance, it would be interesting to see if the role of PrPC to elicit intracellular signals at the cell surface is central to its multiple roles in health and disease. Second, the specificity of these signals is largely determined by extrinsic factors such as the plasma membrane microenvironment and the availability of cell- and tissue-specific protein partners. Third, the ubiquitous expression and functional redundancy of SFKs, along with the diversity of their downstream targets offer plausible explanations for some of the striking facts of PrP biology, such as its functional promiscuity, the viability of PrP knockout mice, and the diversity of PrP transgenic/mutant phenotypes. Based on these considerations, we propose that PrPC acts as a gatekeeper between neuronal survival and toxicity by controlling the activity and/or endocytic trafficking of ion channels, synaptic proteins and cell adhesion molecules via SFKs. Testing these complex scenarios should prove a formidable but rewarding endeavor.Several key observations emerge from the present analysis. First, the ability of PrPThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recent advances in brain connectivity research suggest that the human brain operates as a complex but economic global network. Novel approaches from graph theory have been applied to a variety of neuroimaging studies and have achieved great success. However, the brain network architecture and plasticity patterns vary across different brain developmental periods, learning activities, and disease effects. Translation of descriptive imaging levels into clinical and other exploitation crucially depends on the potential to induce and monitor plastic changes in the network of interest. This special issue is intended to stimulate the continuing efforts in understanding the architecture and plasticity patterns of brain networks. It also aims to broaden the attention not only to the researchers who are currently working on these areas but to the general scientific audience who are interested in the brain structures and functions as well.This special issue includes eleven papers that presented an up-to-date progress of MR neuroimaging methods on brain network architecture and plasticity investigation employing various neuroimaging modalities: structural MRI, diffusion MRI, and functional MRI. In these papers, there are five studies focused on brain diseases, including Alzheimer's disease, mild cognitive impairment, mild traumatic brain injury, and major depressive disorder. Two studies investigated the brain plasticity changes after visual or hearing deprivations. Also, there are two studies that assessed volunteers after mediation or cognitive training, and, finally, the remaining two studies are on the methodological development for brain network construction.Brain Diseases. In the paper entitled \u201cAbnormal Resting-State Functional Connectivity Strength in Mild Cognitive Impairment and Its Conversion to Alzheimer's Disease\u201d by Y. Li et al., an investigation was performed for individuals diagnosed with mild cognitive impairment. With a 2-year follow-up, those individuals converted to Alzheimer's disease were compared with nonconverters for their alterations on functional connectivity strength and seed-based functional connections.The paper entitled \u201cTopological Properties of Large-Scale Cortical Networks Based on Multiple Morphological Features in Amnestic Mild Cognitive Impairment\u201d by Q. Li et al. investigated the topological properties of cortical networks based on geometric measures  change in aMCI patients compared with normal controls.The paper entitled \u201cMultilevel Deficiency of White Matter Connectivity Networks in Alzheimer's Disease: A Diffusion MRI Study with DTI and HARDI Models\u201d by T. Wang et al. conducted an evaluation of how the fiber tractography method could influence the construction of brain white matter network and eventually affect the extraction of brain network properties, as well as group comparison using Alzheimer's disease patients as examples.In the paper entitled \u201cCompensation through Functional Hyperconnectivity: A Longitudinal Connectome Assessment of Mild Traumatic Brain Injury\u201d by A. Iraji et al., patients with mild traumatic brain injury were studied for possible brain functional alterations. Brain functional network was constructed through predefined seeds in a 358-landmark mask and a groupwise clustering algorithm was employed to identify general patterns of functional hyperconnectivity.The paper entitled \u201cReorganization of Anatomical Connectome following Electroconvulsive Therapy in Major Depressive Disorder\u201d by J. Zeng et al. presented a study for patients with major depressive disorder that were treated by electroconvulsive therapy. The plasticity of white matter pathway was evaluated.Sensory Deprivation. In the paper entitled \u201cAlterations of Regional Spontaneous Brain Activity and Gray Matter Volume in the Blind\u201d by A. Jiang et al., authors investigated how the early blindness shapes the regional spontaneous brain activity and gray matter volume in visual areas compared to sighted controls. A correlation analysis is also performed between the onset age of blindness and the brain structure and functions.In the paper entitled \u201cFunctional Reorganizations of Brain Network in Prelingually Deaf Adolescents\u201d by W. Li et al., authors used resting-state fMRI to study prelingually deaf adolescents to access the possible brain network reorganizations due to their experience.Training Influence. The paper entitled \u201cState and Training Effects of Mindfulness Meditation on Brain Networks Reflect Neuronal Mechanisms of Its Antidepressant Effect\u201d by C.-C. Yang et al. designed a longitudinal analysis investigating resting-state fMRI both before and after 40 days of meditation training. Differences in functional connectivity both between states (rest versus meditation) and between timepoints (before versus after training) were assessed and reveal functional specificity of plastic reconfiguration of key networks implied in MDD.The paper entitled \u201cThe Exercising Brain: Changes in Functional Connectivity Induced by an Integrated Multimodal Cognitive and Whole-Body Coordination Training\u201d by T. Demirakca et al. investigated the impact of \u201clife kinetik\u201d training on brain plasticity in terms of an increased functional connectivity during resting-state functional magnetic resonance imaging (rs-fMRI). The training is an integrated multimodal training that combines motor and cognitive aspects and challenges the brain by introducing new and unfamiliar coordinative tasks.Methodology Development. The paper entitled \u201cClosely Spaced MEG Source Localization and Functional Connectivity Analysis Using a New Prewhitening Invariance of Noise Space Algorithm\u201d by J. Zhang et al. proposed a prewhitening invariance of noise space as a new method for localizing closely spaced and highly correlated cortical sources under real magnetoencephalography (MEG) noise, to facilitate the source-level functional connectivity analysis.The paper entitled \u201cNode Detection Using High-Dimensional Fuzzy Parcellation Applied to the Insular Cortex\u201d by U. Vercelli et al. investigated a fuzzy parcellation scheme that partitions insular cortex into a number of regions based on the variances of their functional signals. Furthermore, the identified 12 clusters located in the insular cortex are found to best correlate with distinct brain areas that subserve different brain circuits/functions."}
+{"text": "Functionally matured microRNAs (miRNAs) are small single-stranded non-coding RNA molecules which are emerging as important post-transcriptional regulators of gene expression and consequently are central players in many physiological and pathological processes. Since the biological roles of individual miRNAs will be dictated by the mRNAs that they regulate, the identification and validation of miRNA/mRNA target interactions is critical for our understanding of the regulatory networks governing biological processes. We promulgate the combined use of prediction algorithms, the examination of curated databases of experimentally supported miRNA/mRNA interactions, manual sequence inspection of cataloged miRNA binding sites in specific target mRNAs, and review of the published literature as a reliable practice for identifying and prioritizing biologically important miRNA/mRNA target pairs. Once a preferred miRNA/mRNA target pair has been selected, we propose that the authenticity of a functional miRNA/mRNA target pair be validated by fulfilling four well-defined experimental criteria. This review summarizes our current knowledge of miRNA biology, miRNA/mRNA target prediction algorithms, validated miRNA/mRNA target data bases, and outlines several experimental methods by which miRNA/mRNA targets can be authenticated. In addition, a case study of human endoglin is presented as an example of the utilization of these methodologies. MicroRNAs (miRNAs) are an endogenous family of single-stranded 20-25 nucleotide non-coding RNAs that play a critical role in posttranscriptional gene regulation by acting as guide molecules for the miRNA-induced silencing complex (miRISC) to inhibit gene expression by targeting specific mRNAs for translational inhibition and/or degradation . It is now clear that the expression levels of miRNAs vary widely; some are ubiquitously expressed, while others are expressed in a tissue- and/or cell-specific manner, and many show spatiotemporal expression patterns . Importal., 2009; Dombkowal., 2009; Friedmaal., 2009; Gurtan al., 2009). Computal., 2009). Therefal., 2009; Fabian al., 2009). Althoual., 2009; Bartel,al., 2009; Selbachal., 2009), recental., 2009; Mendellal., 2009).The vast majority of functional miRNAs are produced by a canonical multistep biogenic process which is initiated in the nucleus and is completed in the cytoplasm Figure 1  and is retained within the miRISC Figure 1  is found . ImportWith few exceptions, MREs are primarily located in the 3\u2032-untranslated region (3\u2032-UTR) of mRNAs and once recognized, mature miRNAs imperfectly base pair with MREs following a set of rules which have been experimentally and computationally identified  and/or deadenylation, decapping, and subsequent decay by a number of silencing factors that are scaffolded to this complex by TNRC6A/GW182 Figure 1 . There http://microrna.gr/microT)        even these two algorithms would benefit from more current data input. To begin to address this critical question, several recent review articles have compared and contrasted many of the miRNA/mRNA target algorithms currently available , Targetal., 2009), Pictaral., 2006), and Elal., 2007). The laal., 2007) provideal., 2011; Grimsonal., 2011), DIANA-al., 2013; Reczko al., 2013), and thal., 2010) recentlal., 2010) and Taral., 2010; Grimsonal., 2010) have beIt is also significant to note that updated algorithms identify up to 60 % of all available miRNA/mRNA targets and provide only one valid target in approximately every three predicted targets . It is Given the above review of miRNA biology and miRNA/mRNA target prediction algorithms, we propose the following \u201cwork flow\u201d scheme Figure 2 for the For a case study we have chosen to analyze the human endoglin gene (ENG) for potential MREs. Endoglin  is a homodimeric co-receptor for transforming growth factor beta (TGF\u03b2) and is known to play a regulatory role in TGF\u03b2 signaling  or miRNA of interest has been chosen, it must then be analyzed by miRNA/mRNA target prediction algorithms Figure 2. Both thwww.ensembl.org)  and in the 3\u2032-UTR, the seed sequence binding type, whether or not the predicted MRE is conserved , what sal., 2013). This ial., 2013; Wang etal., 2013) and \u223c70al., 2013). Importal., 2013; Park etal., 2013; Sandberal., 2013; Tan et al., 2013). TherefInterestingly, the human ENG gene generates two distinct mRNAs through alternative splicing, which results in isoforms that differ in a portion of their CDS and 3\u2032-UTR . As a result, Table 1Since the mRNA isoform which encodes S-endoglin harbors the longest 3\u2032-UTR, the Diana-microT-CDS algorithm will only utilize this sequence for computing miRNA/endoglin mRNA target interactions. When this analysis is performed, a total of 259 (threshold set to 0.4) miRNAs are predicted to interact with the human S-endoglin mRNA isoform at 797 individual MREs, with 186 target sites located in the CDS and 611 sites in the 3\u2032-UTR (data not shown). Table 1In contrast to Diana-microT-CDS, the TargetScan algorithm results include the identified miRNAs and the predicted location of MREs in the 3\u2032-UTR but not in the CDS. However, this tool does allow the user to analyze any annotated splice variant for a given gene. For example, TargetScan will analyze both L-endoglin and S-endoglin 3\u2032-UTRs. The TargetScan results also include the number and type of seed match of conserved and poorly conserved miRNA binding sites, and a total context score (predicted efficacy of targeting) . Interehttp://www.microrna.gr/tarbase) . DIANA-al., 2006). http://mirtarbase.mbc.nctu.edu.tw/)   and > 500,000 interactions derived from high-throughput experiments  . At leaal., 2014) and miRal., 2009), are al-throughput sequencing of RNA isolated by crosslinking immunoprecipitation) experimental approach involves the transfection of a given miRNA mimic into a cell line of choice followed by ultraviolet (UV) cross-linking to generate AGO/miRNA/RNA cross-linked regions  Table 7, human eUCUCUAAGGAAGCGCAUUUC 3\u2032, the partially complementary motifs are underlined) was identified 40 nts downstream from the transcription initiation start site. Given that this predicted MRE is harbored in the 5\u2032-UTR region of the human endoglin mRNA isoforms, miR-522-3p/endoglin mRNA interactions would not be identified by the target algorithms discussed above since they are not programmed to analyze this region. Furthermore, with the tendency of miR-522-3p to interact with noncanonical MRE sequences, Tan et al.  Table . These ial. (2014) demonstIn conclusion, it is important to note that although only two of the ten DIANA-TarBase v7.0 cataloged experimentally identified miRNA/human endoglin mRNA interactions Table 7 Selbach, there iFor this review article we subjected the human endoglin mRNA to Diana-microT-CDS and TargetScan miRNA target analyses and examined DIANA-TarBase v7.0 data sets of cataloged and published experimentally supported miRNA/human endoglin mRNA interactions (see above). Given that the majority of the identification and cataloging of miRNA/mRNA target interactions by DIANA-TarBase v7.0 result from high-throughput techniques  withouthttp://www.ncbi.nlm.nih.gov/pubmed). Six publications were identified  demonstal., 2014) . Shyu eal., 2014) speculaal., 2014). Therefal., 2014; Vasudeval., 2014), it is miRNA profiling expression experiments utilizing ovarian cancer cells and ovarian cancer clinical samples demonstrated that a number of miRNAs were aberrantly expressed, including miR-370-3p, which was down-regulated in these studies . ImportTijsen et al. (2014) Table  focused Again, it is important to note that the miR-15/107 family members, miR-16-5p, miR-103a-3p, and miR-107 were identified to interact with human endoglin mRNAs by the HITS-CLIP technique Table 7  demonstGiven that endoglin has been established to play a regulatory role in TGF\u03b2 signaling . This fOnce the plethora of information from prediction algorithms, published validations of miRNA/mRNA interactions, and manual sequence inspections of miRNA binding sites has been assembled, prioritization of specific miRNA/mRNA target interactions to investigate can more effectively proceed. Among the number of putative miRNA/human endoglin mRNA interactions documented above, the remainder of this review article will focus on miR-370 Table 8 since thClearly a given miRNA and its target mRNA must be co-expressed in order for the miRNA to regulate the expression of a given biological target. Therefore, miRNA and target mRNA co-expression experimental studies should be performed first Figure 2, since tCo-expression is typically demonstrated by simply performing Northern blot analysis or quantitative real-time PCR (qPCR) using total RNA isolated from a specific cell type or tissue, and probes or primers specific for a given miRNA and mRNA target . We recin situ hybridization and immunohistochemical experiments utilizing paraffin-embedded, formalin-fixed tissues to address the question of co-expression . Additiovo, 2010; Sansom ovo, 2010).As described in the \u201cAnalysis of the Published Literature\u201d section above Table 8, recent Importantly, Chen et al. (2014) initiatAfter the demonstration of co-expression of the miRNA and target mRNA of interest, the physical interaction of a specific miRNA with a candidate MRE harbored in a target mRNA needs to be confirmed Figure 2. The majFor construction of chimeric luciferase reporter constructs, the predicted MRE sequence from the target gene, most often located in the 3'-UTR but also in the 5'-UTR and CDS see , is clohttp://www.mirbase.org) and a passenger strand that is split in two separate antisense chemically synthesized LNA modified RNA oligonucleotide strands . After transfection into cells, the segmented nature of the passenger strand ensures that only the mature miRNA (guide strand) is loaded into the RISC with no resulting miRNA activity from the passenger strand. Regardless of the chemical makeup of the mimic utilized, transfection of a miRNA mimic into cells will increase the proportion of RISC containing this particular miRNA and therefore, gain-of-function studies can assess the biological consequences (i.e. repression of luciferase reporter levels/activity) resulting from an increase in the activity of the mimicked miRNA . In contrast, miRNA inhibitors, which are utilized for loss-of-function experiments, are chemically synthesized, single-stranded, modified antisense RNA oligonucleotides which are designed to bind with and form highly stable heteroduplexes with the complementary endogenous miRNAs when introduced into cells  engineeAlthough the ability of miRNAs to repress the activity of a chimeric luciferase reporter gene is a useful screening device, it remains a surrogate assay for testing the effects of miRNAs on their putative mRNA targets. Therefore, after confirming the physical interaction of a miRNA with a candidate MRE harbored in target mRNAs by reporter assays, we recommend that miRNA gain- and loss-of-function transfection experiments also be performed to validate miRNA-mediated post-transcriptional regulation of target genes of interest Figure 2. Experimental manipulation of endogenous miRNA activity by miRNA mimic and miRNA inhibitor transfection should correspond to predictable changes in target protein levels  . TherefAlthough gain- and loss-of-function experiments are powerful, it is important to remember that results can be confounded by side effects of transfection . Under in vivo . Recallal., 2014). These al., 2014). Alternal., 2014). Therefal., 2014; Helwak al., 2014; Martin al., 2014; Tan et al., 2014). Chen et al., (2014) demonstAfter miRNA gain- and loss-of-function transfection experiments have confirmed that a given miRNA mimic and inhibitor mediate the inverse protein expression of a target gene of interest, it is finally necessary to demonstrate that this regulation equates to changes in biological function Figure 2. Dependiin vivo gain- and loss-of-function experiments in mice or rats . For ex al, 2014; Montgom al, 2014), by inf al, 2014; Hsu et  al, 2014; Huang e al, 2014), or by  al, 2014; Kota et al, 2014; Miyazak al, 2014). In con al, 2014; McClure al, 2014), by inf al, 2014; Seeger  al, 2014; Tijsen  al, 2014), or by  al, 2014; Baigude al, 2014).Chen et al. (2014) demonstmiRNAs are emerging as important post-transcriptional regulators of gene expression and consequently are central players in many physiological and pathological processes  should equate to altered biological function. To date only a small proportion of miRNA/mRNA target interactions have been functionally validated. The unique experimental outline described here can be applied to the validation of any miRNA/mRNA interaction. As relevant targets are identified, the biological functions of a specific miRNA can be unraveled and assist in development of miRNA therapeutics.The authors declare that they have no conflict of interest.We express our appreciation to Ms. Emily Keeler for generating the figures and tables."}
+{"text": "In March 2014, over 400 individuals from 35 countries in sub-Saharan Africa and 59 international partner organizations gathered in Accra, Ghana for an integrated Community Case Management (iCCM) Evidence Review Symposium. The objective was 2-fold: first, to review the current state of the art of iCCM implementation and second, to assist African countries to integrate lessons learned and best practices presented during the symposium into their programmes. Based on the findings from the symposium this supplement includes a comprehensive set of articles that provide the latest evidence for improving iCCM programs and ways to better monitor and evaluate such programs. Since early 2000 the use of integrated community case management (iCCM) strategy to deliver pneumonia, malaria and diarrhea treatments to children under 5 has dramatically increased. In 2005 there were only 10 countries in sub-Saharan Africa with policies supporting implementation of iCCM of which 7 included pneumonia treatment [iCCM, in the hands of well trained, supplied and supervised community health workers can reduce child mortality ,4. RecogSince the joint statement was released an increasing amount of evidence has been generated on the strengths and limitations of iCCM, as well as the outcome and impact of iCCM within a variety of different country contexts . A numbeBetween 3 and 5 March 2014, over 400 individuals from 35 countries in sub-Saharan Africa and 59 international partner organizations gathered in Accra, Ghana for an iCCM Evidence Review Symposium. The objective of the symposium was 2-fold: first, to review the current state of the art of iCCM implementation by bringing together researchers, donors, governments, implementers and partners to examine the current iCCM implementation landscape and status of evidence in key programme areas, in order to summarize lessons learned and best practices, and identify priorities and gaps in knowledge for improving maternal-newborn and child health. Second, to assist African countries to integrate lessons learned and best practices presented during the evidence symposium into their programmes and identify key actions to include in their national plans.We conceptualized a theory of change model as to what factors may increase utilization of quality iCCM services . In addition lessons learned were documented in each area. This supplement includes articles, based in part on these experiences and lessons learned. The thematic and additional areas, their relationship to the model, and their associated articles are shown in Box 1Coordination, Policy Setting and Scale-up: the current state of iCCM policies in Africa and challenges in development of policy and scale up\u2013 RELATES TO POLICY1. Rasanathan et al. Community case management of childhood illness in Sub-Saharan Africa: Findings from a cross-sectional survey on policy and implementation (article # 020401)Rasanathan et al. Where to from here? Policy and financing of integrated community case management of childhood illness (iCCM) in sub-Saharan Africa (article # 020304)Human Resources and Deployment: community health worker (CHW) selection, geographic disbursement, motivation and retention \u2013 RELATES TO DEPLOYMENT2. Pratt et al. Spatial distribution and deployment of community-based distributors implementing integrated community case management (iCCM): GIS mapping study in three South Sudan states (article # 020402)Supervision & Performance Quality Assurance: strategies to ensure high quality care including strategies for effective training, use of alternative models for supervision, and the role of mHealth to support and motivate CHWs to provide quality care \u2013 RELATES TO QUALITY3. Bosh-Capblanch and Marceau. Training, supervision and quality of care in integrated community case management (iCCM) programmes in sub-Saharan Africa (article #020403)Strachan et al. The scale up of integrated community case management of malaria, pneumonia and diarrhoea across three African countries: A qualitative study exploring lessons learnt and implications for implementation (article # 020404)Supply Chain Management: which systems ensure continuous supply, how best to forecast needs \u2013 RELATES TO SUPPLY4. Chandani et al. Evidence for improving community health supply chains from Ethiopia, Malawi, and Rwanda (article # 0204005)Sheishia et al. Strengthening community health supply chain performance through an integrated approach: Using mHealth technology and multilevel teams in Malawi (article # 020406)Costs, and cost-effectiveness and financing: identifying cost drivers, improving cost-effectiveness and the importance of minimizing patient costs \u2013 RELATES TO POLICY AND DEMAND5. Jarrah et al. The costs of integrated community case management (iCCM) programs: A multi-country analysis (article # 020407)Monitoring, Evaluation and Health Information Systems: innovations in monitoring, integrating with health management information systems, using results to drive programmatic decision-making and improvements, evaluation design and methods \u2013 RELATES TO ALL AREAS6. Guenther et al. Routine monitoring systems for integrated community case management programs: Lessons from 18 countries in sub\u2013Saharan Africa (article # 020301)Oliphant et al. Multi-country analysis of routine data from integrated community case management programs in sub-Saharan Africa (article # 020408)Diaz et al. A proposed model to conduct process and outcome evaluations and implementation research of child health programs in Africa using integrated community case management as an example (article # 020409)Demand generation and social mobilisation: the relationship between iCCM and care-seeking, treatment utilisation and treatment adherence, effective strategies to generate demand \u2013 RELATES TO DEMAND7. Sharkey et al. Demand generation and social mobilisation for iCCM and child health: Lessons learned from successful programmes in Niger and Mozambique (article # 020410)Impact and outcome evaluations: Issues with measuring mortality and using coverage to model mortality\u2013 RELATES TO COVERAGE AND MORTALITY8. Amouzou et al. Assessing the impact of the integrated community case management (iCCM) programmes on child mortality: Review of early results and lessons learned in sub-Saharan Africa (article # 020411)Friberg et al. Using the Lives Saved Tool as part of evaluations of community case management programs (article # 020412)Additional topic areas:Newborns \u2013 Aboubaker et al. Community health workers: a crucial role in newborn health and survival (article # 020303)Research \u2013 Wazny et al. Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI  exercise (article # 020413)Private sector \u2013 Awor et al. Integrated community case management and the private sector in africa \u2013 a relevant experiences and potential next steps (article # 020414)Conclusions \u2013 Young et al. The way forward for integrated community case management programmes (article # 020304)In regards to policy and scale up Rasanathan et al report on the results of survey on iCCM in sub-Saharan Africa and in a viewpoint summarizing policy issues that impact scale up and sustainability. In the area of human resources and deployment Pratt et al detail the use of GIS mapping in three states in Southern Sudan to improve deployment of CHWs. For training and quality Bosh-Capblanch et al provides a systematic review of training supervision and quality of care, while Stratchan et al present a qualitative assessment of implementation practices in 3 African countries. In regards to maintaining supply chains Chandani et al describe how three countries were able to ensure commodities and supplies reached community health workers, while Sheishia et al describe an innovative technology to track supplies in Malawi. To examine costs of iCCM, Jarrah et al describe the cost drivers of iCCM in multiple countries using standardized methods. In the area of monitoring and evaluation Guenther et al put forth components and attributes of a comprehensive monitoring system for iCCM, while Oliphant et al use routine monitoring from multiple country programs to demonstrate the utility of these data to examine key factors of program success or failure. Diaz et al review the study design and data elements collected for multiple recent evaluations of iCCM to suggest how such evaluations can be done in the future. In regards to demand, Sharkey et al present experience in two countries and the lessons learned on demand generation and social mobilization for iCCM. Finally, in the area of impact and outcome evaluation Agbessi et al report on the limitations of measuring and using mortality to assess iCCM as an end point in several countries in Sub-Sharan Africa and Friberg et al demonstrate how the Lives Saved Tool could be used to model the mortality impact of iCCM.In addition to the articles covering the key thematic areas of the symposium we also have three additional articles. Awor et al describe how the private sector can contribute to iCCM. Aboubaker et al also present the role of Community Health Workers in newborn survival. Based on a systematic process to prioritize research areas, known as CHNRI  Wazny et al report on priority iCCM research areas that are still needed. Finally, using the evidence available, Young et al suggest a way forward to improve and sustain iCCM where it is needed. This comprehensive set of articles provides the latest evidence for improving iCCM programs and ways to better monitor and evaluate such programs."}
+{"text": "Among the tools proposed to assess the athlete's \u201cfatigue,\u201d the analysis of heart rate variability (HRV) provides an indirect evaluation of the settings of autonomic control of heart activity. HRV analysis is performed through assessment of time-domain indices, the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals (RMSSD) measured during short (5 min) recordings in supine position upon awakening in the morning and particularly the logarithm of RMSSD (LnRMSSD) has been proposed as the most useful resting HRV indicator. However, if RMSSD can help the practitioner to identify a global \u201cfatigue\u201d level, it does not allow discriminating different types of fatigue. Recent results using spectral HRV analysis highlighted firstly that HRV profiles assessed in supine and standing positions are independent and complementary; and secondly that using these postural profiles allows the clustering of distinct sub-categories of \u201cfatigue.\u201d Since, cardiovascular control settings are different in standing and lying posture, using the HRV figures of both postures to cluster fatigue state embeds information on the dynamics of control responses. Such, HRV spectral analysis appears more sensitive and enlightening than time-domain HRV indices. The wealthier information provided by this spectral analysis should improve the monitoring of the adaptive training-recovery process in athletes. The optimization of the training process in elite athletes requires the quantification of the training loads (Borresen and Lambert, most reliable and practically applicable measure for day-to-day monitoring\u201d (Plews et al., In a recent review (Buchheit, However, despite its accessibility/simplicity, even with all the above-mentioned methodological improvements (see Plews et al., In our view, recording HRV clues in both supine and standing positions is also convenient and provides more information about the actual autonomic settings, their interplay and how they are resorted (Schmitt et al., A recently published study accurately displayed how individual patterns of spectral analysis of HRV divert in \u201cfatigue\u201d states from \u201cno fatigue\u201d condition (Schmitt et al., In summary, RMSSD measures and their derived variables have an effective practical usefulness, which can help the practitioner to identify a global \u201cfatigue\u201d level. However these variables do not allow the clustering of different sub-categories of \u201cfatigue,\u201d at variance with the spectral HRV analysis in both supine and standing positions, which likely consider the current ability to control in a dynamic setting.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Chronic tendinopathy is a painful common condition affecting athletes as well as the general population undergoing to tendon overuse. Although its huge prevalence, little is known about tendinopathy pathogenesis, and even cloudier is its treatment. Traditionally, tendinopathy has been defined as a lack of tendon ability to overcome stressing stimuli with appropriate adaptive changes. Histologic studies have demonstrated the absence of inflammatory infiltrates, as a consequence conventional antinflammatory drugs have shown little or no effectiveness in treating tendinopathies. New strategies should be therefore identified to address chronic tendon disorders. Angiofibroblastic changes have been highlighted as the main feature of tendinopathy, and vascular endothelial growth factor (VEGF) has been demonstrated as one of the key molecules involved in vascular hyperplasia. More recently, attention has been focused on new peptides such as Substance P, nitric oxide, and calcitonin gene-related peptide (CGRP). Those new findings support the idea of a nerve-mediated disregulation of tendon metabolism. Each of those molecules could be a target for new treatment options. This study aimed to systematically review the current available clinical and basic science in order to summarize the latest evidences on the pathophysiology and its effect on treatment of chronic tendinopathy, and to spread suggestions for future research on its treatment. With the increasing number of amateur sport practitioners, a growing prevalence of tendinopathy has been recorded in the last few years in Europe and United States , between June and August 2015. The combinations of key-words used were the following: \u201c(\u201ctendinopathy\u201d[MeSH Terms] OR \u201ctendinopathy\u201d[All Fields]) AND ,\u201d \u201c(\u201ctendinopathy\u201d[MeSH Terms] OR \u201ctendinopathy\u201d[All Fields]) AND (\u201csubstance p\u201d[MeSH Terms] OR \u201csubstance p\u201d[All Fields] OR \u201cp substance\u201d[All Fields]),\u201d \u201c(\u201ctendinopathy\u201d[MeSH Terms] OR \u201ctendinopathy\u201d[All Fields]) AND  OR \u201cneurotransmitter agents\u201d[All Fields] OR \u201cneurotransmitter\u201d[All Fields]).\u201d The search was aimed to retrieve any level of evidence studies concerning molecular pathways involved in pathogenesis of tendinopathy, clinical associated features and therapeutic implications. Both clinical and experimental in vivo and in vitro studies were included. No study types were excluded except for literature reviews and case reports. No time interval for publication was set. Of each of the retrieved articles, the whole bibliography was carefully checked to enrich the research with possible studies relevant for the present work. Results of the studies were read, analyzed, and tabulated. The included studies have been divided into three categories: vascular function, nervous function, and therapeutic studies. The study selection process was carried out as shown in Figure Articles research has been carried out using PubMed online database , fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2), sphingosine kinase-1 (SPHK1), (transforming growth factor) TGF-\u03b1, VEGF-A, and VEGF-C. Comparable results were obtained by Petersen et al. (p = 0.0001 and p = 0.046 respectively). An in vivo study on rabbits, by means of specific exercise protocols, Andersson et al. ; group 2: knock-out (iNOS\u2212/\u2212); and group 3: knockout (iNOS\u2212/\u2212) + systemic NO synthase inhibition through aminoguanidine (AG) administration. When systematically inhibiting the NO synthase in iNOS\u2212/\u2212 mice (group 3), the cross-sectional area of the healing Achilles tendon was significantly reduced. However, no significant differences were found between the wild-type (group 1) and the knock-out mice (group 2) concerning both the cross-sectional area and biomechanical features of the healing Achilles tendon. Moreover, the same authors  and nitric oxide synthase (NOS) expression have been carried out, in order to evaluate endothelial activation during tendinopathy and its effects on tendon tissue. An overuse protocol applied to supraspinatus tendons was evaluated by Szomor et al. , that fo2, in patellar tendons with tendinopathy in respect to normal tendons.It has been recently considered a role for neurotransmitters in the evolution of tendinopathy. The main molecule that has been investigated is Substance P (SP), which is known to play several roles in proliferation of fibroblasts, angiogenesis, and pain transmission  patches on elbow extensors tendon (McCallum et al., The SP administration in tendinopathy has been extensively studied by Burssens et al.  who studThe increasing knowledge concerning tendon dysfunction, clinically expressed as tendinopathy, leads to the individuation of a huge array of factors implied in the pathogenesis and repair mechanisms of this disease. Among single molecules and pathways involved in pathogenesis and healing process of tendinopathy, vascular, and neuronal factors play a major role (Papalia et al., Some studies have investigated the role that VEGF has in both the pathogenesis and to the healing response of tendinopathy, also using VEGF and its splice variants as an efficient treatment (Zhang et al., SP administration in surgically repaired rat tendons (Burssens et al., The local vascular activation is actually considered a still unclear chapter of the wide topic of tendinopathy. Studies have demonstrated an increased expression of NOS isoforms produced by endothelium in diseased tendons (Szomor et al., However, since VEGF and its pathways are the broadly known factors among a so complex pathogenesis, it should probably be the main factor to pay efforts on. An interesting research line is the regulation of VEGF action during the pathogenesis of tendinopathy (Lu et al., Vascularization and neuronal transmission play a key role in determining the pathogenesis of the tendinopathy. The mainly known factors implied in the process are VEGF, Substance P, and Nitric Oxide, although their exact role in the mechanism of tendinopathy is not well determined. More research should be carried out, especially studies involving human subjects, in order to assess the timing of action of those factors, to find out how therapies targeted to the phase of the disease process may fasten the healing process and the clinical recovery.AD, RP, and VD supervised the articles selection process and reviewed the final manuscript. SV, BZ and GT provided articles selection, manuscript writing, and table filling up.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A selection of papers prepared by participants of 7th Young Scientists School SBB\u201915 is presented in three Supplementary Issues to the journals of BMC series, namely, BMC Genomics, BMC Genetics and BMC Microbiology.http://conf.nsc.ru/sbb2015). The series of Young Scientists Schools in Systems Biology and Bioinformatics (SBB) started several years ago, in 2008, as educational workshop associated with the large international conference series on bioinformatics known as BGRS\\SB (Bioinformatics of Genome Regulation and Structure\\Systems Biology) (http://conf.bionet.nsc.ru/bgrssb2016). After its inauguration year of 1998, BGRS/SBB held biannually at the Institute of Cytology and Genetics SB RAS in Novosibirsk. In a recent decade, it became a prime meeting venue for biologists, computer scientists, physicists, mathematicians and biochemists working in an interdisciplinary field of systems biology and computer genomics. Being the largest system biology meeting series in Russia, BGRS\\SB-14 attracted participants from 27 countries. In the past BioMedCentral had published series of special issues based on best materials presented at the conference in BMC Genomics , BMC Evolutionary Biology , BMC Genetics  and BMC Systems biology . In addition, the protein structure related studies presented by BGRS/SBB participants were collated as special issues in Journal of Bioinformatics and Computational Biology . [SBB\u201915 took place June 22nd-25th in Novosibirsk, Russia  and data analysisEvolutionary bioinformaticsSystems biology and gene network modelingThe scientific topics discussed in 2015 were presented at the following sections:In SBB\u201915 Supplements to BMC journals Genomics, we collected the best studies presented at the conference. Due to the general breadth of the field of Systems Biology and Bioinformatic, the manuscripts were accepted into three separate tracks, thus forming three Supplementary Issues, BMC Genomics, BMC Genetics and BMC Microbiology. Below we will describe contents of these issues.The paper by Fedoseeva et al. titled \u201cComparative transcriptional profiling of renal cortex in rats with Inherited Stress-Induced Arterial Hypertension and normotensive Wistar Albino Glaxo rats\u201d dissect genetic underpinnings of arterial hypertension, a disease which cannot be explained as progression along a straightforward route . Hence, The paper of Klimov et al. \u201cGenome-wide transcriptome analysis of hypothalamus in rats with inherited stress-induced arterial hypertension\u201d continues in the wake of previous paper with a systems biology analysis of expression changes in hypothalamus of the same two strains of rats, and pinpointed the changes within three categories of genes: \u2018the regulation of hormone level\u2019, \u2018the regulation of the blood pressure level\u2019, and \u2018the immune system processes\u2019 .The paper of Lavrov and co-authors titled \u201cFrequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia\u201d convincingly demonstrated that the gene variants present or absent in the genome of patient influence relative efficiency of the therapy for chronic myeloid leukemia, thus, paving a way to personalized approach to the treatment of this disease .Finally the paper \u201cGenomic Determinants of Birth Weight Variability in the Pig\u201d by Wang and co-author explored the polimorphisms influencing the weight of newborn piglets, and highlighted a number of genes involved in glucose and lipid metabolism as well as in maternal-fetal lipid transport as important for this agriculturally important trait. Additionally, there a basic science related vibe in this study as it may provide some mechanistic explanation to relative success of intrauterine competition of the fetuses in species with larger size of litter .http://www.biomedcentral.com/1471-2164/16/S13/S1).The paper by Ivanov et al.\u201cNon-random fragmentation patterns in circulating cell-free DNA reflect epigenetic regulation\u201d  convincihttp://www.biomedcentral.com/1471-2164/16/S13/S2) deals with the peculiarities of the exon-intron structure, which affect the functionality of the encoded protein. The paper shows that protein functional sites predominantly encoded by relatively long exons.The paper by Medvedeva et al. \u201cComputer analysis of protein functional sites projection on exon structure of genes in Metazoa\u201d   describes a theoretical model that assesses tissue-specific gene knockout effect on gene expression in various structures of the brain, and predicts that the most pronounced tissue-specific effects are detected for genes that participate in the apoptosis/survival network [The paper by Petrovskiy et al. \u201cPrediction of tissue-specific effects of gene knockout on apoptosis in different anatomical structures of human brain\u201d .Gunbin and colleagues continued the evolutionary analysis of miRNA sequences in brain using unique paleogenetics data described in the manuscript titled \u201cThe evolution of l brain\u201d   presents an in silico analysis of 22 known nucleotide polymorphisms and arrived at functionally important conclusion about the mechanism of action for at least one of these DNA variants.The paper by Arkova et al. \u201cObesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters\u201d  , the functional transcription factor binding sites ranking in the fruitflies , and comparative mining of stress- related expression profiles .Finally, the works by Menzorov et al. , Kozlov The paper by Klimenko et al. titled \u201cBacteriophages affect evolution of bacterial communities in spatially distributed habitats: a simulation study\u201d explored evolutionary scenarios that may be influenced by the spatial location of initial phage invasion and showed that the speciation rate is lower when invasion penetrated the fully formed community of sedentary cells .In their paper \u201cOn the control mechanisms of the nitrite levels in Escherichia coli cells\u201d Khlebodarova, Ree and Likhoshvai describe the mathematical model of nitrite utilization in E.coli cells cultured in the flow chemostat, the process relevant to many biotechnological and clinical applications .The paper of Bryanskaya et al. titled \u201cThe role of environmental factors for the composition of microbial communities of saline lakes in the Novosibirsk region (Russia)\u201d for the first time described microbial composition of these saline lakes, their dependence on physical-chemical parameters of waters, as well as evaluated possible avenues for their bioprospecting .http://conf.bionet.nsc.ru/bgrssb2016/).We wish you an interesting reading and sincerely await you at our next BGRS conference that will take place in Novosibirsk 29 August \u2013 2 September 2016 ("}
+{"text": "Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, \u201c-omics\u201d data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology.The human-pathogenic bacterium  Salmonella enterica is a Gram-negative enterobacterium closely related to Escherichia coli  strike with endotoxins, typhoid fever, and severe systemic illness. The millions of infections and thousands of fatal cases every year are an important reason for a better understanding and control of Salmonella infection . Adaptations include multiple abilities for oxygen and nitrate respiration  deficient strain to utilize gluconate, but not other sources such as glucose  encoding a Fe2+/Mn2+/Zn2+transporter. Thus, to study the mechanisms of systemic disease caused by Salmonella, infection models using Salmonella-susceptible inbred mouse strains such as BALB/c or C57BL/6 with defective Slc11a1 allele are frequently used  facilitate studies on virulence mechanisms and metabolic activities on a molecular level and allow a detailed picture of host-pathogen interactions. Comparative genomics was used for example to identify the presence of different metabolic pathways for non-typhoidal and typhoidal pathovars of Salmonella  for additional high resolution typing of Salmonella isolates by phage types and different PFGE patterns. This allows investigation in unprecedented detail of virulent strains as well as their correlation with metabolic resistance features such as pathways for degradation of antibiotics.Methods useful in analyzing the global impact of gene deletions on Salmonella regulates its metabolic pathways in response to changing nutritional environments. A study performed by Blair et al. focused on changes in transcriptomic profiles when using LB or various minimal media for growth. Transcription profiles were established and the article instructively starts from microarray experiments  and verifies putative differences by quantitative real-time PCR , oxidative , and iron-limiting metabolic protection. In the four ferritins, bacterioferritin (Bfr) was found to be down-regulated in LP strains.The second \u201c-omics\u201d level, namely transcriptomics including microarrays and high throughput sequencing approaches, gives insights into how Salmonella protein is a challenge for MS analyses. Nevertheless, with more effort even quantification of proteins is possible applying different labeling techniques and standards. A good example for the application of the technique to Salmonella is the enzyme quantifications of ex vivo purified Salmonella performed by Steeb et al. (Mass spectroscopy (MS)-based proteomics is a method of choice when analyzing gene products: with this approach protein expression is directly measured. Typically only several matching peptides from a protein are identified applying the knowledge of the genome sequence and identified reading frames. This only partial peptide coverage for a given b et al. , also ilSalmonella metabolism. In particular, isotopolog profiling (IP) allows analysis of current metabolic fluxes under defined conditions. For a detailed method explanation see the study by H\u00e4rtel et al.  coupled to different cell culture techniques (including establishing tissue infection models) offer here a wealth of information. A nice example including bioluminescent Salmonella, the Streptomycin mouse model and bioimaging is Pontier-Bres et al.  with proteins mediating only this function in the complete network. Furthermore, hubs, central nodes in the network receiving many connections and indicating strongly connected genes or proteins, are of interest. For instance, interactome networks describing protein-protein interactions are built up and serve as scaffolds for further analysis  for each condition. This was compared to a genome-scale network connecting genes with metabolic pathways and cellular functions. Looking at the top five connecting hub proteins from the transcriptional network  as well as the hubs in the genome scale metabolic pathway and cellular function network , all these hubs were found to be dispensable for virulence in mutation studies. However, double mutants of these two sets of regulatory proteins showed clear effects on virulence in mouse infection experiments  produced by the NO synthase of several immune cells of the host has a severe impact on central carbon metabolism of Salmonella. NO targets the pyruvate and \u03b1-ketoglutarate dehydrogenase complexes (Richardson et al., ch Table . FurtherSalmonella making it more stress resistant (Figure Citrate is a TCA cycle intermediate Figure  and is at Figure .The broad influence of amino acids on metabolic adaptation during infection. The work on acetylation regulation in Salmonella by Wang et al. (g et al.  also undg et al. .ArgT is an essential virulence determinant which decreases the host's cellular arginine content and reduces by this way the NO production of the host (Das et al., Salmonella appears to be without influence on NO production. Although arginine degradation pathways are up-regulated in Salmonella during infection of macrophage and essential for virulence, this is due to other mechanisms but not related to substrate degradation of iNOS (Choi et al., In particular, the bacterial arginine permease Salmonella. In a study on cysteine biosynthesis during oxidative stress, cysteine biosynthesis regulation was blocked in \u0394cysB and \u0394cysE mutants and oxidative defense pathways encoded by katG and soxS were up-regulated compared to the wild-type strain (Turnbull and Surette, Salmonella survival and replication (Bjur et al., Cysteine is a key amino acid during oxidative stress response in SsrAB virulon controlling SPI2 gene expression is induced under nutrient-poor conditions (e.g., presence in the phagosome, Kuhle and Hensel, The Salmonella enterica (Table Various metabolic pathways which have an impact on the SPI1 activity of ca Table . One exaca Table  and secrca Table .Salmonella invasiveness and to induce strong inflammatory host responses (Humphreys et al., There are also indications for the influence of SPI1 functions on the host's metabolism in order to facilitate survival in the intestine and subsequently intracellular to promote the infection process. Thus, the SPI1-T3SS effector protein SopE is known to increase Salmonella virulence (Table Although SPI1 and SPI2 are induced under very distinct nutritional environments (SPI1 in a nutrient rich environment, SPI2 by nutrient starvation, Kuhle and Hensel, ce Table . One exace Table .Intracellular adaptation and metabolism of Salmonella. While conditions in the intestinal lumen are nutrient rich, the situation changes after Salmonella invades into the epithelial cells and is phagocytosed at the basolateral cell side by macrophages or dendritic cells. Staying inside the SCV, the pathogen has to deal with nutrient limitations. To investigate which metabolites could interact with expression of genes in SPI1 or mainly SPI2, one issue is to define the nutritional situation of Salmonella gain inside the SCV and to figure out which metabolites Salmonella has access to. Mouse infection experiments showed on the one hand that intracellular Salmonella get access to a wide range of nutrients, including nearly all amino acids except proline. On the other hand, it was shown that the ability to manifest a full systemic infection is dependent on the utilization of \u201cglycerol, fatty acids, N-acetylglucosamine, gluconate, glucose, lactate, and arginine\u201d (Steeb et al., Salmonella is able to counteract various defense mechanisms in order to facilitate growth or reduce immune responses (Table es Table . Invasioes Table .Shigella-infected cells, amino acid levels of epithelial cells invaded by Salmonella normalized 3 h after infection, which leads to relocalization of mTor invasion sustaining pathway to the SCV, phosphorylation of ATG protein 13, leading to a low ATG protein 1 activity and thus reduced autophagy (Ganley et al., Salmonella is able to avoid autophagy in epithelial cells. Further investigations are required to clarify if normalization of amino acid levels is directly induced by Salmonella. At least the invasion-induced membrane disturbance is only severe in the first hour of infection and somehow repaired faster than in cases of invasion by other intracellular pathogens (Tattoli et al., However, in contrast to Salmonella adapts rapidly and successfully to changing conditions including intracellular survival in macrophages, in epithelia and in the gut, we will now examine which antibiotic strategies are nevertheless available for Salmonella infections. A seminal work by Becker and co-workers showed that the robust metabolism of Salmonella limits possibilities for new antibiotics (Becker et al., Salmonella virulence (Steeb et al., Salmonella are highly resilient (Barat et al., Salmonella in particular, as well as by exploring novel ways of anti-infectives. One inspiring example is metabolic engineering of Salmonella vaccine bacteria in the mevalonate pathway to boost human V\u03b32V\u03b42 T cell immunity (Workalemahu et al., Salmonella also vulnerable also in conserved and well investigated pathways, such as TCA cycle and its anaplerotic reactions. Thus, Salmonella Typhimurium is controlled by host NO production as shown in mice experiments in vivo. Methionine or lysine auxotrophy results from reduced succinyl-CoA availability as the lipoamide dehydrogenase activity is targeted by NO while compensatory Salmonella pathways to achieve more succinyl-CoA are again blocked by NO (Richardson et al., As Salmonella to facilitate intracellular survival within the SCV in host cells and its nutrient supply.We saw that multiple \u201c-omics\u201d and especially metabolomic data are currently used to determine the needs for Salmonella's generalist metabolic lifestyle meets all types of environmental challenges, be it ROS or nutrient limitation by its broad metabolic capabilities. The broad metabolism suggests nevertheless potential for novel anti-infective strategies. However, under severe conditions Salmonella regulation and metabolism are spiked up by input from SPI1, SPI2, T3SS and T6SS, modified invasion abilities, redox protection and central metabolism to turn the neutral environmental lifestyle of Salmonella into a pathogenic lifestyle for its host. On top of this such genetic modules catalyze rapid genetic exchange between Salmonella strains showing that only an integrated picture will help to sustain antibiotic efficiency against Salmonella infections.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Fusarium graminearum is a phytopathogenic Ascomycota that can cause Fusarium head blight in wheat and other cereals worldwide, leading to important yield losses as well as reduced grain quality. The analysis of the F. graminearum genome sequence revealed the presence of 20 non-ribosomal peptide synthases, 15 polyketide synthases, and 17 terpenoid synthases, all potentially involved in the production of a panel of secondary metabolites, including yet unknown ones, such as the mycotoxins deoxynivalenol (DON) and other type B trichothecenes , and both types can lead to either adaptation and survival, or cell death. Here, cell death does not necessary mean a failure to implement an effective stress response but can be the result of the response pathway itself when a destructive response is implemented. The effects of various stresses that phytopathogenic fungi are likely to encounter in the context of host invasion have been the subjects of numerous works. In particular, oxidative stress, as the result of the early defensive \u201coxidative burst\u201d triggered in the host plant upon infection, has been intensively examined.Stresses caused by variations of the environment can be biotic (the surrounding microbiome) or abiotic  as signals that initiate/modulate biosynthesis (reviewed in Hong et al., Aspergillus nidulans, the Yap-like bZIP factor NapA, was shown to be involved in tolerance to oxidative stress (Asano et al., NapA (Yin et al., Aspergillus ochraceus and the NapA orthologue AoYap1 (Reverberi et al., AoYap1 but toxin accumulation is also enhanced in untreated conditions (Reverberi et al., In Aspergillus parasiticus have binding sites for the same bZIP transcription factor AtfB that is activated upon oxidative stress via MAPK signaling (Hong et al., A. parasiticus is grown in toxin-inducing medium (Roze et al., Aspergillus species (see Reverberi et al., Botrytis cinerea, the BcAtf1 factor was also shown to positively regulate the production of secondary metabolites (Temme et al., On the mechanistic side, mobility shift assays provided experimental evidence that antioxidant and aflatoxin biosynthetic genes in F. graminearum, previous results indicate that oxidative stress with H2O2 could be a pre-requisite for the biosynthesis of the mycotoxin DON, which may suggest that DON production and endogenous oxidative stress could be connected (Ponts et al., FgAP1 that activates the transcription of antioxidant enzymes (Montibus et al., F. graminearum to its own benefit. Recent data may bring clues as of the mechanism of activation of DON biosynthesis upon oxidative stress. A glycogen synthase kinase GSK3 was shown to be essential for both virulence and DON production F. graminearum, and to be up regulated upon oxidative stress by H2O2 (Qin et al., In F. graminearum. An acidic pH is a prerequisite for DON production (Merhej et al., FgPac1, homologous to the member of the pH regulator system PacC in A. nidulans (Merhej et al., The pH of the environment was shown to be particularly critical for the initiation of trichothecene B biosynthesis in F. graminearum, the cell wall integrity pathway involves the MAP kinase FgMgv1 (Hou et al., F. graminearum, FgHOG1 of the osmoregulation MAP kinase pathway, mediated by the FgOS-2 kinase, is involved in hyperosmotic as well as cell membrane stress responses. FgHOG1 also plays a role in ROS-mediated signaling. Its deletion causes a drastic reduction of DON accumulation, also caused by hyperosmotic conditions, as well as other developmental defects (Van Thuat et al., in planta (Van Thuat et al., Different response pathways can be triggered to counteract stresses that modify the organization and stability of the fungal cell wall. For example, the cell wall integrity pathway is responsive to changes in osmotic pressure and oxidative stress (see Hayes et al., F. graminearum, transcription factor Tri6 has been evoked above (Seong et al., Aspergilli, LaeA has been described as a secondary metabolism-specific regulator involved in switching from inactive heterochromatin to the transcriptionally permissive euchromatic state. In F. graminearum, FgLae1 is a regulator of secondary metabolism that activates the production of DON (Kim et al., FgLae1 has pleiotropic effects in F. graminearum, also affecting sexual development for example (Kim et al., Regulators of fungal secondary metabolite biosynthesis that play a role in regulating other aspects of fungal life, including response to stress, have been described. The example of the F. graminearum's response to oxidative stress, i.e., defensive plant-produced H2O2 may serve as a signal to produce DON (Ponts et al., F. graminearum for its own development and secondary metabolism (Audenaert et al., e.g., caspofungin, nikkomycin Z, tunicamycin, fluconazole; see Hayes et al., Previous observations made about A. parasiticus, co-localize with stress response proteins to the endosome/transport vesicles/vacuoles fraction of a fungal cell extract (Linz et al., F. graminearum, previous work showed that the endoplasmic reticulum stress response and oxidative stress are tightly linked (Malhotra et al., F. graminearum secondary metabolism and stress response pathways are indisputably very closely interconnected. Although further investigation is required, an attractive hypothesis is that secondary metabolism pathways could be part of the fungus' stress-response system. Under this scenario, more than a coupling of pathways, the production of DON and other secondary metabolites would be integral part of the fungus' arsenal to cope and adapt to its always-changing environment, including in the context of host-pathogen exchanges.The hypothesis of a coupling between stress response and mycotoxin production is reinforced by recent evidence that proteins involved in secondary metabolite pathways, including the aflatoxin one in The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,et al. reported that abdominal compression reduced the movement of lung tumors (thereby possibly reducing treatment uncertainty), with portal fluoroscopy being used to measure the tumor movement [et al. [et al. [et al. also reconfirmed the validity of abdominal compression using 4D CT and reported that the internal target volume was significantly reduced for lower lobe tumors [et al. reported that abdominal compression increased the variation of tumor motion by referring to their 4D cone-beam CT (CBCT) data, contending that longer treatment time to include the abdominal compression procedure may reduce the reproducibility of tumor motion [et al. [et al. [Several different approaches have been applied to stereotactic hypofractionated radiotherapy for lung tumors, including free breathing, breath-hold, gating, and tracking. Negoro movement . Heinzer [et al.  and Han  [et al.  confirmer motion . Richmon [et al.  and Mamp [et al.  also repUsing a 4D planning CT imager, Aquilion LB,  we calculated 3D lung tumor motion trajectories with an Anzai belt  and stereotactic body frame with an abdominal compression plate  for five patients who received four-fraction VMAT stereotactic ablative body radiotherapy (SABR). In addition, the motion trajectories of lung tumors were calculated using 4D CBCT imaging functionality provided by an X-ray Volume Imaging (XVI) system version 4.5  both immediately before and during treatment. The pre-treatment 4D CBCT data were acquired by the built-in XVI software, Symmetry, whereas in-treatment 4D CBCT was obtained by in-house software using projection images acquired during VMAT delivery . The brex, y and z axes correspond to the lateral, anteroposterior and craniocaudal directions, respectively. A large interpatient variability was observed: Fig. Figure Figure In conclusion, we confirmed the reproducibility of lung tumor movement using 4D planning CT and 4D CBCT for five patients who received four-fraction VMAT SABR under constrained breathing conditions. The results appear to be clinically acceptable, but further study is needed because of the small data size of this preliminary study. It is anticipated that the flattening-filter-free technique may increase breathing trajectory reproducibility due to its faster dose delivery . In addi"}
+{"text": "Allium cepa, Nicotiana tabacum, Vicia faba, or Arabidopsis thaliana but this number largely increased in the last years. Plant comet assay has been used to study the genotoxic impact of radiation, chemicals including pesticides, phytocompounds, heavy metals, nanoparticles or contaminated complex matrices. Here we will review the most recent data on the use of this technique as a standard approach for studying the genotoxic effects of different stress conditions on plants. Also, we will discuss the integration of information provided by the comet assay with other DNA-damage indicators, and with cellular responses including oxidative stress, cell division or cell death. Finally, we will focus on putative relations between transcripts related with DNA damage pathways, DNA replication and repair, oxidative stress and cell cycle progression that have been identified in plant cells with comet assays demonstrating DNA damage.The systematic study of genotoxicity in plants induced by contaminants and other stress agents has been hindered to date by the lack of reliable and robust biomarkers. The comet assay is a versatile and sensitive method for the evaluation of DNA damages and DNA repair capacity at single-cell level. Due to its simplicity and sensitivity, and the small number of cells required to obtain robust results, the use of plant comet assay has drastically increased in the last decade. For years its use was restricted to a few model species, e.g.,  The first reports on the use of comet assay in plants date from the 1990's  and the fact that root is usually the organ directly in contact with contaminated soil and water, have also influenced the establishment of plant comet assays in ecotoxicological approaches. Technical details concerning plant comet assays in different organs and species have been thoroughly reviewed by Gichner et al. .Allium cepa, Nicotiana tabacum, Vicia faba, and Arabidopsis thaliana  that allows the quantification of several comet parameters, including the tail DNA %, tail length, tail extension moment or Olive tail movement  in light excess-induced DNA damages in Ipomoea aquatica root protoplasts, and correlated DNA damages observed by comet assay with chlorophyll degradation. However, these two studies did not take into consideration the potential role of UV in light-induced DNA damages. In a study designed to investigate UV-A and UV-B effects, Jiang et al. , compared to DNA polymerase \u03bb UV-B sensitive mutants. UV-C was also shown to induce both SSBs and DSBs in Arabidopsis plumbaginifolia protoplasts -rays are used to increase seed vigor and/or enhance plant tolerance to environmental stresses. Navarrete et al.  pioneerea et al. , Koppen a et al.  and Verba et al.  optimizea et al. , 2008a uArabidopsis homologous recombination deficient mutants subjected to \u03b3-rays. On the other hand, Vandenhove et al.  seedlings after exposure to \u03b3-rays concomitant with a difference in expression profiles of three miRNAs, and an increase of reactive oxygen species (ROS) levels. Combining the use of the comet assay, and the expression of genes encoding DNA repair-related proteins, Nishiguchi et al. . Don\u00e0 et al.  presented by soils were significantly genotoxic to A. cepa roots, with DNA damages measured by comet assay and compared to the effects of increasing \u03b3-ray doses.Concerning radioactive contaminations, Saghirzadeh et al.  successfMost of the contaminated sites worldwide are contaminated with heavy metals. In Europe, heavy metals contaminated almost 50% of the investigated sites  developed adaptive responses and protection mechanisms against genotoxic effects of the mutagenic agents methylmercuric chloride (MMCl) and ethyl methanesulfonate (EMS)  genotoxicity has been the most studied during the last years. Achary et al. , 2012a aN. tabacum in hydroponic and soil experiments. These results were confirmed on Talinum triangulare roots and correlated with Pb-induced oxidative stress  including genotoxic aspects was reviewed by Pourrut et al. . Using cA. cepa roots  was shown to induce significant DNA damages in V. faba leaves and roots, in a dose-dependent manner and that these effects were associated with oxidative stress. Sturchio et al.  toxicity mechanism in plants involves DSBs and possibly replication blocks, with plant condensin II playing a critical role in DNA damages repair  was shown to induce significant DNA damages  induces higher DNA damages in roots compared to leaves. This differential effect was possibly attributable to the higher accumulation of Zn (II) in roots, compared to shoots. Tkalec et al.  were demonstrated to be relevant genotoxicity biomarkers. Despite still restricted to a few number, some studies have already used plant comet in field ecotoxicology assays of soils contaminated with metals (see Section \u201cContaminated Matrices\u201d below).It is worth noting that the interest of using the comet assay as a reliable biomarker on ecotoxicological assays is increasing, and Bandyopadhyay and Mukherjee  applied o et al.  used a bA. cepa, supporting the genotoxic potential of this type of nanomaterials.Plant comet assays are also increasingly used to assess the phytotoxicity of small-scale materials Table , e.g., n2 NPs in A. cepa  were shown to induce DNA damages in Brassica rapa ssp. rapa, and this result was confirmed by DNA laddering and TUNEL assays.Recently, using higher NPs concentrations, Thiruvengadam et al.  also demA. cepa plants. These data supported the concomitant observation of chromosomal aberrations and mitotic aberrations in the same tissues  oxide NPs increased the nuclear DNA damages in s Liman, .The alkaline comet assay showed an increase of DNA damages in tomato seedlings exposed to NiO-NPs up to 2 mg/ml  oxide and tin (IV) oxide is a mixture widely used in industrial coating. A significant increase in DNA damages was recently observed of Medicago sativa cells. In this and other pioneer studies, the comet assay can play a pivotal role as a tool to assess environmental impacts of suspected emerging nanocontaminants.Besides metal oxide NPs, quantum dots form another type of nanomaterials increasingly prevalent in the environment. Quantum dots are nanomaterials used in electronics which possess semiconducting properties, composed for example of arsenic (As), selenium (Se) and tellurium (Te) in various proportions. Despite their increasing prevalence in the environment, the toxicity of quantum dots in plants is largely unknown. In a pioneer study, Santos et al.  used a bSeveral researchers have used the comet assay to monitor DNA damages induced in plants by numerous organic pollutants Table . The mos2O2 induce DNA damages  and/or HPetunia grandiflora and Gaillardia grandiflora by comet assay, in a pioneer study of plant\u2013plant association for phytoremediation involving the treatment of textile dyes  roots after exposure to doses up to 10 mg/L  roots used treated by two herbicides 2,4-D  and Dicamba . These results were confirmed in the same study by RAPD analysis. Recently, Liman et al.  were demonstrated in plants, e.g., barley  radicles treated with Juglans regia husk water extracts. It should be noted that the authors stressed the need of performing accurate and appropriate statistical evaluations of comet results, an emerging topic of discussion. Ci\u011ferci et al.  may have cytotoxic and genotoxic effects or have protective roles against stressing conditions in a wide number of species, including humans. The way phytocompounds influence oxidative stress balances, and regulate programmed cell death pathways and cell cycle chekpoints, support their wide therapeutic use  was recently shown to inhibit plant growth of Oryza sativa, A. thaliana, Brassica rapa or Lactuca sativa   and AtRad21.1 (SYN2) as important effectors in early repair of DSBs, after treatment with bleomycin  might occur during S phase and stimulate HR in fas mutants. Also, levels of formed DSBs were compared in rice wild type plants vs. an aphidicolin-sensitive phenotype. Without aphidicolin treatment, both WT and osrecql4-2 mutants produced very low levels of DSBs, but these increased in the mutants after treatment  hypersensitive to excess of boron (B). Excess of B induced DNA damages and affected the expression of HEB1 and HEB2, which encode respectively the CAP-G2 and CAP-H2 subunits of the condensin II protein complex, important in maintenance of chromosome structure. These results suggested that DSBs are a cause of B toxicity and that condensin II reduces the incidence of DSBs  and PhAPX (encoding for a cytosolic isoform of ascorbate peroxidase).Roy et al. , 2013 reV. faba  and telomeric regions in Arabidopsis mutants by Roy et al. , top1 (DNA topoisomerase I), MtTFIIS (transcription elongation factor II-S) and MtTFIIS-like. So, despite comet assay has not been consistently applied to these environmental stresses in plants, the available data of their interference with DNA integrity, opens a perspective of their use in the near future. Also, Confalonieri et al. (Medicago truncatula the MtTdp2\u03b1-gene overexpression prevented the accumulation of DSBs in absence or presence of osmotic stress, and that the MtMRE11, MtRAD50 and MtNBS1 genes that are involved in DSB sensing/repair, being up-regulated in the MtTdp2\u03b1-overexpressing plants grown under physiological conditions, were no further up-regulated under osmotic stress (Confalonieri et al., Salt, drought and osmotic stress are ever more emerging as abiotic defies intimately related with soil overuse and climate changes (e.g., Santos et al., y et al.  who suppi et al.  demonstrIn this review we have highlighted most relevant studies that used comet assay in plants to study the impact of stress conditions on plant DNA damages. This work was mostly focused on the most recent major advances in the last five, regarding conventional and emerging contaminants and complex matrices. The recent advances in the use of the plant comet assay to both a larger number of plant species, and a larger number of conditions, support the use of this technique as a robust and sensitive technique to assess DNA damages induced by stress conditions. Data also support that this simple and robust technique may be a powerful tool to complement conventional and -omics tools in situ environmental pollution monitoring. Moreover, new fields of research using plant comet assay are open, not only in environmental studies, but also in plant physiology, as this technique may help elucidating pathways involved in plant development, cell cycle/programmed cell death, or even plant disease resistance. Also, it remains an important field of research deciphering genetic mechanisms underlying processes related with DNA damage/repair, in which comet assay will have undoubtedly a crucial role.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Yet the creatinine concentration decreased significantly (p<0.05) when the cadmium animals treated with 200 and 400 mg/kg body weight of the extract were compared with the cadmium control. Furthermore, histological alterations in the kidney were observed in cadmium untreated rats and these were ameliorated in cadmium treated rats by co-administration of IG extract. IG showed apparent protective and curative effect on Cd-induced nephrotoxicity.Cadmium has been considered a risk factor for humans as it accumulates in body tissues, such as the liver, lungs, kidneys, bones, and reproductive organs. The aim of the present study was to evaluate the effect of Irvingia gabonensis (IG) against cadmium (Cd)-induced nephrotoxicity. The study was performed on twenty (20) male rats divided into four groups: control group, cadmium group , cadmium + extract  and cadmium + extract . Changes in the kidney biochemical markers, namely glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), aminotransferase (ALT), aspartate aminotransferase (AST) activities and levels of malondialdehyde (MDA), urea, and creatinine were determined in serum. Histological examinations were monitored. Exposure to Cd lowered the activities of kidney antioxidants, while it increased LPO levels. Levels of all disrupted parameters were alleviated by co-administration of IG extract. The malondialdehyde concentration of the rats treated with 200 and 400 mg/kg body weight of the extract significantly decreased ( It is a highly accumulative toxicant with very long biological half-life . Cd nephrotoxicity was reported to result from generating free radicals and thus inducing cell necrosis and apoptosis  in membranes of erythrocytes and tissues, such as kidney, liver, brain, and testes, with thiobarbituric acid reactive substances (TBARS) and hydroperoxides used as indicators of oxidative damage  (IG) is a commercial and indigenous fruit tree of West and Central Africa and identified as the most important tree for domestication  were purchased from Aldrich Chemical Co. . Glutathione, hydrogen peroxide, 5, 5\u2019-dithios-bis-2-nitrobenzoic acid (DNTB) and epinephrine were from Sigma Chemical Co., Saint Louis, MO USA. Trichloroacetic acid (TCA) and Thiobarbituric acid (TBA) were purchased from British Drug House (BDH) Chemical Ltd., Poole, UK. Other reagents were of analytical grade and the purest quality available.Irvingia gabonensis was collected on 16th January, 2014 in Ado-Ekiti (Ekiti State) and authenticated at the Department of Plant Science, Ekiti State University. The stem bark of Irvingia gabonensis was air-dried and crushed into fine powder. The powdered part extracted with ethanol using maceration and the extract was concentrated in vacuum at 40 \u00b0C with a rotary evaporator and water bath to dryness. The yield of the extraction was 5.01%.The stem bark of Irvingia gabonensis stem bark for the detection of various phytochemicals. Tests for common phytochemicals were carried out by standard methods  weighing between 80\u2013120 g were bought from the animal house of the Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Nigeria. The animals were kept in aired cages at room temperature (28\u201330 \u00b0C) and received normal laboratory chow  and water ad libitum.Male Wistar rats  for laboratory animal care and use. The ethical committee of the Afe Babalola University approved this study. The use of all animals in this study followed the guidelines of the institutional Animal Ethical Committee given by the Committee for Control and Supervision of Experiments on Animals (CPCSEA).Cadmium was induced in groups II, III and IV. Briefly, Cadmium dissolved in distilled water was given by intravenous injection (through tail vein) at a dose of 4 mg/kg body weight.Irvingia gabonensis (200 mg/kg b.w.) (14 days) + cadmium chloride (4 mg/kg b.w.); Group IV \u2013 Irvingia gabonensis (400 mg/kg b.w.) (14 days) + cadmium chloride (4 mg/kg b.w.) according to the method of Ojo et al. ; Group II\u2013cadmium chloride (4 mg/kg b.w.); Group III \u2013  et al.  .Kidney tissues were quickly removed, washed in ice-cold isotonic saline and blotted individually on ash-free filter paper. The tissues were then homogenized in 0.1 M 2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride buffer, pH 7.4, using a Potter-Elvehjem homogenizer at 4 \u00b0C. The crude tissue homogenate was centrifuged at a speed of 9 000 rpm for 15 min in a cold centrifuge and the supernatant was kept at \u201320 \u00b0C for estimation of GSH, SOD and CAT activities.Blood collected from the heart of the animals into plain centrifuge tubes was allowed to stand for 1 h. Serum was prepared by centrifugation at 3 000 g for 15 min in a Beckman bench centrifuge. The clear supernatant was used for assessing the serum lipid profile and enzymes.et al.  followed by the Duncan multiple range test for analysis of biochemical data using SPSS (20.0). Values were considered statistically significant at The ethanolic extract was found to contain compounds known to have antioxidant activity, like tannins, phlobatannins, flavonoids, anthocyanin, cardiac glycosides and alkaloids .p<0.05) in the relative weight of the kidney of cadmium untreated rats when compared with the control, while treatment with Irvingia gabonensis stem bark (100 and 200 mg/kg) significantly decreased the relative weight of the kidney of cadmium-induced rats to values statistically comparable to the control (p>0.05). All these changes induced by cadmium intoxication restored significantly (p<0.05) to near normal levels on administration of Irvingia gabonensis stem bark.p<0.05) serum and kidney lipid peroxidation (LPO) products measured as thiobarbituric acid reactive substances  confirmed the nephro-protective activity as a significant recovery of nephron damage and decreased necrosis was evident against cadmium-induced nephrotoxicity in the kidney of the rats, comparable to their control. The histological results further corroborated the biochemical findings suggesting the useful effects of Irvingia gabonensis stem bark in cadmium-induced toxicity in rats.Histology of the kidney slide of cadmium untreated rats showed tubular degeneration, necrosis and severe renal cortical congestion . TreatmeIrvingia gabonensis stem bark extracts revealed the presence of polyphenol-rich compounds. Polyphenols have been suggested to decrease oxidative stress in humans. Flavonoids found in the extract may inhibit oxidative stress by scavenging free radicals, acting as reducing agents, hydrogen atom donating molecules or singlet oxygen quenchers, chelating metal ions and sparing other antioxidants   such as alkaloids, glycosides, saponins, tannins, flavonoids and phenolic compounds, which are responsible for the antioxidant activity.Cadmium is a well-known human carcinogen and a potent nephrotoxin. It is a potent inducer of oxidative stress and affects the cellular antioxidant defense potential bi-phasically by reserve and improvement of several antioxidant enzymatic and non-enzymatic molecules. The phytochemical study of Irvingia gabonensis stem bark examined against cadmium-induced nephrotoxicity in rats showed that the mean body weight of the cadmium-exposed group decreased with the increase in relative liver weight, which agrees with the findings of other authors (EI-demerdash et al., et al., et al. (Irvingia gabonensis, the changed body weight and liver weight parameters recovered to near normal levels due to the antioxidant effects of Irvingia gabonensis stem bark.In the present study, the potent chelation therapy with , et al.  reportedet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Many studies have shown that cadmium induces oxidative damage by producing ROS (Liu et al., et al., et al., Irvingia gabonensis in the treated groups, indicating a prominent nephroprotective effect of Irvingia gabonensis against cadmium nephrotoxicity. The increased levels of serum AST and ALT in cadmium exposed rats indicate an increased permeability and damage and/or necrosis of the kidney. In our study, we found that the extract of Irvingia gabonensis at a dose of 400 mg/kg caused a significant decrease in the activities of serum AST, ALT, which further supports the beneficial effects of the extract of Irvingia gabonensis in cadmium-induced rats.Moreover, the protective effects of this extract may be related to its ability to chelate or sequester cadmium via formation of cadmium-flavonoid complexes (el-Ashmawy Serum total protein represents a complex mixture containing a number of components which differ in properties and function. Hypo-proteinemia, protein deficiency in plasma, may be partly due to dietary insufficiency with subsequent impairment of the protein synthetic machinery, or to excessive excretion Chawla, . In the et al., et al., et al., et al., et al., Irvingia gabonensis had a protective effect against cadmium-induced kidney damage, as established by the significant decrease in urea and creatinine levels in the Irvingia gabonensis treated group compared with the cadmium group.It has been postulated that increased levels of serum urea and creatinine are linked to kidney disease Chawla, . Urea isIrvingia gabonensis treatment of cadmium-induced nephrotoxicity in rats revealed that the observed pathological impairments caused by cadmium recovered significantly, indicating that Irvinga gabonensis is capable of preventing the nephron damage induced by cadmium. It is thus suggested that Irvingia gabonensis may inhibit Cd-induced kidney damage. However, further studies are necessary to find out the actual mechanism of action of phytochemicals and their doses in the presence of oxidative stress due to Cd intoxication.Histological examination revealed that cadmium intoxication caused abnormal ultra-structural changes in kidney tissue, including tubular degeneration, necrosis and severe renal cortical congestion. Regarding the histopathological observation, Irvingia gabonensis exhibited protective effects against Cd-induced nephrotoxicity. For populations exposed to Cd, the use of the ethanolic extract of Irvingia gabonensis could thus be recommended.In conclusion, the ethanolic extracts of"}
+{"text": "Dear Editor,Morbilivirus which belongs to family Paramyxoviridae . The dial., 2011; Yanagi al., 2011; Fazlalial., 2011). Measleal., 2011). Howeveal., 2011; Muscat al., 2011). Historal., 2011). Recently, increased number of measles outbreaks with high morbidity and mortality has been observed in various regions of Pakistan during recent years  as outlined in supplemental material . A total of 871/1053 (82.71 %) children from Faisalabad and 647/813 (79.58 %) children from Jhang were found vaccinated either with single or dual dose of measles vaccination Table 1. Out of Samples from non-vaccinated children showed high prevalence (63 %) which was an indication of previous measles infection in these particular children. These findings were suggestive and may be correlated with confirmatory sero-diagnosis of recent outbreaks in these areas. The non-vaccination status against measles was considered as one of the major risk factor in children . The prevalence of anti-measles IgG antibodies from samples collected from Faisalabad was found 79.54 % whereas in Jhang 67.42 % of samples were observed as positive. There was no significant difference of sero-prevalence between Faisalabad and Jhang. The possible explanation for non-significant prevalence could be that these two areas are closely related geographically, traditionally and are closely situated to each other. These factors may be considered for a similar trend towards vaccination coverage and sero-conversion against measles as previously described by Hussain et al. (2008[The prevalence of anti-measles IgG antibodies from samples collected from male children was higher as compared to female children with non-significant difference. However, few of the available literature has reported that risk of measles and level of anti-measles IgG antibodies was observed higher in females as compared to male children (Rahim et al., 2011; FowotadBased on various age groups, prevalence of anti-measles IgG antibodies were observed as 75.35 % in children from 1-6 years of age, whereas 67.56 % in children from 6-10 years of age were positive with no significant difference. These findings were not in accordance with some of the previous studies which showed the highest incidence of measles during the age of 6 months to 3 years (Matsumura et al., 2005; Rahim eIt was concluded from the overall results of present study that vaccination coverage against measles was below the standards of WHO and Health Department, Govt. of Punjab, Pakistan. Further, vaccine efficacy and development of humoral immune response in children was not optimum according to WHO guidelines and higher risk of measles incidence was found in non-vaccinated children. Based on these findings, it is recommended that routine immunization against all vaccine preventable diseases in general and against measles in particular should be carried out as per guidelines of WHO to completely control and eradicate measles from Pakistan.The authors declare that they have no conflict of interest."}
+{"text": "Neural stimulation is a critical technique in treating neurological diseases and investigating brain functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of neural tissues. Second-generation stimulation techniques directly use light, magnetic fields or ultrasound in a non-contact manner. An emerging generation of non- or minimally invasive neural stimulation techniques is enabled by nanotechnology to achieve a high spatial resolution and cell-type specificity. In these techniques, a nanomaterial converts a remotely transmitted primary stimulus such as a light, magnetic or ultrasonic signal to a localized secondary stimulus such as an electric field or heat to stimulate neurons. The ease of surface modification and bio-conjugation of nanomaterials facilitates cell-type-specific targeting, designated placement and highly localized membrane activation. This review focuses on nanomaterial-enabled neural stimulation techniques primarily involving opto-electric, opto-thermal, magneto-electric, magneto-thermal and acousto-electric transduction mechanisms. Stimulation techniques based on other possible transduction schemes and general consideration for these emerging neurotechnologies are also discussed. Neural stimulation is an essential technique for restoring lost neural functions and correcting disordered neural circuits in neurological diseases  the strong cytotoxicity of QDs is a concern, particularly when a thin coating is used to achieve an active QD-neuron interface  nanoparticles were targeted to the biotinylated peptide of a genetically engineered anchor protein in the membrane of neurons expressing the temperature-gated TRPV1 ion channels (Placement II; Huang et al., 2+ influx through the TRPV1 ion channels, depolarized the neurons to fire action potentials in vitro, and triggered thermal avoidance in worms.Widely used superparamagnetic nanoparticles can convert alternating magnetic fields to localized heat via magneto-thermal transduction (Laurent et al., 2+ influx into the cells faster than in the above work (Huang et al., A more specific ion-channel targeting strategy was also implemented in a mouse xenograft model by tethering nanoparticles directly to the TRPV1 ion channels (Placement III; Stanley et al., in vivo stimulation feasibility, untargeted superparamagnetic iron oxide nanoparticles were dispersed in the vicinity of TRPV1-expressing human embryonic kidney HEK-293FT cells, dissociated hippocampal neurons and neurons at the ventral tegmental area of mice (Placement I; Chen et al., 2+ influx in the HEK-293FT cells, stimulated hippocampal neurons to fire action potentials, and activated the neurons at the ventral tegmental area of mice to have an enhanced expression of c-fos, achieving a stimulation response with a latency of 5 s after the onset of the magnetic field. And the stimulation in the mouse model remained effective for at least 1 month thanks to the good biocompatibility, stability and decreased endocytosis of extracellularly dispersed nanoparticles.To improve the temporal resolution for neuronal activation and realize a long-term 2+ permeability, and thus temperature-gated Na+ ion channels are desired as the target (Kn\u00f6pfel and Akemann, Magneto-thermal neural stimulation enabled by superparamagnetic nanoparticles can achieve a uniform stimulation of the target cell population due to the uniform expression of TRPV1 ion channels in these cells across the tissue (Huang et al., As a wirelessly transmitted primary stimulus, ultrasound interacts with tissues weakly and can penetrate deep into soft tissues with minimal energy absorption Tyler, . It can 2+ and Na+ influxes in an ultrasonic field (Placement II; Marino et al., Piezoelectric nanomaterials can convert ultrasound waves to electric fields via acousto-electric transduction due to their piezoelectricity (Wang and Song, Nanomaterial-enabled neural stimulation is an emerging class of neurotechnologies, with numerous exciting breakthroughs in the past decade. As a powerful enabling tool, nanomaterials can be either applied alone or combined with other approaches including synthetic biology to facilitate innovative neural stimulation schemes. These new techniques not only allow non- or minimally invasive neural stimulation of a high spatial resolution and cell specificity, but also improve the safety by significantly reducing the required power of the primary stimulus (Huang et al., Nanomaterials of other transduction mechanisms, such as magneto-mechanical, acousto-mechanical, and opto-optical transductions, are also worth considering for potential development of additional neural stimulation schemes. Magneto-mechanical transduction via magnetic nanoparticles can convert magnetic fields to localized mechanical forces to activate mechanosensitive ion channels such as the TREK-1 channels (Hughes et al., To select the primary and secondary stimuli, several factors are considered. The primary stimulus needs to penetrate tissues deeply, be easy to focus at an appropriate spatial resolution and be safe for long-term exposure. The secondary stimulus needs to be selected according to an adequate expression of the target ion channels in the neuron's membrane. For example, it is not necessary to genetically modify the target neurons with voltage-gated ion channels to use electric fields as the secondary stimulus, whereas, to use heat, the TRPV1 ion channels may need to be genetically inserted into the membrane of target neurons (Huang et al., in vitro. To move forward, many issues including biocompatibility, stability, consistency, efficiency and reliability will need to be addressed (Gomez et al., in vitro and/or in vivo studies. Clinical application is promising, but remains very challenging due to concerns on the safety of nanomaterials, viral vectors for gene delivery, and genetic modification to the target neurons (Manilla et al., This diverse class of nanomaterial-enabled neurotechnologies is still in their early stages of development, with many having only been validated YW and LG analyzed the relevant published work, designed the perspective and structure, and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Preliminary follow-up studies seem to support the efficacy and safety of SVF/ASCs enrichment and the additional benefit from the combined use of autologous platelet-derived growth factors and hormones during breast reconstruction procedures. In the present review we highlighted the complex interplay between resident or grafted ASCs, mature adipocytes, dormant or active breast cancer cells and tumor microenvironment. Actually, data concerning the permissive role of ASCs on breast cancer progression are contrasting, although no clear evidence speaking against their use exists.Breast cancer is the most common cancer in women and autologous fat grafting is an important clinical application in treatment of post-surgical deformities. The simplicity of fat grafting procedures and the absence of subsequent visible scar prompted an increasing interest for this technique. The plasticity of adipose-derived stem cells (ASCs) obtained from stromal vascular fraction (SVF) of adult adipose tissue provided exciting perspectives for regenerative medicine and surgery. The recent discovery that SVF/ASC enrichment further ameliorates clinical efficacy of grafting ASCs suggest as ASC-mediated new adipogenesis and vasculogenesis. ASC adipogenic differentiation involves Akt activity and EGFRs, FGFRs, ERbB2 receptor-mediated pathways that also play a pivotal role in the regulation of breast cancer growth. Moreover, the finding that platelet-derived growth factors and hormones improved long-term maintenance of fat grafting raises new concerns for their use during breast reconstruction after cancer surgery. However, it remains unclear whether grafted or resident ASCs may increase the risk of  However, the term \u201cadipose-derived stem cells\u201d (ASCs) has been successively recommended for the consistency between research groups (Zhao et al. in situ lesions. This finding induced caution and suggested some concerns about the use of fat grafting with SVF/ASC enrichment in breast reconstruction following cancer surgery. In the present review, we tried to describe the biomolecular pathways regulating proliferation and differentiation of ASCs, in order to define potential implications of breast cancer cell biology and risks for their use in post-surgery breast cancer reconstruction.Adult adipose tissue is a multifunctional organ that contains various cellular types, including mature adipocytes, macrophages and stromal cells, supported by connective tissue surrounding fine capillaries (Zuk et al. in vitro as a function of time and/or passage in culture (Mitchell et al. in vitro, ASC surface immunophenotype resembles that of MSCs, with a similarity greater than 90% (Gimble et al. + cells and to differentiate them from circulating precursors (Pittenger et al. + cells and the perivascular origin of ASCs (Figure\u00a0in vitro (Figure\u00a0ASCs share with MSCs the differentiation potential along several mesenchymal lineages (Gimble et al. s Figure\u00a0C-E. Cytoo Figure\u00a0. Besideso Figure\u00a0.Table 1The fascinating differentiative pluripotency of ASCs and their ability to enhance vascularization (Bertolini et al. \u03b1, heparin-binding epidermal growth factor, insulin-like growth factor-II and adipsin (Manabe et al. in vivo and in vitro studies demonstrated relevant phenotypic changes in adipocytes surrounding breast cancer (Dirat et al. Many studies focused the relationship between mature adipocytes and breast cancer cells. Rat mature adipocytes affect the biological behavior of epithelial cells through the production of leptin, adiponectin, tumor necrosis factor-in vivo and in vitro reported that ASCs favor tumor growth, increasing extracellular matrix deposition and vascularization, suggesting that ASCs may directly contribute to the dense network of fibroblasts and desmoplastic reaction surrounding breast cancer (Wang et al. in vitro documented that co-culture of human ASCs and breast cancer cells induce high levels of metalloproteinases (Pinilla et al. Differently from mature adipocytes, the interplay between resident mesenchymal cells, including ASCs, and breast epithelial cells is still partially unknown. In this respect, it is still unclear whether preadipocytes act differently from mature adipocytes. ASCs are located in perivascular niches and contribute to cell turn-over, vascular network for the maintenance of adipose tissue tropism (Strawford et al. in vivo and in vitro have been performed to verify ASCs influence on dormant tumor cells and on their growth and invasiveness. In literature is not yet clear whether dormant tumor cells are out of cell cycle, or persist in a dynamic state of proliferation and death. The transition between dormant and active states requires the presence of various signals, such as cytokines, hormones and growth factors (Donnenberg et al. To better clarify their role in cancer progression, studies in vivo interaction and define how selectively stimulate ASCs regenerative function without influencing tumorigenesis.Altogether, these studies highlight the concept that resident ASCs and cancer cells may interact in a complex and dynamic fashion influencing the tumor behavior. Further studies are needed to better clarify this in vitro (Cervelli et al. In vitro data alone seem to suggest the caution in the local use of growth factors in addition to fat graft and further investigation of the interplay between ASCs and breast cancer cells should be performed also in vivo.The proliferative arrest and/or cell loss are potential limitations in regenerative surgery strategies. So, exogenous growth factors should provide the necessary microenvironmental signals to accelerate cell proliferation, extracellular matrix synthesis and tissue deposition (Chen et al. Autologous fat grafting is a procedure widely used in breast reconstruction after cancer surgical treatment (Gentile et al. in vivo. MSCs can be readily transduced via adenoviral, retroviral or lentiviral vectors without compromising the capability for differentiation or the expression of surface markers. Consequently, MSCs are potentially suitable for a gene approach in cancer therapy through the induction of a more chronic and slow release of drugs that are often limited by their toxicity or short life (Kucerova et al. In vitro, MSCs transduced with adenoviral vector carrying human Interferon-\u03b2 and co-cultured with breast cancer cells induced the reduction of cancer cells growth (Studeny et al. in vivo, when Interferon-\u03b2\u2009\u2212\u2009transfected MSC cells are injected intravenously in a xenograft breast cancer mouse model (Studeny et al. In vitro studies documented that cancer stem cell exert antiapoptotic effect on breast cancer cells and counteract cell-cycle changes caused by tamoxifen, so promoting tumor growth and invasiveness (Wang et al. Conventional cancer therapies include surgery, chemotherapy and radiotherapy. A certain number of preclinical studies recently proposed the use of MSCs as candidates to deliver anti-cancer drugs. Chemokines secreted by breast tumor cells are capable of stimulating MSCs migration and recruitment, suggesting a potential role for MSCs as delivery agents for chemotherapeutic purposes in breast tumours Aromatase inhibitors are used as second-line therapy or as first-line adjuvant therapy, but they have the disadvantage to inhibit indiscriminately aromatases, including those in bone and brain tissues, with adverse effects in terms of bone mineralization and cognitive function, respectively (Rubin et al. in vivo seem to confirm the efficacy of SVF/ASCs enrichment and the beneficial additional use of autologous platelet-derived growth factors and hormones in breast reconstruction. The improvement in long-term maintenance strongly supports the additional combined use of fat grafts with autologous platelet-derived growth factors and hormones, such as insulin. However, additional translational research studies are needed to better clarify the possible impact of these procedures on tumor microenvironment, in particular their potential effect on cancer cells. Different studies confirmed the complex and dynamic interplay between cancer cells and resident ASCs. Latters, in the tumor microenvironment, seem to affect only active cancer cells, so promoting neoangiogenesis, matrix remodeling and intercellular communication via gap-junction. In addiction, it has been hypothesized the presence of cancer stem cells, from resident stem cell or dedifferentiated tumor cells, that may favour the epithelial-mesenchymal transition, supporting tumor growth and invasiveness. In addition, the interaction between grafted ASCs and resting cancer cells doesn\u2019t seem to be responsible for cancer recurrence because resting cancer cells are more resistant to apoptosis and they don\u2019t require stroma or vascular structure for their survival. Preliminary data describe that SVF/ASCs enrichment did not show increased risk of new cancer or relapse compared with control group.Current evidence sustains that ASCs represent a promising tool for innovative therapies in regenerative surgery and play a significant role in lipofilling-mediated breast reconstruction after breast cancer surgery. SVF/ASCs enrichment seems to favor long-term fat graft maintenance in reconstruction of tissue defects, likely promoting vascularization and collagen synthesis. Preliminary studies Finally, ASCs characteristics appear promising for their engineered use as \u201ccarrier\u201d of adjuvant chemotherapeutic agents against residual breast cancer cells. So, the growth of malignant cells may be counteracted by local release of drugs in tumor microenvironment while systemic plasma concentration remain low, avoiding the problems related to toxicity and short life."}
+{"text": "Carragher et al.In an attempt to analyse the cross-sectional data correctly, I obtained information on alcohol consumption for eight of the study regions from published WHO data for 2010,I did a multiple regression analysis using methods described by KronmalIn my regression model, I considered total alcohol consumption in each area as the response, with GDP, population and TEASE-16 score the predictors. Only population size was significantly associated with total alcohol consumption , and exaThe relationship between TEASE-16 and GDP per capita is shown in Neither TEASE-16 score nor income, (measured by GDP), were significantly correlated with alcohol consumption across the eight areas in the year 2010. It seems unlikely that analysis of the original data used by Carragher et al."}
+{"text": "Machine learning (ML) has been well recognized as an effective tool for researchers to handle the problems in signal and image processing. Machine learning is capable of offering automatic learning techniques to excerpt common patterns from empirical data and then make sophisticated decisions, based on the learned behaviors. Medicine has a large dimensionality of data and the medical application problems frequently make the human-generated, rule-based heuristics intractable. In this special issue, we provide a forum to present the cutting-edge machine learning techniques in medical applications, including the learning of similarities across different image modalities, organ localization, learning of anatomical changes, tissue classification, and computer-aided diagnosis. \u201cAdaptive neuro-fuzzy inference system for classification of background EEG signals from ESES patients and controls\u201d introduced an adaptive neurofuzzy inference system for classification of background EEG signals from the patients of slow-wave sleep syndrome and control subjects. Their study showed that the entropy measures of EEG were significantly different between the patients and normal subjects. Therefore, a classification framework based on entropy measures was proposed. S. Jirayucharoensak et al. in \u201cEEG-based emotion recognition using deep learning network with principal component based covariate shift adaptation\u201d proposed the utilization of a deep learning network (DLN) to discover unknown feature correlation between input signals. The DLN was implemented with a stacked autoencoder (SAE) using hierarchical feature learning approach. D. Al-Jumeily et al. in \u201cA novel method of early diagnosis of Alzheimer's disease based on EEG signals\u201d introduced three neural synchrony measurement techniques: phase synchrony, magnitude squared coherence, and cross correlation for classification of mild Alzheimer's disease patients and healthy subjects. K. Zhang et al. in \u201cAdaptive bacteria colony picking in unstructured environments using intensity histogram and unascertained LS-SVM classifier\u201d presented a novel approach for adaptive colony segmentation in unstructured environments by treating the detected peaks of intensity histograms as a morphological feature of images. In order to avoid disturbing peaks, an entropy based mean shift filter was introduced to smooth images as a preprocessing step. The relevance and importance of these features can be determined in an improved support vector machine classifier using unascertained least square estimation. M. Cabrerizo et al. in \u201cInduced effects of transcranial magnetic stimulation on the autonomic nervous system and the cardiac rhythm\u201d demonstrated that repetitive transcranial magnetic stimulation (rTMS) could induce changes in the heart rhythm.The topics of the accepted papers in this Special Issue spread from electroencephalography (EEG) signal processing to image segmentation. Z. Yang et al. in"}
+{"text": "Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson\u2019s.Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression  The major histocompatibility complex (MHC) gene family encodes molecules on the surface of cells that enable the immune system to recognize presented self- and foreign-derived peptides  and beta 2 microglobulin (\u03b22m) chains  is immune-privileged and that MHC-I is not expressed by neurons Lampson, . HoweverThis review summarizes the pattern of expression and the different implications of neuronal MHC-I in the brain, and focuses in particular in the potential role of constitutive MHC-I expression by specific subsets of neurons in neurodegenerative diseases such as PD.in vitro, usually triggered by exposure to interferon gamma (IFN-\u03b3), and in vivo. The initial such study showed that MHC-I genes expression were induced by IFN-\u03b3 in cultured rat hippocampal neurons , and are far more susceptible to MHC-I induction than other neuronal populations tested, including cortical, striatal and thalamic neurons  subunit, CD3zeta , exhibit reduced retinal synaptic activity, incomplete developmental refinement of connections between retina and its central targets, and reduced retinal ganglion cell dendritic motility with increased dendritic density  has been linked to MHC-I and CTLs in the CNS (Friese and Fugger, Our findings in human postmortem samples of adult control individuals and PD patients show that MHC-I is expressed by SN DA and LC NE neurons (Cebri\u00e1n et al., Neuronal MHC-I expression plays multiple roles. First, it regulates synaptic plasticity during brain development. Second, it regulates axonal regeneration and the appropriate specification of synaptic inputs following injury. Third, in neuronal diseases including neurotropic viral infections, neuronal MHC-I expression is upregulated and may initiate T cell mediated responses. While current research in each of these areas is ongoing, the suggestion of a role in neurodegenerative disease is the most recent and the least understood: while there is a consensus that many neurodegenerative diseases feature a robust inflammatory response, it remains unclear how this is related to chronic disease processes.In vitro experiments indicate that DA primary human neurons derived from human embryonic stem cells and primary catecholamine murine neurons are more susceptible to MHC-I induction by IFN-\u03b3 than other neuronal populations (Cebri\u00e1n et al., Our recent study demonstrates neuronal MHC-I expression in both normal and PD adult brain; such expression to date appears to be particular for catecholaminergic/monoaminergic neurons. These possibilities are consistent with recent demonstrations that microglia can be activated by substances released from degenerating neurons in PD, such as \u03b1-syn (Zhang et al., Neuronal display of antigenic MHC-I could participate in a range of additional neurological disorders. For example, Japanese encephalitis virus can induce MHC-I expression in non-neuronal cells by interferon type 1 (Abraham et al., Together, these data indicate that in human brain, neuronal MHC-I expression, antigen presentation and the presence of T cells could occur simultaneously under certain circumstances, leading to the death of targeted neurons. In some neurodegenerative diseases, and in particular for PD, we propose that activation of lymphocytes in the periphery may occur in response to self or non-self proteins, or as an initial insult and disruption of the blood brain barrier, with a subsequent penetration of lymphocytes in the brain. When catecholamine neurons die with subsequent release of \u03b1-syn and NM to the extracellular space, the activation of microglial cells will release proinflammatory substances such as IFN-\u03b3, leading to an upregulation of MHC-I in the membrane of catecholamine neurons that could present neuronally derived antigens. If lymphocytes are close, they could recognize these antigens and target and kill the cell, which would again release \u03b1-syn and NM Figure , leadingFuture studies are necessary to identify which antigens are presented by MHC-I expressing catecholamine neurons and how T cells might interact with them. If these interactions occur, immune therapies used in other diseases including classical autoimmune disorders such as Type 1 diabetes or MS may be adapted to provide future treatments for PD.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Heme oxygenase (HO) is a ubiquitous enzyme with various properties, but its main function is catalyzing the rate-limiting step in heme degradation to produce equimolar quantities of biliverdin, iron, and carbon monoxide (CO)  and Hmox1\u2212\u2215\u2212 mice, Soares et al.   cells, restores placentation, and fetal growth, while normalizing blood pressure (Linzke et al., Zenclussen et al.  review hThe relevance of HO-1 in the regulation of immune responses during pregnancy is further highlighted in the article by George et al. . They inIn summary, the HO-1/CO axis may play a pivotal role in sustaining pregnancy, and thus understanding its biology during pregnancy may reveal promising therapeutic approaches for pregnancy complications.Both the authors contributed in writing the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In a recent study, Cid-Fernandez et al.  tested aOther prior studies have investigated changes in motor changes in aging Light, . In one What is important about this study is Cid-Fernandez and colleagues (a) have tested both motor and cognitive processes in (b) three age groups. Most existing studies on aging often compare younger (aged 18\u201330 or 50 years old) with older (aged 60 or 65 years and over) adults Scott, , and thuImportantly, there are studies that test behavioral performance in more age groups than those recruited in the Cid-Fernandez et al.  study s. One sucOther studies have recruited participants across various age groups and correlated behavioral performance with age (Davis et al., Cid-Fernandez et al.  suggest The Cid-Fernandez et al.  findingsThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Chorioamnionitis (CA) describes an intrauterine status of inflammation and/or infection of placental membranes, refering to both histological and clinical CA . It is c"}
+{"text": "Recent objectification research found results consistent with the sexualized body-inversion hypothesis (SBIH): People relied on analytic, \u201cobject-like\u201d processing when recognizing sexualized female bodies and on configural processing when recognizing sexualized male bodies  processing becomes more important . Because Bernard et al.  presenteIn their first study, Schmidt and Kistemaker examined symmetry in Bernard's stimuli and found that female bodies were more asymmetrical than male bodies. Strikingly, neither the interaction between stimulus gender and stimulus orientation nor the three-way interaction involving stimulus set-up emerged. These results suggest that differences in symmetry between inverted (vs. upright) female bodies  are not more pronounced in the Bernard set-up than in the counterbalanced set-up.In their second study, these authors replicated Bernard et al. 's findindirectly address this putative symmetry confound as they allow comparison within symmetry-matched stimuli . A visual inspection of Figure 2  and asymmetrical female bodies (seventh vs. fourth bar); (ii) asymmetrical inverted female bodies (fourth bar) were not recognized better than symmetrical inverted female bodies (eighth bar).Schmidt and Kistemaker identified a potential stimulus set-up confound in their second study (contrary to Bernard et al., In sum, contrary to Bernard et al. , SchmidtSchmidt and Kistemaker also found an inversion effect for male and female bodies and this pattern occurred for naked bodies with or without masked sexual body parts. They concluded that Bernard et al.'s findings are not driven by target sexualization (Schmidt and Kistemaker, conceptual replication perspective, Schmidt and Kistemaker provide evidence in favor of restricted generalizability of Bernard et al.'s findings but from a direct replication perspective Schmidt and Kistemaker's paper cannot address the role of target sexualization in Bernard et al.'s stimuli because they did not manipulate sexualization of these stimuli. Bernard et al. (First, although informative with regard to the role of target sexualization and inversion, the SBIH was posited to explain differences in recognition of sexualized male vs. sexualized female bodies (i.e., stimulus gender effect: Bernard et al., d et al. , howeverIn sum, contrary to Bernard et al. , SchmidtThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of meduloblastoma. Cancer and Metabolism 2013, 1(2):17A response to Gershon et al. : Gershon et al. have invfl/fl conditional knockout that they have used to study the metabolism and migratory behavior of CGNPs during their development not only targets those neurons[Gershon et al. interpretation of the results of their Fig. 5 may also be discussed as the hGFAP-cre;Hk2 neurons. Thus anOne might thus feel that in their work, Gershon et al. may have overlooked an important aspect of the cerebellar developmental process and one could suggest that they give more attention to the possible involvement of Bergmann glia in modulating the role of Hexokinase-2-mediated aerobic glycolysis during cerebellar neurogenesis."}
+{"text": "Reelin, a multifunctional extracellular protein that is important for mammalian brain development and function, is secreted by different cell types in the prenatal or postnatal brain. The spatiotemporal regulation of Reelin expression and distribution during development relates to its multifaceted function in the brain. Prenatally Reelin controls neuronal radial migration and proper positioning in cortical layers, whereas postnatally Reelin promotes neuronal maturation, synaptic formation and plasticity. The molecular mechanisms underlying the distinct biological functions of Reelin during and after brain development involve unique and overlapping signaling pathways that are activated following Reelin binding to its cell surface receptors. Distinct Reelin ligand isoforms, such as the full-length protein or fragments generated by proteolytic cleavage differentially affect the activity of downstream signaling pathways. In this review, we discuss recent advances in our understanding of the signaling transduction pathways activated by Reelin that regulate different aspects of brain development and function. A core signaling machinery, including ApoER2/VLDLR receptors, Src/Fyn kinases, and the adaptor protein Dab1, participates in all known aspects of Reelin biology. However, distinct downstream mechanisms, such as the Crk/Rap1 pathway and cell adhesion molecules, play crucial roles in the control of neuronal migration, whereas the PI3K/Akt/mTOR pathway appears to be more important for dendrite and spine development. Finally, the NMDA receptor (NMDAR) and an unidentified receptor contribute to the activation of the MEK/Erk1/2 pathway leading to the upregulation of genes involved in synaptic plasticity and learning. This knowledge may provide new insight into neurodevelopmental or neurodegenerative disorders that are associated with Reelin dysfunction. Cleavage at this site releases a six amino acid carboxy-terminal peptide, reducing signaling activity and hindering dendrite development in the postnatal neocortex  and the very low-density lipoprotein receptor (VLDLR). These proteins belong to the low-density lipoprotein receptor (LDLR) family. They have partial functional redundancy and play an essential role in Reelin-mediated neuronal migration based on the observation that double knockout mice display a in vitro  is an intracellular adaptor protein that is essential for Reelin signal transduction. This protein binds the cytoplasmic tail of lipoprotein receptors, including ApoER2 and VLDLR (Trommsdorff et al., Crk/CrkL mutant mice display a reeler-like cortical phenotype (Park and Curran, Genetic studies demonstrated that Dab1, and thus Reelin signaling, is specifically required for a specific mode of radial migration termed somal or terminal translocation, but not for glial-guided locomotion (Franco et al., PAFAH1b1 gene that is responsible for human lissencephaly type I, may be particularly relevant to cortical development. Lis1 binding to phospho-Dab1 is Reelin-dependent, and genetic interaction between Dab1 and PAFAH1b1 demonstrates a functional relationship between these proteins (Assadi et al., PAFAH1b alpha subunits bind specifically to VLDLR, potentially promoting the interaction between Lis1 and Dab1 downstream of this receptor (Zhang et al., In addition to Crks and Rap1, biochemical studies identified several molecules that may be involved in Reelin-dependent neuronal migration. These include proteins that regulate cytoskeletal dynamics and cell motility, such as Lis1, Nck\u03b2 and N-WASP (Assadi et al., reeler mice. Dendritic defects are also apparent in immature hippocampal or cortical cultures isolated from mutant mice, but not in mature cultures (Niu et al., . Since Reelin treatment rescued these defects, these in vitro studies first demonstrated that Reelin directly promotes dendrite development. Following studies further demonstrated that Reelin enables initial dendritic outgrowth by promoting the extension of the Golgi apparatus into apical dendrites (Matsuki et al., in vitro in a manner that is dependent on SFK activity and Dab1 phosphorylation (Beffert et al., in vivo studies demonstrated that the Crk adaptor proteins are required for Reelin-induced Akt phosphorylation, placing the kinase functionally downstream of these adaptors (Park and Curran, Dendrite outgrowth is disrupted in homozygous Other molecules that have been implicated in Reelin-dependent dendrite outgrowth include the amyloid precursor protein (APP; Hoe et al., reeler mice exhibit altered hippocampal synaptic plasticity and multiple behavioral abnormalities, such as defects in executive function and contextual fear conditioning learning (Brigman et al., in vivo (Beffert et al., ++ influx through the NMDAR (Beffert et al., ++ influx, Erk1/2 signaling and CREB-dependent IEGs transcription (Telese et al., Heterozygous ++ signaling (Hellwig et al., Reelin gene in adult mice does not result in impaired synaptic plasticity. However, it renders the adult brain strikingly sensitive to amyloid-induced synaptic suppression, leading to profound learning disabilities (Lane-Donovan et al., In addition to its well-documented postsynaptic effects, Reelin also acts presynaptically, causing a rapid enhancement of spontaneous neurotransmitter release. This effect is due to the mobilization of VAMP7-containing synaptic vesicles, and requires canonical ApoER2/VLDLR receptors, PI3K and CaGHL wrote the first draft of the manuscript and made the figures. GD wrote and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The grant number is GR09/0021.In the Funding section, the second grant number from the funder Instituto de Salud Carlos III (Madrid, Spain;"}
+{"text": "Morbilivirus . The clal., 2011; Fazlalial., 2011). Expandal., 2011; Liu et al., 2011). Furtheal., 2011; Leuridaal., 2011). Vaccinal., 2011; Sheikh al., 2011). Many ial., 2011). Among al., 2011). Furtheal., 2011). Therefore, keeping in view the importance and significance of measles, this preliminary study was designed to develop an ELISA for detection of humoral immunity. For this purpose ELISA plates were coated with measles virus CAM-70 strain  which contain not less than 1000 CCID50 in 0.5 ml. Coating of plates was performed using carbonate buffer as described by van der Werff (2008). BrieflThe authors declare that they have no conflict of interest."}
+{"text": "The fossil record of crocodylians and their relatives (pseudosuchians) reveals a rich evolutionary history, prompting questions about causes of long-term decline to their present-day low biodiversity. We analyse climatic drivers of subsampled pseudosuchian biodiversity over their 250 million year history, using a comprehensive new data set. Biodiversity and environmental changes correlate strongly, with long-term decline of terrestrial taxa driven by decreasing temperatures in northern temperate regions, and biodiversity decreases at lower latitudes matching patterns of increasing aridification. However, there is no relationship between temperature and biodiversity for marine pseudosuchians, with sea-level change and post-extinction opportunism demonstrated to be more important drivers. A \u2018modern-type' latitudinal biodiversity gradient might have existed throughout pseudosuchian history, and range expansion towards the poles occurred during warm intervals. Although their fossil record suggests that current global warming might promote long-term increases in crocodylian biodiversity and geographic range, the 'balancing forces' of anthropogenic environmental degradation complicate future predictions. Crocodylians and their relatives have a rich evolutionary history. Here the authors show long-term decline of terrestrial crocodylians driven by decreasing temperatures but no relationship between temperature and biodiversity for marine crocodylians over their 250 million year history. Ecological models can predict the responses of extant species distributions to rising temperatures. However, only the fossil record provides empirical evidence of the long-term interactions between climate and biodiversityOngoing climate change, with projected global warming of 2.0\u20134.8\u00b0C over the next centurySarcosuchus, which reached around 12\u2009m in length and weighed up to 8 metric tons68Pseudosuchia is a major reptile clade that includes all archosaurs closer to crocodylians than birds, and made its first fossil appearance nearly 250 million years ago, at the time of the crocodile\u2013bird split8101112Here we examine the effect of climate on spatiotemporal patterns in pseudosuchian biodiversity over their 250 million year history, using a comprehensive fossil occurrence data set. Our study is the first to analyse climatic drivers of pseudosuchian biodiversity through the group's entire evolutionary history, applying rigorous quantitative approaches to ameliorate for uneven sampling across both time and space. Furthermore, this is the only comprehensive, temporally continuous fossil occurrence dataset for a major extant vertebrate group: equivalent datasets are not currently available for mammals, birds, squamates, teleosts, or other groups with evolutionary histories of similar durations.An uncorrected global census of pseudosuchian genera  shows anN=38, R2=0.221; Subsampled pseudosuchian biodiversity reached a peak during the earliest intervals of the group's history and shows a long-term pattern of gradual decline towards the present day . SubstanOnly the crocodylomorph clade survived the Triassic/Jurassic mass extinction (201 Myr ago)10162416Sampling of palaeotropical non-marine crocodylomorphs is limited throughout the Jurassic\u2013Cretaceous  and 4a. 88The Cretaceous witnessed the non-marine radiations of notosuchians819931The effect of the K/Pg mass extinction on crocodylomorphs has previously been perceived as minor or non-existent192819283436353636\u03b418O palaeotemperature proxy17Relative changes in subsampled non-marine biodiversity in both North America and Europe track each other and the 7  during the early Paleogene greenhouse world 66\u201341 Myr ago). There is no evidence for transient biodiversity increases driven by the short-term Paleocene\u2013Eocene Thermal Maximum (56 Myr ago), possibly because the timescale of species origination and phenotypic divergence that would allow speciation to be recognisable in the fossil record is longer than that of this rapid climatic event  includes a near-comprehensive dataset of all published pseudosuchian occurrences spanning the Middle Triassic through to the Pleistocene, a period of nearly 250 million years. Pseudosuchian body fossil occurrences that could be assigned to genera  were downloaded from this database , accessed via Fossilworks (http://fossilworks.org), on 23 February 2015.Following extensive work to ensure that occurrences and taxonomic opinions were consistent and up-to-date with the literatureGenera were used so as to incorporate specifically indeterminate material, enabling us to include more data points in our analyses, and also to avoid problems with using species as a unit for estimating palaeobiodiversityAlligator and Crocodylus, have been used as \u2018wastebasket taxa' for indeterminate or non-referable fossil species. Therefore, we modified occurrences of Crocodylus and Alligator before analysis, as explained in the Extant genera, especially et al. (in review). Environmental assignment (marine versus non-marine) for post-Ypresian taxa was based primarily on facies data recorded in the PaleoDB and information presented in refs et al.Aktiogavialis, Piscogavialis and Siquisiquesuchus; these were omitted from the marine crocodylomorph data set of Martin et al.Tomistoma were probably marineT. schlegelii) are non-marine, or their environments are unknown; as such, here we treat Tomistoma as non-marine.The resultant pseudosuchian data set was subdivided into non-marine  stratigraphic time bins . Althougu, singleton taxa were defined based on occurrences within collections58In determining Good's Patterns in non-marine and marine taxa were analysed separately, to avoid problems with sampling from heterogeneous environments58http://www.scotese.com) to obtain reconstructed palaeogeographic positions for each occurrence.In addition to producing sub-sampled terrestrial and marine biodiversity curves through time, we also analysed the palaeolatitudinal distribution of terrestrial biodiversity. This was implemented through plots of subsampled regional biodiversity against the regional palaeolatitudinal centroid, as well as plots of subsampling curves within time bins . Plots o\u03b418O palaeotemperature proxies and sequence stratigraphic eustatic sea level estimates in two sets of analyses: (1) terrestrial pseudosuchian biodiversity in North America and Europe were each compared to the Zachos et al.et al.\u03b418O from the Prokoph et al.We compared subsampled genus biodiversities at a quorum of 0.4 to \u03b418O and sea level, with and without the application of first differencing.Although a contentious issue in crocodylomorph phylogeny, we follow the most recent placement of Thalattosuchia as a basal clade outside of Crocodyliformeset al.\u03b418O values of fish teeth from the Western Tethys. One potential problem with this method is that the fish teeth are from a variety of different species and genera, with L\u00e9cuyer et al.\u03b418O can occur. In addition, there might be differences between the isotopic fractionation that occurs between phosphate and water, and that which takes place in the fish teeth\u03b418O curves of Prokoph et al.et al.\u03b418O dataset for deep sea palaeotemperatures of Zachos et al.et al.1716The similarity of these independent isotopic databases17Statistical comparison was made using time series approaches, specifically generalised least squares (GLS) regression incorporating a first-order autoregressive model .Supplementary Figures 1-7, Supplementary Tables 1-2, Supplementary Methods and Supplementary ReferencesNon-marine pseudosuchian dataMarine pseudosuchian dataTime intervals tablePERL script for SQS (provided by John Alroy)et al. (2008) palaeotemperature proxy isotope dataZachos et al. (2005) sea level dataMiller et al. (2008) palaeotemperature proxy isotope dataProkoph"}
+{"text": "Key components in this response include enzymes involved in the biosynthesis of deoxymugineic acid , the deoxymugineic acid efflux transporter (TOM1), the Fe(III)-deoxymugineic acid transporter (OsYSL15), and Fe2+ transporters . In whole roots, these proteins are expressed in a coordinated manner with strong transcriptional induction in response to Fe deficiency. Radial transport of Fe to xylem and phloem is also mediated by the mugineic acid family phytosiderophores, as well as other chelators and their transporters, including Fe(II)-nicotianamine transporter (OsYSL2), phenolics efflux transporters (PEZ1 and PEZ2), and citrate efflux transporter (OsFRDL1). Among these, OsYSL2 is strongly induced under conditions of Fe deficiency. Both transcriptional induction and potential feedback repression mediate the expressional regulation of the genes involved in Fe uptake and translocation in response to Fe deficiency. The transcription factors IDEF1, IDEF2, and OsIRO2 are responsible for transcriptional induction, whereas the ubiquitin ligases OsHRZ1 and OsHRZ2, as well as the transcription factors OsIRO3 and OsbHLH133, are thought to mediate negative regulation. Furthermore, IDEF1 and OsHRZs bind Fe and other metals, and are therefore candidate Fe sensors. The interacting functions of these regulators are thought to fine tune the expression of proteins involved in Fe uptake and translocation.Iron (Fe) is an essential element for most living organisms. To acquire sparingly soluble Fe from the rhizosphere, rice roots rely on two Fe acquisition pathways. The first of these pathways involves Fe(III) chelators specific to graminaceous plants, the mugineic acid family phytosiderophores, and the second involves absorption of FeThe online version of this article (doi:10.1186/s12284-014-0027-0) contains supplementary material, which is available to authorized users. Among u et al. ). The tr2+ uptake is coupled to ferric-chelate reductase activity on the root surface, which is strongly induced under conditions of Fe deficiency . Howevearschner ), thus i2+ uptake, although this effect may be limited as the PEZ2 transcript shows little induction under conditions of Fe deficiency . To avoUnder Fe-deficient conditions, the enzymes and transporters responsible for Fe uptake are induced not only in the epidermis/exodermis, but also in the cortex and vascular bundle Table  . The Ose et al. ; Ishimare et al. ). The NAe et al. ) are thoOsFRDL1 is specifically expressed in root pericycle cells, with no apparent induction under conditions of Fe deficiency (Table Citrate is an Fe(III) chelator and is thought to play a dominant role in xylem Fe transport in non-graminaceous plants . In ricPEZ1 is expressed specifically in the vascular bundle, while PEZ2 is expressed in the epidermis/exodermis, cortex, and vascular bundle . Both PArabidopsis thaliana (AtFPN1/AtIREG1) is a likely candidate  for theOsVIT1, OsVIT2, and MIT expression are repressed under conditions of Fe deficiency . The miAs reviewed above, the levels of expression of numerous rice genes involved in Fe uptake and translocation are strongly induced under conditions of Fe deficiency at the transcriptional level. Highly conserved temporal and spatial patterns of expression are observed, especially with regard to genes involved in DMA-based Fe uptake . IDE1 ai et al. , 2004]))cis-actii et al. , 2009];;cis-actii et al. ). IDEF1 on Table . At latei et al. , [2009],i et al. ). IDEF2 o et al. ), whereai et al. , 2013]))cis-actii et al. , [2009],i et al. ; Ogo et i et al. ; Itai eti et al. ). Both Ig et al. ).OsIRO2 itself is positively regulated by IDEF1, forming a transcriptional cascade enhancing the expression of genes involved in Fe(III)-DMA uptake and translocation . Howeveg et al. ).in silico prediction of cis-sequences over-represented in Fe deficiency-induced gene promoters revealed that the IDEF1-, IDEF2-, and OsIRO2-binding sequences are enriched within the 500-bp promoter regions of Fe deficiency-induced genes  and AGCTAGCT (designated DCEp1 for putative downstream core element 1), as well as common regulatory sequences, such as TATA-box and upstream TFIIB-recognition elements near the transcription start sites of Fe deficiency-inducible genes . The eni et al. ). Regulavs. other metals.IDEF1 binds ferrous Fe and other divalent metals, such as zinc (Zn) and nichel, via its histidine-asparagine repeats and proline-rich regions . In ricOsHRZ1 and OsHRZ2 knockdown show substantial tolerance to low Fe availability, and accumulate large amounts of Fe in shoots and seeds irrespective of Fe nutritional conditions. These knockdown lines also show enhanced expression of Fe deficiency-inducible genes involved in Fe uptake and/or utilization even under Fe-sufficient conditions, but this enhancement is much less obvious under prolonged Fe deficiency  interacts indirectly with the OsIRO3 homolog POPEYE (PYE) by binding another subset of basic helix-loop-helix transcription factors  from thcy Table . OsHRZ1 y Figure . In Arabg et al. ). BTS ang et al. ). BTS kng et al. ).OsHORZ1 knockdown show increased susceptibility to Fe deficiency and repression of Fe deficiency-inducible genes . OsHORZi et al. ). Thus, OsNAS1, OsNAS2, OsYSL15, and OsIRT1 under both Fe sufficiency and deficiency, and this enhancement may be mediated by the OsIRO2 pathway . Knockoi et al. ). GibberTakasaki ; Yoshii Takasaki ). A jasmTakasaki ) has recg et al. ). OsRMC In Strategy-I plants, systemic Fe signal derived from shoots is thought to determine whether Fe deficiency response in roots takes place (Giehl et al. ; Garc\u00eda 2+ uptake. Research has also elucidated the function of DMA in internal Fe translocation, in addition to its known role in Fe uptake. The differential spatial expression of genes responsible for Fe uptake and translocation in response to Fe deficiency is highly coordinated and is well correlated with their physiological functions. In addition to positive regulation of these genes at the transcriptional level, negative regulation at both the transcriptional and translational levels may also function in fine tuning the Fe deficiency response. Although the Fe-sensing mechanism remains unclear, further characterization of IDEF1 and OsHRZs may in fact consolidate their respective roles as Fe sensors. Despite these advances in our understanding, a potentially large proportion of the molecules involved in intercellular and subcellular Fe movement have not yet been identified. Further investigation into these issues will help to develop novel tools for producing Fe-efficient and Fe-fortified crops with increased versatility.Rice responds to low Fe availability by inducing enzymes, transporters, and regulators that participate in Fe uptake from the rhizosphere and Fe translocation within the plant body. Recent studies demonstrated that rice utilizes both classical DMA-based Fe uptake and direct FeTK and RNI analyzed the microarray data. TK wrote the manuscript with critical revision by RNI and NKN. All of the authors read and approved the manuscript."}
+{"text": "Ependymal cells (ECs) form a barrier responsible for selective movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. Here, we demonstrate that metabolic and barrier functions in ECs decline significantly during aging in mice. The longevity of these functions in part requires the expression of the myristoylated alanine-rich protein kinase C substrate (MARCKS). Both the expression levels and subcellular localization of MARCKS in ECs are markedly transformed during aging. Conditional deletion of MARCKS in ECs induces intracellular accumulation of mucins, elevated oxidative stress, and lipid droplet buildup. These alterations are concomitant with precocious disruption of ependymal barrier function, which results in the elevation of reactive astrocytes, microglia, and macrophages in the interstitial brain tissue of young mutant mice. Interestingly, similar alterations are observed during normal aging in ECs and the forebrain interstitium. Our findings constitute a conceptually new paradigm in the potential role of ECs in the initiation of various conditions and diseases in the aging brain. They are highly polarized with adherens junctions at their apical interface allowing them to form a highly selective barrier between the interstitial tissue and cerebrospinal fluid (CSF) in the ventricles  is critical for previously unappreciated biological functions in ECs related to their aging. Selective deletion of MARCKS in ependyma results in precocious emergence of biomarkers for aging, both in ECs and in the brain interstitium. MARCKS is a known regulator of cell polarity, cytoskeletal signaling, cell migration, and embryonic brain development  was confirmed using antibody labeling, which additionally revealed that its subcellular localization mirrored the distribution of MARCKS in 2M ECs, enriched at the apical surface   mouse brains revealed MARCKS loses its apical clustering and becomes less polarized in the cytosol, whereas p-MARCKS is sparsely distributed Fig. and S5. ines Fig.. Thus, M\u03b6 in ECs, we focused on determining how the phosphorylation state of MARCKS may influence its localization and function. In lung epithelial cells, phosphorylation of MARCKS is known to regulate its association with filamentous actin (F-actin) near the plasma membrane. MARCKS dissociates from actin networks and the plasma membrane upon phosphorylation by PKC -bisphosphate P\u2082) in neurons  and by performing a FITC\u2013dextran (FD4) assay in wholemounts using Ussing chambers Fig.. TER, a Finally, the impact of precocious aging of MARCKS-cKO ECs on potential gliosis and neuroimmune responses in interstitial brain tissue was assessed. First, effects of normal aging on the integrity of the ependymal layer in the forebrain were documented in wholemount preparations of the ventricular walls in young and old brains. Imaging clearly illuminated scarring of ECs accompanied by astrocyte infiltration into the scarred regions . These pet\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., MARCKS-dependent mechanisms used as a model in our study likely represent one of many that can influence aging and maintenance of ECs. ECs have been credited with multiple functional attributes which are possibly influenced by MARCKS-dependent cellular and molecular mechanisms. For example, a unique population of ependyma in the choroid plexus is responsible for the production of CSF and various transport proteins  may be indicative of a potential role for MARCKS on biomechanical properties of stroke in EC cilia. Indeed, the apical clustering of MARCKS near the base of EC cilia is suggestive of potential interaction with molecular motors that facilitate the beating of motile cilia. Ependyma in the young adult brain have been described to be heterogeneous based on their multiciliated or biciliated morphology  was originally identified in intestinal goblet cells and gained attention for its selective expression in the lung epithelium and its role in mucus secretion during airway hyper-responsiveness (Nakanishi et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., et\u00a0al., Ependyma have been shown to accumulate lipids in the aged mouse brain (Bouab et\u00a0al., We also found elevation of 4-HNE and nitrotyrosine in ECs of MARCKS-cKO mice similar to aged wild-type brains. 4-HNE is an \u03b1,\u03b2-unsaturated hydroxyalkenal that is produced by lipid peroxidation and tyrosine nitration. It is upregulated in instances of elevated reactive nitrogen species and, together with nitrotyrosine, is routinely used as a biomarker for oxidative stress. Interestingly, elevated intracellular oxidative stress has been demonstrated to lead to induction of lipid droplet formation and fatty acid accumulation in several cell types (Kuramoto et\u00a0al., et\u00a0al., et\u00a0al., Our findings have revealed that selective disruption of barrier functions in ECs can age the interstitial brain tissue Fig.. This paet\u00a0al., et\u00a0al., However, ependyma-infiltrated astrocytes may contribute toward elevated oxidative damage in periventricular tissues. For example, it was recently demonstrated that age-associated increase in mitochondrial metabolism in astrocytes produces detrimental reactive oxygen and nitrogen species (Jiang & Cadenas, in\u00a0vivo model for assaying the role of ECs in maintenance of brain homeostasis under various disease states and environmental stimuli with potential relevance to human aging.In summary, our study demonstrates for the first time that MARCKS is required for maintaining the ependymal barrier integrity and sustaining forebrain homeostasis during normal aging. In addition, we have identified that mucins are expressed by, and may be secreted from, ependymal cells into the brain interstitium in an age- and MARCKS-dependent manner. These functions are correlated with lipid droplet formation in ependyma raising the possibility that MARCKS-dependent mucin expression and distribution in the brain parenchyma may be related to lipid metabolism in aging ECs. Thus, conditional MARCKS deletion in ependyma together with the apparent precocious aging of ECs provides a highly suitable Experimental Procedures are available in Supporting information."}
+{"text": "Escherichia coli and related enteric species is cytoplasmic accumulation of phosphorylated sugars such as glucose-6-phosphate or the non-metabolizable analog \u03b1-methylglucoside-6-phosphate. This \u201cglucose-phosphate stress\u201d triggers a dedicated stress response in \u03b3-proteobacteria including several enteric pathogens. The major effector of this stress response is a small RNA (sRNA), SgrS. In E. coli and Salmonella, SgrS regulates numerous mRNA targets via base pairing interactions that result in alterations in mRNA translation and stability. Regulation of target mRNAs allows cells to reduce import of additional sugars and increase sugar efflux. SgrS is an unusual sRNA in that it also encodes a small protein, SgrT, which inhibits activity of the major glucose transporter. The two functions of SgrS, base pairing and production of SgrT, reduce accumulation of phosphorylated sugars and thereby relieve stress and promote growth. Examination of SgrS homologs in many enteric species suggests that SgrS has evolved to regulate distinct targets in different organisms. For example, in Salmonella, SgrS base pairs with sopD mRNA and represses production of the encoded effector protein, suggesting that SgrS may have a specific role in the pathogenesis of some \u03b3-proteobacteria. In this review, we outline molecular mechanisms involved in SgrS regulation of its target mRNAs. We also discuss the response to glucose-phosphate stress in terms of its impact on metabolism, growth physiology, and pathogenesis.Bacteria adapt to ever-changing habitats through specific responses to internal and external stimuli that result in changes in gene regulation and metabolism. One internal metabolic cue affecting such changes in  Over the last decade, small RNAs have emerged from relative obscurity to take their places as central regulators of gene expression in organisms from all three domains of life. While hundreds of small RNAs in dozens of bacterial genomes have been identified by computational or experimental methods, the functions of the vast majority of these remain a mystery. Nevertheless, we have learned a great deal about a small number of \u201cmodel\u201d bacterial sRNAs, including how their production is regulated, what targets they in turn regulate and the physiological outcomes of sRNA-mediated regulation. In this review, we first provide a brief overview of features of regulatory sRNAs that act on mRNAs through base pairing interactions. We then focus on one well-characterized sRNA, SgrS (sugar transport related sRNA) and describe its activities on target mRNAs and how these activities regulate bacterial metabolism and pathogenesis.Several mechanistic classes of sRNAs have been identified in diverse bacterial species. Many characterized sRNAs act by base pairing with mRNA targets to control mRNA stability and translation. Such sRNAs are often between 50 and 300 nucleotides in length and require an RNA chaperone, Hfq, for their stability and regulatory effects on target mRNAs  Hfq-binding sRNA  and this is independent of manX regulation , a glutamate-pyruvate aminotransferase  is highly conserved, suggesting that SgrR regulates sgrS expression in all these organisms. All identified SgrS homologs contain a Rho-independent terminator and most possess an additional stem-loop structure upstream of the terminator; these two structures are important for Hfq binding to SgrS   was not sufficient to allow growth rescue during glucose-phosphate stress conditions. This is in part due to very low levels of SgrT produced from the native sgrS allele in E. coli -1 and SPI-2 (Brumell et al., sopD by SgrS involves base pairing interactions between the conserved region of SgrS and the early coding sequence of sopD mRNA (Figure sopD mRNA degradation (Papenfort et al., Salmonella encodes a second SopD protein, SopD2, which shares 42% identity with SopD and likely arose from a duplication (Jiang et al., sopD2 base pairing interaction differs from SgrS-sopD at only a single position, a wobble G:U base pair instead of the G:C base pair. Remarkably, this interaction that differs by only a single hydrogen bond prevents regulation of sopD2 by SgrS (Papenfort et al., Although SgrS is conserved among enteric bacteria, divergence in primary sequence has resulted in species-specific target regulons, exemplified by the finding that A Figure ; the intsopD regulation by SgrS is not yet clear, the inclusion of sopD in the Salmonella SgrS regulon illustrates plasticity in the evolution of sRNA regulons. The presence of sgrR-sgrS-sgrT in the same genomic context in pathogenic and non-pathogenic \u03b3-proteobacteria (Horler and Vanderpool, Salmonella. Studies of other SgrS homologs in pathogenic and non-pathogenic enteric bacteria will surely shed light on the breadth of regulatory activities of this fascinating dual-function sRNA.While the biological significance of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Moreover, growing evidence suggests a key role of intracellular CuAOs and PAOs in several facets of plant development. Here, we discuss recent advances in understanding the contribution of different CuAOs/PAOs, as well as their cross-talk with different intracellular and apoplastic metabolic pathways, in tissue differentiation and organ development.Plant polyamines are catabolized by two classes of amine oxidases, the copper amine oxidases (CuAOs) and the flavin adenine dinucleotide (FAD)-dependent polyamine oxidases (PAOs). These enzymes differ to each other in substrate specificity, catalytic mechanism and subcellular localization. CuAOs and PAOs contribute to several physiological processes both through the control of polyamine homeostasis and as sources of biologically-active reaction products. CuAOs and PAOs have been found at high level in the cell-wall of several species belonging to Fabaceae and Poaceae families, respectively, especially in tissues fated to undertake extensive wall loosening/stiffening events and/or in cells undergoing programmed cell death (PCD). Apoplastic CuAOs and PAOs have been shown to play a key role as a source of H In Arabidopsis thaliana 10 CuAO genes are present, among which only eight encode for putative functional CuAOs AtCuAO\u03b51  and AtCuAO\u03b52  are consecutive fragments of a copy of AtCuAO\u03b4 gene. Phylogenetic analysis evidenced that plant CuAOs form three clades (I-III), clade I being composed of three subgroups (Ia-Ic) and clade II of two  putrescine (Put), cadaverine (Cad), spermidine (Spd), spermine (Spm), and thermospermine (Therm-Spm) are involved in several physiological processes, such as cell proliferation, differentiation and defense responses  are localized in the apoplast  and the other members of clade III in peroxisomes , AtCuAO\u03b31 (clade IIa) as well as Nicotiana tabacum CuAO1 (NtDAO1), oxidize mainly Put, Cad, and Spd , which shows preference for N-methyl-Put and is involved in nicotine biosynthesis, although all three proteins are clustered together in clade III  was shown to produce Nor-Spd from Therm-Spm , which are localized intracellularly and show an -AtPAO5, 2O2; hydroxyl radical, \u2022OH; singlet oxygen, 1O2) and nitric oxide (NO) in orchestrating developmental processes, as well as in being involved in signaling of both local and systemic defense responses in plants. The apoplast is a major \u201chub\u201d for these chemical species. Their accumulation in large amounts and the complexity of the regulatory mechanisms involved in their biosynthesis reflect the peculiar role of this compartment in physiological events that depend on temporarily regulated and spatially restricted ROS and NO signatures , transition metal ions and H2O2 -mediated NO production  distribution  in plants , which is clustered together with AtCuAO\u03b4 in clade IIb, was attributed to the implication of PA metabolism in physiological processes taking place during fruit ripening , are controlled by Therm-Spm and Spm  and an AtPAO5-like (GhPAO4) PAO may play a crucial role in the generation and differentiation of embryogenic callus during somatic embryogenesis  have a role in shoot regeneration from root cultures (Lim et al., Some studies suggest that in CuAO and PAO gene families regarding catalytic activity, subcellular localization, expression pattern and physiological roles of the encoded proteins. Indeed, important links to developmental and stress-related events are emerging for CuAOs and PAOs through ROS/NO production and regulation of specific PA levels.Numerous recent studies have evidenced an extraordinary complexity in All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Although their causative mechanisms are quite diverse, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrous tissue macromolecules in affected organs leading to their dysfunction and ultimate failure. The pathogenesis of fibrotic diseases is complex and despite extensive investigation has remained elusive. Numerous studies have identified myofibroblasts as the cells responsible for the establishment and progression of the fibrotic process. Tissue myofibroblasts in fibrotic diseases originate from several sources including quiescent tissue fibroblasts, circulating CD34+ fibrocytes, and the phenotypic conversion of various cell types including epithelial and endothelial cells into activated myofibroblasts. However, the role of the phenotypic transition of endothelial cells into mesenchymal cells  in the pathogenesis of fibrotic disorders has not been fully elucidated. Here, we review the evidence supporting EndoMT\u2019s contribution to human fibrotic disease pathogenesis.Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft  The resulting fibrosis disrupts the normal architecture of the affected organs, leading to their progressive dysfunction and eventually to their functional failure ,2,3. Thee (GVHD) , and IgG disease ,11, as w disease ,13, and  disease , pulmona disease , liver [ disease , and kid disease . Further disease , asbesto disease , or aris disease , and oth disease  and Chag disease . The mosFibrotic disorders collectively affect a very large number of individuals, and owing to the current lack of effective therapeutic approaches, result in very high morbidity and mortality rates. Indeed, it has been estimated that the mortality caused by fibrotic diseases in the Western developed countries is as high as 45% of the total mortality . AlthougGiven the wide variety of affected organs, the chronic nature of the fibrotic processes, the lack of effective antifibrotic therapies, and the large number of individuals suffering their devastating effects, fibrotic diseases pose a serious public health problem representing an enormous challenge to health services worldwide and causing a serious economic burden to society. Despite the remarkable detrimental consequences of the fibrotic disorders for human health, there are very few approved therapeutic agents for these conditions. However, the recent elucidation of important alterations in crucial regulatory pathways involved in the fibrotic process and the identification of the central role of activated myofibroblasts in the production and abnormal deposition of ECM in this process provide a sound basis for the search and eventual identification of novel and effective means of therapy for these devastating diseases ,28,29.in vivo, myofibroblasts induce changes in the biomechanical properties of the affected tissues causing a progressive increase in tissue stiffness, a newly recognized extremely potent profibrotic stimulus [Numerous recent studies have demonstrated that myofibroblasts are the cells ultimately responsible for the severe fibrotic process in the fibrotic disorders ,31,32,33stimulus ,37.et al. [Given the crucial role of myofibroblasts in the pathogenesis of systemic and organ-specific fibrotic disorders including SSc and Idiopathic Pulmonary Fibrosis (IPF), there has been extensive investigation aimed at the precise identification of their cellular origin ,39,40,41et al. . Indeed,et al. ,70. HoweIn the following sections, we will review the available evidence that supports a role for EndoMT in the pathogenesis of various human fibrotic disorders. First, we will review studies of the molecular mechanisms of EndoMT emphasizing various pathways known to participate in the pathogenesis of tissue fibrosis, then, we will briefly discuss the occurrence of EndoMT in various experimentally-induced animal models of tissue fibrosis, and finally, we will review the occurrence of EndoMT in cultured human EC and in tissues from patients with various human fibrotic disorders.In contrast with the extensive studies on the molecular events and pathways involved in EMT , the mecThe TGF-\u03b2 family of proteins comprises several pleiotropic growth factors that play crucial roles in numerous physiological processes including embryogenesis, cellular development and differentiation, immunologic system development, inflammatory response functions, and wound repair ,72. Owinin vitro; (2) TGF-\u03b2 induction of EndoMT was associated with a strong upregulation in the expression of the transcriptional repressor Snail1 indicating that Snail1 is directly involved in TGF-\u03b2-induced \u03b1-SMA expression; and (3) induction of \u03b1-SMA expression involved the c-Abl kinase and protein kinase C-\u03b4 (PKC-\u03b4), as specific inhibition of their kinase activities with imatinib mesylate and rottlerin, respectively, or by knockdown of their corresponding transcripts with specific siRNA abrogated the marked increase in TGF-\u03b2 induced \u03b1-SMA and Snail1 expression and protein levels. These observations confirmed the potent induction of EndoMT by TGF-\u03b21 in vitro [in vivo studies. The study of Cooley et al. demonstrated that a TGF-\u03b2-neutralizing antibody decreased EndoMT and resulted in a profound reduction in neo-intima formation in a mouse model of interpositional vein grafts [et al. generated heterozygous mice with endothelium-specific knock-out of the TGF-receptor II (T\u03b2RII) gene and demonstrated that the resulting partial T\u03b2RII deletion abrogated EndoMT and reduced tubulointerstitial kidney fibrosis in two murine models of renal fibrosis [Given the crucial role that the TGF-\u03b2 family of profibrotic growth factors plays in the development of tissue fibrosis and in the pathogenesis of numerous fibrotic diseases, several studies have demonstrated that TGF-\u03b2 is involved in the generation of myofibroblasts through EndoMT ,82,83,84n grafts . In anotfibrosis . The rolfibrosis .The morphogens Notch and Hedgehog play crucial roles during embryonic development. Although in the adult these pathways are very highly regulated, their aberrant activation may lead to various pathological consequences, including the development of fibrotic diseases ,88,89. TRecently, the Sonic Hedgehog (SHh) pathway, another important morphogen, has also been shown to participate in the pathogenesis of various fibrotic disorders ,96,97,98The Wnt proteins comprise a multigene family of secreted glycoproteins that play crucial roles during embryogenesis signaling through canonical and non-canonical pathways ,100. NumCav1 knock out mice (Cav1\u2212/\u2212) showed that these mice exhibited extensive skin and lung fibrosis [Cav1\u2212/\u2212 mice [Cav1\u2212/\u2212mice in vivo and suggested that CAV1 deficiency participates in the development and progression of tissue fibrosis and fibrotic diseases through the establishment of EndoMT.CAV1, the main protein component of caveolae plays an important role in the internalization, trafficking and degradation of TGF-\u03b2 receptors and, therefore, is involved in the regulation of TGF-\u03b2 signaling and TGF-\u03b2-mediated fibrotic responses ,109,110.fibrosis . Subsequfibrosis ,112,113,fibrosis . These s\u2212/\u2212 mice . The resThe important role of ET-1, the most potent endogenous vasoconstrictor polypeptide identified to date, in the regulation of multiple vascular functions and its participation in various human diseases including Primary and Secondary Pulmonary Arterial Hypertension (PAH) has been well recognized. However, numerous recent studies have shown that ET-1 also displays strong profibrotic effects and it is involved in various aspects of the fibrotic process ,117. Recin vitro and in vivo [Numerous recent studies have demonstrated an important role of hypoxia in the development or progression of various fibrotic diseases including SSc, kidney, and cardiac fibrosis ,123,124. in vivo . However in vivo  and anot in vivo .One novel pathway that has been recently recognized as a potentially important participant in the pathogenesis of fibrotic processes through reciprocal interactions with TGF-\u03b2 involves reactive oxygen species (ROS) ,131. AltAlthough there are multiple sources of intracellular ROS, extensive studies have shown that most ROS production derives from the activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system. NOX4 is one of seven NADPH isoforms, however, unlike other members of the NOX family, it is constitutively active and the regulation of its effects occurs mainly at the expression level. The role of NOX4 as an important downstream mediator of TGF-\u03b2-induced myofibroblast generation, its contribution to the potent TGF-\u03b2 profibrotic effects, and its participation in the pathogenesis of tissue fibrosis in various fibrotic disorders such as IPF and liver fibrosis have been recently demonstrated ,143,144.MicroRNAs (miRNAs) are small non-coding RNA that modulate the expression of a large number of protein coding genes at the post-transcriptional level . Recent et al. [The pioneering studies of Zeisberg et al.  clearly et al. . Anotheret al. . Other set al. ,118. Howet al. .et al. [et al. [et al. [Li and Bertram  recentlyet al.  examinedet al. . In anot [et al.  employed [et al. . These s [et al.  employin [et al. ,167.et al. [in vivo in this animal model.The role of EndoMT in experimentally induced pulmonary fibrosis and pulmonary arterial hypertension was examined in several recent studies. The pioneering studies of Hashimoto et al.  evaluateet al. . The resin vitro with EC isolated from affected tissues. The study of Zeisberg et al. [in vitro studies with isolated human coronary artery EC. These studies showed that, following TGF-\u03b21 treatment, the cells became spindly shaped and lost their EC molecular markers and acquired the ability to produce various fibroblast-specific macromolecules including vimentin and type I procollagen. Several other studies have examined the occurrence of EndoMT in cultured human EC of various types. A study by Kitao et al. [in vitro in cultured human dermal microvascular EC and demonstrated the induction of a mesenchymal cell phenotype by TGF-\u03b21 with a change to a spindle cell morphology in monolayer culture and initiation of expression of \u03b1-SMA and COL1A. In another study Rieder et al. described the phenotypic conversion of human microvascular intestinal EC into mesenchymal cells following exposure to a combination of proinflammatory cytokines  in vitro and suggested that intestinal EC exposed to an inflammatory environment may participate in the intestinal fibrotic process which accompanies intestinal inflammatory diseases in vitro [et al. examined the effects of interferons \u03b1 and \u03b3 on human dermal microvascular EC and demonstrated that interferon \u03b3 induced morphological and molecular/gene expression changes in these cells consistent with their transdifferentiation into profibrotic myofibroblasts [in vitro [In contrast with the extensive evidence from animal models demonstrating the occurrence of EndoMT in the development of experimentally-induced tissue fibrosis there are only few studies that have provided evidence indicative of the occurrence of EndoMT in human fibrotic disorders. Most studies have been performed g et al.  describio et al.  examinedin vitro . Chrobakroblasts . Recentlin vitro . The resin vitro . The samin vitro .in vitro following exposure to TGF-\u03b21 or to other cytokines or inducing agents. In contrast, there are few studies that have demonstrated the occurrence of EndoMT directly in vivo, although some recent publications have described results demonstrating the presence of EC expressing simultaneously EC molecular markers such as, for example, CD31/PECAM-1 or von Willebrand Factor and proteins such as \u03b1-SMA, or type I and III interstitial collagens that are specific for myofibroblastic mesenchymal cells. Most of these studies identified cells co-expressing both types of molecular markers in the affected tissues employing immunofluorescence microscopy studies with confocal microscopy. These studies are summarized in All the studies described in the previous section demonstrated that EC isolated from fibrotic tissues from various human fibrotic disorders were capable of undergoing EndoMT et al. [et al. [et al. [Despite the clinical importance and the demonstration of morphological and molecular alterations indicative of EndoMT during experimentally-induced pulmonary fibrosis , there aet al.  were amoet al.  and the et al. . In the  [et al.  employed [et al. , assesseWe recently performed a study to examine the possibility that EndoMT is involved in the fibrotic process of SSc-associated pulmonary fibrosis . ImmunohTissue fibrotic reactions represent the most serious complications of radiation therapy and intense investigation is being conducted to understand the intimate mechanisms involved in the devastating organ fibrosis and dysfunction induced by radiation therapy. Recent studies have examined the potential role of EndoMT in the severe radiation-induced fibrotic process. One study examined the role of EndoMT in the development of radiation-induced pulmonary fibrosis . Using iet al. [et al. [in vivo during the development of diabetic kidney disease-associated kidney fibrosis [Several studies have described evidence supporting the occurrence of EndoMT in human tissues from patients with cardiac fibrosis ,171 and et al.  examinedfibrosis .The possibility that EndoMT of portal vein endothelium via TGF-\u03b2/Smad activation may be involved in portal venopathy was examined recently . The resin vitro studies with human EC of various tissue origins, experimental animal models of tissue fibrosis, and analysis of tissues from patients with various fibrotic diseases certainly indicate that EndoMT plays an important role in the pathogenesis of these common and often fatal disorders. The extensive literature published about the participation of EndoMT in the fibrotic process and the demonstration of its occurrence in affected tissues from patients with SSc-associated pulmonary fibrosis and PAH, vein graft fibrosis, intestinal fibrosis, and radiation-induced organ fibrosis indicate that such a role should no longer be considered controversial but it is a reality, as discussed recently [The results of the numerous studies reviewed here including recently ,176. A c"}
+{"text": "For entry and infection viruses have developed numerous strategies to subjugate indispensable cellular factors and functions. Host cell lipids and cellular lipid synthesis machinery are no exception. Not only do viruses exploit existing lipid signalling and modifications for virus entry and trafficking, they also reprogram lipid synthesis, metabolism, and compartmentalization for assembly and egress. Here we review these various concepts and highlight recent progress in understanding viral interactions with host cell lipids during entry and assembly. The biological functions of lipids range from membrane formation to energy storage and signalling , glycophosphatidylinositol (GPI)-anchored proteins, and transmembrane proteins can cluster into discrete domains, called lipid rafts  or glycosphingolipids . Upon specific binding to ganglioside GM1, SV40 reduces GM1\u2019s diffusion rate. This stabilized SV40-GM1 complex then recruits cholesterol to generate a lipid raft. The interaction induces actin-dependent immobilization of the virus-ganglioside complex, followed by virus-induced invagination of the plasma membrane. An elegant study by Ewers et\u2009al., et\u2009al., et\u2009al., Low-density lipoprotein receptors, also known as cholesterol receptors, are used by several members of the Flaviviridae family, including hepatitis C virus (HCV)  and Niemann-Pick C1-like 1 (NPC1L1) are important entry factors for filovirus . Entry of VSV has been suggested to require the interaction between the viral glycoprotein G and the negatively charged phospholipid phosphatidylserine (PS) on the cell surface  is the least abundant phospholipid in the cell membrane, but it is also one of the most versatile signalling molecules in cells and plays a central role in endosome trafficking and maturation. Differential phosphorylation of PI, regulated by specific PI kinases and phosphatases, results in the formation of different PI phosphate (PIP) species  signalling pathway is one of the most important PI-mediated signalling cascades activated during virus entry. Activation of PI3K and subsequent generation of PIP3 serves as docking platform for proteins carrying lipid-binding domains, including Akt, the main effector of PI3K signalling  provide a scaffold for the viral replication machinery, serve to concentrate the viral and cellular factors needed for assembly of new virions, and provide a protective environment for avoidance of cellular innate immune responses. Examples include the large dsDNA poxviruses which transiently recruit endoplasmic reticulum (ER)-derived cisternae around viral RCs , for instance, recruits PI4K-III\u03b1 to virus replication sites to increase local levels of PI(4)P  for assembly of infectious viral particles  cycle or by manipulating the carbon source used by the cells to generate energy and macromolecules, several viruses take control of central energy metabolism to promote synthesis of cholesterol and fatty acids. This phenomenon has been described for two large enveloped viruses: HCMV  or endosomes  (Ichihashi and Oie, et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Since its inception, viral apoptotic mimicry has proven to be a widespread lipid-mediated entry mechanism used by several enveloped viruses including: pichinde, cytomegalo, lassa fever, lenti, dengue, ebola and Marburg viruses (Callahan The fundamental role of lipids in virus biology and infection is becoming increasingly clear. New technologies, such metabolomics, and advances in mass spectrometry-based lipidomics are allowing for systematic characterization of the alterations in host lipid metabolism, as well as cellular and viral lipid profiles induced by viral infection.As highlighted in this review, lipids serve to orchestrate different stages of viral replication, ranging from entry to spread. Viruses take control of lipid-mediated signalling to co-ordinate viral entry and intracellular trafficking. Later during infection, they actively modify intracellular membrane for replication, re-direct lipid metabolism to produce sufficient membrane for the assembly of new particles, and modify cell membrane lipid content to ensure infectivity of those virions.Systematic characterization of how viruses take control of and alter lipid metabolism is now needed to unravel the common strategies used by these different viruses. Such studies may serve for the identification of infection biomarkers; and together with the development of therapeutics targeting subsets of lipid synthesis enzymes it may be possible to identify novel broad-spectrum therapeutic agents that target virus modified lipid metabolism. Overall, a deeper understanding of how viruses manipulate the host cells lipid program will serve to further our understanding of the cellular mechanisms that govern lipid modification, compartmentalization and metabolism."}
+{"text": "The Editorial on the Research TopicImmunogenic Cell Death in Cancer: From Benchside Research to Bedside RealityGarg et al.; .Immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced antitumor immunity \u20133. ICD i et al.; ]. The imDerer et al. (Udo S. Gaipl lab). It is noteworthy that ICD can also be achieved by various \u201csmart\u201d combinatorial strategies\u2009\u2013\u2009an important point for clinically applied non-ICD inducers, discussed in details by Bezu et al. (Guido Kroemer lab).Most potent ICD inducers, characterized so far, elicit danger signaling through oxidative-endoplasmic reticulum stress . SeveralFucikova et al. (Radek Spisek lab). The promising results generated by systemically administered ICD inducers have also paved way for application of ICD-based dendritic cell (DC) vaccines  and lymphoma by Zappasodi et al. (Massimo Di Nicola lab). In the latter case, it is clear that the field is moving toward chimeric antigen receptor (CAR)-T cell\u2019s application, and it will be interesting to see its combination with ICD in near future.Several lines of experimental evidence have established the validity of ICD. However, the overreliance on usage of prophylactic vaccination in transplantable (heterotopic) tumor models has attracted some criticism . While tvaccines . This imKersten et al. (Karin E. de Visser lab). The strategies for targeting epigenetic processes to improve immunotherapy are further discussed by Wachowska et al. (Jakub Golab lab).Nevertheless, the insurmountable complexity of cancer makes it inevitable that in certain contexts, ICD may fail. This failure may stem from various factors, e.g., tumor heterogeneity , MHC-levGarg et al.). This classification paper brings together >50 authors from the fields of ICD and DAMPs, and tries to reach a comprehensive accord on various terminologies related to DAMPs/ICD, the historical background of these concepts, ICD classification system (Type I vs. Type II inducers), and the relevant preclinical/clinical criteria crucial for the field(s) . We hope that this consensus paper will be a useful literature resource for various researchers/clinicians. These contributions, while summarizing the status quo, have also exposed a set of major questions and challenges that still need to be addressed.We believe that the valuable contributions of key researchers/clinicians toward this research topic/special edition have largely fulfilled its primary aim, i.e., to foster a critical discussion on experimental and clinical relevance of ICD. In fact, to further summarize and organize the fields of ICD and DAMPs, we have produced a multi-author consensus paper within this research topic that attempts to classify DAMPs and ICD inducers with an eye on translational potential of ICD  apoptosis-associated immunosuppressive processes?Does the role of ROS in ICD extend beyond a proximal stressor? e.g., ROS-elicited oxidation-associated molecular patterns/OAMPs have been shown to mediate immunogenic potential  cancer mice models  clinical trial.Can ICD withstand the operational/regulatory (GLP/GMP/GCP) hurdles associated with anticancer vaccines-production? [indications for which are emerging (emerging ]Characterizing ICD-resistance mechanisms in the clinic.Characterizing reliable ICD-biomarker(s) detectable in patient tumor/sera-samples.Investigating ICD as a source of robust prognostic/predictive/mechanistic biomarkers [a point investigated recently in some studies  is incontrovertibly valid; but, owing to the incomprehensible complexity of cancer, the \u201cspecifics of ICD\u201d  will always remain open to amenability and variations. We envisage that overtime various \u201cvariants\u201d of ICD may emerge that differ from each other in a manner dependent upon, the type of anticancer therapy, cancer cell death pathways, cancer-types, tumor antigen make-up, the ADG wrote the manuscript. PA provided senior supervision and critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy  or atrophy . The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments. HTT) gene which are normally observed in healthy objects. Neurodegeneration, particularly widespread in the striatal nuclei, basal ganglia and cereberal cortex, is a source of neurological symptoms that involve motor, cognitive and psychiatric disturbances  is neurodegenerative disorder caused by the expansion of polyglutamine stretch within the huntingtin protein (HTT)  developed signs of a slowly progressing myopathy with elevated creatine kinase levels many years before first signs of chorea were detected. Muscle biopsy revealed a mild myopathy with mitochondrial pathology including a complex IV deficiency  could be considered as an additional mechanism of HD pathology  transcripts were significantly reduced and defects in mRNA processing were detected (Waters et al., Transcriptional deregulation is a typical feature of HD pathology in the brain (Luthi-Carter et al., To better understand a mechanism underlying muscle wasting in the R6/2 mouse model, key pathways governing protein metabolism, apoptosis and autophagy were examined. R6/2 mice exhibited increased adiposity and elevated energy expenditure without altered food intake. A total protein synthesis was unexpectedly increased in the gastrocnemius muscle by 19%, which was associated with over-activation of rapamycin mTOR signaling (She et al., HTT resulted in increased PGC-1\u03b1 expression in HD myoblast, while PGC-1\u03b1 rescue led to increased expression of markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice (Chaturvedi et al., c oxidase by 15%. Complex I\u2013dependent respiration of HD mitochondria showed more sensitivity to inhibition by Ca2+ than in wild-type mitochondria (Gizatullina et al., Since mitochondrial dysfunction might play a crucial role in HD pathology (Quintanilla and Johnson, As it has been mentioned in the previous paragraph, enhancing PGC-1\u03b1 activity might be a good strategy to improve skeletal muscles function in HD. Indeed, pharmacologic treatment with the pan-PPAR agonist bezafibrate restored the PGC-1\u03b1, PPARs and downstream genes to wild type levels. It also prevented conversion of type I oxidative to type II glycolytic muscle fibers as well as increased muscle mitochondria numbers. Finally, bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice (Johri et al., in vivo (Fujimoto et al., The other strategy to improve muscle function in HD is based on the heat shock machinery modulation that could suppress mHTT aggregation (Labbadia and Morimoto, Recent studies also showed that HDAC4 function in the cytoplasm (Mielcarek et al., HD is a complex disease that has a peripheral component to its pathophysiology. Transcriptional changes in the HD skeletal muscles were comparable to those observed in the different brain regions and skeletal muscle wasting/atrophy is likely to be an important portion of HD pathogenesis. Some of the molecular and physiological changes in HD muscles can be detected, even in the pre-symptomatic HD individuals. On the molecular level, mitochondrial dysfunctions, PPAR alpha signaling and HSF1 activation were identified as major players in the muscle HD-related pathology. The major pathological pathways identified in skeletal muscles have been summarized in Figure Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Adeno associated vectors (AAV) have shown considerable promise to treat various genetic disorders in both preclinical and clinical settings mainly because of its safety profile. However, efficient use of AAV to deliver genes in immune-competent sites like muscles and liver requires very high doses which are associated with concomitant cellular immune response against the viral capsids leading to destruction of the transduced cells. Coupled with that, there are enough evidences that at high doses, AAV particles are subjected to increased cellular phosphorylation/uniquitination leading to proteasome mediated degradation and loss of the viral particles. The presence of preexisting immunity against AAV further adds on to the problem which is acting as a major roadblock to efficiently use it as a gene therapy vector in the clinics. To overcome this, rational bioengineering of AAV capsid becomes a prime tool by which specific amino acid residue(s) can be suitably modified/replaced by compatible residue(s) to create vectors having lower host immune response and higher intracellular trafficking rate. This article reviews the various aspects of rationally designing AAV capsids like by site-directed mutagenesis, directed evolution and combinatorial libraries which can create vectors having not only immune evasive property but also enhanced gene expression and transduction capability. One or more combinations of these strategies have strong potential to create novel vectors which will have suitable clinical efficiency even at a low dose. Despite the reported success it is becoming increasingly clear that humoral and cell mediated immune response against the vector is a major impending factor towards the efficacy of gene therapy [Adeno-associated virus (AAV) is a non-pathogenic parvovirus that has been widely used as a vector of choice for gene therapy. Although the virus has been detected in many different tissues of several animal species  it has n therapy . Preexis therapy ,11.AAV has been used in several clinical trials for both inherited and non-inherited diseases with considerable success Table\u00a0. In the In contrast to these clinical studies, which targeted immune privileged sites, AAV has limited success when it came to treat monogenic diseases like haemophila B and lipoprotein lipase (LPL) deficiency following intravenous, intrahepatic or intramuscular administration Table\u00a0. For exaet al., tried to transiently suppress the immune system to inhibit AAV capsid specific T cell response against transduced hepatocytes expressing F.IX transgene in rhesus macaques [One of the major barriers to successful gene delivery with AAV vectors is the humoral immunity to wild type vectors. Humans are natural carriers of AAV genome. Neutralizing antibodies (NAb) to AAV AAV1 and 2) in humans was first reported in the early 60s and 70s ,19. Rece and 2 inmacaques . But no To summarize, immune-suppression can be advantageous as it represses the body\u2019s immune response long enough for the AAV capsid proteins to be not recognized by our defense mechanism thereby preventing NAb formation and allowing readministration of the vector. However this strategy will not be useful to circumvent preexisting NAb against AAV capsid. Thus, alternate strategies like rational capsid modifications must be looked into to evade these neutralizing antibodies.invitro. Extending this finding invivo the authors were able to elucidate a negative effect of tyrosine phosphorylation on viral intracellular trafficking and transgene expression [invitro (~10 fold) and invivo  transduction efficiency of the novel vectors.The ubiquitin\u2013proteasome pathway has been shown to play an essential role in AAV intracellular trafficking ,27 and tpression . Thus baFollowing this finding, tyrosine mutant AAV vectors were used in other target sites like retina , skeletaApart from tyrosines, serines (S), threonines(T) and lysines(K) are also potential sites for phosphorylation and or ubiquitination on the AAV capsids and traditionally mutating them could augment AAV transduction efficiency. It has been shown earlier that targeted inhibition of the serine/threonine kinase phosphorylation of a cellular protein FK506-binding protein (FKBP52), improved AAV mediated gene transfer by 30-fold compared to ~5 fold increase seen with inhibition of tyrosine kinases alone . It is aGoing by this logic, several studies by our laboratory at Christian Medical College, Vellore, India, had generated S/T/K mutants on AAV1, 2, 5 and 8 which has proven to be more efficient in hepatic gene delivery as compared to their wild type counterparts -40. S/T Tenney et al., [In summary, rational point mutations on AAV capsids have shown considerable promise and this field is still wide open to explore especially since we have access to the 3 dimensional (3D) structures of several clinically important AAV serotypes -49. Usin et al.,  could deet al., [et al., [et al., in 1999 [et al., [et al., described a rationally designed chimeric AAV2.5 [et al., [Another approach to create novel AAV variant is to insert known ligands into the AAV capsid thereby allowing retargeting to specific cell types to which the WT vectors have a low affinity . By thiset al.,  where th[et al.,  demonstr in 1999 . In this in 1999 . However[et al.,  generate[et al., . Two new[et al., -59. Bowl[et al.,  describe[et al.,  as well [et al., .in vitro evolution strategy was first described by Grimm et al.,, in 2008 [et al., in 2008 [et al., [in vivo at serum levels which were much higher than what is required to neutralize the wild type vector. Additionally, both the mutants elucidated increased gene expression when compared to the wild type. Using DNA shuffling in an in vitro model of human ciliated airway epithelium, Li et al., [et al., [invivo. In this study they enriched for an AAV variant which showed widespread delivery to the outer retina and reverses the disease phenotypes of X-linked retinoschisis and Leber\u2019s congenital amaurosis in murine models. This vector also efficiently transduced primate photoreceptors from the vitreous.Chimeric capsids based on  in 2008 . In this in 2008  created [et al.,  utilized et al.,  were abl[et al.,  successfet al., [et al., [et al., [et al., [We have seen in clinical trials using AAV that in targeting immune competent sites like liver and muscles, preexisting humoral immunity acts as an impediment to long term gene expression. Thus it necessitates basic knowledge of immunogenic epitopes on AAV capsids to rationally design AAV variants that can evade this immune response. Peptide scanning to map neutralizing epitopes for antibodies against AAV capsid opens up another rational approach to bioengineer AAV capsids. In one such early study Moskalenko et al.,  identifi[et al.,  where th[et al., . These A[et al., . In late[et al.,  which le[et al.,  created [et al.,  and Hutt[et al.,  demonstrAlthough AAV has gained immense popularity as a gene therapy vehicle to treat several genetic disorders, there is still a persistent need to further improve on the vector capsid design and engineering which can bypass the problem of neutralization by preexisting antibodies as well as T-cell mediated immune clearance. Over the past decade, many technologies have been used to make the AAV capsids less immunogenic and more efficient. For example, coating of AAV particles by inert polymers like polyethylene glycol (PEG) has been shown to modestly decrease its immunological properties. Site directed mutagenesis of amino acid residues (S/T/K/Y) on AAV capsids based on their phosphorylation status and presence on B- cell epitope has created novel vectors with reduced antibody response as well as high transgene expression. Rationally creating point mutations does not seem to interfere with their overall safety profile or packaging efficiency when compared to wild type vectors. Thus, it enables us to achieve high gene expression at a low vector dose which will further reduce the chance of eliciting immune response against the viral particles. Also, inserting known peptides at specific sites on AAV capsids can alter the natural tropism of AAV which is extremely helpful for targeted gene delivery at specific organs. Finally directed evolution of AAV can create novel chimeric vectors which can also have reduced neutralizing antibody response along with high target site specificity.An alternate strategy that can be employed in quest of a \u2018stealth\u2019 vector is to isolate/screen novel AAV\u2019s from human sources . This st"}
+{"text": "Listeria monocytogenes and highlights recent discoveries on the molecular mechanisms evolved by this intracellular bacterium to subvert IFN responses.Interferons (IFNs) are secreted proteins of the cytokine family that regulate innate and adaptive immune responses to infection. Although the importance of IFNs in the antiviral response has long been appreciated, their role in bacterial infections is more complex and is currently a major focus of investigation. This review summarizes our current knowledge of the role of these cytokines in host defense against the bacterial pathogen  Listeria monocytogenes is a pathogenic Gram-positive bacillus responsible for a foodborne disease in humans and animals called listeriosis , activation of pathogen-recognition receptors (PRRs) and subsequent production of pro-inflammatory cytokines  production during infection. Type I IFN production by infected cells can be controlled by Listeria multidrug efflux pumps MdrM and MdrT, via the secretion of the second messenger cyclic-di-AMP , Salmonella typhimurium and some viruses  is a paradigm for this, being an important mediator of innate and adaptive immune responses with a key role in clearance of viral and bacterial pathogens and in tumor control. IFN-\u03b3 was first described as an antiviral protein , Brucella abortus, Chlamydia muridarum, Francisella novicida, Salmonella enterica, Staphylococcus aureus, and Yersinia pestis , which encode proteins involved in a broad range of cellular functions (reviewed in MacMicking, Listeria infection has mostly been studied in the context of the IFN-\u03b3 pathway.The beneficial or detrimental effects of IFNs on Listeria cytoinvasion (Myers et al., Listeria infection by coordinating a potent oxidative and vesicular trafficking program (Kim et al., L. monocytogenes (Sonoda et al., L. monocytogenes (Cole et al., Listeria within granulomatous structures, thus avoiding massive T cell activation (Popov et al., The antilisterial activity of IFN-\u03b3 in phagocytic cells involves induction of oxidative and nitrosative defences, via increased expression of enzymes that control production of reactive oxygen and nitrogen species, such as NOX2/CYBB, DUOX2, and iNOS/NOS2 (MacMicking, Listeria infection is less documented. Zwaferink et al. have observed that upregulation of iNOS/NOS2 by IFN-\u03b2 promotes necrotic death of macrophages (Zwaferink et al., Listeria infection of epithelia is not understood.The function of type I IFN-associated ISGs in L. monocytogenes (Archambaud et al., Of interest, a subset of ISGs is amongst the most induced genes in the intestinal tissue of gnotobiotic humanized mice infected orally with Listeria has evolved several mechanisms to avoid immune detection and evade IFN responses. It has been demonstrated that deacetylation of Listeria peptidoglycan by the deacetylase PgdA confers resistance to host lysozyme, thus preventing release of MAMPs, such as DNA, RNA and lipopeptides, that trigger IFN-\u03b2 production (Boneca et al., Listeria pgdA mutants are rapidly killed in murine macrophages, which produce lysozyme, and induce a strong secretion of IFN-\u03b2 compared to wild-type Listeria. The role of PgdA is not limited to the control of type I-IFN production as a pgdA mutant hyperinduces pro-inflammatory cytokines as well. Modification of peptidoglycan by PgdA is an extremely efficient mechanism of immune escape used by Listeria, which correlates with its critical role in virulence.Listeria has evolved a sophisticated strategy to modulate, either negatively or positively, the expression of ISGs in epithelial cells, by targeting a chromatin-repressive complex, BAHD1 (Bierne et al., Listeria infection promotes, albeit via an unknown mechanism, the targeting of BAHD1 at the promoter of a set of ISGs, thereby downregulating type I- and type III-IFN responses. On the other hand, Listeria can produce a nucleomodulin, LntA, which when secreted by intracellular bacteria, enters the nucleus of infected cells, binds BAHD1 and inhibits its function (Lebreton et al., Remarkably, Listeria-host interactions. Yet, our understanding of the immune response to Listeria, and more specifically the role IFNs and of their downstream effectors, is far from complete and often relies on studies performed in cultured cells or in mice. However, murine and human listeriosis differ in many aspects (Lecuit, Listeria in epithelial cells, is not functional for Listeria uptake in the mouse. Thus, the route of entry of Listeria is not strictly the same in mice and humans. Moreover, ISGs induced in response to infection are not identical in mice and humans. Additionally, murine hepatocytes do not respond to type III-IFNs (Hermant et al., L. monocytogenes. Altogether, species-specific differences provide limits to the use of mouse models in characterizing IFN pathways engaged during Listeria infection in humans, especially in key epithelial organs such as the gut, liver and placenta. It will be important to perform future studies using adapted animal models, such as humanized mice permissive to oral infection or transgenic mice with human xenografts (Walters et al., Listeria infection depends on the route and time of infection (Pontiroli et al., Listeria infection in vitro, but the relevant ISGs and their cellular functions remain to be identified. Validation of ISGs identified in cultured cells in adequate in vivo models or deduced from analyses of patient samples, will be required to address the complex role of IFNs and bacterial subversion strategies and provide new insights into Listeria pathogenesis.We have an extensive knowledge of the molecular and cellular mechanisms involved in  Lecuit, . For insThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "S-nitrosoglutathione (GSNO) indicates the involvement of these organelles in the sulfur metabolism. This could suggest the participation of a new family of molecules designated as reactive sulfur species (RSS) which will possibly provide new functions for peroxisomes.Peroxisomes are ubiquitous organelles with a notable oxidative metabolism. In plants, these subcellular compartments have been shown to be involved in the metabolism of reactive oxygen and nitrogen species (ROS and RNS), whose components, hydrogen peroxide and nitric oxide (NO), are important molecules involved in signaling processes. The presence of new elements in plant peroxisomes such as glutathione reductase (GR), sulfite oxidase (SO), glutathione (GSH), and \u00b7\u22122), hydrogen peroxide (H2O2), and RNS  and GSNO which are characterized by a broad spectrum of physiological/pathological activities. Both these molecular families (ROS and RNS) include radical molecules containing an unpaired electron as well as non-radical molecules and can also have dual effects depending on their cellular concentration. Thus, H2O2 and NO at low concentrations can function as signal molecules in the cell or may cause damage to cell components when overproduced as a consequence of adverse conditions  which does not reflect the complexity of their enzymatic composition  has been shown to be generated from L-cysteine by the pyridoxal-5\u2032-phosphate-dependent enzyme. Thus, endogenous H2S can act as a neuromodulator in rat brain . Thus, high cellular GSH concentrations in an oxidative environment and the decomposition of S-nitrosothiols generate disulfide-S-oxides  is an essential mineral for plant growth and development  . This RNS is a highly oxidant compound capable of catalyzing the conversion of xanthine dehydrogenase to xanthine oxidase . SO catalyzes the conversion of sulfite to sulfate with the concomitant generation of H2O2  (Jim\u00e9nez et al., In this context, the interactions of ROS, RNS and possibly RSS components in plant peroxisomes open up new challenges and a new area of research to determine the biochemical interactions and potential functions of these reactive species of oxygen, nitrogen and sulfur in peroxisomes, some of which play a very important role as signaling molecules in physiological and phyto-pathological processes (Yamasaki, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Within this physiologic range of RBC turnover, a small fraction of hemoglobin (Hb) is released into plasma as free extracellular Hb. In humans, there is an efficient multicomponent system of Hb sequestration, oxidative neutralization and clearance. Haptoglobin (Hp) is the primary Hb-binding protein in human plasma, which attenuates the adverse biochemical and physiologic effects of extracellular Hb. The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization. When Hb is released from RBCs within the physiologic range of Hp, the potential deleterious effects of Hb are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. In the present review we discuss the components of physiologic Hb/heme detoxification and their potential therapeutic application in a wide range of hemolytic conditions.Hemolysis, which occurs in many disease states, can trigger a diverse pathophysiologic cascade that is related to the specific biochemical activities of free Hb and its porphyrin component heme. Normal erythropoiesis and concomitant removal of senescent red blood cells (RBC) from the circulation occurs at rates of approximately 2 \u00d7 10 Hemolysis with release of free hemoglobin (Hb) and heme occurs in a wide range of disease states and clinical interventions, including genetic and acquired anemias such as sickle cell disease, burns, extracorporeal circulation and massive blood transfusion  state. The 32-kD Hb dimer readily passes through the glomerulus\u2014if not bound by Hp\u2014and is rapidly cleared by the kidneys , Hb exists as a tetrameric heme containing protein with a molecular weight of 64 kD. Following release from RBCs during intravascular hemolysis, extracellular Hb is in a dynamic tetramer \u2194 dimer equilibrium  16-fold faster than tetrameric Hb (kox = 0.015 h\u22121)  Hb. While oxidized ferric (Fe3+) Hb usually remains below the level of detection in plasma, a large fraction of excreted Hb ultimately appears in the urine in the oxidized ferric state  may accumulate. The large Hb-Hp complex cannot be filtered by the kidney and in vitro translocation across endothelial monolayers is almost completely blocked  stabilizes Hb in a reduced state  oxidation state -6 effector pathway, increases expression of Hp in the liver and many parenchymal and non-parenchymal cells. In many species, Hp is one of the most extensively responding acute-phase plasma proteins. IL-6 has also been reported to enhance expression of CD163 on macrophages, suggesting that enhanced Hb sequestration and clearance capacity are general adaptive responses to infection and tissue injury . Additionally, NO synthase (NOS), may be uncoupled due to oxidation of the essential cofactor BH4, thus leading to the generation of O\u00b7\u22122 in place of NO. Accumulation of ONOO- may further contribute to the reduction of NOS activity and the disruption of the NOS dimer.Hx also appears to support vascular NO homeostasis as demonstrated by studies in heme-overloaded Hx-null mice and mouse models of hemolytic disorders  or lipid peroxides] occur in many disease states, particularly within the context of inflammatory reactions and during cycles of ischemia followed by reperfusion  oxo-ferryl Hb [Hb(Fe4+ = O)] generation, (2) ferric Hb [Hb(Fe3+)] generation, and (3) protein radical generation [\u00b7Hb(Fe4+ = O)]  during the peroxidative reaction sequence. However, Hp binding limits secondary reactions of these compounds with internal  and/or external substrates  or it can transfer to susceptible external molecules such as lipoproteins (\u201cextrinsic reactions\u201d). During the \u201cintrinsic\u201d free radical reactions within Hb, a defined peptide hotspot that is located at the \u03b1-globin/\u03b2-globin interface becomes the primary site where amino acid oxidation occurs. Among these amino acids is the highly susceptible \u03b2-chain Cys93, which can be oxidized to cysteic acid, as well as the \u03b1-chain Tyr42, which appears to be an important radical hub within Hb  Hb to low-affinity heme acceptors  Hb \u2014the substrate for heme transfer\u2014does not usually accumulate in plasma, even under severe hemolytic conditions  Hb-Hp to accumulate and to reach significant plasma concentrations. In a hemolysis model in guinea pigs, we detected up to 50% of ferric Hb-Hp 24 h after infusion of an Hp bolus for treatment of severe blood transfusion-associated hemolysis. Conceptually, the Hb-Hp complex in plasma may therefore be better compared with a polymerized Hb such as a hemoglobin-based oxygen carrier (HBOC). The intentionally slow clearance rates of HBOCs also allow these substances for significant accumulation of ferric species in vivo. Following infusion of most HBOCs there is no barrier against heme release and the oxidative damage that is associated with heme loss may be a significant component of vascular toxicity that accompanies administration of these therapeutic candidates . Hx sequesters heme in an oxidatively inert conformation in a complex with a 1:1 stoichiometry, until it is cleared by the liver. Heme transfer to more reactive biomolecules is therefore suppressed by Hx. Accordingly, heme-overloaded Hx-null mice show increased oxidative stress in blood vessels, endothelial activation, enhanced inflammation and decreased NO bioavailability  are therefore likely to modulate pathologies of the cardiovascular system such as atherosclerosis or typical vascular complications of hemolytic anemias. Oxidized lipoproteins are an established promoter of atherosclerosis and both Hb and heme can promote LDL oxidation (Balla et al., In humans, an Hp gene polymorphism exists that determines the three major phenotypes: 1-1, 2-1, and 2-2 (Levy et al., in vivo administration studies. These experimental Hp products resulted from industrial efforts to develop phenotype-specific therapeutic Hp products from pooled human plasma. Comparative investigations of two Hp products with predominant Hp 1-1 or Hp 2-2 composition found no significant differences in the intravascular sequestration or renal and vascular short term protection provided by dimeric and multimeric Hp phenotypes in a therapeutic setting of acute intravascular Hb exposure in guinea pigs and dogs (Lipiski et al., In the past, multiple functions of Hp, such as its anti-oxidative and CD163 adaptor functions, have been reported to be phenotype dependent (Asleh et al., Epidemiologic studies have also found controversial associations of Hp genotypes with the prevalence and clinical sequelae of atherosclerosis in the general population and in specific patient populations, particularly those with diabetes mellitus. However, more stratified analysis of several large observational studies now convincingly revealed that the Hp 2-2 genotype/phenotype is associated with increased relative risk of coronary artery disease of up to 10-fold in diabetic patients with a glycosylated HbA1c > 6.5 (Cahill et al., Thus, far, the pathophysiology underlying these associations is unknown. According to studies discussed above, the primary Hb detoxifying functions of Hp 1-1 and Hp 2-2 are comparable and can therefore not easily explain the epidemiologic differences. However, the biologic functions of Hp that have been investigated so far are more representative of the short term protective functions of Hp during acute hemolysis and may not fully reflect longer term antioxidant or immune modulatory functions of the protein that might be more relevant for chronic vascular disease development.Most epidemiologic studies of phenotype association with cardiovascular disease have been controlled for overall population heterogeneity and for established cardiovascular risk factors; however, these studies were not systematically controlled for differences in Hp plasma concentrations (Cahill et al., The controversial findings related to Hp phenotype-specific functions and associated disease state risks should certainly stimulate more extensive investigations. However, it now appears that, for therapeutic considerations, the Hp phenotype selection of a product will likely not be a primary determinant of clinical success (Lipiski et al., A genetic Hx polymorphism has been reported in populations of African ancestry (Kamboh et al., The only available data suggesting a strong association between plasma Hx level and disease risk come from studies evaluating the mouse model of Hx deficiency (Tolosano et al., Mouse models of sickle cell disease have a phenotype of chronic heme-driven endothelial activation and dysfunction that could be recovered by repeated Hx administration (Vinchi et al., Hemolysis has also been recognized to exacerbate some renal and vascular complications related to the transfusion of stored red blood cells. Retrospective clinical observation studies suggested a link between the storage duration of red blood cells and the incidence of cardiovascular complications such as myocardial infarction, stroke and death. One component of the so-called red blood cell storage lesion is an increased RBC fragility, which may lead to hemolysis post-transfusion. In a guinea pig transfusion model, increased fragility of older RBC could be linked to increased hemolysis in the post-transfusion period, appearance of free Hb in the circulation and Hb-triggered injury in the kidney and vasculature. All these pathologic changes could be prevented by Hp treatment at the time of old blood transfusion (Baek et al., Hemolysis with increased free Hb/heme levels and accompanying Hp/Hx depletion can be observed in some patients with severe sepsis. In a mouse sepsis model, Hx administration significantly reduced organ injury and mortality (Larsen et al., The rationale for the use of Hp and Hx as therapeutic agents is based on the idea that they act by scavenging circulating Hb and heme, with particular relevance to pathological conditions associated with hemolysis. Central to this concept is the notion that acute and chronic hemolytic conditions are characterized by depletion of the Hb and heme scavengers. Pre-clinical proof-of-concept animal models have demonstrated that Hp and Hx effectively attenuate Hb- and heme-induced vascular and renal pathologies. Based on these preliminary observations, it would appear rational to develop Hp and Hx for therapeutic use (Boretti et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Blood pressure homeostasis is maintained by several mechanisms regulating cardiac output, vascular resistances, and blood volume. At cellular levels, reactive oxygen species (ROS) signaling is involved in multiple molecular mechanisms controlling blood pressure. Among ROS producing systems, NADPH oxidases (NOXs), expressed in different cells of the cardiovascular system, are the most important enzymes clearly linked to the development of hypertension. NOXs exert a central role in cardiac mechanosensing, endothelium-dependent relaxation, and Angiotensin-II (Ang-II) redox signaling regulating vascular tone. The central role of NOXs in redox-dependent cardiovascular cell functions renders these enzymes a promising pharmacological target for the treatment of cardiovascular diseases, including hypertension. The aim of the present review is to focus on the physiological role of the cardiovascular NOX-generating ROS in the molecular and cellular mechanisms affecting blood pressure. Blood pressure is regulated by a dynamic equilibrium of different complex mechanisms Opie, . The maiNOX enzymes are membrane NADPH oxidases with the unique role of producing superoxide anions by one electron reduction of oxygen using NAD(P)H as electron donor  have been identified Lambeth,  Figure  and togeROS have been for long time considered as toxic byproducts of the chemical utilization of oxygen within the cells and oxidative stress has been linked to the pathogenesis of many disorders Sies, . It was Multiple physiological functions have been so far attributed to NOX enzymes. DUOX1 and 2 enzymes, first discovered in thyroid with a role in thyroid hormones synthesis , vascular smooth muscle cells (VSMCs), and adventitial fibroblasts.ECs express NOX1, NOX2, NOX4, and NOX5 , is involved in many vascular processes including vasoconstriction, fibrosis, hypertrophy, inflammation, and aging . For the role of NOX-dependent Ang II signaling in the endothelium see NOXs in the endothelium-dependent relaxation.Ang II induces activation of the enzymatic activity and increases expression of NOXs both in cultured VSMCs and intact arteries  generated by endothelial nitric oxide synthase (eNOS). The liposolubile NO diffuses across the membranes reaching VSMCs, where it increases cGMP levels by activating the soluble guanylate cyclase; the subsequent activation of cGMP-dependent kinases leads to a decrease of intracellular calcium levels and relaxation. Superoxide anions produced by NOXs react with NO to produce peroxynitrite  close to NOX2. Then, ryanodine receptors-2 activation leads to an increase of local cytosolic Ca2+ concentration and force development (Prosser et al., in vitro results in an increase of ROS levels correlated with the amplitude and the frequency of stretch (Prosser et al., in vivo during the normal cyclic stretching and shortening of cardiomyocytes at each heartbeat, where the Ca2+ spark can be dynamically modulated by ROS in dependence of pre-load and heart frequency.NOX-generating ROS contribute to the positive inotropic response to mechanical stretch in cardiomyocytes. Physiological stretch triggers a microtubule-mediated activation of NOX2 localized at t-tubule membranes. This mechanism referred by Prosser et al.  as X-ROS2+ concentration and myocardial contractility due to mechanical stretch, known as Anrep effect. This slow response follows within 1\u20132 min an increase of the afterload reaching a maximum after 10\u201315 min. In this case, NOX2-derived ROS mediates Ang II dependent ET-1 release. In cardiomyocytes, Ang II released by mechanical stretch (Sadoshima et al., +/H+ exchanger-1 (Akram et al., +, inhibition of Na+/Ca2+ exchanger, increase of cytosolic calcium concentration and contraction.NOX2 is also involved in the slow enhanced increase in intracellular Ca2+-ATPase, plasma membrane Ca2+ ATPase, L-Type Ca2+ channels and Nav are some examples of molecular target of ROS leading to modulation of intracellular Ca2+ levels linked to myocyte contractility (Sag et al., The role of NOXs in cardiomyocytes are not limited to mechanosensing. ROS produced by NOXs and by other sources such as mitochondria, are able to modulate different kinases phosphorylating proteins involved in calcium signaling; sarco/endoplasmic reticulum CaThe role of ROS in hypertension has been well documented (Lee and Griendling, Numerous studies using ROS scavengers or more specific NOX inhibitors, were aimed at evaluating the role of NOXs in the elevation of blood pressure in hypertensive animals (Lass\u00e8gue et al., 2O2 could mediate compensatory relaxation acting as an endothelium-derived hyperpolarizing factor (Yada et al., NOX2 elevation is correlated with hypertension. Indeed, in transgenic mice with endothelial-specific overexpression of NOX2, Ang II causes a greater increase in ROS production and attenuated acetylcholine-induced vasorelaxation compared to wild-type (Murdoch et al., Human studies aimed at linking NOX dysfunction with hypertension, have shown that some polymorphisms in the gene encoding p22 phox and affecting enzymatic activity, are associated with hypertension (Zalba et al., Finally, another interesting aspect of NOX involvement in blood pressure homeostasis impairment is related to cigarette smoke, a risk factor of hypertension. Cigarette smoke condensate exposures have been correlated with ROS production, downregulation of enzymatic antioxidant cellular systems and cell toxicity (Russo et al., in vitro experiments. However, due to the low bio-availability, peptide inhibitors are not promising therapeutic tools.NOXs are now being considered as target of pharmacological intervention in patients with hypertension (Cai et al., A number of small molecule NOXs selective inhibitors have been developed. Among them there are NOX1 and NOX 4 selective inhibitors like GKT137831, GKT136901, and GKT901 (Takac et al., Multiple molecular mechanisms regulating blood pressure involve NOX signaling. Of great importance is the central role of NOXs in angiotensin signaling, in the availability of NO and in the cardiac mechanosensing. A general scheme of the main overall effects of NOX-mediated signaling in the cells of the cardiovascular system leading to blood pressure modulation are shown in Figure The current challenge in the NOX biology research field is represented by the better understanding of the mechanisms by which NOX isoforms exert their differential biological effects leading to the development of substances able to modulate specific redox-dependent cell functions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Many neurological disorders, including neurodevelopmental disorders, report hypersynchrony of neuronal networks. These alterations in neuronal synchronization suggest a link to the function of inhibitory interneurons. In Fragile X Syndrome (FXS), it has been reported that altered synchronization may underlie hyperexcitability, cognitive dysfunction and provide a link to the increased incidence of epileptic seizures. Therefore, understanding the roles of inhibitory interneurons and how they control neuronal networks is of great importance in studying neurodevelopmental disorders such as FXS. Here, we present a review of how interneuron populations and inhibition are important contributors to the loss of excitatory/inhibitory balance seen in hypersynchronous and hyperexcitable networks from neurodevelopmental disorders, and specifically in FXS. FMR1) gene and the consequent loss of the gene product of FMR1\u2014Fragile X Mental Retardation Protein  repeat located in the 5\u2019 untranslated region of the gene expands to a length of more than 200 repeats. The loss of this protein is far reaching because FMRP interacts with approximately 4\u20138% of all synaptic mRNAs and regulates the translation of numerous synaptic proteins and receptor systems  is one of several disorders associated with autism spectrum disorders (ASDs)\u2014a heterogeneous group of behaviorally identified neurodevelopmental disabilities. The prevalence rate of autism in FXS reportedly ranges from 25% to 52% , but not in the cornu ammonis area 1 (CA1) subregion  played by this large and heterogeneous cell population (Buzs\u00e1ki et al., 2+-dependent spike initiation and/or propagation (Miles et al., As earlier stated, cortical networks in FXS are hyperexcitable and highly synchronous (Gon\u00e7alves et al., Fmr1 KO mouse model (Gibson et al., Fmr1 KO mice (Selby et al., Fmr1 KO mice compared to wild type animals (Paluszkiewicz et al., Fmr1 KO mice reduces inhibitory output which in turn alters the synchronization and spike output of excitatory neuronal networks in layer II/III (Paluszkiewicz et al., Fmr1 KO mice (Gibson et al., In FXS, EEG recordings show elevated relative theta power and reduced relative upper-alpha power (Van der Molen and Van der Molen, Fmr1 KO mouse model (Xu et al., There is additional evidence that suggest a role for interneurons in FXS with respect to specific activation via neuromodulators. Inhibitory interneurons have differential response to neuromodulators, among them, acetylcholine muscarinic receptors (Cea-del Rio et al., Interestingly, inhibitory neurotransmission dysfunction appears to be region selective. As stated above, studies in the cerebral cortex reveal interneuron specific problems. There is a clear lack of excitatory drive to FS interneurons in layer IV (Gibson et al., In summary, while enhanced excitatory neurotransmission leads to hyperexcitable phenotypes, inhibitory interneurons are not just contributing factors but are likely playing a major role in hyperexcitable, hyperresponsiveness and hypersynchronicity of neuronal networks in FXS (Gibson et al., Since many FXS patients also present with one or more features of ASDs, insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of the role of inhibitory interneurons in autism. At this point most of the evidence for interneuron participation is indirect in terms of neuromodulatory activation and downstream excitatory network activation, but very promising in terms of the relevance of their contribution. Thus, understanding how interneurons participate in neuronal network abnormalities seen in FXS lends to a greater understanding for neurodevelopmental disorders that fall in the autism spectrum.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Plants form the foundation for our global ecosystem and are essential for environmental and human health. With an increasing number of available plant genomes and tractable experimental systems, comparative and functional plant genomics research is greatly expanding our knowledge of the molecular basis of economically and nutritionally important traits in crop plants. Inferences drawn from comparative genomics are motivating experimental investigations of gene function and gene interactions. This special issue aims to highlight recent advances made in comparative and functional genomics research in plants. Nine original research articles in this special issue cover five important topics: (1) transcription factor gene families relevant to abiotic stress tolerance; (2) plant secondary metabolism; (3) transcriptome-based markers for quantitative trait locus; (4) epigenetic modifications in plant-microbe interactions; and (5) computational prediction of protein-protein interactions. The plant species studied in these articles include model species as well as nonmodel plant species of economic importance .Evolution of Transcription Factor Gene Families Relevant to Abiotic Stress Tolerance. The extant flowering plants have experienced multiple rounds of genome duplication and gene duplication is the primary source of gene family evolution. X.-L. Wang et al. in \u201cDivergence of the bZIP Gene Family in Strawberry, Peach, and Apple Suggests Multiple Modes of Gene Evolution after Duplication\u201d explored the evolutionary dynamics of the bZIP family, which contains transcription factors associated with plant tolerance to abiotic stress. They performed evolutionary analysis of the bZIP family in three rosaceous species in multiple aspects such as selection pressure on protein-coding sequences and genomic synteny. Another transcription factor gene family relevant to abiotic stress, the CCCH zinc finger family, was studied by W.-J. Chen et al. in \u201cSignificant Microsynteny with New Evolutionary Highlights Is Detected through Comparative Genomic Sequence Analysis of Maize CCCH IX Gene Subfamily.\u201d They performed comparative analysis of the CCCH IX subfamily in three cereal grain species  and found that segmental duplication has played an important role in the expansion of this gene family. Their analysis also indicates that deletions, multiplications, inversions, and purifying selection have contributed to the evolution of the CCCH IX subfamily.Plant Secondary Metabolism. Plants produce a wide range of secondary metabolites that underpin functional diversity in plants. Gene expression profiling through transcriptome sequencing is a powerful approach for understanding the molecular basis of plant secondary metabolism. H. Tian et al. in \u201cAnalysis of Polygala tenuifolia Transcriptome and Description of Secondary Metabolite Biosynthetic Pathways by Illumina Sequencing\u201d analyzed expression of secondary metabolite biosynthetic genes in P. tenuifolia, a well-known medicinal plant, using RNA-seq approach. Their analysis revealed candidate genes that are potentially involved in biosynthesis of several important secondary metabolites such as triterpene saponins and phenylpropanoid. Similarly, R. Li et al. in \u201cDe Novo Transcriptome Sequencing of the Orange-Fleshed Sweet Potato and Analysis of Differentially Expressed Genes Related to Carotenoid Biosynthesis\u201d performed RNA-seq analysis of secondary metabolism in Ipomoea batatas, an important food crop. Through comparing the global gene expression profile in relation to the differences in the carotenoid content of two I. batatas cultivars, they identified more than 50 genes potentially involved in carotenoid biosynthesis. Also, Y. Wei et al. in \u201cGenome-Wide Identification of Genes Probably Relevant to the Uniqueness of Tea Plant (Camellia sinensis) and Its Cultivars\u201d performed comparative analysis of RNA-seq data in several species of the genus Camellia, an important source for tea production. They identified differentially expressed genes relevant to the biosynthesis of flavonoid, theanine, and caffeine. Furthermore, their sequence comparison revealed nonsynonymous mutations that are potentially related to the diversity between the two cultivars of C. sinensis.Transcriptome-Based Markers for Quantitative Trait Locus. Quantitative trait locus (QTL) analysis has been widely used for elucidating the genetic basis of complex traits in plants. Molecular makers are prerequisites for QTL analysis. QTL makers can be developed from either genome sequences or transcriptome sequences. Development of genome-based markers requires genome-sequencing data, which are available only in model plant species or major crop species. For nonmodel plant (crop) systems, transcriptome-based markers can be a better choice for QTL analysis with a limited budget. E. S. Seong et al. in \u201cExpressed Sequence Tags Analysis and Design of Simple Sequence Repeats Markers from a Full-Length cDNA Library in Perilla frutescens (L.)\u201d developed simple sequence repeats (SSR) markers based on approximately 1,000 expressed sequence tags (ESTs) derived from cDNA libraries for this member of the mint family used in traditional Asian medicine. They identified 18 SSR makers that could be very useful for understanding of genomic basis of medicinal function in P. frutescens. Recent advance in next-generation sequencing technology greatly enhances the capability for molecular marker development. Q. Ding et al. in \u201cCharacterization and Development of EST-SSRs by Deep Transcriptome Sequencing in Chinese Cabbage (Brassica rapa L. ssp. pekinensis)\u201d identified 10,420 SSR markers from 51,694 nonredundant unigenes assembled from RNA-seq data. This large set of SSR makers could facilitate genome-wide discovery of QTLs in Chinese cabbage. Also, R. Li et al. in \u201cDe Novo Transcriptome Sequencing of the Orange-Fleshed Sweet Potato and Analysis of Differentially Expressed Genes Related to Carotenoid Biosynthesis\u201d identified 1,725 SSR markers in the transcriptome data for sweet potato.Epigenetic Modifications in Plant-Microbe Interactions. While it is widely accepted that genetics governs plant growth, development, and response to environment, an increasing number of studies have showed that epigenetics also plays an important regulatory role in plants. The paper by K. Melmaiee et al. entitled \u201cQuantification and Gene Expression Analysis of Histone Deacetylases in Common Bean during Rust Fungal Inoculation\u201d revealed that epigenetic modification via histone deacetylases is involved in the response of common bean to rust fungal inoculation. The results from this paper provide new insight into the molecular mechanism underlying plant-microbe interactions.Computational Prediction of Protein-Protein Interactions. Protein-protein interaction (PPI) is an important molecular mechanism underlying various biological processes. Computational prediction of protein-protein interactions based on protein sequences is a straightforward approach to the utilization of whole-genome gene annotation for the global view of protein-protein interaction network in an organism. Various algorithms have been developed for protein sequence-based PPI prediction, though with limited success. J. Yao et al. in \u201cPPCM: Combing Multiple Classifiers to Improve Protein-Protein Interaction Prediction\u201d present a machine learning approach for PPI prediction based on various features derived from protein sequences. Their results demonstrated that integration of multiple features could significantly improve the PPI prediction accuracy as compared with prediction classifiers based on individual features. This novel approach has a great potential for PPI prediction in nonmodel organisms, including plant species."}
+{"text": "Valero-Mu\u00f1oz et al. showed that heart failure with preserved ejection fraction (HFpEF) induced beiging in adipose tissue. They reported that in HFpEF brown adipose tissue (BAT) reduced the expression of some browning markers, such as uncoupling protein 1 (ucp-1), cell death-inducing DFFA-like effector a (cidea), and epithelial V-like antigen (eva), which were yet expressed by white adipose tissue (WAT) during beiging  and further deepen the role of immune cells, particularly M1 and M2 macrophages (Liu et al., A complex machinery of interactions between bone marrow precursors, pre-adipocytes, mature adipocytes and de-differentiated/mesenchymal progenitors, strongly suggests that the \u201cadipose\u201d compartment is a complex dynamic system that acts on several physiological districts to regulate energy balance, survival and tissue renewal (Hausman and Hausman, Further markers and investigations are needed to elucidate the role of adipose tissue and its beiging in heart function and heart failure.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Assessments of climate change impacts on forests and their vitality are essential for semi-arid environments such as Central Asia, where the mountain regions belong to the globally important biodiversity hotspots. Alterations in species distribution or drought-induced tree mortality might not only result in a loss of biodiversity but also in a loss of other ecosystem services. Here, we evaluate spatial trends and patterns of the growth-climate relationship in a tree-ring network comprising 33 juniper sites from the northern Pamir-Alay and Tien Shan mountain ranges in eastern Uzbekistan and across Kyrgyzstan for the common period 1935\u20132011. Junipers growing at lower elevations are sensitive to summer drought, which has increased in intensity during the studied period. At higher elevations, juniper growth, previously favored by warm summer temperatures, has in the recent few decades become negatively affected by increasing summer aridity. Moreover, response shifts are observed during all seasons. Rising temperatures and alterations in precipitation patterns during the past eight decades can account for the observed increase in drought stress of junipers at all altitudes. The implications of our findings are vital for the application of adequate long-term measures of ecosystem conservation, but also for paleo-climatic approaches and coupled climate-vegetation model simulations for Central Asia. Uzbekistan (UZ) and Kyrgyzstan (KG) belong to a region commonly referred to as Central Asia. This largely semi-arid to arid mountainous region is particularly vulnerable to ongoing and predicted climate change , 2. TempObserved impacts of anthropogenic climate change include an increase in health risks , decreasJuniperus spp.) dominates with around 80% of the forested areas at mid-to high elevations in Central Asia ).et al [et al [2 concentrations have been related to increased intrinsic water-use efficiency, where increased drought stress can lead to reduced stomatal conductance to compensate water loss at the expense of secondary growth [Although changes in climate during the past eight decades were remarkable and comparatively rapid, trends in juniper growth are less obvious and uniform. Combining the obtained results, we can summarize that juniper trees at the sites in Karakol, KG, with humid growing season climate  seem to et al  found sil [et al , reviewiy growth \u201354. Howey growth  and 2) ty growth .Over the full 1935\u20132011 period, the growth-climate relationships of the juniper sites generally showed benefiting effects on tree growth from warm temperatures at high altitudes and abundant moisture supply at low elevation sites , agreeinJ. seravschanica in the Zaamin National Park, UZ [et al [et al [Conversely, junipers at lower altitudes showed distinct and persistent drought responses, which has previously been shown for Park, UZ . Liu et Z [et al  or Liangl [et al  noted all [et al , are likl [et al . Moreovel [et al .The identified growth-climate response shifts in our study, which occurred only within the past 40 to 50 years, most likely indicate impacts of the ongoing climate change on juniper growth in Central Asia. We therefore stress the importance of long-term conservation measures to counteract possible losses or reductions of the mountain juniper forest ecosystems in UZ and KG. Our findings also highlight the need of time-dependency analyses in paleo-climatological studies when using high elevation juniper trees, as well as the integration of growth-climate response shifts when assessing and predicting vegetation dynamics in Central Asia.Juniperus spp. and local drought-induced juniper die-backs in this biodiversity hotspot. Consequently, alterations in the floral composition of the temperate coniferous forest biome in Central Asia can be expected. We therefore stress the need to apply adequate long-term measures for ecosystem conservation and to consider this ongoing response shift in paleo-climate and model simulation approaches for this region.Using a unique and extensive juniper network established for the Tien Shan and northern Pamir-Alay mountain ranges, we detected changes in growth-climate responses during the past eight decades. Junipers at low elevation sites mainly increased their climate sensitivity to drought during summer and the entire growing season. At the highest elevation sites, however, juniper growth was favored by high summer temperatures during 1935\u20131964, but was limited by increasing drought conditions during the past ~30 years. This change in climate sensitivity of the junipers likely demonstrates the effect of the ongoing climate change, and also explains the low reconstruction skills of high elevation juniper sites in Central Asia. Across the study area, changes in climate response were detected at all regions during summer, but also during winter, spring and autumn. This may be the cause of the spatially non-uniform changes in growth trends across the study region. Finally, our results indicate that a further rise in temperature together with decreasing rainfall amounts, as predicted for the coming decades, will most likely increase the risk of altitudinal range shifts of S1 TableJuniperus sp. (JUSP), J. seravschanica (JUSE), J. semiglobosa (JUSM), and J. turkistanica (JUTU)), the number of trees (n) and TRW series (n), start and end year over the full and truncated (n(i) < 5 series) period, interseries correlation (Rbar), mean segment length (MSL), mean sensitivity (MS), Expressed Population Signal (EPS), and highest correlations with climate (rMAX) for the analyzed 1935\u20132011 period.Information include country code (CC), latitude , longitude , elevation , exposition (Exp), species ((EPS)Click here for additional data file.S2 TablePearson correlation results for all juniper sites and sites closest grid point data for monthly (current year January to December) and seasonal a) temperature means and b) precipitation sums for the full 1935\u20132011 period. Sites within the region are sorted based on increasing longitude and within the region from high to low elevation sites . Seasons include previous year December to current year February (pDJF), March\u2013May (MAM), June\u2013July (JJ), June\u2013August (JJA), September\u2013November (SON), May\u2013September (M\u2013S), April\u2013October (A\u2013O), and the entire year.(EPS)Click here for additional data file.S3 TableDifferences in climate response from 1935\u20131964 to 1982\u20132011 of all juniper sites for monthly (current year January to December) and seasonal a) temperature means and b) precipitation sums. Sites within the region are sorted based on increasing longitude and within the region from high to low elevation . Seasons include previous year December to current year February (pDJF), March\u2013May (MAM), June\u2013July (JJ), June\u2013August (JJA), September\u2013November (SON), May\u2013September (M\u2013S), April\u2013October (A\u2013O), and the entire year.(EPS)Click here for additional data file.S1 FigSee (EPS)Click here for additional data file.S1 File(XLSX)Click here for additional data file."}
+{"text": "Loss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored. Auditory hair cells (HCs) are important for the conversion of acoustic sound energy into electrical impulses that travel to the auditory centers of the brain for hearing. Sensorineural hearing loss (SNHL) is a form of hearing impairment that occurs most commonly from damagedHCs within the cochlea; it is a prevalent disability, affecting one in five people and more than 48 million Americans , endonuclease G (EndoG), apoptosis inducing factor (AIF), second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low pI (Smac/DIABLO), and mammalian homolog of bacterial high temperature requirement protein A2  and recruits pro-caspase-9 to form an apoptosome . XIAP is a cytosolic protein that has three baculoviral inhibitory repeat (BIR) domains\u2014BIR1 and BIR2 specifically bind and inhibit caspase-3 and -7, while BIR3 is a specific inhibitor of caspase-9  binding of a death ligand to its complementary receptor; 2) recruitment of adaptor molecules such as FAS-associated death domain protein (FADD) and tumor necrosis factor receptor type 1-associated death domain protein (TRADD); (3) binding, dimerizing, and activation of initiator caspase-8 and -10; and (4) formation of a death-inducing signaling complex , respectively  are important regulators of cell survival and cell death. Necroptosis refers to a RIPK3-dependent molecular cascade of events that promotes regulated necrotic cell death  polymerase 1 (PARP1) dependent form of non-apoptotic death. PARP1 is recruited to sites of DNA damage where it is able to catalyze ADP ribosylation of various proteins and histones and generate negative charges by overconsumption of nicotinamide adenine dinucleotide (NAD) during the ADP ribosylation process. Ultimately, other factors important for DNA repair are recruited. However, when PARP1 becomes hyper-activated in situations of persistent DNA damage, there is a depletion of NAD and inhibition of mitochondrial ATP synthesis, which is essential in ATP-dependent apoptosis pathways , caspase-3 activation, and intrinsic cell death , and hydroxyl  expression of extracellular pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF\u03b1) and recruited of neutrophils and macrophages to the cochlea; and 2) generation of oxidative stress in the form of ROS and reactive nitrogen species (RNS) such as superoxide  on the cell surface of auditory HCs and initiate a signaling cascade that can lead to cell death  that promotes mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFkB) signaling  have also been detected in OC and cochlea following various inner ear challenges such as exposure to gentamicin, electrode insertion trauma, and autoimmune responses mediated by inner ear tissues  1 and 2 (ERK1/2), c-Jun N-terminal kinases , and p38 kinases  and blocking transcription of anti-apoptotic genes (such as Bcl-2)  have demonstrated protection against HC and hearing losses following aminoglycoside, acoustic, and electrode insertion injury to the cochlea  contains two unpaired electrons. Superoxide anion -mediated apoptosis; however there is some recent evidence that oxidative stress can turn on extrinsic cell death signaling. This again demonstrates the many levels of communication that occur both upstream and downstream in events of programmed cell death. ROS can activate apoptosis signal-regulating kinase-1 (ASK-1), which is a MAPKKK that can phosphorylate and activate mediators of the JNK and p38 pathways of extrinsic programmed cell death  that can trigger up regulation of genes important for cell death such as Bim and Bcl-6 . Acoustic trauma can also initiate inflammation and edema of the stria vascularis and compromise the blood supply to the cochlea (Smith et al., Acoustic trauma can lead to ROS release by the marginal cells of the stria vascularis as a result of reductions in cochlear blood flow and cochlear hypoxia (Yamane et al., c (Wang et al., When TNF\u03b1 binds to its complementary receptor TNFR1, TRADD and FADD are recruited along with caspase-8. Caspase-8 can activate executioner caspase-3 to promote extrinsic cell death through DNA fragmentation and chromatin condensation via CAD, ACINUS, and HELI-CARD or it can cleave BID into tBID, which can activate Bax-mediated intrinsic, mitochondrial cell death (Liu et al., c into the cytoplasm, generation of apoptosomes, and activation of caspase-3 dependent cell death. AIF and EndoG are also released into the cytosol, translocate into the nucleus, and can initiate chromatin condensation and DNA fragmentation of auditory HCs (Nicotera et al., Oxidative stress from noise exposure can also initiate intrinsic apoptotic cell death in auditory HCs, resulting in mitochondrial release of cyt In addition to apoptosis, acoustic trauma can result in regulated necrosis through RIPK3/RIPK1 activation in rats, that was reversed with necrosis inhibitor necrostatin-1 (Zheng et al., Acoustic trauma can also promote swelling and rupture of dendritic terminals of cochlear nerve afferent fibers (Spoendlin, Furthermore, intense noise exposure can increase intracellular calcium in auditory HCs and activate calcium-dependent calpains\u2014cysteine proteases that promote proteolysis and breakdown of cytoskeletal and membrane proteins, kinases, phosphatases, and transcription factors (Wang et al., Otoprotective drugs can target different levels in apoptosis and necrosis signaling pathways following acoustic trauma Figure . GlucocoNumerous diverse insults to the inner ear can cause auditory HC damage and hearing loss. The evolutionarily conserved apoptotic and necrotic cell death signaling that occurs in auditory HCs is shared among many ototoxic and traumatic stressor events. The most well studied molecular mechanisms behind cell death in auditory HCs involve TNF\u03b1 signaling, JNK and p38 activation and the effect of high levels of oxidative stress. Although their effects on intrinsic and extrinsic pathways of apoptosis have been studied extensively, there are likely many levels of cross communication between signaling cascades that are still undiscovered. Research in this area is becoming more prevalent, as well as research into mechanisms of regulated necrosis in auditory HCs. A number of otoprotective drug therapies target different levels along this pro-inflammatory pro-death signaling cascade to block downstream events that lead to cell death and promote auditory HC viability and hearing protection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "CYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I \u2013 control , II \u2013 chronic alcoholism (15% ethanol self-administration during 150 days). Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (\u201353%) and methionine (+133%). The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure.There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 ( Spermatet al., et al., et al., Ethanol can cause disturbance in the main metabolic pathways Zakhari, . AlcoholCYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and proteins thiol groups in rat testes.Based on these facts and considering that alcoholism is a chronic disease highly prevalent in the world population, the present work reports the effects of chronic ethanol consumption on free amino acids, levels of cytochrome P450 3A2 , relative humidity of 40% to 70%, lighting (12 h light-dark cycle), and on a standard pellet feed diet . The study was performed in accordance with the recommendations of the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes and approved by the Institutional Animal Care and Use Committee. For the experimental  model, reproducing male rats were selected according to the method for measuring voluntary alcohol self-administration in rats, which provides a continuous choice between an alcohol solution and water (two-bottle preference test)  were used as controls. From the beginning of the experiment, they were kept in the same conditions as the experimental animals, but were given only water After 150 days, both the experimental and control rats were sacrificed under a mild diethyl ether anesthesia by decapitation. The right testis was used for histochemical analysis and the left testis for other investigations.et al.  activity in the testes was demonstrated by the method of Nachlas et al.  was histochemically detected according to the technique of Hess g, 10 min, 4 \u00b0C)  equal volumes of 3% sulfa-salicylic acid were added and the obtained mixtures were left for 10 minutes in the refrigerator at 4 \u00b0C. The formed sediments were removed by centrifugation  and then fractionated through 2% agarose gels . After electrophoresis, the gels were stained with ethidium bromide and visualized under a UV transilluminator . Analysis of electrophoresis data was carried out with Quantity One Software (USA).The DNA from the testes was isolated by a modified method from Current Protocols in Toxicology . Data were compared using Student's t-test. Differences were considered to be statistically significant at Investigation of chronic alcoholism effects on rat testis pools of free amino acids  showed tInvestigation of rat testes DNA fragmentation demonstrated its essential intensification following 150 days of ethanol administration in comparison with control . In the In testes of alcohol-treated rats 8 fractions of DNA fragments with weights over 1000 (4 different fractions), 700, 550, 30 and 20 b.p. were present. Main of high-weighted DNA fragments were fractions with weights over 1000 b.p., while among low-weighted DNA fragments fractions were approximately equal (by peak intensity).CYP3A2 mRNA expression was indicated in testes of rats with chronic alcoholism  and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), both at the stage of glycolysis (changes of glycine and serine) and in the citric acid cycle (changes of methionine) , with superoxide anions, oxygen molecules, hydroperoxide, organic peroxides and peroxide radicals Stepuro, . Thus, cet al., et al., et al., et al., Changes of methionine in testicular pools deserve special attention. This amino acid can act as antioxidant and immunomodulator Pavlov, . Methionet al., et al., et al., et al., It is reasonable to propose that biosynthesis of S-adenosylhomocysteine and homocysteine could be also broken due to excessive alcohol intake. Changes in contents of methionine, glycine and serine \u2013 amino acids involved in the synthesis of these compounds , changes in its contents can cause changes in free amino acid contents .Changes of such amino acids as glycine in the testis pool are of special importance because of the involvement  in glutathione biosynthesis  Marks, . Such chet al., et al., et al., DNA is an important molecular target for toxicants  by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms . In our previous study, we showed CYP2E1 mRNA expression and protein content elevation in alcohol-treated rat testes with simultaneous spermatogenesis violations , which are involved in testosterone biosynthesis , a member of the nuclear receptor superfamily, regulating gene transcription in a ligand-dependent manner   and much of this function is attributed to the thiol groups present on them. One or more reduced thiol (-SH) groups are essential for the function of many proteins (Top\u00e7uoglu et al., Our results on the decrease of protein SH-groups in testes of alcohol-treated rats are in good accordance with data of clinical studies on the decrease of total thiol in alcohol abusers (Prakash Our results suggest that the self-administration of 15% alcohol in rats during 150 days led to multidirectional changes of the activity of testicular dehydrogenases, which play a crucial role in supplying energy needed for various metabolic functions in germ cells Mathur, . Dehydroet al., Forming part of complex II of the respiratory chain, SDH, is situated at the intersection of the citric acid cycle and oxidative phosphorylation. This combination of functions places SDH at the center of two essential energy-producing metabolic processes of the cell (Cervera et al., It is well known that spermatogonia may utilize glucose as the major energy substrate, but spermatocytes and spermatids suffer a rapid decline in their ATP content in glucose-supplemented media and require lactate/pyruvate for the maintenance of their ATP concentrations (Jutte et al., et al., Glucose transport into the cell and the lactate LDH isoenzyme system, which reversibly catalyzes the inter-conversion of pyruvate and lactate, are biochemical steps which participate in the regulation of lactate production (Riera Chemically induced stress causes elevated LDH activity, which can be used as a good diagnostic tool in toxicology (Ksheerasagar & Kaliwal, CYP3A2 mRNA expression and DNA fragmentation processes, as well as changes in cholesterol and protein thiol group contents allowed us to obtain complex estimation of this pathologic influence in male gonads, especially on the metabolism of amino acids, proteins, ATP and NADPH. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed testicular metabolic disorders could have negative implications on cellular regulation of spermatogenesis under long-term ethanol exposure.Thus investigation of chronic alcoholism effects on testicular levels of free amino acids, rates of"}
+{"text": "Cilia are whip-like projections that are widely conserved in eukaryotes and function as a motile propeller and/or sensory platform to detect various extracellular stimuli. In vertebrates, cilia are ubiquitously found in most cells, showing structural and functional diversities depending on the cell type. In this review, we focus on the structure and function of cilia in choroid plexus epithelial cells (CPECs). CPECs form one or two dozen non-motile 9+0 cilia, which display transient acquisition of motility during development. Genetic malfunction of cilia can lead to failure of multiple organs including the brain. Especially, several groups have demonstrated that the defects in CPEC cilia cause the communicating form of hydrocephalus. In order to elucidate the molecular mechanisms underlying the hydrocephalus, we have previously demonstrated that the cilia possess an NPFF receptor for autocrine signaling to regulate transepithelial fluid transport. In this perspective, we also discuss the potential involvement of cilia in the other aspects of choroid plexus functions, such as the regulation of brain development and neuroinflammation. Cilia are hair-like projections on the cell surface with a diameter of ~250 nm and various lengths of typically 5\u201310 \u03bcm Figure . Their sFor example, ependyma (ependymocytes) lining brain ventricles form hundreds of motile cilia to circulate the cerebrospinal fluid (CSF). The axoneme of this ciliary subtype has a central pair of singlet microtubules (termed \u201c9+2\u201d), and is heavily equipped with axonemal dyneins and their regulatory complexes, which collectively drive the back-and-forth movement of cilia Figure . In contGenetic defects leading to ciliary malfunctions cause disorders with clinically variable phenotypes. Such disorders are called ciliopathies and include primary ciliary dyskinesia, polycystic kidney disease, Leber congenital amaurosis, nephronophthisis, Senior-L\u00f8ken syndrome, Joubert syndrome, Bardet-Biedl syndrome, and Meckel Gruber syndrome  carries tubulin and other materials along the axoneme  that produce CSF with high efficiency (Damkier et al., As described above, mature ependyma form hundreds of motile 9+2 cilia that beat in a concerted manner to circulate CSF. In mouse, the multiciliogenesis initiates after birth and requires about 2 weeks for full maturation Figure . In contCelsr2, an ortholog of the planar cell polarity gene Flamingo, an impairment of ciliogenesis is observed in ependyma but not in CPECs (Tissir et al., Genetically modified mouse models have also shown differences in the mechanism of ciliary formation and/or the maintenance of cilia in CPECs and ependyma. In a knockout mouse for Tg737RpwIft88 mouse that has defects in IFT88 expression and function, Banizs et al. observed a communicating form of the hydrocephalus at neonatal periods, when most ependyma lack mature motile cilia. During these stages, CPEC cilia show an accumulation of polycystin-1, the defects of which cause autosomal dominant polycystic kidney disease, in a bulb-like structure at the tip. This abnormal ciliary structure and protein localization coincide with an increase in cellular cAMP levels and aberrant regulation of intracellular pH and ion transport activities in CPECs (Banizs et al., Pkd1 knockout mice, which encodes polycystin-1, and observed hydrocephalus at perinatal periods in both mouse lines.Regarding the unique function of CPEC cilia, several groups including ours have reported the potential involvement of CPEC cilia in the regulation of CSF production. Analysis of CPEC cilia in relation to the hydrocephalus was first described by Yoder et al. (Banizs et al., We used a primary culture system for swine CPECs to analyze ciliary function and showed that deciliation by chloral hydrate increases both intracellular cAMP levels and basolateral-to-apical transepithelial fluid transcytosis, which is consistent with the above observations by Banizs et al. (Narita et al., Bbs1, Bbs2, Bbs4, and Bbs6 mutant mice (Swiderski et al., Swiderski et al. investigated the mechanism of ventriculomegaly that is common in ciliopathy models of Kif3a in cranial neural crest cells, using a Wnt1 promoter-driven Cre recombinase (Liu et al., cre expression in E16.5 choroid plexuses, they concluded that the hydrocephalus is due to overproduction of CSF (Liu et al., Recently, Liu et al. generated a conditional knockout of Rfx3 knockout mouse also exhibits corpus callosum agenesis (Benadiba et al., The above studies implicate defects in CPEC cilia as a cause of the communicating form of hydrocephalus. However, reports by Durand et al. suggest additional mechanisms. They generated mice deficient for Rfx3, a transcription factor that regulates ciliogenesis, and demonstrated marked inhibition of ciliogenesis in both CPECs and ependyma, which is associated with the communicating form of hydrocephalus (Baas et al., A growing body of evidence suggests that the choroid plexus functions as a selective and educative gate for circulating immune cells in the immune surveillance of the CNS to resolve neuroinflammation under pathological conditions (Schwartz and Baruch, Recently, we performed proteomic analysis of CPEC cilia from swine and identified >800 proteins (Narita et al., According to the traditional view, CPECs have been regarded as solely responsible for the production of CSF. However, based on our current understanding of CSF production, we should re-interpret or re-evaluate the traditional views of CSF homeostasis (Iliff et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The most common diseases resulting in irreversible blindness or vision impairment include age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, cataract, and dry eye. These diseases seriously affect the quality of life in elderly people worldwide. Therefore, understanding their pathogenesis and the development of strategies allowing earlier detection and treatment demands more effort and attention from both basic and clinical fields. This issue focuses on different aspects of these diseases in elderly population.\u03b2, IL-18, or IL-17\u201d by S. Chen et al., the authors investigated the responses of multipotent retinal stem cells (RSCs), isolated from mice, to the proinflammatory signaling molecules including IL-1\u03b2, IL-18, and IL-17A. They found that the addition of IL-1\u03b2, IL-18, or IL-17A in the cultured cell decreased RSC viability but increased pyroptotic and/or necroptotic cells. The study is innovative and unique, because, instead of RPE19, a new cell type was used as the model system. Additionally, the results fill gaps in understanding immunological mechanism of AMD pathogenesis.AMD is one of the most common diseases resulting in irreversible blindness worldwide in the elderly population. Among multifactorial pathogenesis, immune dysregulations are leading theories of AMD pathogenesis. Recently IL-17 pathway was reported to be involved in AMD pathogenesis. In the original article \u201cResponses of Multipotent Retinal Stem Cells to IL-1Like AMD, glaucoma and diabetic retinopathy are common causes of blindness in older adults. Glaucoma is often caused by damage to the optic nerve due to an abnormally high pressure in your eye, while diabetic retinopathy is a diabetes complication, caused by damage to the retinal blood vessels. However, both of them have no symptoms or warning signs at early stage. Thus, it is important to have regular eye exams to measure intraocular pressure and ocular blood flow. In the review paper \u201cOcular Blood Flow Autoregulation Mechanisms and Methods\u201d by X. Luo et al., the authors summarized the methods for ocular blood flow evaluating and discussed mechanism and treatment of ocular blood flow regulation, particular in glaucoma and diabetic retinopathy.Cataract is one of the major causes of visual impairment of elderly people. Although recent bioinformatics studies revealed susceptibility genes, such as EPHA2, for age-related cataract, the mechanism underlying its pathogenesis remains elusive. In the original paper \u201cThe Polymorphisms with Cataract Susceptibility Impair the EPHA2 Receptor Stability and Its Cytoprotective Function\u201d by J. Yang et al., the authors found that EPHA2 signaling can protect the lens epithelial cells from oxidative stress-induced cell death. In the original paper \u201cEpigenetic Regulation of Werner Syndrome Gene in Age-Related Cataract\u201d by X. Zhu et al., the authors investigated the promotor methylation and histone medication of Werner syndrome gene (WRN). They found that both mRNA and protein levels of WRN were significantly decreased only in anterior lens capsules in age-related cataract, suggesting that the strategies to intervene epigenetic alteration in this disease should aim to anterior lens capsules. By investigating very large cataract patient population in rural China, X. Cao et al. presented a normative ocular biometry of adult cataract patients in rural China. They found that the axial length is normally distributed with a positive skew and a big kurtosis and corneal astigmatism may affect rural Chinese vision acuity.Dry eye is a multifactorial disorder of the tears and ocular surface and is a common and often unrecognized disease affecting tens of millions of individuals worldwide. Q. Long et al. evaluated the biomechanical behavior of the cornea in dry eye using, for the first time, Corneal Visualization Scheimpflug Technology (CorVis ST), a new noncontact tonometry system. Their results provide insight into its full usefulness for dry eye patients. B. Wang et al. compared dry eye disease that resulted from two refractive surgeries [small-incision lenticule extraction (SMILE) versus femtosecond laser in situ keratomileusis (FS-LASIK)] in high myopia. They found that SMILE is a safe and successful alternative for the correction of refractive error and may provide a more superior and safer refractive outcome than FS-LASIK in the first six months following surgery. CorVis ST, the very latest technology, has been used by J. Wang et al. to assess the biomechanical parameters of the cornea in myopic and emmetropic eyes.Vitreous hemorrhage (VH) is one of the ophthalmologic emergency situations. In the paper contributed by D. Y. Kim and colleagues, the authors analyzed causes and prognosis of acute-onset preoperatively unknown origin VH in 169 eyes and found that retinal vein occlusion, retinal break, and AMD are the most common causes. In addition, aging may be an important factor for influencing visual prognosis following vitrectomy.Optic neuritis is one of the common optic neuropathies and is highly associated with multiple sclerosis. In the original paper \u201cEvaluation of Retinal Nerve Fiber Layer and Ganglion Cell Complex in Patients with Optic Neuritis or Neuromyelitis Optica Spectrum Disorders Using Optical Coherence Tomography in a Chinese Cohort\u201d by G. Tian et al., the authors reported that spectral-domain optical coherence tomography, SD-OCT, is a very useful and objective method to evaluate the thickness of the peripapillary retinal nerve fiber layer and macular ganglion cell complex in optic neuritis and neuromyelitis optica.Common age-related ocular diseases demand attention as a global health problem. This special issue covered pathogenesis, diagnosis, and treatment of most of these diseases.Jun ZhangJun ZhangJingsheng TuoJingsheng TuoZhongfeng WangZhongfeng WangAiqin ZhuAiqin ZhuAnna Machali\u0144skaAnna Machali\u0144skaQin LongQin Long"}
+{"text": "Hypoxia is an important micro-environmental characteristic of rheumatoid arthritis (RA). Hypoxia-inducible factors (HIF) are key transcriptional factors that are highly expressed in RA synovium to regulate the adaptive responses to this hypoxic milieu. Accumulating evidence supports hypoxia and HIFs in regulating a number of important pathophysiological characteristics of RA, including synovial inflammation, angiogenesis, and cartilage destruction. Experimental and clinical data have confirmed the upregulation of both HIF-1\u03b1 and HIF-2\u03b1 in RA. This review will focus on the differential expression of HIFs within the synovial joint and its functional behavior in different cell types to regulate RA progression. Potential development of new therapeutic strategies targeting HIF-regulated pathways at sites of disease in RA will also be addressed. It is an autoimmune and polyarthritic condition, characterized by inflammation of the synovium (synovitis), progressive cartilage destruction, and bone erosion, which ultimately results in loss of integrity of the affected joints  are activated as an adaptive mechanism. HIFs are considered the \u201cmaster regulators\u201d  and macrophage-like synoviocytes  and an underlying loose connective tissue called the sub-lining (sub-intima) layer Smith, . The arcInflammatory factors are known to upregulate the expression HIF-1\u03b1 and HIF-2\u03b1 in RA. Pro-inflammatory cytokines such as IL-1, TNF-\u03b1, and IL-33 have previously been reported to increase the expression of HIF isoforms in synovial fibroblasts  are pattern recognition receptors that are mainly expressed in immune cells and RASF cells in RA to regulate inflammatory responses (Brentano et al., Immune cells also play an important role in synovial inflammation. HIF-1\u03b1 and HIF-2\u03b1 are highly expressed in immune cells, in particular macrophages, in the RA synovium (Hollander et al., Synovial angiogenesis is likely a consequence of synovial hypoxia in RA (Konisti et al., The articular cartilage is an avascular, aneural, and alymphatic tissue, which is composed primarily of chondrocytes. The role of HIFs in cartilage destruction in RA is not yet fully characterized, with the majority of the work conducted in healthy articular cartilage. Cells in the articular cartilage normally reside in a hypoxic environment, with oxygen tension varying from 6\u201310% at the joint surface to 1% in the deeper layers (Gibson et al., in vitro on cells derived from RA synovium, further ex vivo and in vivo studies are warranted to assist in strengthening our understanding of the complex role of HIF in cartilage degradation in RA.Hypoxia has been demonstrated to upregulate the levels of MMPs in cells derived from RA synovium, although additional pathways independent of HIF may also be involved (Canning et al., Studies to date suggest that HIFs are promising targets for novel RA treatments. Approaches that may be considered for targeting hypoxia in RA cells include the use of hypoxia-activated prodrugs, specific HIF inhibitors, gene therapy, or targeting indirect pathways important in hypoxic cells. The majority of these targeted therapies have come from research on the effects of hypoxia on the growth of tumors (Phillips, A number of HIF inhibitors have been developed that possess inhibitory activity against cancer and HIF-related diseases (Ban et al., in vivo model of RA (del Rey et al., The use of delivery carriers may improve the efficacy of HIF-related therapeutic agents following systemic administration, by overcoming the pharmacokinetic and stability issues. The best example of this is in the delivery of gene therapy targeting HIFs, which have previously been shown to modulate cellular responses in hypoxia-related diseases (Post et al., Indirect strategies to target downstream HIF signaling pathways have also been investigated in RA. For example, many therapeutic approaches have successfully resolved angiogenesis in preclinical animal models of RA by administering antibodies targeting VEGF or small molecule inhibitors targeting the VEGF receptor (Maruotti et al., Accumulating evidence supports hypoxia and HIFs in regulating a number of important pathophysiological characteristics of RA, including synovial inflammation, angiogenesis, and cartilage destruction. Therefore, HIF inhibitors are likely to target multiple important RA processes. Experimental and clinical data have confirmed the upregulation of both HIF-1\u03b1 and HIF-2\u03b1 in RA. At this time, the relative importance of each isoform in RA pathology and disease severity is still unclear. These two isoforms show different sensitivity to oxygen tension and display distinct, and sometimes opposing, cellular activities. In addition, further studies are required to clarify the interrelationship between HIFs and other simultaneous pathways in perpetuating RA disease. This will allow us to determine whether specific HIF-1\u03b1 or HIF-2\u03b1 inhibition is likely to be required for successful clinical outcomes in RA. To optimize their effects, HIF inhibitors may require encapsulation within delivery vehicles directed toward affected RA tissue to improve therapeutic accumulation and stability following systemic administration, as well as reduce off-target effects.SH was responsible for assembling, drafting and revising the manuscript, and preparing the associated figure and table. TD contributed to the drafting of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The liver is famous for its strong regenerative capacity, employing different modes of regeneration according to type and extent of injury. Mature liver cells are able to proliferate in order to replace the damaged tissue allowing the recovery of the parenchymal function. In more severe scenarios hepatocytes are believed to arise also from a facultative liver progenitor cell compartment. In human, severe acute liver failure and liver cirrhosis are also both important clinical targets in which regeneration is impaired, where the role of this stem cell compartment seems more convincing. In animal models, the current state of ambiguity regarding the identity and role of liver progenitor cells in liver physiology dampens the enthusiasm for the potential use of these cells in regenerative medicine. The aim of this review is to give the basics of liver progenitor cell biology and discuss recent results vis-\u00e0-vis their identity and contribution to liver regeneration. The liver has the amazing potential to regenerate when mild liver damage occurs. During this process, remnant resting hepatocytes will re-enter the cell cycle and efficiently replenish the liver through proliferation. A good example of the capacity of adult hepatocytes and bile epithelial cells to proliferate is seen during recovery from partial hepatectomy in rats and mice, when two-third of the liver is removed , liver stem cells (LSCs), atypical ductal cells (ADCs), or intermediate hepatobiliary cells, it is sometimes difficult to deducewhether researchers are studying the same cell. While it is desirable to come to a nomenclature and classification of these -maybe different- cells, in this review we will use the term HSPCs to encompass the various liver stem/progenitor cell populations irrespective of species or injury model.Liver regeneration can be broadly characterized into hepatocellular or biliary regeneration, which is dependent on the type of injury. Adaptive, but flexible crosstalk between the microenvironment (i.e. extracellular matrix (ECM) and neighboring cells, like Kupffer cells, myofibroblasts and hepatic stellate cells) and the stem-cells themselves are required to allow the activation of HSPCs . Differin vitro for their cell renewal and differentiation capacity or in vivo for their ability to repopulate an injured liver with HSPC-derived hepatocytes and cholangiocytes ), Prom1 Figure 2.The problem with the aforementioned markers is that they are also expressed on regular biliary epithelial cells. The current view is that, once awakened by signals from the surrounding liver tissue, HSPCs become transit amplifying cells expressing some proteins not expressed by regular biliary epithelial cells such as Foxl1 (Forkhead Box l1), TACSTD2/Trop2  or LGR5 ((leucine-rich-repeat-containing G protein-coupled receptor 5) -like weak inducer of apoptosis (TWEAK), which is produced by monocytes, T lymphocytes and macrophages whose expression increases in contexts of acute injury, inflammatory disease and cancer. The expression of its receptor Fn14, normally expressed by epithelial and mesenchymal cells, is also relatively low in healthy tissue but is dramatically induced in injured and diseased tissue, such as in livers following a DDC treatment. HSPC activation by DDC was significantly reduced in Fn14-null mice and by the use of an anti-TWEAK antibody while overexpression of TWEAK in hepatocytes  or exogal., 2005). Indeedal., 2005; Murakamal., 2005; Steilinal., 2005). FGF7-dal., 2013). Obvioual., 2013). Contraal., 2013). This sin vivo /c-MET and Epidermal growth factor (EGF)/EGF receptor (EGFR) are key regulatory elements to determine HSPC activation and differentiation. In c-MET knockout mice, HSPC response was significantly less upon DDC injury al., 2012) suggestal., 2012). Wnt3a al., 2012, 20137]in vivo  ).+/EpCAM+ cells are defined as hepatoblasts expressing albumin and they are capable of differentiating into hepatocytes (EpCAM-/Dlk1-/Alb+/CK19-) and cholangiocytes (EpCAM+/Dlk1-/Alb-/CK19+) . These ductal plate derived YFP positive cells co-expressed SOX9, OPN and other oval cell markers , the caal., 2012; Tanaka al., 2012). Only o4. This was in contrast to a later study that showed that lineage tracing of LGR5-CRE positive cells yielded hepatocyte-like cells after one single injection of CCl4 or the DDC and MCDE diets   Figure. Until ral., 2013). None oal., 2013; Schaub al., 2013) or regual., 2013) and appal., 2013; Feil etal., 2013). Severaal., 1989) and traal., 1989). If theal., 2011). Carpenal., 2011) showed al., 2011) is likeal., 2011; Yanger al., 2011). The real., 2011), ~ 28.7al., 2011), ~ 10.5al., 2011) to 7 % al., 2011); the fiAn alternate hypothesis that might at least partially explain the obtained results from these studies, is that the low hepatocyte repopulation from HSPCs is a matter of hepatobiliary linkage but not of massive hepatocyte production . In thide novo formation of mature hepatobiliary cells  An overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation  Gut-derived endotoxins play a central role in the initiation of acute liver injury and progression to chronic liver disease ; (iii) An imbalanced intestinal homeostasis results in a breach of the gut barrier and subsequent microbial translocation ; (iv) Selective intestinal decontamination with antibiotics is beneficial for patients and prevents experimental liver injury ; (v) Mice with genetic deletions in the lipopolysaccharide (LPS) signaling pathway are resistant to experimental liver injury and fibrosis  Transplantation of microbiota from diseased mice to germfree mice transfers some aspects of diseased phenotypes, indicating that altered microbiota plays a role in disease establishment and manifestation . Thus, \u03b1,\u03b2)  into hepatocytes. Many research efforts are focused on ways to expand hepatocytes or have perfect differentiation conditions of stem cells towards functional hepatocytes. Both are not current practice; hepatocytes in culture lose their functionality very quickly while stem cell differentiation towards hepatocytes often only reaches the hepatocyte-like cell level . Currenal., 2012; Snykersal., 2012; Takase al., 2012) and manal., 2012) ). The seid, 2000). CurrenIn vivo, HSPCs are not only influenced by growth factors and cytokines, changes in the extracellular matrix (ECM) seem to effect the proliferation and differentiation as well. The ECM is a complex structure made up of protein fibers that serve as a dynamic substrate that supports tissue repair and regeneration . Changeal., 2011; Kallis al., 2011; Van Hulal., 2011) and Lamal., 2011; Espanolal., 2011) deposital., 2011; Shupe eal., 2011). Uygun al., 2011) successal., 2011).Similar decellularized matrixes also increased hepatocyte differentiation of human fetal HSPCs when used as a coating substrate for regular tissue culture plates . ClearlIn these last couple of years we have learned much about the pathways and conditions involved in HSPC activation thanks to sophisticated genetically modified mouse models. These same models are currently in conflict about the existence and function of HSPCs during liver injury and regeneration. Perhaps novel mouse liver injury models, more representative of human disease, need to be developed to fully unravel the existence, identity and function of HSPCs.LD & LvG: Interuniversity Attraction Poles (IAP) - phase VII - contract P7/47  (10/2012-09/2017); SV: Flemish Government Agency for Innovation by Science and Technology, IWT/SB/121548 (2013-2016).Leo A. van Grunsven and Laurent Doll\u00e9 contributed equally to this publication."}
+{"text": "In continuation of the last year's special issue \u201cTCM Zheng Classification and Clinical Trials,\u201d the time for 2014 issue has come. Now we are on the way from TCM Zheng classification in clinical trial to development of clinical practice guideline. Clinical effectiveness is what matters most in any treatment, including traditional Chinese medicine (TCM). Many clinical trials have been conducted in China to evaluate the effectiveness of TCM, but many of the studies are with poor quality and may be inaccessible to non-Chinese scientists. As shown in This 2014 special issue contains 9 articles accepted from a total of 19 submissions consisting of 6 research articles, 1 systematic review (SR) article, and 2 narrative review articles.Two cohort studies were gathered, \u201cChinese Herbal Decoction Based on Syndrome Differentiation as Maintenance Therapy in Patients with Extensive-Stage Small-Cell Lung Cancer: An Exploratory and Small Prospective Cohort Study\u201d; 357 herbal decoctions were prescribed for 29 patients based on Zheng classification to observe the treatment effect and treatment length of herbal decoctions. Another cohort study \u201cThe Functional Difference of Dendritic Cells in HBeAg Negative Chronic Hepatitis B Patients with Three Different Spleen Deficiency Syndromes and the Therapeutic Evaluation of Chinese Medicine Intervention Based on Syndrome Differentiation\u201d by H. Song et al. suggested that Chinese medicine intervention according to Zheng classification could advance the maturity and function of dendritic cells and improve the therapeutic effect.One case analysis study, \u201cStudy on TCM Syndrome Differentiation of Primary Liver Cancer Based on the Analysis of Latent Structural Model\u201d by X. Yue et al., analyzed 559 inpatients records to provide evidences for TCM Zheng classification of primary liver cancer.Another paper focuses on clinical practice guideline; \u201cEnhanced Evidence-Based Chinese Medicine Clinical Practice Guidelines in Hong Kong: A Study Protocol for Three Common Diseases\u201d by A. Lu et al. presented a novel of three-phases clinical practice guidelines research protocol for insomnia, chronic gastritis, and cerebral infarction. This study may serve as model for future guidelines development in the area.To answer the question of what are the differences between different types of Zheng? \u201cThe Th17/Treg Immune Balance in Ulcerative Colitis Patients with Two Different Chinese Syndromes: Dampness-Heat in Large Intestine and Spleen and Kidney Yang Deficiency Syndrome\u201d by M. Jiang et al. identified different mechanism on immune imbalance of ulcerative colitis patients with two types of TCM Zheng. D. Wang et al. identified that 26 potential biomarkers in the plasma of coronary heart disease (CHD) patients and 19 differential metabolites contributed to the classification of two main types of TCM Zheng \u201cphlegm Zheng\u201d and \u201cblood stasis Zheng\u201d in \u201cA Metabonomics Profiling Study on Phlegm Syndrome and Blood-Stasis Syndrome in Coronary Heart Disease Patients Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry.\u201dWeijing Decoction) Combined with Pharmacotherapy for the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease\u201d by C. C. Xue's research group included 15 RCTs, 986 subjects. They concluded that Weijing decoction, a universally used herbal formula for treating chronic obstructive pulmonary disease (AECOPD), appeared to be beneficial for acute exacerbations of AECOPD and well-tolerated when taken concurrently with routine pharmacotherapy (RP).Systematic review paper \u201cChinese Herbal Medicine , would be valuable for the researchers for conducting TCM clinical trials. We, the editors, appeal that more proper designed clinical trials on long term major outcomes should be funded. Hopefully, this special issue will give helpful insights to scientists, physicians, and patients and will also be able to make a progress in the field of TCM clinical studies."}
+{"text": "Cognitive impairment is the final outcome of a complex network of molecular mechanisms ultimately leading to dementia. Despite major efforts aimed at unraveling the molecular determinants of dementia of Alzheimer type (DAT), effective disease-modifying approaches are still missing. An interesting and still largely unexplored avenue is offered by nutraceutical intervention. For instance, robust epidemiological data have suggested that moderate intake of red wine may protect against several age-related pathological conditions  as well as DAT-related cognitive decline. Wine is highly enriched in many polyphenols, including resveratrol. Resveratrol is a well recognized antioxidant which may modulate metal ion deregulation outcomes as well as main features of the Alzheimer\u2019s disease (AD) brain. The review will discuss the potentiality of resveratrol as a neuroprotectant in dementia in relation to the oxidative stress produced by amyloid and metal dysmetabolism. French paradox arises from the epidemiological fact that French people, despite their indulgence to a high fat diet, show a relative low incidence of cardiovascular diseases  extracellular deposition of misfolded \u03b2-amyloid (A\u03b2) in senile plaques (SPs); (2) intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs); (3) severe brain atrophy; and (4) the presence of areas of chronic inflammation  has been considered the main trigger for AD-related synaptic dysfunction. Amyloid has been therefore the major target for therapeutic intervention  can lead to direct deacetylation of acetylated tau, thereby promoting its proteasomal degradation  dependent deacetylase) which in turn sets in motion a cascade of PGC-1\u03b1-dependent events that ultimately lead to improved mitochondrial functioning and biogenesis and boost cellular ROS scavenging  by efficiently scavenging hydroxyl, superoxide, and metal-induced radicals , Amyotrophic Lateral Sclerosis (ALS), Prion Protein disease, Huntington\u2019s disease (HD), and AD. All these neurodegenerative conditions share common pathological features that include deposition of misfolded proteins, metal ion deregulation and exposure to oxidative stress  (Shin et al., Iron deregulation has been linked to AD (Weinreb et al., Zinc dyshomeostasis has been proposed as a risk factor for AD. Accumulation of excessive zinc, or its deficiency, are both involved in the neuronal loss which leads to AD and aging related cognitive decline Brewer, . While zin vitro (Granzotto and Zatta, in vivo the downstream events of aluminum overload, namely the aluminum-related ROS production and neuroinflammatory response activation (Zaky et al., Aluminum lacks modulatory functions in biological processes; however, its accumulation in the brain has been demonstrated to be linked to several neuropathological conditions (Zatta et al., Resveratrol is a multi target compound and may represent an effective therapeutic tool in aging-related neurodegenerative processes. Consistently, several clinical trials are ongoing to test its effectiveness as dietary supplement to slow dementia progression (ClinicalTrials.gov, in vivo may act on other uninvestigated biological targets (Herskovits and Guarente, In summary, major effects are associated with its scavenging activity as well as in the activation of SIRT1 (see Bordone and Guarente, Resveratrol is a multi-target, simple, safe, and cost-effective dietary supplement. Nevertheless, it should be reminded that its role as therapeutic agent is not devoid of potential problems. The pro-oxidant activity in presence of labile copper, the poor bioavailability and ease degradation all represent major issue that require new sophisticated efforts (Goldberg et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This volume features state-of-the-art approaches to determining the effects of ageing on visual perception, visual cognition, and visually guided behavior. They incorporate psychophysics, eye movements, electrophysiology, and neuroimaging to determine how ageing affects vision in health and pathology.Brockmole and Logie  present 2 ingestion, they observed age-equivalent fractional cerebral blood flow (\u0394CBF) in the presence of age-related increases in fractional cerebral metabolic rate of oxygen (\u0394CMRO2). Reductions in \u0394CBF responsiveness to increased \u0394CMRO2 in elderly participants led to paradoxical age-related BOLD decreases. Age-related \u0394CBF/\u0394CMRO2 ratio decreases were associated with increases in behavioral reaction times, suggesting that age-related slowing resulted from less efficient neural activity. Alichniewicz et al. (Hutchison et al.  investigz et al.  used funz et al.  examinedz et al.  present Bieniek et al.  investigIt is our hope that these studies contribute to a better understanding of the effects of ageing on visual perception and visual cognition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: This study was funded by the FIS  co-financed by the European Union through the Fondo Europeo de Desarrollo Regional , and by the Grupo de Excelencia Investigadora URJC-Banco Santander No. 30VCPIGI03: Investigaci\u00f3n traslacional en el proceso de salud\u2014enfermedad (ITPSE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "Plasmopara viticola, the causal agent of grapevine downy mildew, is one of the most devastating grape pathogen in Europe and North America. Although phytochemicals are used to control pathogen infections, the appearance of resistant strains and the concern for possible adverse effects on environment and human health are increasing the search for alternative strategies. In the present investigation, we successfully tested two protein hydrolysates from soybean (soy) and casein (cas) to trigger grapevine resistance against P. viticola. On Vitis vinifera cv. Marselan plants, the application of soy and cas reduced the infected leaf surface by 76 and 63%, as compared to the control, respectively. Since both hydrolysates might trigger the plant immunity, we investigated their ability to elicit grapevine defense responses. On grapevine cell suspensions, a different free cytosolic calcium signature was recorded for each hydrolysate, whereas a similar transient phosphorylation of two MAP kinases of 45 and 49 kDa was observed. These signaling events were followed by transcriptome reprogramming, including the up-regulation of defense genes encoding pathogenesis-related (PR) proteins and the stilbene synthase enzyme responsible for the biosynthesis of resveratrol, the main grapevine phytoalexin. Liquid chromatography analyses confirmed the production of resveratrol and its dimer metabolites, \u03b4- and \u03b5-viniferins. Overall, soy effects were more pronounced as compared to the cas ones. Both hydrolysates proved to act as elicitors to enhance grapevine immunity against pathogen attack. Vitis vinifera) has a surveillance system considered as the first defense line against invader pathogens, activated after signal molecule perception. These molecules may come from infectious agents or non-pathogenic microorganisms and therefore be designated as pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs), respectively; they may correspond also to secondary products released during pathogen invasion, called damage-associated molecular patterns (DAMPs)  into elicited cells, considered cardinal for defense response activation , proved to enhance efficiently grapevine defense responses , dwarf pea (Pisum sativum), and tomato (Solanum lycopersicum)  susceptible to P. viticola, were grown in glasshouse conditions, as described by Gauthier et al. (V. vinifera cv. Gamay) were cultivated as described by Vandelle et al.  and casein (cas), produced for the pharmaceutical and food industry were supplied by \u201cA. Costantino & C. S.p.A.\u201d . Since the two products are not yet on the market and protected by a trademark, their physicochemical characteristics cannot be reported. Solutions at 1.6 mg/ml in sterile ultra-pure or distilled water were prepared 24 h before use, 0.20 \u03bcm filtered and stored at 4\u00b0C. This concentration was selected based on previous trials . Plants were placed for 5 h in a humid chamber , and then transferred back to the greenhouse. Five days post inoculation (dpi), plants were placed again in the humid chamber overnight to stimulate sporulation. Disease was assessed estimating the leaf surface area (%) covered by sporulation. Five plants were used per condition, evaluating three leaves per plant that were marked before treatment.Both faces of leaves of 8-weeks old grapevine plantlets were sprayed by 2+ and MAPK), cells were transferred in the M10 buffer , re-suspended at 0.1 g of fresh weight of cells (FWC) per ml and equilibrated for 1 h in light (130 rpm at 24\u00b0C) before treatments  as described in Dubreuil-Maurizi et al. (In vivo reconstitution of aequorin was performed adding 5\u03bcl of coelenterazine (5 mM stock solution in DMSO) to 5 ml of aequorin-transformed cell suspension for at least 3 h in the dark. Aequorin was quantified adding 300 \u03bcl of lysis buffer . Finally, variations in [Ca2+]cyt were calculated following the calibration equation developed by Rentel and Knight  and 50 \u03bcl of 0.3 mM luminol. Relative luminescence was recorded within a 10-s period using a luminometer  and expressed as nmol H2O2 per gram of FWC.Hr et al. . BrieflyWestern blot analyses were performed as described by Trd\u00e1 et al. . AliquotDead cells were quantified according to Binet et al. . Briefly\u2212\u0394\u0394Ct method  and reaction efficiencies were calculated.Aliquots (2 ml) of treated cells were harvested by filtration on GF/A filters following a time course , frozen and ground in liquid nitrogen. Total RNA isolation was obtained by Trizol . The RNA yield and quality were determined by NanoDrop 2000 . cDNAs were synthesized by reverse-transcribing 400 ng of total RNA using Superscript III reverse transcriptase kit . Amplifications were run in a 96 well-plates iCycler iQ thermal cycler  and quantification was performed with the iCycler iQTM associated software . Differential expression was determined according to the 22) ranging from 0.94 to 0.99  separated by filtration on GF/A filters following the same time course of qPCR analyses. The culture medium samples were directly analyzed, whereas cell samples were stirred vigorously and incubated in 2 ml absolute ethanol for 24 h at 4\u00b0C to extract stilbenes. Samples were analyzed by an Acquity UPLC system  equipped with a model 2996 photo-diode array detector, as described by Boutegrabet et al. . Each sasoy and cas), data were subjected to ANOVA . Significant differences (P \u2264 0.05) were identified by the General Linear Model (GLM) procedure with the Duncan's Multiple Range Test (DMRT). Percentage data of incidence of decay underwent arcsine-square-root transformation before ANOVA analysis. For gene expression data, since just two conditions were compared (relative expression by soy and cas), Student's t-test was applied. Data were processed using the software package Statistics for Windows .When more than two conditions were present . Thereafter, plants were sprayed by soy and cas at 1.6 mg/ml, inoculated by P. viticola sporangia 24 h later and evaluated for the leaf sporulating area at 5 dpi. A significant reduction of disease severity by 76% for soy and 63% for cas was observed as compared to the control. However, no difference was found between the two hydrolysates .Generation of Hsoy and cas hydrolysates was also evaluated by cell viability assays, in which the number of red colored grapevine cells was assessed at 24 hpt. We did not recorded any toxic effect of the two hydrolysates compared to the water control (data not shown).The toxicity of PR1), a \u00df-1,3-glucanase (PR2), a chitinase 4c (PR3), a protease inhibitor (PR6), a polygalacturonase-inhibiting protein (PGIP) and a stilbene synthase (STS). Overall, soy and cas induced a rapid and high transcript accumulation of most of the tested genes with different kinetics and intensities; a more pronounced effect of soy was generally observed , showed a biphasic expression profile. It peaked at 4 or 8 hpt for soy- and cas-treated cells, respectively.In this study we evaluated by qPCR in time-course experiments the expression in grapevine cell suspensions of six selected defense genes known to be activated in response to various elicitors: those encoding a pathogenesis-related protein 1 .soy and cas hydrolysates to trigger resistance against gray and green mold (Lachhab et al., in vitro of the different pathogens (Lachhab et al., 2+]cyt variations, H2O2 production, MAPK activation, defense genes expression, and phytoalexin production. Both soy and cas induced specific changes of [Ca2+]cyt, considered essential for defense response activation (Lecourieux et al., 2+]cyt, as compared to water control, similarly to other elicitors as OG, cryptogein, BcPG1, and Flg 22 (Lecourieux et al., soy and cas showed two specific signatures, characterized by different kinetics and duration, suggesting different active molecules in each hydrolysate (Blume et al., soy-treated cells, the increase in [Ca2+]cyt was more rapid than that triggered by cas, and the level of free cytosolic calcium remained higher as compared to water and cas treatments. A similar behavior was observed in [Ca2+]cyt signatures induced by the polypeptide cryptogein in tobacco cells (Lecourieux et al., soy is likely not an oligosaccharide as assumed elsewhere (Lachhab et al., soy and cas chemical composition by the manufacturer is in progress.On the bases of the effectiveness of soy-treated cells a fast, strong, and lasting MAPK activation, which is consistent with the high level of free cytosolic calcium concentration. These results are similar to those of Lecourieux et al. (2+]cyt and MAPK stimulation is more evident considering the cas- effect. Indeed, the rapid decrease of the [Ca2+]cyt level is correlated with a very low activation of MAPKs after 60 min, as previously demonstrated in cryptogein-treated tobacco cells (Lecourieux et al., Calcium signaling is known to act upstream of the MAPK pathway in some plant defense responses (Link et al., x et al.  who reco2+]cyt variations and MAPKs activation, many authors described the rapid release of H2O2 in cell suspensions as a response to various elicitors (Poinssot et al., soy- and cas-elicited cells did not show any variation in H2O2 production. Furthermore, similarly to the \u03b2\u2013glucan derivative PS3, the two hydrolysates did not have any toxic effect on grapevine cells, supporting the hypothesis that the resistance to pathogen invasion may depend on other defense responses rapidly activated during pathogen infection (Aziz et al., 2O2 generation is not necessary for the induction of defense reactions. As shown by Galletti et al. (Arabidopsis, without affecting the expression of genes involved in defense responses effective against B. cinerea. In addition, Pauw et al. (Catharanthus roseus.In addition to [Cai et al. , a null w et al.  showed tP. viticola of some Vitis species as V. riparia, was associated to a more rapid and stronger induction of defense gene expression, as compared to susceptible cultivars, e.g., V. vinifera (Polesani et al., PR1 and PR6 (Lu et al., PR6 is in agreement with the protective effect provided by the two hydrolysates to grapevine against Botrytis attack (Lachhab et al., STS the key gene of the biosynthesis of resveratrol, known to increase resistance against pathogens (Coutos-Th\u00e9venot et al., Phomopsis viticola and B. cinerea and affecting P. viticola zoospore mobility (Adrian et al., Consistently with previous reports, the two tested hydrolysates caused an up-regulation of 6 known defense-related genes (B\u00e9zier et al., soy, induced a high and rapid accumulation of resveratrol at 4 hpt, the first time-assessment in our trials, meaning that STS gene was induced even before. This finding is in agreement with the concept that stilbene is the primary inducible response of grapevine against a number of biotic and abiotic stresses (Adrian et al., As expected, the two protein hydrolysates, in particular Interestingly, resveratrol was present at high amounts in culture medium, but showed low accumulation in cells. As suggested by Adrian et al. , part ofP. viticola (Pezet et al., soy showed pronounced efficiency in inducing defense responses, as compared to cas treatment, in particular concerning stilbene accumulation. The different results may be ascribed to their different proteic origins. Indeed, soybean contains different proteins as lipid transfer proteins (Kido et al., P. viticola.The \u03b4- and \u03b5-viniferin dimers, considered as important markers for resistance of grapevine to pathogens (Malacarne et al., cas and particularly soy hydrolysates as enhancers of grapevine innate immunity and thus good candidates to replace or reduce fungicide applications in modern sustainable viticulture, as they are cheap, easily available and safe to humans and the environment.In conclusion, the presented data support the use of Nihed Lachhab: conducted the experiments, analyzed data and prepared the manuscript; Simona M. Sanzani: designed the experiments, analyzed the data and prepared the manuscript; Marielle Adrian: supervised phytoalexin quantification, analyzed the data and edited the manuscript; Annick Chiltz and Suzanne Balacey: helped in conducting the experiments; Maurizio Boselli: helped to design the experiments and edited the manuscript; Antonio Ippolito: helped to design the experiments and edited the manuscript; Benoit Poinssot: designed the experiments, analyzed the data and prepared the manuscript. All authors have read the manuscript and agree with its content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recently, Bin Zhao and colleagues from the Chinese Academy of Science in Beijing and University of California, Sacramento, have published a review about identification of cardiotoxic compounds by rapid screening methods  derived cardiomyocytes have been introduced and several gene and microRNA cardiotoxicity markers have been identified . Meanwhal., 2015). Currenal., 2015, 20139]in vitro al., 2015; Grinberal., 2015), kidneyal., 2015; Bulacioal., 2015) and neual., 2015; Shinde al., 2015), which al., 2015; Vartak al., 2015; Ghallabal., 2015; Schliesal., 2015; Hoehme"}
+{"text": "Renal fibrosis represents a common pathway leading to progression of chronic kidney disease. Renal interstitial fibrosis is characterized by extensive fibroblast activation and excessive production and deposition of extracellular matrix (ECM), which leads to progressive loss of kidney function. There is no effective therapy available clinically to halt or even reverse renal fibrosis. Although activated fibroblasts/myofibroblasts are responsible for the excessive production and deposition of ECM, their origin remains controversial. Recent evidence suggests that bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. Understanding the molecular signaling mechanisms underlying the recruitment and activation of the bone marrow-derived fibroblast precursors will lead to novel therapy for the treatment of chronic kidney disease. In this review, we summarize recent advances in our understanding of the recruitment and activation of bone marrow-derived fibroblast precursors in the kidney and the development of renal fibrosis and highlights new insights that may lead to novel therapies to prevent or reverse the development of renal fibrosis. Chronic kidney disease (CKD) is a global public health problem. Worldwide, over 1 million people die from CKD yearly. It is estimated that more than 20 million Americans have CKD and more than 450,000 Americans suffer from end-stage renal disease (ESRD) requiring renal replacement therapy. CKD has become the eighth leading cause of death in the United States. Regardless of various etiologies, a common pathological feature of CKD is renal fibrosis, which is characterized by accumulation of fibroblasts/myofibroblasts with increased production and deposition of extracellular matrix (ECM) including collagen type I, III, IV, fibronectin, vimentin, and proteoglycans , macrophages, and immune cells, which suggest that interaction and communication among these cell types regulates the development of fibrotic disorders (Kisseleva and Brenner, The recruitment of circulating cells into sites of injury is mediated by locally produced chemokines. Chemokines are classified based on the relative position of cysteine residues near the NH2 terminus into four major families: CC, CXC, C, and CX3C Rollins, . Recent in vivo in a murine model of renal fibrosis induced by obstructive injury (Okamura et al., in vitro (Xia et al., in vitro and in vivo (Izquierdo et al., The chemokine CXCL16 is a recently discovered cytokine belonging to the CXC chemokine family (Matloubian et al., CXCR6 is the receptor for CXCL16. CXCR6 was first cloned as an orphan receptor by three independent groups and was termed STRL33, BONZO, or TYMSTR (Alkhatib et al., In these studies, we have observed that genetic deficiency of CXCL16 or CXCR6 does not completely block bone marrow-derived fibroblast precursor infiltration into the kidney and renal fibrosis development, suggesting that other chemokine/receptor pairs may be involved in the process of recruiting bone marrow-derived fibroblast precursors into the kidney. Consistent with this notion, CCR2 and CCL21/CCR7 have been reported to play a role in the recruitment of bone marrow-derived fibroblast precursors into the kidney and the development of renal fibrosis (Sakai et al., in vitro and in vivo (Chen et al., in vitro. Smad3-knockout mice accumulate significantly fewer bone marrow-derived fibroblasts in the kidney after obstructive injury, exhibit less myofibroblast activation, and express less \u03b1-SMA in the obstructed kidney. Furthermore, genetic deletion of Smad3 reduces total collagen deposition and suppresses expression of extracellular matrix proteins. Additionally, wild-type mice engrafted with Smad3\u2212\u2215\u2212 bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidney with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with Smad3+\u2215+ bone marrow cells. These results indicate that Smad3 of bone marrow-derived cells plays an important role in bone marrow-derived fibroblast activation. However, Samd3 deficiency does not completely abolish bone marrow-derived fibroblast activation, collagen deposition, and ECM protein expression in vivo. These results suggest that other factors may be involved in bone marrow-derived fibroblast activation.The activation of bone marrow derived fibroblast precursors plays a crucial role in the pathogenesis of renal fibrosis (Yang et al., + T cells can differentiate into two major distinct phenotypes, Th1 and Th2 cells, which are characterized by specific cytokine expression patterns (Wynn, in vitro. Furthermore, CP690550 treatment or STAT6 deficiency inhibits bone marrow-derived fibroblast activation and ECM protein production in the kidney in response to obstructive nephropathy. To further confirm the role of bone marrow STAT6 signaling in myeloid fibroblast activation, we performed bone marrow chimeric experiments. Wild-type mice transplanted with STAT6 null bone marrow cells exhibit fewer bone marrow-derived fibroblasts and develop a lesser degree of renal fibrosis. These results suggest that inhibition of JAK3/STAT6 signaling may serve as a novel therapeutic target for fibrotic kidney disease.The activation of bone marrow-derived fibroblasts is modulated by inflammatory cells in the microenvironment. T cells plays an important role in the pathogenesis of renal fibrosis (Tapmeier et al., ns Wynn, . Th2 celns Wynn, . Howeverns Wynn, . SpecifiAdiponectin is a multifunctional cytokine and an important regulator of lipid and carbohydrate metabolism. Emerging evidence suggests that circulating adiponectin levels are elevated in patients with CKD, and a high level of adiponectin is linked to increased cardiovascular mortality (Zoccali et al., It is generally thought that macrophages do not produce ECM proteins. These cells promote fibrosis indirectly by producing profibrotic cytokines that activate fibroblasts (Wynn and Barron, Recent studies have shown that renin angiotensin system plays an important role in the development of fibrotic kidney disease (Mezzano et al., Recent studies have demonstrated that bone marrow derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. Recruitment and activation of bone marrow-derived fibroblasts are mediated through the interaction between chemokines/cytokines and their receptors Figure . TherefoAlthough chemokines are involved in recruiting bone marrow-derived fibroblasts into the kidney in response to injury, the molecular signaling mechanisms underlying chemokines-induced bone marrow-derived fibroblast recruitment remains to be defined. Ras proteins are members of a family of small GTPase that control signaling pathways involved in cell migration, proliferation, differentiation, and survival (Rodr\u00edguez-Pena et al., JY drafted the manuscript. ZZ, LJ, and YW reviewed and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ginsenoside-Rb1 is a chemically pure steroid glycoside from the root of Panax ginseng, which has a 3000-year history of medicinal use in the Orient.Betts et al 2011) reported that Rb1 inhibits vascular endothelial growth factor (VEGF) release by retinal pigment epithelial cells, which is a major source of VEGF in the eye  of ginsenosides and their derivatives. By simple acylation of the panaxadiol, an analog of ginsenoside, its anti-tumor activity was significantly enhanced, compared with the non-acylated parent  (Using a different cancer cell line (lung fibroblast), Dong et al. (2011) noted that the removal of the sugar moiety (by hydrolysis) significantly increased its cytotoxic potency, based on MTT assays, to measure viable cell numbers . Du et aSuch SAR reports are not limited to chemical modification of ginsenosides leading to inhibition of cancer cell proliferation only. Wei et al (2009) reported that oxidation of panxadiol leads to triperpene derivatives with a significant increase in the ability to inhibit the HIV-1 protease enzyme, which is required for maturation and infectivity of the HIV virus . FinallyRecently, there has been an increased interest in SAR in medicinal chemistry. These reports provide further evidence for the need of exploring how chemically modified ginsenosides may enhance inhibition of VEGF in ocular and other cell types. Such discoveries will provide new knowledge for novel intervention methods to treat angiogenic diseases such as diabetic retinopathy, AMD and cancer."}
+{"text": "Stem cell research is of high interest, because precursor cells can be directed to differentiate into practically all mature cell types. This represents a potential perspective for therapeutics of severely damaged organs and also an alternative to animal drug and toxicity testing. Nonetheless, an essential question still remains: How similar are differentiated stem cells to the desired mature cells, e.g. liver cells? This highlight report focusses on a study recently published in the Journal of Hepatology  where tThe liver has a spectacular ability to regenerate  developThe authors applied biostatistical techniques to compare gene clusters using real liver cells (primary human hepatocytes), stem cells and six different stem cell-derived hepatocyte-like cells . The coin vitro systems play a major role in testing of neurotoxicity  represe represe5al., 2014; Krug etal., 2014), nephroal., 2014; Yang etal., 2014) and hepal., 2014; Godoy eal., 2014; Godoy 2al., 2014; Godoy aal., 2014; Grinberal., 2014; HengstlThis is the first time that such a systematic genome wide comparison of stem cell derived and genuine hepatocytes has been performed. The recent published study in the Journal of Hepatology  offers"}
+{"text": "Progression of solid tumors is characterized by an evolutive growing cellular mass containing variable proportions of a complex network of tumor stroma cell populations  surrounding cancer cell (CC) foci. This cellular intricacy determines mechanical, molecular and functional interactions involved in multiple mechanisms driving reciprocal aspects of paracrine and justacrine crosstalks between TSC and adjacent CC. There is increasing evidence that tumor stroma is a multicellular organ containing vascular structures and a large variety of cellular populations, including resident carcinoma-associated fibroblasts (CAF), myofibroblasts (MF), leucocytes and macrophages, bone marrow-derived mesenchymal stem cells, and in breast cancer, adipose progenitor cells. This cellular heterogeneity sustains tumor growth and angiogenesis, deregulated cancer cell proliferation, survival, chemoresistance, epithelial-to-mesenchymal transitions (EMT), invasion and tumor metastasis.In primary tumors and their metastases, these intercommunications between cancer cells and their surrounding TSC are organized in part by the convergent secretion of various ECM components building the architectural formation of ECM interfaces between these two critical cellular populations. ECM remodeling during cancer progression is regulated by the concomitant secretion of CC and TSC soluble factors and cytokines as well as subcellular exosomes involved in genetic tranfer between cancer cells and their stromal microenvironment (reviewed in ref. ). PlastiSeveral studies pointed the critical roles played by the ECM, CAF and MF in tumor progression. Decorin is a member of the Small Leucine-rich Repeat Proteoglycan (SLRP) family expressed and secreted in the interstitial ECM in breast stroma (reviewed in ref. ). In ECMIn this context, decorin was shown to sequester latent form of TGF\u03b21 (L-TGF\u03b21) in the ECM and to interact with the active TGF\u03b21 ligand, thus preventing its binding to TGF\u03b21 receptors . Most imIn the background of ductal carcinoma in situ (DCIS) of the breast, Van Bockstal et al reveal that the function of decorin is involved in breast cancer cell spreading and that both TGF\u03b21 and bFGF down-regulated the ECM protein decorin in CAF-associated breast tumors . In turnin vitro and in vivo will provide a rationale for new therapeutic options aimed to neutralize the oncogenic role of TGF\u03b21 as a repressor of the decorin tumor suppressive functions. As reported by Van Bockstal et al [These findings collected in breast cancer-associated fibroblasts  are of pal et al  this ass"}
+{"text": "The integration of information from genome to metabolome allows the establishment of associations between genetic potential and final phenotype, a feature not realizable by only considering single \u2018omes\u2019. Therefore, in our opinion, integrated omics will become the future standard for large-scale characterization of microbial consortia including those underpinning biological wastewater treatment processes. Systematically obtained time and space-resolved omic datasets will allow deconvolution of structure\u2013function relationships by identifying key members and functions. Such knowledge will form the foundation for discovering novel genes on a much larger scale compared with previous efforts. In general, these insights will allow us to optimize microbial biotechnological processes either through better control of mixed culture processes or by use of more efficient enzymes in bioengineering applications.Biological wastewater treatment plants harbour diverse and complex microbial communities which prominently serve as models for microbial ecology and mixed culture biotechnological processes. Integrated omic analyses  are currently gaining momentum towards providing enhanced understanding of community structure, function and dynamics  Biological wastewater treatment plants host diverse and dynamic microbial communities possessing varied metabolic capabilities over changing environmental conditions, e.g. microorganisms accumulating various storage compounds of biotechnological importance. Given their structural and functional diversity, BWWT processes hold great potential for future sustainable production of various commodities from wastewater as well as from other mixed substrates  with well-defined physico-chemical boundaries and are widespread in developed and developing countries  biomolecular extractions protocols and computational analyses ineffective  yet highly active populations  minimizing errors by cancelling out noise and biases stemming from single omic analyses and (ii) optimizing/maximizing overall data usage.Following standardized and systematized biomolecular isolations, multi-omic datasets are generated in addition to the physico-chemical parameters recorded at the time of sampling Fig.\u2009; step 2.et\u2009al., et\u2009al., et\u2009al., in silico data processing and analysis methods, which in turn will allow integrated omics to provide comprehensive multi-level snapshots of microbial population structures and functions in situ , fully integrated omic analyses should be applied routinely in the study of microbial consortia for greater effectiveness. For instance, despite this wealth of information, current metagenomic assemblies and analysis schemes, metagenomic (and metatranscriptomic) data resulting from the use of current short-read sequencing and assembly approaches do not allow the comprehensive resolution of microdiversity, e.g. genetic heterogeneity of microbial populations , coupled to carefully controlled laboratory experiments, will allow the effective elucidation of novel functions within BWWT plant microbial communities with potential biotechnological applications.Although integrated omics-based approaches are highly effective for large-scale analysis and formulation of hypotheses (including within the context of BWWT plant communities), these efforts are limited due to current high-throughput measurement methods (see previous section) and the reliance on et\u2009al., et\u2009al., et\u2009al., et\u2009al., Knowledge of gene function, regulation and physiological potential derived from integrated omic data over different spatial and temporal scales holds great promise in harnessing the biotechnological potential of microbial consortia. In particular, advancements in integrated omics followed by hypothesis testing may generate new knowledge (Muller None declared."}
+{"text": "Phenotypic integration among different anatomical parts of the head is a common phenomenon across vertebrates. Interestingly, despite centuries of research into the factors that contribute to the existing variation in brain size among vertebrates, little is known about the role of phenotypic integration in brain size diversification. Here we used geometric morphometrics on the morphologically diverse Tanganyikan cichlids to investigate phenotypic integration across key morphological aspects of the head. Then, while taking the effect of shared ancestry into account, we tested if head shape was associated with brain size while controlling for the potentially confounding effect of feeding strategy.The shapes of the anterior and posterior parts of the head were strongly correlated, indicating that the head represents an integrated morphological unit in Lake Tanganyika cichlids. After controlling for phylogenetic non-independence, we also found evolutionary associations between head shape, brain size and feeding ecology.Geometric morphometrics and phylogenetic comparative analyses revealed that the anterior and posterior parts of the head are integrated, and that head morphology is associated with brain size and feeding ecology in Tanganyikan cichlid fishes. In light of previous results on mammals, our results suggest that the influence of phenotypic integration on brain diversification is a general process. Brain size is highly variable among vertebrates,2. This The cichlids of Lake Tanganyika are an interesting model group to investigate the integration between skull and brain because of their remarkable diversity in both brain size and head morphology. The relative brain size  of Tanganyikan cichlids is correlated with several ecological and social factors such as diet,24, habiAnolis lizards[The high degree of integration between the different parts of the head is widely reported across vertebrates . Intere lizards. These a lizards. Hence,  lizards which wo lizards,15. AlteIn this study, we use landmark-based geometric morphometric phylogenetic analyses to test for the existence of phenotypic integration between various aspects of head morphology and brain size in Lake Tanganyika cichlids. According to our hypothesis, we test two aspects of integration. First, we test if the head is composed of morphologically independent modules or if it represents an integrated morphological unit. We then investigate whether head morphology is integrated with brain size or brain region volumes while considering the potentially confounding effect of prey utilization patterns that may affect head morphology.Benthochromis tricoti) for which we had two specimens  was much higher than within-species between-sex variation  and the interaction between species and sex . Our data should thus be robust against within-species sex differences. Specimens were sacrificed using an overdose of benzocaine. After measuring standard length and head width , the head was severed and preserved in 4% paraformaldehyde in a phosphate buffer for tissue fixation and preservation. Whole brains were obtained from dissected heads following fixation and weighed using a Precisa 125A electronic scale . All cranial nerves, optic nerves and meningeal membranes were removed and the brain was severed from the spinal cord just posterior of the dorsal medulla. Since brain volume and brain weight are highly correlated in our dataset , we use\u2009=\u20090.96,,36. Feed\u2009=\u20090.96,,47. To a\u2009=\u20090.96,. Therefo,[et al., Konings,[et al.,50, Yama,[et al.-53, Yuma,[et al., Takeuchl.[et al., Ochi[5l.[et al..p\u2009>\u20090.62 in all cases). We measured the head length as the distance between the foremost point of the snout and the rearmost point along the operculum using a scale photographed in the background of the images. Using TpsDig version 2.16, we digitized six homologous landmarks and seven semi-landmarks along the edge of the forehead to capture the variation in forehead shape where the largest proportion of variation is concentrated[F550, 2112\u2009=\u20093.58, p\u2009<\u20090.001) than intraspecific between-sex differences . Generalized Procrustes Analysis (GPA) was performed to mathematically remove the variation of position, size, and rotation of the landmark configurations[Images of the lateral sides of 156 individuals were taken with a reflex digital camera (Nikon D 70 with an AF Micro Nikkor 60\u00a0mm 1:2.8 D macro lens). Assuming symmetry, we used the best quality images either from the right or left side. A permutation test using Procrustes distance confirmed that the shape was not different between the photos of the separate sides , 0.08 (PC2), 0.005 (PC3), 0.003 (PC4)), suggesting the use of residuals would not introduce bias in the analysis[\u03bb\u2009=\u20090.95) and PSC (\u03bb\u2009=\u20091), indicating the necessity for phylogenetic correction. PPCA and PSC were performed using the phytools package[In order to control for the allometric effect of body size on brain weight, we used phylogenetic principal component analyses (PPCA). Prior tanalysis. We perf package in R ver package.\u03bb\u2009<\u20090.001). Following Horn\u2019s parallel analysis[\u03bb\u2009=\u20091 for the residuals of the model. Then, we performed mPGLS with \u03bb\u2009=\u20091, i.e. a Brownian motion model, to test the integration between head shape and brain size. We also tested the robustness of our test using overall brain size against structural heterogeneity of the brain by performing mPGLS on size of the six major brain regions  as a predictor variable and head shape (PC1-4) as a response matrix, using overall brain weight to control for the effect of size  and brain size  were correlated with head shape. The direction of the shape change associated with brain size is presented in Figure\u00a0The associations between head shape  and the three independent variables  are summarized in Table\u00a0Our study represents one of the first macro-evolutionary studies of phenotypic integration between brain size and head morphology in non-mammalian vertebrates and several insights can be gained from our results. First, we found support for phenotypic integration rather than modularity between the pre-orbital and post-orbital parts of the head. Second, head morphology was linked to prey utilization. Third, when controlling for the association between food utilization and head morphology, we found that brain size in Lake Tanganyika cichlids was closely associated with variation in head morphology. Together, these findings indicate that brain evolution and trophic adaptations may interact through phenotypic integration of brain size and head shape.et al.[et al.[Perissodini) in their dataset while we did not. Second, our choice of landmarks and semi-landmarks are slightly different from Parsons et al.[et al.[et al.[et al.[Our test for modularity did not support the existence of independent modules within the head. Our result therefore disagrees with a previous comparative analysis which suggested the existence of independent modules within the head of East African cichlids. We propet al.. First, l.[et al. includedns et al.. Howeverns et al.,31, diffns et al., while Pl.[et al. investigl.[et al.. It is tl.[et al.,23,60. Hl.[et al. did not l.[et al., it is pInstead, our results indicated phenotypic integration between the pre-orbital parts (which included the skull) and the post-orbital parts (which included the upper and lower jaws) of the head. Given the close association between forehead shape and skull shape this intper se, a round forehead with a downward-pointing mouth are thought to be adaptations for grazing algae from the substrate[Our results confirmed the widely reported evolutionary link between head morphology and feeding ecology in Lake Tanganyika cichlids-37. The ubstrate. Howeverubstrate,24-26.After controlling for the interaction between feeding mode and head morphology, our results confirmed a strong association between head morphology and brain size. We showed that species with a high head profile have larger brains while species with a more elongated head profile have smaller brains. Given that an elongated body shape is associated with a smaller head volume in cichlid fishes, our resOur multivariate phylogenetic comparative study found support for integration of the head morphology of Lake Tanganyika cichlids, and that evolutionary associations exist among head morphology, feeding mode, and brain size. Our study therefore indicates that head-brain phenotypic integration might have played an important role in forming the macro-evolutionary variation of brain size in cichlid fishes, a group which has been an important model system for the study of phenotypic diversification. Given the strong and general association of ecology and head shape in teleost fishes-36, our We declare that we have no competing interests.All authors have read and approved the final manuscript. MT participated in the design of the study, carried out the analyses, and drafted the manuscript. AG-V conducted brain dissections and data collection, assisted in the analyses, and critically revised the manuscript. NK conceived the study, obtained funds, participated in the design of the study and helped to draft the manuscript.Heterogeneity of the brain.Click here for file"}
+{"text": "Zhao and Devine  exhaustiShevchuk and co-workers  describeOstermeier and collaborators  review eCasagrande and co-workers  focus onAlthough a large body of evidence points out to a negative role of platelet activity during pathological conditions, a protective role is also well-established. Accordingly, due to their enriched cargo in bioactive compounds, including growth factors and anti-inflammatory molecules, platelet preparation lysates represent a successful strategy for treatment of inflammatory conditions and regenerative medicine. By investigating the in vitro anti-inflammatory activity of various platelet-rich fibrin preparations (PRFs), Kargarpour and colleagues  highlighEvodia rutaecarpa), as therapeutic agents against thromboembolic disorders is the focus of two Chinese studies [The potential of two phytochemicals, i.e., pterostilbene  and rutaecarpine (a bioactive component of the well-known Chinese medicine  studies ,9. Lin a studies  find tha2+ channel ORAI and its activating Ca2+ sensor STIM that are associated with platelet activation. These two proteins are upregulated by hyperphosphatemia occurring in chronic kidney disease and the authors reported the beneficial action of MgCl2 and the CaSR agonist GdCl3 in counteracting this detrimental phenomenon, thus suggesting that pharmacological modulation of CaSR by both Mg2+ and Gd3+ might restore calcium homeostasis in blood.Zhou\u2019s group  investigFinally, a rapid and reproducible test for routine laboratory identification of platelet activation is described by Watanabe\u2019s group , who set"}
+{"text": "Why does Frontiers in Multiple Sclerosis and Neuroimmunology publish Case Reports? There are several reasons. First, we can learn from case reports regarding novel disease entities and rare diseases. Second, case reports can give insight into better pathophysiological understanding of rare diseases. Third, case reports can be of interest regarding translational aspects and modeling in animal models. Fourth, case reports can be important regarding exploration of novel treatment regimen. Possibly, more reasons in favor of case reports can be found, the above indicated are most relevant for the Speciality Chief Editors of Frontiers in Multiple Sclerosis and Neuroimmunology. Of course, it is important that the presented cases bring additional value to the field. The ideal type of case report would contain data regarding the clinical manifestation, immunological, genetic, and pathological aspects of the disease and a novel treatment approach would be presented. Also, the findings should be discussed in the context of the relevant literature. Ideally, there should be two or more similar patients per case report. This is not trivial, especially if the case reports are coming from an individual center. Sometimes, case reports are the entrance into research for the involved physicians especially early in career, since the case has initiated a scientific argument. Therefore, the value of case reports also in gaining scientific thinking should not be underestimated. Frontiers of Multiple Sclerosis and Neuroimmunology is proud to present the \u201cMultiple Sclerosis and Neuroimmunology\u2014Case Report Collection I\u201d. This collection contains 27 case studies that were published between 2021 and 2022. We would like to thank the Associate and Review Editors who have evaluated the manuscripts and significantly contributed with their constructive criticism.The 27 case reports of \u201cMultiple Sclerosis and Neuroimmunology\u2014Case Report Collection I\u201d can be ordered as follows: (1) Reports regarding neurological manifestations of coronavirus disease 2019 (COVID-19). (2) Case reports regarding vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) and nervous-system related side effects. (3) Case reports with novel aspects of the emerging field of autoimmune encephalitis (AE). (4) Case reports of viral encephalitis. (5) Case reports regarding autoimmune peripheral nervous system disease. (6) Reports of cases of neuroimmunological side effects by pharmacological treatment. (7) Case reports regarding rare disease variants leading to demyelination within the central nervous system (CNS). (8) Case reports of rare disease variants successfully treated by immune therapy.Ishaq et al. present a case of a patient with opsoclonus myoclonus syndrome a rare neurological disease entity that was successfully treated with intravenous immunoglobulins (i.v. Ig). Gilio et al. present findings regarding the overlap of functional neurological disorders with long COVID. They indicate that stress and inflammation might drive disease precipitation of functional neurological disorders. Kimura et al. reports a patient with Bickerstaff brainstem encephalitis possibly triggered by COVID-19 and emerging Takotsubo cardiomyopathy (TC). They indicate that TC should be considered early when hemodynamic status remains unstable in patients with Bickerstaff brainstem encephalitis.There are several neurological manifestations that can be associated with COVID-19 and post- and long COVID. Maniscalco et al. present a patient with multiple sclerosis (MS) with a relapse shortly after vaccination with BNT162b2 from Pfizer-BioNTech. Nistri et al. present 16 cases regarding relapse manifestation of MS triggered by vaccination against SARS-COV-2 with 10 patients vaccinated with BNT162b2 from Pfizer-BioNTech, two patients vaccinated with mRNA-1273 from Moderna and four patients vaccinated with ChAdOx1 from AstraZeneca. In a case series by Ancau et al. three patients are reported with acute hemorrhagic encephalomyelitis (AHE) after SARS-COV-2 vaccination with ChAdOx1 from AstraZeneca. The authors indicated that these vaccination-related neurological diseases are rare events. They argue for the need of a robust post-vaccination surveillance.Song et al. report a patient with coexistence of anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis and biomarkers of Alzheimer\u2018s disease. There are AE that are antibody-negative. Possibly, the relevant antigen has not been defined for these disease entities so far. Park and Kim present a patient of antibody negative AE that was successfully treated with B cell depletion by rituximab arguing for an underlying immunological disease-driving pathophysiology. Beside autoimmunity as driver for AE, there is paraneoplasia as disease initiator of AE, mediated by the anti-neoplasia-directed immune response. Gogia et al. report a case with amphiphysin antibody-associated stiff limp syndrome and myelopathy in a patient with breast cancer. Fang, Pan, et al. report a patient with relapses of anti-AMPA encephalitis with progressive brain atrophy and speculate regarding the underlying mechanisms. They observe partial functional recovery even in presence of severe brain atrophy after treatment with immunotherapy. Vaux et al. present a patient that was diagnosed with schizophrenia and was subsequently identified as a patient with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Treatment with immune therapy led to improvement of symptoms in this patient. This case argues that patients with psychiatric diagnosis should be routinely explored for AE as a potential cause of their disease. This is important since immunotherapy can lead to improvement of symptoms and can in some patients even result in cure. Hashimoto\u2018s encephalopathy is a highly debated and questioned disease entity. Amano et al. present a patient with Hashimoto\u2018s encephalopathy associated with lymphomatosis cerebri and periodic synchronous discharges resembling prion, namely Creutzfeld-Jacob disease.Different types of autoimmune encephalitis (AE) are rare diseases with varying clinical presentations. Much can be learned regarding neurobiology from these diseases. Kolesnik et al. report a patient with herpes simplex virus 2 (HSV-2) encephalitis presenting with the clinical manifestation of chorea. This is a very rare clinical manifestation in HSV-2 encephalitis.Huang et al. report a patient with Guillain-Barr\u00e9 syndrome (GBS) and unilateral facial palsy. They summarize the current literature regarding such clinical presentations and report 28 cases. They speculate regarding the underlying immune response. Belgrado et al. had two patients with GBS and posterior reversible encephalopathy (PRES). They speculate that autoimmune dysregulation associated with GBS may be a trigger factor for co-emergence of PRES. A patient with reported combined central and peripheral demyelination (CCPD) was presented by Alshamrani et al. This patient had the coexistence of radiologically isolated syndrome (RIS) and Miller-Fisher-syndrome (MFS). Most so far reported cases of CCPD were diagnosed as having co-existence of MS and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Koska et al. (a) report a patient with MS with severe lymphopenia due to treatment with fingolimod. The discontinuation of fingolimod treatment led to clinical deterioration with presence of neuropsychological symptoms that was difficult to overcome. Progressive multifocal leukoencephalopathy (PML) should be also taken early into consideration regarding differential diagnosis in such patients. Tang et al. present a patient with recurrent encephalopathy after treatment with ornidazole. Ornidazole is an antibiotic used for the treatment of protozoan infections. The patient recovered after discontinuation of the treatment with ornidazole. Longitudinal extensive transverse myelitis (LEMS) evolved and novel autoantibodies emerged in a patient treated with pemprolizumab reported by Charabi et al. The humanized antibody pemprolizumab targets programmed cell death protein 1 (PD1) on lymphocytes. Pemprolizumab is used in the treatment of various types of cancers. The emergence of LEMS was B cell mediated. A putative novel autoantigen was hypothesized in this disease condition that has not been defined so far.Baert et al. APRIL provides a favorable environment for plasmocytes in the NMO lesion. In addition, APRIL induces an anti-inflammatory response in the NMO lesion. This indicates that targeting of APRIL by novel immunological therapies should only be executed with extreme caution since there is a dichotomy of APRIL-related functions in the NMO lesion. Differential diagnosis can be challenging in patients with atypical clinical presentations. Fang, Tong, et al. report a patient with primary CNS lymphoma that was initially misdiagnosed with glial fibrillary acidic protein (GFAP) astrocytopathy. Early diagnosis to differentiate these diseases is important, due to grossly different treatment approaches. Gao et al. report a patient with GFAP astrocytopathy associated with an area postrema syndrome. Ma et al. report a patient with bilateral meningo-cortical involvement of anti-myelin-oligodendrocyte-glycoprotein (MOG) IgG associated disease. \u0160toura\u010d et al. present the difficulties in the diagnosis and treatment of progressive tumefactive demyelination. The presented patient had an unfavorable outcome. Neurosarcoidosis can be difficult to diagnose. Braun et al. present a patient with myelopathy that was finally diagnosed with neurosarcoidosis.The expression of a proliferation inducing ligand (APRIL), belonging to the TNF superfamily, in the CNS was investigated in a patient with neuromyelitis optica (NMO) reported by Koska et al. (b) report a patient with Marburg variant of MS who was successfully treated with cyclophosphamide and ocrelizumab. Eculizumab was successfully used to treat a patient with seronegative NMO by Digala et al. This argues for a role of complement in seronegative NMO.The case series \u201cMultiple Sclerosis and Neuroimmunology\u2014Case Report Collection I\u201d demonstrates the power of case studies as well as their limitations. Possibly, the cases will help to gain progress regarding clinical, pathophysiological, immunological, and treatment-related understanding in clinical and research environments dealing with related patient groups and evolving scientific topics in neuroimmunology. Interested physicians, physician-scientist and researchers will possibly have a benefit that will help to transform scientific thinking in medicine to a patient-focused research approach regarding disease biology and rationally well-founded medical and rehabilitative treatments.RW outlined and wrote the editorial.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Neurodegenerative diseases are a heterogeneous group of disorders characterized by gradual progressive neuronal loss in the central nervous system . These iThis Special Issue of Medicina, entitled \u201cBiomarkers in Alzheimer Disease and Other Dementias: What\u2019s Next into Pathophysiology to Support Clinical Practice and Drug Development\u201d, includes seven articles dealing with the role of CSF plasma/serum biomarkers in the understanding the biochemical mechanisms and  diagnosis of dementing disorders, and their drug development.The CSF AD profile  is highly predictive of the progression of cognitively unimpaired subjects to mild cognitive impairment (MCI) and dementia. In their interesting study, Scarmeas et al. [Using ultrasensitive single-molecule array assays (Simoa), it is possible to measure low concentrations of NfL, not only in the CSF but also in blood samples, with very high sensitivity. In this prospective study of patients with AD conducted by Kern et al. , higher In the future, biomarkers should be available not only for early diagnosis, but also for indicating responses to specific therapeutic interventions that help to guide treatment decisionsfor AD. Alharbi et al.  demonstrPrion diseases are rare, irreversible neurodegenerative disorders with rapidly progressive dementia, cerebellar ataxia and myoclonus. Altuna et al.  reviewed\u03b1-syn species measured for further validation of these biomarkers in clinical practice.Continuous efforts will be also necessary to establish useful CSF biomarkers for the early diagnosis of dementia with Lewy bodies (DLB). In their review, Foska et al.  highlighCompared to protein-based biomarkers, miRNAs are more stable inbodily fluids; moreover, their easy measurement usingvarious commonly used laboratory methods make them potential biomarkers for atypical dementing disorders such asmultiple system atrophy (MSA) and progressive supranuclear palsy (PSP). In our systematic review , three sPotagas et al.  suggesteOverall, the papers published in this Special Issue contribute to a deeper understanding of biochemical markers in dementing disorders, including neurodegenerative proteinopathies with novel biomarkers. Thereby, this Special Issue might initiate hypothesis-driven refinement of current and novel biomarkers in AD and other dementias."}
+{"text": "It is unclear whether seven interventions recommended by Public Health England for preventing and managing common musculoskeletal conditions reduce or widen health inequalities in adults with musculoskeletal conditions.We used citation searches of Web of Science (date of \u2018parent publication\u2019 for each intervention to April 2021) to identify original research articles reporting subgroup or moderator analyses of intervention effects by social stratifiers defined using the PROGRESS-Plus frameworks. Randomized controlled trials, controlled before-after studies, interrupted time series, systematic reviews presenting subgroup/stratified analyses or meta-regressions, individual participant data meta-analyses and modelling studies were eligible. Two reviewers independently assessed the credibility of effect moderation claims using Instrument to assess the Credibility of Effect Moderation Analyses. A narrative approach to synthesis was used (PROSPERO registration number: CRD42019140018).Of 1480 potentially relevant studies, seven eligible analyses of single trials and five meta-analyses were included. Among these, we found eight claims of potential differential effectiveness according to social characteristics, but none that were judged to have high credibility.In the absence of highly credible evidence of differential effectiveness in different social groups, and given ongoing national implementation, equity concerns may be best served by investing in monitoring and action aimed at ensuring fair access to these interventions. Studies had to be of adults aged 18\u00a0years and over with a relevant musculoskeletal condition  and not restricted only to patients with inflammatory disease or trauma/injury. Protocol papers, editorials, correspondence, conference abstracts and non-English language articles were excluded.Screening of titles and abstracts and review of full-text articles for inclusion were conducted by two independent reviewers with disagreement resolved by consensus, using RayyanData extraction was conducted by one reviewer using a form that we designed before data extraction began. Data extraction was checked by a second reviewer resolving discrepancies through discussion. In addition to standard descriptive fields, we extracted information on (i) baseline distribution of PROGRESS-Plus characteristics; (ii) methods, results  and author conclusions on moderator analyses by each PROGRESS-Plus variable; (iii) selective participation or attrition by PROGRESS-Plus characteristics.We assessed the credibility of potentially relevant treatment effect moderation reported in analyses of a single RCT or in meta-analysis of multiple RCTs using the Instrument to assess the Credibility of Effect Moderation Analyses (ICEMAN).Given heterogeneity in populations, interventions and outcomes, we anticipated a narrative synthesis approach rather than formal meta-analysis. Where available, we sought to summarize both relative and absolute differences in effectiveness of interventions by social stratifier.The citation search yielded 1480 potentially relevant articles after removal of duplicates, of which 12 were included .,,,Six of the 12 included studies were moderator (subgroup) analyses of data from single RCTs, typically the original trial, of the BeST,Within the economic analysis of the BeST trial data,et al.In addition to pre-specified moderator analyses of the BeST trial, Underwood et al.Using latent class analysis of baseline psychological and symptom severity variables in the BeST trial, Barons et al.In a complier average causal effects analysis of the BeST trial data, Knox et al.et al.Bernard et al.Martinez-Calderon et al.P\u00a0=\u00a00.028) with the beneficial effect of the STarT Back intervention greatest among higher SES participants and least in lower SES participants. This is suspected to be due to a lack of effect of promoting self-management without further face-to-face physiotherapist support in lower SES patients with low health literacy . The interaction term for educational level was in the same direction, suggesting greater benefit among more educated participants, but was statistically non-significant (P\u00a0=\u00a00.109). Interaction terms for age, sex and employment status were non-significant (P\u00a0>\u00a00.20).In a secondary analysis of STarT Back trial data, Beneciuk et al.et al.,et al.\u2019s review included Yoga for Healthy Lower Backs trial findings alongside other forms of mindful exercise for chronic low back pain on the outcomes of pain intensity and disability. Martinez-Calderon et al.\u2019s included various exercise intervention trials for low back pain with a focus on self-efficacy outcomes up to 12\u00a0months after intervention.Meta-regression analyses by Zou et al.,In pre-specified moderator analyses Salisbury et al.Meta-regression analyses by Niknejad et al.In contrast, Kroon et al.,et al.,et al.,et al.,We applied ICEMANTheoretically informed, pre-specified subgroup analyses of RCT data, adequately powered and appropriately conducted and reported, provide the best available evidence of differential effectiveness of interventions. We found no claims of differential effectiveness of interventions recommended in the PHE ROI tool that met this high bar of evidence. Some evidence that low back pain (LBP) patients of lower occupational class might benefit less from the STarT Back stratified care intervention was judged as moderately credible. However, this was not a pre-specified subgroup analysis in the original trial and, unlike secondary analyses of the BeST intervention,,et al.,,,,The absence of highly credible, \u2018confirmatory\u2019 evidence of differential effectiveness of interventions is not unexpected: a similar conclusion was reached in previous reviews in the general medical literature,,,,,The most comprehensive body of research to date has been on therapist-delivered interventions for low back pain, spanning subgroup analysis of the BeST trial,Our review extends previous research to specifically consider equity issues and provide a critical synthesis of currently available evidence on differential effectiveness for the range of interventions recommended in the ROI tool. Despite the high burden of musculoskeletal conditions there has been surprisingly little focus on equity when investigating the effects of interventions. Given the well-recognized challenges in obtaining rigorous evidence on equity effects from quantitative analysis of single and multiple trials, our review underscores the importance of embedding equity considerations across the research cycle including intervention development and process evaluation. While none of the interventions in our review was designed deliberately to be \u2018equity focussed\u2019, they have demonstrated overall effectiveness in populations with varying degrees of social diversity and many are now already at fairly advanced stages of implementation. At the time of this review almost 1300 health professionals had been trained to deliver ESCAPE-pain. Prior to COVID-19, it was offered at 295 NHS facilities and leisure/community centres across UK, including some in more deprived neighbourhoods. In total, 19\u00a0300 people have taken the programme and an online version has been released .We used a citation search strategy that will tend to miss relevant studies of other similar interventions. We restricted our attention to studies with an appropriate comparison of effect between social groups. There may be other studies, including those excluded at title/abstract stage, which include useful information or discussion on equity-related matters in relation to these or similar interventions, but we think it unlikely that we missed additional rigorous evidence of effect moderation. For example, one systematic reviewWe found no highly credible evidence against the assumption that seven interventions recommended for the prevention and management of musculoskeletal health are equally effective in different social groups. A policy of restricting or targeting these interventions to subpopulations is not supported. Most of these interventions are already being actively implemented, many achieving substantial reach nationally. Equity concerns may be best served by investing in equity-focussed action aimed at ensuring fair access to, and participation in, these interventions. Routine collection of key social variables during implementation should underpin this.Effects_on_health_inequalities_PHE_systematic_review_SUPPLEMENT_fdac014Click here for additional data file."}
+{"text": "Direct care workers play a key role in supporting the health and wellbeing of older adults and people with disabilities across care settings\u2014yet their own health risks are largely overlooked. The four papers in this symposium address this critical knowledge gap. First, McCall and colleagues will present a comparative analysis of the health status, health insurance coverage, and healthcare experiences of direct care workers across long-term care using National Health Interview Survey data. Next, Lee et al. will present the trends and characteristics of occupational injuries and illnesses among California\u2019s long-term care workers from 2019 to 2020 using California Workers\u2019 Compensation data, assessing the impact of COVID-19 on their occupational health. Sterling will characterize the physical and mental health of the direct care workforce before and during COVID-19 using data from the CDC's Behavioral Risk Factor Surveillance Survey, as well as drawing on qualitative and survey-based studies of unionized, agency-employed home care workers in New York. Sterling will also present findings from a pilot feasibility study of an intervention aimed at improving home care workers\u2019 well-being. Finally, Quinn et al. will synthesize findings on home care workers\u2019 occupational hazards\u2014including needlesticks, musculoskeletal strain, violence and infections\u2014and examine how preventing these risks can improve safety for both workers and clients. The discussant will draw out themes and implications from across these complementary studies, highlighting the importance of safeguarding direct care workers\u2019 health as a key step toward improving care quality and outcomes for older adults and people with disabilities."}
+{"text": "The prevalence of aging-related neuronal diseases is increasing. However, there is still a huge unmet need for diagnosis, treatments, and drug discovery of these diseases. With the development of modern high-throughput omic measurement platforms, vast amounts of biological data have been generated which can be integrated in multi-omics studies to examine the complex molecular underpinnings of diseases, thus impacting the development of aging-related neuronal diseases' therapy.In this editorial, we presented an account of how integrative multi-omics studies have greatly facilitated the diagnosis, treatments, and drug discovery of aging-related neuronal diseases. This editorial is based on 13 research articles and 3 regular reviews which shed light on the power of integrative multi-omics studies to improve aging-related neuronal diseases' therapy including but not limited to Alzheimer's disease (AD), ischemic stroke (IS), and Parkinson's disease (PD).Han et al.'s cross-sectional study, chi square test, correlation analysis, and regression analysis were employed to analyze the influencing factors of cognitive impairment. Consequently, gender, age, education level, hypertension, and LDL-C were found to have significant differences in the incidence of cognitive impairment, providing a basis for the early screening and intervention in the elderly . Two research articles create prediction models based on variables of interest. Kang et al. developed an accurate, efficient nomogram with a model created by Cox regression method and further built a corresponding website to help clinicians improve their assessment of patient outcomes. In Li J. et al.'s study, they applied machine learning classification model light gradient boosting machine (LightGBM) to analyze presurgical variables of endovascular treatment (EVT) for acute ischemic stroke (AIS) induced by large-vessel occlusion (LVO) and construct a unique prediction model which was used to establish feasible and accurate presurgical prediction scale in identifying unfavorable outcomes of AIS after EVT.Several research articles analyze variables for prediction. In Zhang C. et al. first employed the limma R package to the got the significant differentially expressed genes (DGEs) in Depression. These DEGS were then put into weighted gene co-expression network analysis (WGCNA) and protein\u2013protein interaction (PPI) analysis and at last the common gene general transcription factor IIF polypeptide 2 (GTF2F2) which may serve as a promising diagnostic biomarker and treatment target of depression was thus identified . Most of the bioinformatic approaches in this study were implemented in the article of Gu et al., where Stepwise regression and logistic regression analyses were employed to get hub genes and diagnostic model related to Iron Metabolism in AD. They also retrieved eight drugs targeting hub genes from the DrugBank database . A similar study in IS was completed by Wang X. et al. where Boruta algorithm was used for genes' further screening. Importantly, they validated the gene signature with many methods, such as enrichment analyses through GO, KEGG, and GSEA pathways, ROC curves, and immune cell infiltration. Moreover, Li D. et al. demonstrated that gene methylation can also be utilized as signatures. In their research, least absolute shrinkage and selection operator cox regression analysis were carried out to construct a diagnostic signature related to PD . In Zhang W. et al.'s study, the molecular mechanism of Xingnao Kaiqiao Pill in the treatment of perioperative neurocognitive disorder (PND) was investigated from the perspective of network pharmacology and molecular docking technology. They constructed the network of \u201cXingnao Kaiqiao Pill\u2013traditional Chinese medicine\u2013compound\u2013common target\u201d by Cytoscape software. Molecular docking stimulation was used to further verify the interaction between the active components and key targets . Huang et al. and Chen Y. et al. both performed multi-omics integration analysis based on single cell technology. In their study, scRNA analysis, differential expression analysis, cell-cell communication analyses, and cell trajectory inference analyses were performed to identify candidate ligands or receptors, as well as the corresponding cell types. Combined with molecular docking, Huang et al. found that Quercetin targets VCAM1 to prevent diabetic cerebrovascular endothelial cell injury , while Chen Y. et al. further identified differentially expressed transcription factors in AD associated with exercise using a modified SCENIC method. Chen Y. et al. finally constructed a network of exercise-regulating TFs in monocytes, revealing the mechanism by which exercise regulated monocytes to confer therapeutic benefits against AD and its complications. Furthermore, through target gene's knockdown and bioassays, Xia et al. found that GDF15 effectively alleviated neuronal ferroptosis post Spinal cord injury (SCI) via the p62-Keap1-Nrf2 signaling pathway and promoted locomotor recovery of SCI mice, which is suggested as a potential target on SCI pathogenesis and treatment.Eight research articles capture gene signature (models) by integrating multi-omics information through different bioinformatics analysis and machine learning approaches. Zhu et al. exploited a novel iterative method called linear neighborhood similarity-based protein multifeatures fusion (LNSPF) to predict potential key proteins. The gene expression data downloaded from the benchmark database are used for further optimization through linear neighborhood similarity . To find biologically important imaging genetic relations more powerfully, Wang et al. imposed the GraphNet regularization penalty on the existing model and presented an improved fusion paired group lasso structured sparse canonical correlation analysis algorithm (FGLGNSCCA). Experiment results shown that the new FGLGNSCCA model proposed in their manuscript is superior or equivalent to traditional methods. With FGLGNSCCA algorithm, more AD-related biomarkers can been found .Notably, two research articles focus on the development of computational approaches which can integrate multi-omics information. Based on topological features extracted from a protein-protein interaction (PPI) network and functional features extracted by integrating subcellular localization and homologous information of proteins, Chen W. et al.'s review focuses on optogenetics in neurobiology, including how to use optogenetics to control nerve cells, study neural circuits, and treat diseases by changing the state of neurons. Wang Y. et al. revealed potential protective role of polysaccharides of Neurodegenerative Diseases (NDs), highlighting the contributions of polysaccharides and the prospects of their mechanism studies for the treatment of NDs. Ji et al. concentrated on body fluids biomarkers of early neurological deterioration (END) that have shown potential to be transferred into clinical practice.Finally, three reviews give a comprehensive understanding of the progress in the field of aging-related neuronal diseases from different aspects. In conclusion, the research articles and reviews in this Research Topic show how integrative multi-omics are applied to better understand and treat aging-related neuronal disease. For fully utilizing data from various omics sources to gain insights into disease, multi-omics approaches are becoming more relevant every day.This editorial was designed by MT and XG and written by CS and XL. YL, HZ, and YG had revised it. All authors have made a direct and intellectual contribution to this topic and approved the article for publication.This work was supported by grants from Jiangsu University (19JDG039) and the National Natural Science Foundation of China (32002235).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "APOE \u03b54 allele is the greatest genetic determinant for AD and is widely reported to mediate detrimental effects on mitochondria function and mitophagic process. Given the continuity of the physiological process, this review takes the mitochondrial dynamic and mitophagic core events into consideration, which highlights the current knowledge about the molecular alterations from an APOE-genotype perspective, synthesizes ApoE4-associated regulations, and the cross-talk between these signaling, along with the focuses on general autophagic process and several pivotal processes of mitophagy, including mitochondrial dynamic , mitophagic induction . These may shed new light on the link between ApoE4 and AD and provide novel insights for promising mitophagy-targeted therapeutic strategies for AD.Alzheimer's disease (AD) is one of the major worldwide causes of dementia that is characterized by irreversible decline in learning, memory loss, and behavioral impairments. Mitophagy is selective autophagy through the clearance of aberrant mitochondria, specifically for degradation to maintain energy generation and neuronal and synaptic function in the brain. Accumulating evidence shows that defective mitophagy is believed to be as one of the early and prominent features in AD pathogenesis and has drawn attention in the recent few years.  Alzheimer's disease (AD) is the most common and well-known form of dementia and features age-related and progressive recognition impairment, memory loss, and learning failure, accompanied by encephalatrophy, and extracellular amyloid-\u03b2 (A\u03b2) plaques, intracellular tangles of hyperphosphorylated Tau  allele remains the strongest genetic risk for sporadic AD , inner mitochondrial membrane (IMM), intermembrane space, and mitochondrial matrix performs diverse essential roles in multiple intracellular homeostasis events, including tricarboxylic acid cycle, \u03b2-oxidation of fatty acids, genetic information storage, CaHere, we have reviewed emerging findings for the central and multi-faceted roles that mitophagy plays in the pathogenesis of AD, described physiological changes from the pre-mitophagy events to mitophagy proceeding considering the continuity of the physiological processes, integrated the signaling pathways suggesting the relationships between ApoE4 and mitophagy deficit, and discussed the underlying mechanisms that how ApoE4 triggers these abnormalities and ultimately contributes to AD pathogenesis, while highlighting potential therapeutic targets that may correct these dysfunctions .Autophagy is a ubiquitous event highly conserved from yeast to mammals and functions as a recycling system for maintaining metabolic homeostasis and cellular self-renewal , and mitophagy-specific induction.Mitochondria is a highly dynamic organelle that can form long tubular networks for highly interconnected networks, and continually undergoes the cycle of fusion and fission in response to environmental changes  and higher phosphorylation level of dynamin-related protein1 (DRP1), leading to reductive mitochondria fragmentation and neuronal energy dysfunction  possess pro-fission activation and fusion inhibition  are the most broadly investigated fission regulators network in recent years Chan, . Mitochoin vivo and in vitro, ApoE4 interferes with SIRT1 transcription, expression, and enzyme activity more than ApoE3  in the frontal cortex tissue from AD patients  are growing and the polyubiquitinated level of MFN-2 is reduced, while the fission proteins (FIS1 and GLP1) are not distinctively altered in HEK293 cells overexpressing human Tau, and rat primary hippocampal neurons  machinery, then is cleaved by PARL in a mitochondrial membrane potential (MMP)-dependent manner followed by degradation  and mitophagic genes (BNIP3 and PINK1)  in APOE \u03b54 carriers. Collectively, ApoE4 mediated full-scale inhibition of mitophagy via FOXO3a signaling, including its expression, activity-dependent on chemical modification, and the induction of its downstream effects.FOXO3a served as a transcription factor highly represented in the brain and a new target of AD diagnosis  is a deacetylase, highly expressed in high-metabolic tissues, and strongly associated with mitochondrial quality (Meng et al., via direct interaction with TOMM40 (Bertolin et al., 2a cells by proteomic profiling (Mise et al., APOE (Simonovitch et al., TOMM40 expression is closely associated with APOE expression (Mise et al., APOE-TOMM40-APOC1 variants are strongly associated with a high instance of AD (Gottschalk et al., APOE \u03b54 has closely linked to various TOMM40 polymorphisms carried adverse impacts (Roses et al., APOE \u03b54, and its degradation is blocked under an ApoE4-induced context, which may be helpful to explore the underlying mechanisms of AD.TOMM40, a channel-forming subunit at OMM constituting the TOMM40 complex for protein import into mitochondria (Humphries et al., 2a cells performed by proteomic profiling assays (Orr et al., via double-labeling analysis, and reconfirmed the interaction without isoform-dependent difference via co-IP in H9c2 cells, a type of embryonic rat heart-derived cells (Chen et al., APOE-TR mice or AD model mice, even the APOE \u03b54 carriers and AD subjects, in order to explore whether the interaction exists in the neuronal system, whether there is a differential interaction between ApoE3 and ApoE4, and whether it is associated with AD pathogenesis. Incidentally, the VDAC1-A\u03b2 and VDAC1-Tau interaction is confirmed by double-labeling analysis and co-IP in the brains of AD subjects and several AD model mice (Manczak and Reddy, VDAC1, a porin protein abundantly located at OMM that mediates ATP production and the trafficking of nucleotide and metabolites, functions as a target for Parkin-directed poly-ubiquitin chains, and regulates Parkin recruitment (Sun et al., A\u03b2 aggregation causes reductive cytosolic Parkin and PINK1 levels in the cytoplasm (Kerr et al., via multi-faced downstream regulators (Sohn et al., Collectively, ApoE4 and PINK1-Parkin comprise a potential mitochondrial signaling cascade response pathway, and these observations indicate ApoE4-mediated inhibition on PINK1-Parkin mitophagy Deficient mitochondrial quality control is established to interfere with cellular bioenergetic metabolisms and neuronal survival, leading to the occurrence and development of neurodegenerative disorders (Chinnery, 2+ (Cereghetti et al., APOE genotype. Third, the neuro-degeneration processes may share a common mechanism with AD and other neurodegenerative diseases. ApoE has been extensively studied in multiple fields and displays new findings, such as the interaction of ApoE4-TFEB promoter (Parcon et al., SIRT1 promoter (Theendakara et al., APOE-genotype perspective, hence, completing a related investigation may be helpful to better understand the complicated alterations in AD (Sun et al., in vivo and in vitro studies and further develop specific therapies.Despite current studies about mitophagic control, some important issues are required to be addressed. First, ApoE4 participates in diverse mitophagic signaling pathways at various processes in direct or indirect manners (Horner et al., In general, mitophagy is a multifunctional event preventing AD pathogenesis along with multiple challenges to its beneficial effects. Current findings of the ApoE4 role of mitophagy in AD seem to be limited to some extent, and remain controversial still need further investigation in detail. Discovering the gaps in the underlying mechanisms are greatly enlightened to screen for possible and predominant mechanisms and open a new avenue of research to facilitate earlier diagnosis or potential neuroprotective therapies for AD.GC had the idea for the article and made the final approval of version to be submitted. HC wrote and critically revised the manuscript the work. YiJ and FC supervised the overall writing and edited the manuscript. GH and LZ performed the literature search, sorting, and integration. FS and MZ provided guidance, helpful discussion, and careful revision. YC and YaJ helped the schematic diagrams. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The Women in Avian Physiology Research Topic is part of an inclusive Frontiers series across all sections focused on Women in Physiology. The purpose of the series is to showcase physiological research of women and to highlight their achievements. Submissions were welcomed covering all areas of Avian Physiology. Submissions were encouraged from early career researchers and/or where the lead/last author were females. A total of 12 submissions were accepted for publication in this Research Topic covering the areas of: 1. Skeletal Muscle Physiology and Meat Quality; 2. Female Reproduction; 3. Pathobiology; 4. Genetic Selection; and 5. Neurobiology.Swanson et al., Bordini et al., and Xu et al.Swanson et al. reviewed phenotypic plasticity to environmental variation focusing on metabolic rates and skeletal muscle physiology in wild birds. The ultrastructural plasticity of skeletal muscle with regard to thermal variation and increased workload was reviewed and correlated with myostatin, Insulin-like growth factor-1, and satellite cell proliferation. Xu et al. examined the effects of temperature and selection for growth on the proliferation, differentiation, adipogenic potential of turkey myogenic satellite cells through frizzled-7-mediated Wnt planar cell polarity (Wnt/PCP) pathway. It was found that thermal stress altered frizzled-7 regulation of the Wnt/PCP pathway in a growth-dependent manner affecting the growth potential of the breast muscle and protein to fat ratio. Bordini et al. contributed an original Research Topic studying molecular pathways and key genes associated with White Striping and Wooden Breast in chickens. Using Weighted Gene Co-expression Network Analysis to identify clusters of co-expressed genes associated with White Striping and Wooden Breast, they found that endoplasmic reticulum stress may underly the inflammatory condition in affected breast muscles and Collagen type IV may have significant role in the events leading to White Striping and Wooden Breast.Three contributions addressed skeletal muscle physiology and/or meat quality by Hanlon et al. provided a comprehensive review on the roles of 17\u03b2-estradiol in non-gonadal tissues and its impact on reproduction in both laying and broiler breeder hens. Estradiol-17\u03b2 are involved in reproduction, liver metabolism, and medullary bone formation. Thus, this hormone may regulate all aspects of egg formation and hence the timing of estradiol-17\u03b2 is critical to reproduction which has been altered by genetic selection for intense growth. Mehlhorn et al. investigated how hen line, age and housing affect estradiol-17\u03b2 on egg laying performance. High performance hen lines had higher estradiol-17\u00df concentrations compared to low performing hens. Regardless of line, maximal estradiol-17\u00df concentration was measured at their 49th to their 51st week of age. Furthermore, cages hens had highest estradiol-17\u03b2 levels compared to floor housed hens. We could show that laying performance is strongly linked with estradiol -17\u00df concentration. This concentration changes during laying period and is also influenced by the housing system.Salmonella vaccine  was shown to decrease Salmonella enterica serovar enteritidis load in immunized broiler chickens by Acevedo-Villanueva et al.Shanmugasundaram et al. contributed an original Research Topic demonstrating that subclinical doses of combined fumonisins and deoxynivalenol (mycotoxins contaminating poultry diets) predispose Clostridum perfringens inoculated broilers to necrotic enteritis, an economically important disease negatively impacting digestion and absorption of nutrients in broilers.Use of an oral-killed chitosan nanoparticle Bernardi et al. reported on chemerin as a possible genetic selection tool for embryo survivability pending larger scale testing. Research on how the somatotrophic axis has changed with commercial growth selection and its relationship to increased growth was reported by Vaccaro et al. They found the expression of insulin-like growth factors 1 and 2 was greater in the modern commercial chicken and maybe linked with increased breast muscle growth and overall muscle accretion. In broilers divergently selected for ultimate pH, it was found by Beauclercq et al. that there is an association between serum lipid profile, ultimate pH and meat quality. Furthermore, since ultimate pH can be obtained on live birds, it may be a useful marker in genetic selection.Two contributions addressed the effects of genetic selection. Loveland et al. contributed a perspective paper on how inversion variants can affect neural circuitry. This review covered how behavior polymorphisms can evolve from genetic inversions, especially when inversions are associated with sets of genes involved with hormonal regulation. Primary focus was on the three-morph system of the ruff , two alternative morphs (Satellites and Faeders) each with distinct behaviors and low circulating testosterone that is genetically determined by an inverted region on an autosomal chromosome. Franco et al. examined the bird sense of sight and found that broilers raised under blue light were more hyperopic than those raised with white light. The blue light reared broilers had better spatial vision and higher success in selecting the right feeder."}
+{"text": "Advances made in the Internet of Things (IoT) and other disruptive technological trends, including big data analytics and edge computing methods, have contributed enabling solutions to the numerous challenges affecting modern communities. With Gartner reporting 14.2 billion IoT devices in 2019 , smart aHowever, there remain practical challenges in large-scale and rapid deployment of sensors for diverse applications, such as problems affecting siting optimization methods and participant recruitment and incentive mechanisms. On a higher level, the deluge of data sources that drive the IoT phenomenon grows every day. With the rise of smartphone-enabled citizen sensing data via social networks or personal health devices, as well as with increasing connectedness in transport, logistics, utilities, or manufacturing domains, this range and complexity of available data calls for even more advanced data processing, mining and fusion methods than those already applied.The goal of this Special Issue was to solicit high-quality original papers aimed at demonstrating effective and efficient deployment of sensor networks in the IoT, encompassing both physical and virtual sensor networks (through modelling) as well as social networks. Related issues of data processing, in addition to challenges of the fusion and visualisation of the resultant IoT big data, are also reflected in the published papers. This Special Issue consists of 11 papers. All submissions were strictly and thoroughly peer-reviewed by experts. These submissions cover many of the relevant research issues. In the following sections, we summarize these articles and highlight their major contributions.In the article entitled \u201cegoDetect: Visual Detection and Exploration of Anomaly in Social Communication Network\u201d, Pu et al . presentThe article entitled \u201cRecognizing Context-Aware Human Sociability Patterns Using Pervasive Monitoring for Supporting Mental Health Professionals\u201d, contributed by Moura et al. , presentZurbuchen et al. , in theiThe article entitled \u201cIoTCrawler: Challenges and Solutions for Searching the Internet of Things\u201d by Iggena et al.  addresseThe paper entitled \u201cEnergy Management Expert Assistant, a New Concept\u201d by Linan-Reyes et al.  presentsThe topical theme of user device location privacy is explored in the paper \u201cPerturbed-Location Mechanism for Increased User-Location Privacy in Proximity Detection and Digital Contact-Tracing Applications\u201d by Lohan et al. , which pThe predictive maintenance of sensors is addressed in the article entitled \u201cProviding Fault Detection from Sensor Data in Complex Machines That Build the Smart City\u201d by Gasc\u00f3n et al.  through The application of IoT-enabled services to smart tourism scenarios is explored in the article \u201cAn Architecture for Service Integration to Fully Support Novel Personalized Smart Tourism Offerings\u201d by Sabbioni et al. . The artThe use of short texts from social networks as a data source in the IoT is the focus of the article entitled \u201cInvestigating the Efficient Use of Word Embedding with Neural-Topic Models for Interpretable Topics from Short Texts\u201d, submitted by Murakami and Chakraborty . The aut\u201cA Novel Privacy Preserving Scheme for Smart Grid-Based Home Area Networks\u201d, submitted by Ali et al. , presentA review article, entitled \u201cApplications of Wireless Sensor Networks and Internet of Things Frameworks in the Industry Revolution 4.0: A Systematic Literature Review\u201d by Majid et al. , complet"}
+{"text": "Determination of antisuicidal factors (AF) in balance with risk factors for suicidal behavior (SB) is essential for treatment and prophylactic measures.Study AF in a sample of schizophrenic recovered patients  according to operational criteria R.P. Liberman et al. (2002).The content analysis of published self-reports of a sample (n = 13) of Russian and foreign psychiatrists and clinical psychologists with psychotic experience was used as a part of a more extensive qualitative analysis of \u00abwounded healers\u00bb.In the history of > \u00bd  ex-patients, repeated SPs (aborted suicides), as well as non-suicidal self-harm , were noted during the active period of the disease, and in four of them \u2013 during untreated psychosis. Following AFs can be distinguished in recovery state: clinical  social , and existential .AF is an important integral component of recovery in schizophrenia as a process of personality development despite a burden of severe mental disorders.No significant relationships."}
+{"text": "Enterobacter faecalis MSI12 and its effect on the disruption of Candida albicans biofilm\u2019 by G. Seghal Kiran et al., RSC Adv., 2015, 5, 71573\u201371585, DOI: 10.1039/C5RA10302A.Correction for \u2018Characterization of an exopolysaccharide from probiont  The authors regret that incorrect versions of Accordingly, the experimental methods followed in the phase contrast microscopy and large-size images of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The second volume of the Special Issue on \u201cMicro-Electro Discharge Machining: Principles, Recent Advancements and Applications\u201d confirms the growing interest in the micro-EDM technology as a suitable and efficient technology for machining novel, multi-material components, with demanding requirements in terms of precision, accuracy and productivity.This volume consists of 10 original research papers which involve several approaches to micro-EDM and cover the enhancement of the process performance, such as the material removal rate, surface roughness, or accuracy of the machining, using advanced optimization methods. Some studies also consider several dielectric fluid additives and investigate the processability of new materials. Others investigate the combination of Reverse-micro-EDM with laser beam micromachining or explore new applications for the micro-EDM for fabricating antimicrobial nanosilver colloid.In more detail, in order to improve the machining accuracy of detail features in micro-EDM milling, a theoretical model is developed by Jing et al.  to simulThe influence of the near-dry WEDM technique to reduce the environmental impact of wet WEDM was investigated by Chaudhari et al. . The stuA mathematical\u2013statistical computational (MSC) model for predicting high productivity and quality of the machined area is formulated by Straka et al.  by the aWire-cut electro-discharge machining (Wire-EDM) of polymer composite material (PCM) was studied by Ablyaz et al. . Tests wSidhu et al.  used theAblyaz et al.  investig2O3). The study evaluated effects on material removal rate (MRR), relative electrode wear rate (REWR), and surface roughness on machining (EDM) of ultrafine particle type tungsten carbide and observing single discharge crater and hole machining tests. The results showed that adding CnF enhanced the material removal rate under all conditions. In contrast, Si and Al2O3 powders only improved the machining performance at a high discharge energy of 110 V. Improvement in surface roughness was observed prominently at high voltages for all the powders. However, alumina improved the surface roughness the most among the three powders.Gattu et al.  mixed thEsser et al.  observedReverse-\u00b5EDM was considered by Kishore et al.  with theFinally, an alternative study has been performed by Tseng et al.  with theWe thank all the authors who submitted their papers to this Special Issue, \u201cMicro-Electro Discharge Machining: Principles, Recent Advancements and Applications\u201d. We would also like to acknowledge all the reviewers for dedicating their time to providing careful and timely reviews to ensure the quality of this Special Issue."}
+{"text": "Research focusing on innovative nanomaterials for applications in biomedicine and bioengineering has steadily gained attention over the last 20 years. This is due to the unique physical and chemical characteristics that can be provided by nanomaterials compared to their bulk counterparts, including augmented surface reactivity; improved mechanical, electrical, magnetic, optical and thermal properties; and their enhanced bioactivity, drug loading capacity or permeability through biological barriers. Advanced nano-biomaterials with tailored surface topography and chemistry can be designed to create environmental conditions favorable for proper protein and consequently for accelerated cell adhesion, proliferation and differentiation ,2. In thNanostructured modifications of metal scaffolds represent a promising approach to accelerate implant osseointegration through the increasing in endothelial commitment of mesenchymal stem cells (MSC). Gardin et al. explored the possibility that exosomes secreted by hMSCs grown on the different nanotubular Ti surfaces  could act as biomimetic tools to modulate the biological properties of human umbilical vein endothelial cells (HUVECs) in vitro . The resNanoscale surface modifications may also have an impact on peri-implant cell fate and implant loading, both of which have an impact on early bone healing. This issue was addressed by De Barros E Lima Bueno et al., who studied how mechanical loading affects healing around implants with nanotopography . At 7 daIn addition to nanotopography, the composition of the composition certainly plays a key role in determining the final performance of biomedical devices. Poly:polystyrene sulfonate (PEDOT:PSS) is a widely used conductive polymers for a plethora of applications, including electroactive scaffolds for bone tissue regeneration. As a viable alternative, PEDOT:Nafion is emerging due to its better electrochemical properties than PEDOT:PSS. However, its biocompatibility has not yet been studied. Guzzo et al. investigated the in vitro cytotoxicity of nanostructured PEDOT:Nafion coatings obtained from a water-based formulation of PEDOT:Nafion, using a primary cell culture of rat fibroblasts . The resMagnetic iron oxide nanoparticles are widely used in applications for targeted anti-cancer radiotherapy and imaging techniques using radioisotopes emitting \u03b2+, \u03b2\u2212, \u03b1, and \u03b3 radiation. In this context, Nieciecka et al. demonstrated that the conjugation of iron oxide nanoparticles with terbium ions and guanosine-5\u2032-monophosphate  were more promising for hypothermia-based treatments than standard unconjugated nanoparticles .4:Yb3+/Er3+ UCNPs coated with SiO2 using the hydrothermal method [Up-conversion rare-earth nanoparticles (UCNPs) are an extremely interesting class of materials due to their high fluorescence intensity as well as the possibility to absorb near-infrared radiation and converting into visible light through non-linear optical processes. Zhang et al. reported a new method for synthesizing Ag-NaYFl method . These nA new and promising strategy for cancer therapy is sonodynamic therapy (SDT). In SDT, effective sonosensitizers are of paramount importance. Ma et al. showed that urchin-shaped copper-based metalloporphyrin liposome nanosystem can be considered highly effective sonosensitizer, as it was found to massively generate reactive oxygen species capable to kill 4T1 tumor cells under ultrasound irradiation . In the This Special Issue also contains four review articles on key topics in the field, which can be very interesting and useful, especially for young researchers involved in this multidisciplinary and highly fascinating field of research. The first review by Duta et al. covers the production of biphasic calcium phosphate materials derived from fish wastes , known as fish discards, in the context of material recycling and the circular economy . This woNanomaterials covers a wide range of different nanomaterials, including nanostructured coatings, nanoparticles, nanosystems, biomimetic devices and drug carriers that are expected to be the building blocks of next-generation of biomaterials. Although not fully representative of the huge number of different nanomaterials and solutions available for biomedical applications, this Special Issue manages to provide a quick overview of some of the most promising solutions in this rapidly evolving and interdisciplinary field.In summary, this Special Issue of"}
+{"text": "F. Duffy et al. Nature Communications 10.1038/s41467-022-32996-5 (2022)P. falciparum transcriptomic datasets with approaches centred on the tight transcriptional pattern governing P. falciparum along its ~48\u2009h intraerythrocytic asexual cycle, and we showed a relation between circulation of more developed parasites within each ~48\u2009h asexual cycle and lower parasitaemias or milder malaria symptoms1. Previously unpublished data from Duffy and colleagues is not fully aligned with our published conclusions. Here we discuss their comments on our recent study.We have recently reanalysed several 1 we included among others, the 2018 publication by Tonkin-Hill et al.2 which at the time did not report individual patients\u2019 parasitaemias, total parasite biomass estimates in the form of Ptot or the levels of HRP2, haematocrit, and weight for its calculation, or that parasitaemias of the subset of the patients whose samples they used for differentially expressed gene (DEG) analysis were significantly different between samples of severe and uncomplicated malaria cases, contrary to their report for the comparison including the entire group of samples2, hence we could not have included these data in our publication.In our manuscript2, we included their reported DEG list in the analyses of our manuscript similarly to what we did for other studies1. We concluded that the comparison between non-severe and severe cases without reported strong parasitaemia differences in Tonkin-Hill et al. resulted in less pronounced differences in peak of expression of DEGs and in proportions of predicted parasite stages. We agree with Duffy et al. that we could have more clearly transmitted to the reader that the normalization efforts originally applied to their dataset would prevent showing such clear trends as the other studies, and accept their criticism. Nevertheless, despite the normalizations implemented, using the reported DEG list by Tonkin-Hill et al. we still estimate higher ring-stage proportion in severe versus non-severe malaria cases ; and we observed gene expression patterns associating with number of housekeeping-gene reads, which we used instead of individual parasite levels, given that those were not originally reported 2. Duffy et al. now report that RNAseq read counts of this housekeeping gene and individual parasitaemias do not correlate, which we had no possible way of knowing at the time of publication of Thomson-Luque et al.1. We do not fully agree with the additional arguments based on correlations proposed by Duffy et al. The proportion of ring- and non-ring- asexual stages is expected to sum up to 1 (or very close to 1 whenever gametocytes are present). Positive correlations to one of the groups imply negative correlations to the other, as in fact Duffy et al. observed. That the correlation found by Duffy et al. is positive with the proportion of rings, supports our rational that severe cases have higher proportion of rings  and higher parasitaemias . The variation of the glycine tRNA ligase shown on PlasmoDB highlights slightly lower expression of the gene at very young ring stages or schizonts, which would lead to proportionally lower normalised glycine tRNA ligase reads in parasites of younger developmental stage, and not reflect youth of parasites as proposed by Duffy and colleagues.Although we were aware of the different efforts Duffy and colleagues performed in Tonkin-Hill et al. to statistically normalize by developmental stage the differential expression between parasites causing severe and non-severe malaria1 as only Lee et al. reported individual values of HRP23 of the ten studies included.In Fig. 5 of Thomson-Luque et al. we have not investigated transcriptome correlates with circulating parasite density within each individual study, as we believe these would be difficult to detect due to small sample size, and short ranges in parasite densities in the vast majority of the included studies. We also did not report nor inferred any correlates between total parasite biomass and circulating parasite age in Thomson-Luque et al.2. At the time of publishing Thomson-Luque et al. we referred to the parasite density comparison reported in Tonkin-Hill et al.2, showing a non-significant difference between severe and uncomplicated malaria cases n\u2009=\u200944 p\u2009=\u20090.87262, and we could not foresee that the authors would now present an analysis of the same cohort with a lower sample number  showing a significant difference .Duffy et al. now report that parasitaemias of the subset of the patients whose samples they analysed for differentially expressed gene (DEG) analysis were significantly different between samples of severe and uncomplicated malaria cases, however, this data is novel and different from the one they published in Tonkin-Hill et al.2. And in Thomson-Luque et al. we wrote: \u201cTonkin-Hill et al. detected no differences between severe and uncomplicated malaria cases in total number of var gene reads, but identified segregation at the multidomain and individual domain level between severe and uncomplicated disease. However, Tonkin-Hill et al. also found genes involved in PfEMP1 transport and regulation to be downregulated in severe malaria\u201d. We believe we did not interpret Tonkin-Hill data or statement wrongly.Regarding a possible misinterpretation of Tonkin-Hill var gene expression data, objectively, in Tonkin-Hill et al. can be read \u201cgenes involved in PfEMP1 transport and a gene involved in regulation of var genes were down-regulated in severe malaria. This suggested that var gene expression was modulated but PfEMP1 surface presentation was reduced.\u201d4, in line with the with the conclusions in Thomson-Luque et al. Nevertheless, we acknowledge that our combination of very different datasets may be a limitation, and we believe that future studies, including parameters like the ones now presented by Duffy and colleagues, alongside novel approaches like single-cell analysis should provide greater resolution of the parasite life-cycle stages. This may help improve interpretations and correct any unintended imperfect conclusion in Thomson-Luque et al. and the other bulk RNAseq-studies.We published a series of observations obtained through multiple approaches and applied to several studies, which we interpreted considering the data included in the original reports, to allow the detection of broad patterns that could otherwise be overseen. Since the publication of Thomson-Luque et al., a study investigating expression profiles of cerebral malaria and uncomplicated malaria isolates from Benin found that the mean parasite age expressed in hour post invasion was statistically lower in cerebral malaria cases, and confirmed the difference by microscopic reading of thin blood smearsFurther information on research design is available in the\u00a0Reporting Summary"}
+{"text": "Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in the regulation of gene expression at transcriptional, posttranscriptional, and epigenetic levels. Several studies in cell lines, animal models, and humans, have revealed that non-coding RNAs play crucial roles in the pathogenesis of Alzheimer's disease (AD). Detailed knowledge on their mechanism of implication in the AD pathogenesis can help to develop novel therapeutic and disease management strategies. The two main pathological hallmarks of AD are amyloid plaques resulting from the \u03b2-amyloid accumulation, and neurofibrillary tangles (NFT) due to the phosphorylated tau accumulation. Several lncRNAs and miRNAs play crucial roles in both these hallmarks of the AD pathogenesis and other AD-related pathological procedures such as neuronal and synaptic plasticity, neuroinflammation, neuronal differentiation and neuronal apoptosis. In this review, we outlined the non-coding RNAs and further discussed how they are implicated in these AD-related pathological procedures. Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia, accounting for approximately 60 % to 80 % of cases among the elderly worldwide  comprise a class of endogenous regulatory RNA molecules that are over 200 nucleotides (nt) in length, without protein-coding capacity, and make up the largest proportions of the mammalian non-coding transcriptome , and th2O2 increase the expression of lncRNA BACE1-AS, which in turn makes BACE1 mRNA more stable, leading to enhanced APP processing and toxic A\u03b2 production by a post-transcriptional feed-forward mechanism  is an enzyme central to the pathology of AD that contributed to the formation of A\u03b2 peptides and extracellular plaque deposition . BACE1 al., 2008). Producal., 2008) . Besideal., 2008). BACE1-al., 2008; Fotuhi al., 2008).The neuronal sortilin-related receptor 1(SORL1) gene encodes SORLA protein, which is involved in the processing of amyloid-\u03b2 protein precursor (APP) and decrease A\u03b2 peptides production in neurons . StudieLow density lipoprotein receptor-related protein 1(LRP1), as a receptor is involved in a variety of cellular processes including cell signaling, lipoprotein metabolism, and APP trafficking and processing . LRP1 iOne of the neuropathological features of AD is synaptic dysfunction that occurs in the first stages of the disorder , is widely synthesized in the central nervous system, has a physiological role in synaptic plasticity and survival of neurons . BDNF gal., 2016, 2009[98al., 2012). Guo etal., 2012). It wasal., 2012; Ding etal., 2012), and thal., 2012). More rGlial cell line-derived neurotrophic factor (GDNF) is an important biologically active trophic factor for development and survival of the midbrain dopaminergic neurons . It hasNeuroblastoma differentiation marker 29 (NDM29), a RNA pol II-transcribed lncRNA, mapped to a genomic region of chromosome 11, and its synthesis is regulated by an extragenic type 3 promoter . NDM29 Sox2 is a component of the core transcriptional regulatory network that is essential for maintaining pluripotency of stem cells and neurogenesis . Sox2 oRecently, Magistri et al. used RNA sequencing in order to discover significant alterations in expression profile of the lncRNAs from AD brains and found that lncRNA EBF3-AS is abundantly expressed in the brain of late-onset AD cases compared to control individuals . FurtheLee and colleagues identified 47 upregulated and 158 downregulated lncRNAs in rat model of AD compared with healthy controls using microarray analysis . MoreovMicroRNAs (miRNAs) are endogenous ~22 nucleotide non-coding RNAs, responsible for direct posttranscriptional regulation of gene expression, either by targeting mRNA degradation or by inhibition of protein translation at both mRNA and protein levels . After \u2032-UTR region of the BACE1 to reduce A\u03b2 accumulation, which makes it as a novel drug target , a rate-limiting enzyme involved in the formation of A\u03b2, plays a crucial role in AD progression . Similaal., 2014; Zhu et al., 2014). Other al., 2014). Furtheal., 2014). In anoal., 2014). Du et al., 2014). In sum\u2032-UTR of the APP mRNA resulted in decreased level of APP in patients with AD . Intereal., 2020).in vitro and in vivo . Severaal., 2016). Smith al., 2016). It hasal., 2016). Studieal., 2016). Moreoval., 2016).In this review, we summarized the relationship between ncRNAs and AD pathogenesis based on recent evidence. Multiple studies have shown the critical role of ncRNAs in various biological processes, including cell growth, apoptosis, and differentiation, indicating that they might be involved in the occurrence and progress of neurodegenerative diseases including AD  can be used as potential therapeutic targets and biomarkers.Reliable biomarkers for early diagnosis are required to halt the disease development and improve the effects of therapeutic strategies.Authors appreciate the Cognitive Sciences and Technologies Council of Iran for supporting this work.This work was supported by the Cognitive Sciences and Technologies Council of Iran, grant number 6300.The authors have no relevant financial or non-financial interests to disclose.Majid Khodayi-Shahrak performed research and wrote the manuscript; Mohammad Khalaj-Kondori supervised research, reviewed and edited the manuscript; Mohammad Ali Hosseinpour Feizi reviewed and edited the manuscript; Mahnaz Talebi reviewed and edited the manuscript."}
+{"text": "Snowdon et al., RSC Adv., 2019, 9, 6752\u20136761, DOI: 10.1039/C9RA00034H.Correction for \u2018Comparative study of the extrinsic properties of poly(lactic acid)-based biocomposites filled with talc  The authors regret that the values given for oxygen and water vapor permeability in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The intensive genetic selection of broiler (meat-type) chickens over the past 80\u00a0years has focused narrowly on economically important traits, namely growth rate, feed efficiency, and breast yield . AlthougGrowth rates have dramatically increased by over four times between 1957 and 2005  and modede novo lipogenesis  and/or endogenous (adipogenesis/lipogenesis) sources. As commercial broilers are fed lipid-poor diets (<10%), the majority of the accumulated fat is derived from the liver, which is the main site for ogenesis . Fat metKato et al. showed that two-week intracerebroventricular infusion of neurosecretory protein GM (NPGM) increased body mass, and the mass of abdominal and gizzard fat in chickens, without effects on feed intake. At molecular levels, they showed that NPGM might induce hepatic fat deposition via down regulation of the hepatic PPAR\u03b1 gene expression.At the central level, Massimino et al., on the other hand, used high throughput real-time quantitative PCR to determine the effect of embryonic thermal manipulation on the hepatic lipid and carbohydrate metabolism, stress, cell proliferation, and thyroid hormone pathways in mule ducks. They identified several key genes that might be involved in thermal long-term programming of hepatic metabolism. Surugihalli et al. used mass spectrometry-based metabolomics to evaluate the rapid remodeling of hepatic mitochondrial and cytoplasmic networks in chicken E18 embryo and d3 post-hatch chicks. Several metabolites were profiled in both plasma and liver showing a transition from lipid oxidation in embryonic liver to de novo lipogenesis in neonatal liver. Using forced molting laying hens, cecal metabolomics, and liver transcriptomics, Ruirui (abstract only) identified regulatory intestinal-liver lipid metabolism factors affecting reproductive performance in laying hens.At the peripheral level, the Bonnefont group has used a high throughput metabolomics approach to identify hepatic biomarkers for Foie Gras quality in duck. A total of eighteen quality-associated metabolite signatures were determined, with five specific to liver weight and four specific for technological yield at cooking. Zhao et al. determined the developmental changes of adipocyte differentiation, lipid synthesis, lipolysis, fatty acid \u03b2-oxidation, and lipid content from chicken embryo day 12 to day-9 post hatch. They showed that the mitochondrial copy number and fatty acid \u03b2-oxidation increased during the post hatch period, indicating that subcutaneous adipose tissue plays an important role in energy supply. Sun et al. used the Iso-Seq technology and identified several long non-coding RNA and alternative splicing in abdominal and subcutaneous adipose tissues of pekin ducks. Na et al. reported several reference genes for real-time quantitative PCR in chicken adipose tissue and adipocytes. Kim et al. determined the effect of in ovo injection of different doses of all-trans retinoic acid on quail embryonic adipogenesis. They found that all-trans retinoic acid promoted hypertrophic fat accretion in quail embryos via upregulation of PPAR\u03b3 and FABP4 and down regulation of Dlk1. The Gilbert group studied the effect of dietary baicalein supplementation on adipose tissue gene expression profiles during the first week post hatch in chickens. They showed a reduction of growth performance , breast muscle weight, and subcutaneous and abdominal fat weights along with a modulation of several genes involved in adipogenesis and fat storage. In a separate paper, the Cline group reviewed the effects of dietary flavonoids on lipid metabolism in liver, skeletal muscle, and adipose tissue of poultry species. Finally, Kim and Voy provided a thorough review associated with the beneficial effects of n-3 polyunsaturated fatty acids in reducing fat accretion in poultry.In adipose tissue, In summary, the papers within the current Research Topic provide new insights and discoveries related to lipid metabolism in various avian species  and suggest some solutions and perspectives for future investigations aiming to reduce fat accretion in poultry. It is my fervent hope that this ebook and the Research Topic is a great resource for the readers, and we look forward to a second volume to expand more research and knowledge associated with other molecular pathways of lipid metabolism in various other avian species."}
+{"text": "Protein kinases regulate nearly every aspect of cell life, and changes in their expression or gene mutations cause cancer and other diseases. As many human diseases result from mutations and overexpression of kinases, this enzyme class symbolizes an important targeted strategy for drug development. Kinases are also essential in signaling pathways that regulate tumor cell functions. Kinase dysregulation causes a number of pathophysiological changes that promote cancer cell proliferation and metastasis. This targeted, structure-based drug design is gaining traction; several anticancer drugs targeting specific kinases are in various stages of clinical trials. When compared to a decade ago, the new opportunities, developments, and results in this field are almost unbelievable.The development of superior drugs that target specific signaling molecules has had a significant impact on the pipelines of pharmaceutical companies, leading to the development of multiple marketed kinase inhibitors. The development of selective small molecules against kinases has the potential to provide greater potency and selectivity than was previously possible.The authors included in this Research Topic discuss how various classes of kinases are used as potential drug targets, with a particular emphasis on anticancer therapy. The content covers both the challenges and opportunities for future kinase inhibitor development for anticancer therapy. Contributions also discuss how the problem of drug resistance to kinase inhibitors is being addressed, as well as the future of kinase drug discovery. Kinases are currently being studied extensively for the treatment of a variety of life-threatening diseases. This Research Topic brings together several reviews and research articles, contributed by scientists and researchers in the fields of medicinal chemistry and molecular biology, as well as new emerging multi-drug targets.Hepatic Rupture as the Initial Presentation of an EGFR-Mutated Lung Adenocarcinoma: A Case Report\u201d by Mirallas et al., which describes a female patient who presented with a metastatic hepatic rupture and was later diagnosed with EGFR-mutated lung adenocarcinoma. Hepatic rupture is a rare complication in patients with solid tumor malignancies, particularly lung adenocarcinomas, and it is associated with a very poor prognosis.This Research Topic starts with a research article on \u201cAlam et al. examining \u201cBax/Bcl-2\u2019s Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer.\u201d The review summarizes recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and the EGFR pathway in NSCLC and targets them for therapeutic implications. This study looked at the therapeutic potential of Bax/Bcl-2/EGFR SMIs, particularly those with higher potency and selectivity, such as gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. Furthermore, they also discuss the EGFR pathway and ongoing in vitro, in vivo, and clinical studies in NSCLC. Exploration of such inhibitors facilitates future NSCLC treatment and management.The next article in this Research Topic is a review by Wu et al. in their contribution, \u201cLestaurtinib Has the Potential to Inhibit the Proliferation of Hepatocellular Carcinoma Uncovered by Bioinformatics Analysis and Pharmacological Experiments,\u201d identifies a new candidate STAT family. This factor is involved in the development of HCC and new treatment Candidate STAT family genes for HCC were found using bioinformatics web resources such as Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), and GSCALite. In this study, the author performed in vitro experiments using lestaurtinib as a treatment for patients with liver cancer and verified that lestaurtinib, a tyrosine kinase inhibitor, can inhibit the growth of liver cancer cells. The author explores the effects of lestaurtinib in hepatocellular carcinoma through in vitro and in vivo systemic studies to provide a new strategy for the treatment of hepatocellular carcinoma. In vivo studies focus on addressing how to limit toxicity at optimal biological doses.Research by Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases,\u201d is a review by Alam et al. that focuses on the chemical, physical, and pharmacological properties of caffeine, including its antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The features, therapeutic potential, and future possibilities of CA are also discussed by the author.The fourth article in this Research Topic, \u201cChen et al. identified a novel LDLR-ROS1 fusion in patients with resectable stage IIIA NSCLC, entitled \u201cCase Report: Adjuvant Crizotinib Therapy Exerted Favorable Survival Benefit in a Resectable Stage IIIA NSCLC Patient With Novel LDLR-ROS1 Fusion.\u201d After receiving crizotinib as adjuvant therapy, the patient experienced no substantial harmful side effects and maintained recurrence-free survival (RFS) for 29\u00a0months. This example supports the use of adjuvant treatment with the ROS1 inhibitor exhibiting clinical survival advantage in ROS1 fusion-positive resected NSCLC, according to the authors\u2019 report of a novel LDLR-ROS1 fusion responding to crizotinib in a patient with lung adenocarcinoma.The fifth article in this Research Topic by Avery et al. on \u201cOnco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.\u201d This article outlines the rationale and concepts for utilizing the immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while emphasizing the role of MEK inhibition in combinatorial and intermittent anemia treatment. The considerable scientific efforts made to address the difficulties encountered during the clinical transition of different therapeutic drugs were also highlighted in the hunt for the most efficient and secure patient- and tumor-tailored treatment strategy.The sixth article in this Research Topic is a review by Case Report: A Lung Adenocarcinoma With Brain Metastasis Harbored Novel MET 14 Skipping Alteration Sensitive to Savolitinib,\u201d was written by Li et al. and describes a 61-year-old woman who had lung adenocarcinoma and was treated with Savolitinib after having a novel MET exon 14 skipping (c.3004). These two MET changes were also validated by the CytoTest MET/CCP7 FISH Probe (c-MET/CCP7 Ratio:1.41 and mean gene copy number:6) and qPCR, which used the ABI 7500. Savolitinib treatment lasted for 2\u00a0months, and the clinical assessment showed a partial response (PR). In conclusion, this discovery not only broadened the range of the MET exon14 variation (METex14). Targeted NGS analysis may enhance the ability to detect MET changes in everyday practice.The seventh article in this Research Topic, \u201cRET Signaling Pathway and RET Inhibitors in Human Cancer,\u201d by Regua et al. reviews biological understanding of RET signaling, the effects of RET hyperactivity on tumor progression in a variety of tumor types, and the efficacy of RET inhibitors in preclinical and clinical settings.The final article in this Research Topic, \u201cKinase Inhibitors in Cancer Therapy.\u201dI would like to thank all authors who contributed to this Research Topic on \u201c"}
+{"text": "After tBritish Medical Journal, Wallis et al. [Annals of Thoracic Surgery, Rong et al. [Addressing the issue of disparities between men and women can seem redundant, since this dichotomy is well recognized in the professional world. It is nevertheless essential in our surgical field since it is still a male-dominated world: most recent data from the public report of the American Association of Medical Colleges (AAMC) in 2019 on active physicians sex and specialtyindicates that 92% of practicing cardio-thoracic surgeons are men . Despites et al.  reportedg et al.  reported\u2018I do not wish to give (women) a first place, still less a second one\u2014but the complete freedom to take their true place, whatever it may be\u2019.\u2014Elizabeth BlackwellSadly, despite this documented equality in operative results, the academic career ladder still seems steeper for female surgeons: women with an MD are less likely to author a paper than men with the same degree and instead, a PhD becomes much more essential for women . They alThe Women in Cardio-Thoracic Surgery Committee currently consists of seven female surgeons from various career levels and countries: Prof. Jolanda Kluin (The Netherlands); Dr Indu Deglurkar (UK); Dr Lena Emrich (Germany); Dr Francesca D\u2019Auria ; Dr Julie Cleuziou (Germany); Dr Miia Lehtinen (Finland); and Dr Maroua Eid (France). This heterogeneity seems essential, allowing all female surgeons to relate to the committee.female surgeons [The committee holds an important mission: establishing a network for surgeons . Such coet al. \u2018attention should be given to the potential unconscious bias in leadership in cardiothoracic surgery\u2019 [Gender should not intervene in one\u2019s career choices; only abilities and perseverance should be considered. A shift towards an increased representation of female surgeons is to be expected in our field, and as suggested by Shemanski surgery\u2019 . For our"}
+{"text": "Artificial intelligence (AI) has emerged as a key player in modern healthcare, especially in the pharmaceutical industry for the development of new drugs and vaccine candidates. AI technology has shown promising results in target identification, protein\u2013protein interactions, protein\u2013drug interactions, metabolic pathway identification, drug repurposing, facilitating de novo drug design to combat diseases, and increasing short-term research productivity. This Special Issue highlights recent advances in computational modeling and dynamics simulations for elucidating phosphodiesterase 9 (PDE9) inhibitors with different metal systems; the identification of potential inhibitors of coronavirus disease 2019 (COVID-19); the prediction of convolutional network-based drug\u2013target interaction modules; the building of transformer-based deep neural networks for metabolomics; and the development of autoencoder-based deep learning models for drug repurposing for Alzheimer\u2019s disease. Signal transduction systems such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) regulate cellular functions in organisms, and the dysregulation of these signaling pathways leads to various diseases. To minimize the dysregulation of signaling pathways and the disruption of cellular function, Sivakumar et al.  targetedThe repurposing of \u2018existing\u2019 drugs to treat common and emerging diseases increasingly involves the targeting of lower-risk compounds and results in reduced development costs and times. The COVID-19 pandemic has disrupted healthcare systems globally since 2019, calling for new therapeutics that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the disease. Antiviral treatments have been known to reduce disease spread, infection, and severity for over 30 years. Mohammad et al. [The prediction and identification of compound\u2013protein interactions (CPIs) play an important role in the recent discovery and development of safe drug candidates. Many studies point to the advantages of deep learning models for learning task-related functions from large datasets on compound\u2013protein interactions. Wang et al.  developeIn the past decades, high-throughput screening (HTS) experiments have greatly accelerated the identification of drug\u2013target interactions (DTIs). However, HTS experiments are costly and cumbersome, and cannot meet the need to reveal DTIs for millions of existing drug and target combinations. Jin et al.  developeMass spectrometry (MS) fingerprinting is key to metabolomics . The identification of metabolite molecules is currently performed primarily by comparing MS data with those of a limited number of authentic chemical standard libraries. Only 10% of molecules can typically be identified experimentally from reproducible spectral features of complex matrices , despite many heuristics . To address the above issues, Shrivastava et al.  developeFinally, Chyr et al.  proposedBiomolecules for the opportunity to work with them on this enlightening editorial journey.We hope that the interdisciplinary topics covered in this collection will prompt further discussion among researchers and promote innovation in the field of artificial intelligence for drug design and development. Above all, we would like to thank the authors for their excellent contributions. We also thank the scientific experts in AI, computational modeling, and drug design who offered invaluable comments and suggestions to improve the quality of this Special Issue. Finally, we would like to thank the Editor-in-Chief, Section Managing Editor, and all the editorial staff of MDPI\u2014"}
+{"text": "Matson et al., RSC Adv., 2021, 11, 32269\u201332274. DOI: 10.1039/D1RA06151HCorrection for \u2018X-ray absorption spectroscopy of exemplary platinum porphyrin and corrole derivatives: metal-  The authors regret that the one of the author affiliations was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The COVID-19 pandemic dramatically changed the nature of social interaction, creating negative impacts and challenges, but also opportunities for progressing how we communicate, as humans. Social distancing policies, lockdown measures, and mandatory quarantines accelerated technological communication. For example, Artificial Intelligence (AI) mediated communication grew at an unprecedented rate, willingly or otherwise. As part of pandemic control efforts, many activities, such as workplace meetings, education, and conferences, moved online, using social media platforms, the metaverse, and specialized programs accessed through mobile devices or laptops. As a result, digitally mediated channels became critical for information acquisition and communication across a wide spectrum of human activities in our personal and professional lives. As the scientific understanding of COVID-19 improved, pandemic restrictions loosened. However, it remains to be seen whether the pandemic communication paradigm, characterized by heavy technological mediation and reliance on non-human agents, will gradually decline, or whether the paradigm shift will become deeply entrenched with further acceleration of the dependency on technological mediation and non-human agents.Such unprecedented reliance on technological mediation and non-human agents for information and communication is akin to a social-psychological experiment on a global scale. Much remains unknown, however, since this communication paradigm shift began almost 3 years ago. There are two main problems that require attention. First, the psychological impact of and underlying mechanisms behind the extended and extensive reliance on technological mediation and non-human agents is not yet well understood, especially regarding the influence of AI technologies. Second, the extent to which the impact of this reliance is likely to persist and influence future communication is also not well understood, especially in different national and cultural contexts. Research involving new approaches to data collection, such as big data techniques, together with more traditional data techniques, can help in providing greater insights into these two problems.In this Research Topic, we sought to extend current understanding about how the COVID-19 pandemic has reshaped human communication, especially cognitive, psychological, and behavioral shifts in social interactions. We focused on research that explored new possibilities for interpersonal communication practices in the post-pandemic era. Eighteen manuscripts were selected for inclusion and draw intensive attention with more than 26,000 views.Information technologies, such as social media platforms, offer individuals various functionality to support the maintenance, development, and sustainability of individuals and organizations. For instance, when COVID-19 emerged, the provision of resources and social support became a major concern for many.The Importance of Project Description to Charitable Crowdfunding Success: The Mediating Role of Forwarding Times,\u201d Lu et al. considered 205 COVID-19 charitable projects and 11,177,249 donors to assess the process by which nonprofit organizations raise funds through information descriptions about project descriptions. The results of the study indicated that understandability and a negative tone for descriptions help to improve the amounts raised. A question remains: might quarantines and economic disadvantages exacerbate social anxiety among impoverished individuals?In the article titled \u201cSocial Media as Online Shelter: Psychological Relief in COVID-19 Pandemic Diaries,\u201d Feng et al. explored how individual narratives on social media affect people's psychological health during a state of emergency using data collected from 19 interviews with Chinese diary writers. The study found that a pandemic diary could promote self-relief, public communication, emotional drive, meaning connection, and identity construction in public spaces, thus helping shape a sense of unity and belonging and facilitating the psychological reconstruction of people who are vulnerable to potential mental health crises.In the article titled \u201cOnline Collaborative Documents as Media Logic: The Mediatization of Risk Response in the Post-pandemic Era,\u201d Jiang et al. used a mixed-method design approach to examine treating online collaborative documents as a special approach to risk response in public health and natural disaster situations. The study found that the editability, accessibility, activability, and normality of technological affordances connected the functional features of a digital platform with users' potential actions.In the article titled \u201cIn this Research Topic, the authors also explored the drawbacks of information technology adoption. As the COVID-19 pandemic progressed, human reliance on information technology increased. For example, social media and the metaverse are now routinely being used for entertainment, learning, daily communication, and work.Personal network protects, social media harms: Evidence from two surveys during the COVID-19 pandemic,\u201d Ren and Yan demonstrated the increasingly critical and multifaceted role of communication technologies in affecting mental health conditions, indicating the destructive outcomes of the overuse of social media.In the article titled \u201cHow do Internet moms raise children? The reshaping of Chinese urban women's parenting psychology by COVID-19 online practices,\u201d Zhao and Ju, focusing on a special group of internet mothers, examined how they raised their children using the internet during the pandemic. The study found that social media created a new platform for information empowerment, mutual action, and ideation of motherhood for urban women formerly bound to family and parenting matters.In the article titled \u201cMetaverse as a possible tool for reshaping schema modes in treating personality disorders,\u201d Yin et al. showed the potential role of the metaverse and virtual worlds in reshaping schema modes for treating personality disorders by reconstructing a new object world for a patient with the prescription of a psychotherapist.In the article titled \u201cPsychological distance and user engagement in online exhibitions: Visualization of moir\u00e9 patterns based on electroencephalography signals,\u201d Li J. et al. followed an Electroencephalography (EEG) signaling approach to highlight the possibility of EEG-visualization media devices in reducing the psychological distance and promotion of interpersonal communication between two participants experiencing an online exhibition.In the article titled \u201cSocial media also provides new opportunities for many as we enter a post-pandemic era, including the public, institutions, media, and governments.The application of network agenda setting model during the COVID-19 pandemic based on latent Dirichlet allocation topic modeling\u201d and \u201cEvent history analysis of the duration of online public opinions regarding major health emergencies,\u201d Liu K. et al.  and Liu X. et al. explored the public opinion landscape of the pandemic, as well as the dynamics of public opinion evolution.In the articles titled \u201cSocial media interactions between government and the public: A Chinese case study of government WeChat official accounts on information related to COVID-19\u201d and \u201cGovernment crisis communication innovation and its psychological intervention coupling: Based on an analysis of China's provincial COVID-19 outbreak updates,\u201d Shao et al. and Zhou et al. drew on the perspective of government-public relationships to focus on issues pertaining to government-public interactions and government crisis communication in an attempt to provide practical implications for crisis communication systems and public administrations during a public health crisis.In the articles titled \u201cRelationship Between Hardiness and Social Anxiety in Chinese Impoverished College Students During the COVID-19 Pandemic: Moderation by Perceived Social Support and Gender,\u201d Cheng et al. studied 673 impoverished Chinese college students and found that perceived social support moderated the effect of hardiness on social anxiety.In the article titled \u201cSelf-Efficacy, Proxy Efficacy, Media Literacy, and Official Media Use in COVID-19 Pandemic in China: A Moderated Mediation Model,\u201d Li Q. et al. explored the determinants of self-efficacy for fighting against the COVID-19 pandemic under social cognitive theory. The authors found that official media use was a negative moderator of the association between media literacy and proxy efficacy.In the article titled \u201cUnpacking the effects of personality traits on algorithmic awareness: The mediating role of previous knowledge and moderating role of internet use,\u201d Fang and Jin revealed that previous knowledge of algorithms and internet use are mediators and moderators between personality and algorithm awareness.In the article titled \u201cThe mediating role of personal values between COVID-19-related posttraumatic growth and life satisfaction among Chinese college students: A two-wave longitudinal study,\u201d Xie et al. established that COVID-19-related posttraumatic growth is positively associated with life satisfaction, while self-transcendence and self-enhancement values partially mediate this association.In the article titled \u201cPersonal space increases during the COVID-19 pandemic in response to real and virtual humans,\u201d Holt et al. suggested that personal space boundaries were expanded during the pandemic. The authors provided an index of recovery from the psychological effects of the crisis.In the article titled \u201cExploring factors that influence COVID-19 vaccination intention in China: Media use preference, knowledge level and risk perception,\u201d Chen et al. examined the role of media use preference, knowledge level, and risk perception in predicting people's intentions to take a COVID-19 vaccine in the Chinese context.In the article titled \u201cInfluence of personality traits on online self-disclosure: Considering perceived value and degree of authenticity separately as mediator and moderator,\u201d Lv et al. revealed the role of personality traits in online selfdisclosure, while separately assessing the perceived value and degree of authenticity as mediator and moderator.Finally, in the article titled \u201cIn summary, this Research Topic aimed to unite efforts to explore various aspects of communicative practices during and after a major crisis, although most of the studies were situated in the Chinese context. While we cannot say that this Research Topic provides a comprehensive knowledge map of post-pandemic communication practices, we hope that it will contribute to broadening the scope of conventional theoretical versions of information, media technology, and psychology.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "In the published article, there was an error. We mistakenly described the trend of changes in the levels of some metabolites after treatment of SpA patients.Results, \u201cDynamic alterations in the metabolic profile before and after treatment of spondyloarthritis,\u201d Paragraphs 2 and 4. These sentences previously stated:A correction has been made to \u201cKapoor et al.  and BoguAnd\u201cIn addition, in the serum of JIA patients, MTX therapy increased the level of omega-3 unsaturated fatty acids (docosahexanoic acid and linoleic acid), which are anti-inflammatory mediators.\u201dThe corrected sentence appears below:\u201cKapoor et al.  and BoguAnd\u201cIn addition, in the serum of JIA patients, MTX therapy reduced the level of omega-3 unsaturated fatty acids (docosahexanoic acid and linoleic acid), which are anti-inflammatory mediators.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Cells, several up-to-date reviews and original studies have provided new insights into the basic and translational aspects of AMPK signaling.5\u2032-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme regulating numerous cellular processes involved in cell survival as well as health- and lifespan. AMPK has emerged not only as a key cellular energy sensor but also as an important integrator of signals that manages cellular energy balance. Due to this property and being ubiquitously expressed in all mammalian cell types, AMPK has attracted interest in virtually all areas of biomedical research. In this Special Issue of Visnjic et al.  considerIn the other review paper, Aslam and Ladilov  describeObesity has been categorized by the American Medical Association as a chronic progressive metabolic disorder and is a growing public health concern worldwide. In the paper by van der Vaart et al. , an impoFinally, an original study by Li et al.  providedIn a sophisticated study, Olivier et al.  investigNon-alcoholic fatty liver disease (NAFLD) is emerging as a leading cause of chronic liver illness affecting > 30% of the European population, and even higher rates can be seen in the US population ,12. The Both transcriptional and genetic alterations in AMPK pathways may impact tumor microenvironments in a tissue-dependent manner either positively or negatively . This asLastly, Bhutta et al.  reviewed"}
+{"text": "Many researchers rely on animal studies to elucidate the mechanisms underlying diverse disease processes and to test the safety of emerging medical interventions. Animal research serves as a bridge between in vitro experiments and human trials in the preclinical stage. The majority of animal research employs almost genetically identical laboratory-bred mice or rats. Testing genetically similar individuals in a laboratory environment provides a level of control not available in clinical trials and is crucial for all phases of biomedical research. Numerous animal models have been developed to imitate pathophysiological abnormalities observed in humans. For an animal model of a human disease to be optimal, it must have similar pathophysiology, phenotypic, and histopathological traits; predictive biomarkers for disease progression or prognosis; therapeutic responsiveness; and levels of pharmacological safety or toxicity responses ,2. Thus,Various animal models have been critical in basic scientific and preclinical research on human neurological disorders, including traumatic or non-traumatic, neuroinflammatory, neuropsychological, and neurodegenerative diseases. The animal models are designed to mimic several facets of the disorders, including their genetic basis, neuropathological lesions, and clinical symptoms . These aHence, the Special Issue \u201cModeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles \u201d aimed tThe research articles in this Special Issue have mostly focused on the alterations of behavioral and histopathological characteristics and signal transduction, as well as the testing of potential therapeutic compounds in genetically manipulated and/or exogenous factor-induced animal models for neurological disorders. To begin, the articles by Ang et al., entitled \u201cTranscriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice\u201d  and \u201cSREThis Special Issue contains two additional research articles on animal models of schizophrenia. Chang et al. reported in their article \u201cInteraction of Prenatal and Postnatal Risk Factors in the Behavioral and Histological Features of a \u201cTwo-Hit\u201d Non-Genetic Mouse Model of Schizophrenia\u201d  that disAnother article in this Special Issue demonstrated a non-genetic and exogenous factor-induced animal model of neurological disorders. Although exposure to radiofrequency electromagnetic fields (RF-EMFs) has increased in the pediatric population, data on the consequences of the exposure to the central nervous system to RF-EMFs in them are scarce. The article by Kim et al. entitled \u201cExposure to RF-EMF Alters Postsynaptic Structure and Hinders Neurite Outgrowth in Developing Hippocampal Neurons of Early Postnatal Mice\u201d  reveled This Special Issue featured a research article testing a prospective therapeutic drug in a genetically manipulated mouse model of neurological disorder. Ding et al., in their article \u201cCarbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome\u201d , uncoverAdditionally, in a research paper on the hormonal effect on maternal behavior, the article by Leko et al. entitled \u201cTranscriptome Sequencing in the Preoptic Region of Rat Dams Reveals a Role of Androgen Receptor in the Control of Maternal Behavior\u201d  revealedsgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA\u201d by Douek et al. [sgsh (Deltaex5-6) zebrafish mutant could be a valuable resource for gaining a better understanding of MPS IIIA pathobiology and developing timely and effective therapeutic interventions.Apart from the rodent models mentioned above, this Special Issue included an article describing the development of a zebrafish model that mimicked a human disease. Mucopolysaccharidosis IIIA , a pediatric neurological lysosomal storage disease, is caused by a deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (sgsh), resulting in an impairment in heparan sulfate-glycosaminoglycan catabolism and its accumulation in tissues. The article \u201cAn Engineered k et al.  suggesteThe review articles presented in this Special Issue demonstrated the ingenuity of researchers in addressing the critical task of modeling human neurological disorders in animals in meaningful ways. The articles mainly reviewed various animal models for neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer\u2019s disease (AD), epilepsy, Parkinson disease (PD), peripheral nerve injury, and post-traumatic stress disorder (PTSD). These animal models will be useful to gain better understanding of the mechanisms leading to signs of neurological disorders, validating drug targets, and providing assurance that therapeutic approaches will ultimately benefit patients. ALS is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuronal loss. Bonifacino et al.  reviewedAD is the most common cause of dementia, and its pathogenesis is complex, including A\u03b2 deposits, tau aggregates, excitotoxicity, and neuroinflammation. Robert et al.  reviewedPD is the second most prevalent neurodegenerative disorder after AD. No cure for PD has been discovered, and treatment strategies are aimed at relieving symptoms through the restoration of dopaminergic functions. Liu and Cheung  reviewedNeurons are structurally distinct and have injury-prone dendrites and axons. Peripheral nerves that have been injured, but not central nerves, have the ability to recover and reinnervate their target organs. Numerous animal models have been used to elucidate the mechanisms of axon regeneration. Lee and Cho  reviewedKetamine has evolved into a versatile drug, which is used for a number of indications ranging from trauma analgesia to depression and PTSD therapy. Due to the inherent ethical problems associated with performing prospective clinical studies on traumatic events and stress-related diseases in humans, researchers frequently use preclinical rat models to investigate the effects of ketamine on fear memory and PTSD-like behaviors. A review by Choi et al.  summarizConsequently, this Special Issue provides an update on current knowledge of the importance of animal models in mechanistic and therapeutic research on neurological disorders. I hope that readers will gain an understanding of current research trends and insights on future research directions through this Special Issue. However, I recognize that this Special Issue is insufficient to address the diverse animal models for a variety of neurologic disorders and that the articles included in this issue cannot possibly cover all on this topic. Thus, to complement any latest research data or research trends, I have re-launched the Special Issue \u201cModeling Neurologic Disorders in Experimental Animals: New Insights and Emerging Roles 2.0 \u201d to soli"}
+{"text": "Pseudomonas aeruginosa via LasIR/RhlIR circuitry\u2019 by Mayank D. Shah et al., RSC Adv., 2019, 9, 40228\u201340239.Correction for \u2018Potassium 2-methoxy-4-vinylphenolate: a novel hit exhibiting quorum-sensing inhibition in  The authors would like to add affiliation d as the current affiliation for Prashant S. Kharkar. The corrected list of affiliations is as shown above.The authors regret that one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Countrywide multi-serotype outbreak of Salmonella Bovismorbificans ST142 and monophasic Salmonella Typhimurium ST34 associated with dried pork sausages in France, September 2020 to January 2021\u2019 by Pardos de la Gandara et al., upon publication on 12 January 2023, the title was missing the year of 2020 after September. This was corrected on 13 January 2023 at the request of the authors.In the article \u2018"}
+{"text": "Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive triglyceride (TG) accumulation in hepatocytes, have become a serious health problem worldwide . Due to Decades of studies have demonstrated that cytokines derived from metabolic organs, including liver, adipose tissues and skeletal muscles, play crucial role in the regulation of hepatic and systemic lipid homeostasis . These oGuo et\u00a0al., identified dysregulated myokines in the development of NAFLD and NASH through comprehensive transcriptome profiling. Mao et\u00a0al., identified adipokines and hepatokines associated with high-salt-diet in mice. Wang et\u00a0al., analyzed the relationship between circulating Ism1 and diabetes and diabetes-associated NAFLD. Gao et\u00a0al., provided a novel view on endoplasmic reticulum-related and secretome gene in NAFLD progression.Therefore, at this stage, we set up a Research Topic entitled \u201cThe Roles and Mechanisms of Hepatokines, Adipokines and Myokines in the Development of Non-Alcoholic Fatty Liver Disease (NAFLD)\u201d in the Frontiers in Endocrinology. Through this Research Topic, we aimed to further establish the roles of hepatokines, adipokines and myokines in NAFLD and NASH. In this collection, Overall, these studies together identified some new cytokines associated with NAFLD pathogenesis, which further strengthened our understanding of metabolic liver disease. However, intensive work is still required, such as investigations into the roles and mechanisms of these cytokines through genetic models, translational studies in human subjects, and screening potential therapeutic target for treatment. We hope that more and more studies on this Research Topic would help us better understand the molecular mechanisms of NAFLD development and identify more therapeutic targets for its treatment.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Berrones-Reyes et al., RSC Adv., 2019, 9, 30778\u201330789.Correction for \u2018Quantum chemical elucidation of the turn-on luminescence mechanism in two new Schiff bases as selective chemosensors of Zn The correct email address is The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "As a result of their rapid development, polymer composites are seeing wider use in transportation infrastructure in China and worldwide. Styrene\u2013butadiene\u2013styrene (SBS), epoxy resin (ER), polyethylene (PE), expanded polyethylene (EP), polyurethane (PU), crumb rubber and other polymer materials can be used to modify asphalt and improve the performance of asphalt mix. Meanwhile, the application of polymer admixtures such as PE fiber, polyvinyl alcohol (PVA) fiber, polypropylene (PP) fiber, etc., in bituminous, cementitious or soil materials also improves their strength and durability. Polymer materials are also widely used in pavement maintenance and treatment; they can quickly restore road function and extend the road\u2019s service life.This Special Issue contains sixteen research papers and one systematic review. The low-temperature properties of SBS-modified asphalt are not satisfactory; thus, Chen et al. analyzed the main factors for improving the low-temperature performance of SBS-modified asphalt base on the orthogonal tests . To solvSome research studies are devoted directly to the polymer materials applied in bituminous, cementitious or soil materials. Ren et al. studied the fatigue life and the material design of polymer concrete including ER and PU . Ji et aThe Special Issue concludes with a review on fiber-reinforced geopolymers and highlights the difficult aspects of current research, in addition to assessing the literature records ."}
+{"text": "Humulus lupulus L.) as a potent monoacylglycerol lipase inhibitor for treatments of neuroinflammation and Alzheimer\u2019s disease\u2019 by Min-Che Tung et al., RSC Adv., 2021, 11, 31062\u201331072, https://doi.org/10.1039/D1RA05311F.Correction for \u2018Discovery of 8-prenylnaringenin from hop ( The authors regret that the name of one of the authors (Hsing-Mien Hsu) was shown incorrectly in the original article. The corrected author list is as shown above.The authors also regret an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The brain weighs approximately 2% of the body, but utilizes about 20% of the total energy and oxygen supply, thus energy supply is critically important for the brain. In addition, the brain has no energy reserve, except some glycogens in the astrocytes, and the neurons can only use ATP, which comes from glucose degradation in the essential structure mitochondria. Mitochondria impairment, such as electron transport chain damage, can induce decreased ATP levels, decreased antioxidant defense, which is prevalent in many neurodegenerative disorders. For example, ATP dysfunction has been suggested to be the major impaired in depression . NumerouIt is critically important to understand the central facets of physiology and pathophysiology of energy supply in the brain, however, the energy supply regulation in the brain is not clear, for example how emotion affects energy supply, and does it activated by monoamine neurotransmitters. Emotion plays an important role in the regulation of the energy supply for the brain. Emotion parallels with behavior all the time, from the initiation of a behavior, the process of behavior to the end of the behavior. Emotion is the tendency for behavior, is also the motivation of a behavior. Emotion is also important for appraisal of behavioral consequences, marking the behavior as reward or punishment . Emotionvia autonomous nervous system, but also affect the energy supply in the brain. For example, the monoamine transmitters stimulate Na+, K+-ATPase activity in astrocytes and facilitate their role in ion concentrations , and suggested the berberine might be used as encouraging antidepressants to modulate depressed emotion.In another paper titled \u201cCurrent evidence and future directions of berberine intervention in depression\u201d, via TRPV1\u201d, the authors Meng et al. studied the effects of berberine on transient receptor potential vanilloid (TRPV1) in dorsal root ganglia inflammation via inhibiting NF-\u03baB and activating the JNK/p38 MAPK pathways in early injury, which inhibited the overexpression of TRPV1. The study suggested that berberine can reverse neuropathic pain response via inhibiting TRPV1 expression.In the experimental study about berberine titled \u201cBerberine Alleviate Cisplatin-induced Peripheral Neuropathy by Modulating Inflammation Signal Li et al. introduced another kind of natural product, echinacoside, which is a kind of phenylethanoid glycoside (PhG) in Cistanche tubulosa. In the paper \u201cTherapeutic potential and molecular mechanisms of Echinacoside in neurodegenerative diseases\u201d, they reviewed many recent studies about its mechanisms in neuroprotective efficacy in the prevention and treatment of neurodegenerative diseases, and proposed that the major effect of echinacoside is improving mitochondrial function and reducing anti-oxidative stress.In another review, the authors Tao et al. summarized recent in vitro and in vivo studies about Chinese herbs in treating dementia, and found that the extracts of these Chinese herbs work on reducing generation of reactive oxygen species and inhibiting inflammation and neurotoxicity.In the review paper titled \u201cProgress in the mechanism of autophagy and traditional Chinese medicine herb involved in dementia\u201d, Lyu et al. studied a kind of Chinese herb Yi-zhi-fang-dai formula, and its effects on pyroptosis and glymphatic dysfunctions. The study suggested that the Chinese herb Yi-zhi-fang-dai formula could inactivate pyroptosis via inhibiting caspase-1/11 activation and gasdermin D cleavage, and induce AQP-4 depolarization thus increase glymphatic function to reduce neuronal damage.In the experimental paper titled \u201cYi-zhi-fang-dai formula exerts neuroprotective effects against pyroptosis and blood-brain barrier-glymphatic dysfunctions to prevent amyloid-beta ccute accumulation after cerebral ischemia and reperfusion in rats\u201d, the authors Yin et al. studied the antioxidant activity of natural product rhein, and also its effects in clearance of \u03b2-amyloid (A\u03b2) in Alzheimer\u2019s disease. The study found that rhein could significantly reduce reactive oxygen species, and activate mitochondrial biogenesis by increased cytochrome C oxidase and superoxide dismutase activities.In the experimental paper titled \u201cRhein relieves oxidative stress in an A\u03b21-42 oligomer-burdened neuron model by activating the SIRT1/PGC-1\u03b1-regulated mitochondrial biogenesis\u201d, the authors Liu et al. introduced a study about a kind of Chinese herb named danzhi xiaoyao powder and its effects on the symptoms of generalized anxiety disorder. The results suggested that the power could improve the weight growth and improve appetite and reduce the anxious mood via notch signaling pathway in the hippocampus. The study suggested that danzhi xiaoyao powder is a good therapy method for mood disorders.In the experimental paper \u201cNeuronal Regeneration by Downregulating Notch Signaling Pathway in the Treatment of Generalized Anxiety Disorder\u201d, the authors He et al. introduced a kind of classic Chinese herb formula, qiangji decoction in the paper \u201cQiangji Decoction alleviates neurodegenerative changes and hippocampal neuron apoptosis induced by d-galactose via regulating AMPK/SIRT1/NF-\u03baB signaling pathway\u201d. The herbs have been widely used in the traditional Chinese medicine, but the mechanisms are not clear. This paper found the major effect of qiangji decoction is reducing inflammation via reducing TNF-\u03b1, IL-1\u03b2 and IL-6 in the hippocampus via regulating AMPK/SIRT1/NF-\u03baB signaling pathway in hippocampal neuron apoptosis.In the experimental study, Zheng et al. introduced a kind of Chinese herb ginkgo biloba extract and donepezil on Alzheimer\u2019s disease. In the paper titled \u201cEffects of ginkgo biloba extract and donepezil on functional recovery in Alzheimer\u2019s disease: a multi-level characterized study based on clinical features and resting-state functional magnetic resonance imaging\u201d, they used neuroimage study and found that the herbs could change the ALFF values in right gyrus rectus and decreased PerAF values in left fusiform gyrus. And the authors concluded that the imaging metrics in specific brain regions may serve as biomarkers for therapeutic efficacy of medicines.In the experimental study, Zheng et al. introduced a study on the mechanism of sytisine on temporal lobe epilepsy, in the paper titiled \u201cCytisine exerts an anti-epileptic effect via \u03b17nAChRs in a rat model of temporal lobe epilepsy\u201d. Cytisine is an agonist of \u03b17 nicotinic acetylcholine receptors (\u03b17nAChRs) and has shown neuroprotection in many neurological diseases. This study found that sytisine could increase hippocampal function via enhancing ACh levels and \u03b17nAChR expression, and decrease glutamate level to reduce seizures. The authors Arrodi et al. introduced one paper titled \u201cModulatory effects of alpha- and gamma-tocopherol on the mitochondrial respiratory capacity and membrane potential in Alzheimer\u2019s disease an in vitro model of Alzheimer\u2019s disease\u201d, which suggested that mitochondrial abnormalities are an early feature in the pathogenesis of AD. They found that alpha-tocopherol or gamma-tocopherol could modulate mitochondrial function by increasing the production of ATP and reducing mitochondrial reactive oxygen species via altering mitochondrial metabolic pathways such as oxidative phosphorylation.The authors in vitro: implication for a potential therapy of Alzheimer\u2019s disease\u201d, Cheng et al. investigated the role of mitochondrial dysfunction in the pathogenesis of Alzheimer\u2019s disease. In addition, they investigated the effects of tortoise plastron gelatin and dear antler gelatin in preventing neuronal mitochondria function. The found that these two natural products could increase cell viability by modulating intracellular ATP and calcium level, and also regulate mitochondrial membrane potential (MMP) and ultrastructure, and finally inducing anti-dementia effects.In the paper titled \u201cTortoise plastron and dear antler gelatin prevents against neuronal mitochondrial dysfunction In all, these studies demonstrate that astrocytic function and neuronal mitochondria function play important roles in many neurodegenerative disorders. In addition, this topic introduced many natural drugs in treating these diseases. We expected that this Research Topic will stimulate interest in the study of the mechanisms of modulating the energy supply."}
+{"text": "Current studies in the domain of cognitive neuroscience are devised to ensure a high signal-to-noise ratio. Measures from numerous participants are averaged to allow for commonalities to emerge, washing out possible differences. Albeit generally a good thing, a \u201cone-size-fits-all\u201d approach has a drawback: it fails to take inter-individual variability into account, a limitation that is no longer tenable given the increasing attention to so-called precision medicine , to relatively innocuous, though possibly intrusive, routines (as in superstitions), to frankly pathological states (as in compulsions). The common thread is the reliance on the mechanisms supporting habit formation. Neurofunctional models of OCD describe an imbalance between the goal-directed and the habit system of action control, which would lead to over-reliance on the latter (Gillan and Robbins, disturbance in the way in which one's body weight or shape is experienced,\u201d the other criteria being significantly low weight and intense and persistent fear of becoming fat. In AN body size is generally overestimated (Schneider et al., Perceiving our body in space is instrumental to all approach/avoidance interactions with the environment (Sirigu et al., Overestimation of bodily space is not exclusive to AN. Young and perfectly healthy individuals misjudge their body size, particularly along the width dimension (Casper et al., So far, we provided two among many possible examples (e.g., agoraphobia, Indovina et al., For example, detecting and learning associations, a relevant step in habit formation, varies considerably based on personality traits and cognitive style (Kaufman et al., In sum, susceptibility factors for pathology may be nested within cognitive variability and\u2014though still poorly explored\u2014should be considered alongside psychosocial and biological markers (Jacobi et al., variability into the newly developing models of disease.Recent neuropsychological approaches to psychiatry have underlined the multifactorial origin of mental illnesses, drawing attention to cognitive variables (Wood et al., The study of cognitive variability is notoriously laden by methodological and reliability issues (Hedge et al., and applying the visuospatial skills required to view oneself \u201cfrom the outside\u201d (deVignemont, and constitute a vulnerability trait for disease. Detecting this trait within the healthy population (whereby variability exists; Samuel et al., Consider the example of body-size delusions. Describing one's body implies reporting beliefs and/or attitudes related to it Thus, while not implying a causal link between one cognitive style and development of a psychiatric condition, investigating cognitive variability could prove fruitful in characterizing disease and informing on the most probable direction malfunctioning could take, should other factors co-occur.ED drafted the paper. All authors discussed the ideas presented in the paper. All authors reviewed and approved the submitted version."}
+{"text": "Xu et al.) respectively.Our interest in Non-coding RNA and Wnt/\u03b2-catenin Signaling Pathway in Human Cancer were initiated from our earlier studies: one was that the long non-coding RNA (LncRNA-NEF) antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/\u03b2-catenin signaling  and anotOut of the many manuscripts that we have received, seven were published in this research topic, including 2 reviews and 5 original research articles.Mu et al. summarized recent studies on the function and mechanisms of tumor resistance to cisplatin mediated by circular RNAs (circRNAs). The authors described various types of mechanisms in detail and the role of circRNAs in regulation of tumor proliferation, invasion, chemosensitivity, and other biological behaviors in the tumor microenvironment (TME). The authors emphasized that circRNA can be used as a promising target gene to reverse drug resistance and improve therapeutic efficacy.One review contributed by Li et al. summarized studies on the regulatory mechanisms of lncRNAs and their target gene signaling pathways in laryngeal squamous cell carcinoma, which is the second most frequent tumor of the respiratory system. This has significance in that by summarizing ncRNAs biological functions and important regulatory mechanisms in laryngeal squamous cell carcinoma the authors provide ideas for the improvement of diagnosis, prognostic evaluation, and development of pre-clinical targeted drugs.A second review contributed by Zhu et al. reported that the lncRNA LINC-PINT suppresses cell proliferation, invasion and Epithelial\u2013Mesenchymal Transition (EMT) by blocking Wnt/\u03b2-catenin signaling in glioblastoma. They started with bioinformatics prediction of the role of LINC-PINT, followed by in vitro RT-PCR, clonal assays, and wound healing experiments to study the mechanism, and then they used in vivo tumor grating experiments to confirm the role of this lncRNA.The article contributed by Liu et al. and colleagues reported that microRNA (miRNA)-142-3p inhibits tumorigenesis of colorectal cancer (CRC) via suppressing the activation of Wnt signaling by directly targeting \u03b2-catenin. They used clinical samples and compared miRNA expression profiles between healthy donors and CRC patients. Colony formation and MTT assays were used to test cell proliferation. Luciferase assay, immunohistochemistry, and Western blotting were employed to explore the molecular mechanisms.Chen et al. reported that the lncRNA SNHG1 regulates the proliferation, apoptosis and autophagy of prostate cancer cells (PCa) via the Wnt/\u03b2-catenin and PI3K/AKT/mTOR signaling pathways. The PCa cells were transfected with a small interfering RNA plasmid (si-SNHG1) and si-SNHG1+multicellular protein EZH2 small interfering RNA plasmid (si-EZH2) to study the molecular mechanisms. Another article related to PCa was contributed by Jia et al. who reported that a traditional Chinese medicine Astragalus polysaccharides (APS) inhibits tumorigenesis and lipid metabolism through the miR-138-5p/SIRT1/SREBP1 pathway in prostate cancer. The approach used was microarray studies upon drug (APS) exposure, and they have successfully shown that ecoptic expression of SIRT1 inhibits the expression and nuclear translocation of SREBP1 via activating AMPK phosphorylation.The article contributed by Shao et al. studied the anti-tumor mechanisms of curcumin in hepatocellular carcinoma (HCC). The authors reported a novel role for curcumin in inducing cell cycle arrest and apoptosis by downregulating the lncRNA LincROR, in turn reducing \u03b2-catenin and inactivating Wnt signaling. They approached the study by choosing lncRNAs that were previously reported to be related to tumorigenesis, and LincROR was the most down-regulated in the curcumin-treated HCC cells by examination of their expression levels.Altogether, this research topic on non-coding RNA and Wnt/\u03b2-catenin Signaling Pathway in Human Cancer provided new ideas and mechanistic data on the role of several ncRNAs in cancers, shedding new light on the current state of the field and, more importantly, providing new avenues for future diagnostic and therapeutic avenues."}
+{"text": "Chronic Inflammation and Neurodegeneration in Retinal Disease, Volume II\u201d presents eight original research articles and one mini review from seven different countries with important contributions in the field of retinal inflammation. Most of the contributions are related to diabetic retinopathy (DR), the others cover age-related macular degeneration (AMD), retinitis pigmentosa, and the spontaneous polygenic model of inherited retinal dystrophy.Inflammation and neurodegeneration have a widely recognized role in the pathogenesis of the main retinal conditions. However, the exact mechanism through which inflammation causes alteration of the retinal structure\u2014with consequent dysfunction of the retinal pigment epithelium, of neurons, and ultimately of photoreceptors\u2014is not entirely known. This Research Topic \u201cStravalaci et al. focused on long pentraxin 3 (PTX3), an emerging new player in ocular homeostasis and a potential pharmacological target in neurodegenerative disorders of the retina. Physiologically present in the human eye and induced in inflammatory conditions, this protein is strategically positioned at the blood retinal barrier interface, where it acts as a \u201cmolecular trap\u201d for complement and modulates inflammation both in homeostatic and pathological conditions such as AMD and DR. Gesualdo et al. presented an interesting study on fingolimod and DR, investigating the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 . This Research Topic is a typical example of repurposing since fingolimod is a drug approved to treat relapsing-remitting multiple sclerosis. The authors demonstrated, in an in vivo model of DR, that fingolimod has anti-angiogenic activity mediated not only through S1P1R, but also by melanocortin receptors. Another interesting pre-clinical study on DR was provided by Canovai et al. The authors showed the efficacy of a novel substance containing cyanidin-3-glucoside (C3G), verbascoside, and zinc to maintain the integrity of the blood retinal barrier and retinal function in streptozotocin-induced diabetic rats.The review by in vitro study by Schmalen et al. underlined the importance of M\u00fcller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation. These authors demonstrated an intense signaling capacity of M\u00fcller cells, which reacted in a highly discriminating manner upon treatment with different cytokines, showing several characteristics of atypical antigen-presenting cells.Accumulating data provide evidence for a pivotal role of M\u00fcller cells in the pathogenesis of DR. In this regard the Parravano et al., where the authors carried out a randomized clinical trial on patients with diabetic macular edema (DME) treated with a special oral curcumin formulation with a polyvinylpyrrolidone-hydrophilic carrier and intravitreal injections of dexamethasone. They demonstrated a significant reduction in central retinal and inner retinal layer thickness with the combined therapy in patients affected by DME. This study also showed that the pharmacological combination therapy (curcumin and dexamethasone) was well-tolerated. On this regard, a good long-term safety profile of intravitreal dexamethasone has been demonstrated on real-world studies when used to manage DME -induced macular edema, steroid implant is a valid option for DME patients not responding to anti-VEGF therapy and non-DME patients with macular edema. The final contribution on the topic of DME focused on the anti-inflammatory effects of subthreshold micropulse yellow laser (SMYL). The authors, Bonfiglio et al., demonstrated that SMYL may reduce macular thickening and improve best-corrected visual acuity in eyes with persistent macular edema after pars plana vitrectomy and membrane peeling for tractional DME.An important clinical contribution on the Research Topic of DR has been provided by nage DME . Furthernage DME . AnotherHollingsworth et al.) have used systems genetics to identify possible models of spontaneous polygenic AMD by mining the BXD family of mice using single nucleotide polymorphism analyses of known genes associated with the human retinal disease. The goal of these scientists was to propose a pre-clinical mouse model (BXD32) to better understand the pathophysiology of progressive retinal dystrophies and discover efficacious treatments. Their study demonstrated that the BXD32 mouse strain exhibits a severe neurodegenerative phenotype accompanied by adverse effects on the retinal vasculature. Finally, Canto et al. showed that sulforaphane, a natural compound, modulates the inflammation and delays neurodegeneration in a retinitis pigmentosa (RP) mouse model. Specifically, they assessed the modulation of glial cells in the RP rd10 mouse model showing that sulforaphane treatment regulated the microglial activation state.A group of scientists from University of Tennessee (Overall, the contributions of the present Topic Research focused on inflammation and retinal degeneration, highlighting new insights in retinal diseases mechanisms and novel pharmacological approaches."}
+{"text": "Inflammation is a well-known consequence of many traditional cancer treatments that can serve to enhance antitumor immunity and promote unwanted side effects. These side effects are often sustained long after cancer treatment has ended and may coincide with sustained chronic low-grade systemic inflammation that compromises the health of organs in the body and central nervous system (CNS). Assessment of circulating cytokines and their downstream products are considered to serve as potential biomarkers for systemic inflammation, identifying cancer survivors at risk of inflammation-associated disorders. In relation to the CNS, inflammatory markers are associated with cancer-related fatigue ; anxietyWe congratulate Bower et al.  for condThe longitudinal nature of the study  is a majBower et al.\u2019s  findings\u039aB) transcription pathway. Studies in patients with schizophrenia who, apart from psychosis, share several anxiety, depression, and cognitive symptoms with cancer patients, have identified a subgroup of patients that exhibit elevated brain and blood cell NF-\u039aB\u2013mediated cytokines. These low-grade cytokine elevations are explained by dysregulation of the NF-\u039aB, including reduced expression of NF-\u039aB pathway inhibitors (Although CRP and cytokine levels in Bower et al.\u2019s  study arhibitors . Althoughibitors  compelliIn addition to providing a platform for new approaches and discoveries regarding the measurement of inflammatory biomarkers in cancer patients, Bower et al.\u2019s  work claAnother direction for investigation is related to the evolving treatment landscape. For example, an increasing number of women are receiving T-DM-1. Given there are more prevalent and severe toxicities associated with T-DM1 compared with Trastuzumab , future As the RISE study focuses on fatigue and longitudinal design , we awaiNo funding was used for the writing of this editorial.Role of the funder: Not applicable.Disclosures: The authors have no disclosures to declare.Author contributions: AKW, RJC, JLV: writing\u2014original draft, writing\u2014review & editing."}
+{"text": "Renal fibrosis is the progressive and complicated process manifested by histological aberrance and functional decline in the kidney. The pathogenesis involves multiple molecular pathways and cellular targets leading to myofibroblast activation and accumulation of extracellular matrix, which is in response to excessive epithelial injury and inflammation. Formation and exacerbation of fibrosis during the development of chronic kidney disease (CKD) is the common pathway to end-stage renal failure. However, few interventions are available that specifically target the pathogenesis of renal fibrosis. Emerging evidences prove that natural product therapy directly targets the pathogenesis of renal fibrosis, and exhibits beneficial effects in clinical. Further research (such as multi-omics studies and network pharmacology) is urgently needed to investigate the puzzle from the active compounds to underlying mechanisms and therapeutic targets of natural product against renal fibrosis.The Research Topic intends to highlight the latest advances from the active compounds to underlying mechanisms and therapeutic targets molecular mechanism of natural product against renal fibrosis. The issue includes 25 articles that is contributed by more than 200 authors in the fields of renal pharmacology. We have generated a collaborative discussion that facilitated the development of new mechanisms, new therapeutic targets, and candidate drugs from natural product against renal fibrosis.Zheng et al. illustrate that astragalus polysaccharide extract plays a beneficial role in reducing renal inflammation and fibrosis and in improving renal function by regulating the TGF-\u03b2/ILK pathway in hypertensive mice. Ren et al. confirm that natural flavonoid pectolinarigenin alleviates renal fibrosis to delay hyperuricemic nephropathy via suppressing TGF\u03b2/SMAD3 and JAK2/STAT3 signaling pathways. By targeting non-TGF-\u03b2 pathway, Yu et al. report the medical leech saliva extract, hirudin, protects the kidney from fibrotic injury by ameliorating renal autophagy impairment via PI3K/Akt pathway. Liu et al. demonstrate that quercetin alleviates podocytes apoptosis in vitro and in vivo by regulating the EGFR pathway, providing a novel approach to reveal the therapeutic mechanisms of quercetin against DN. Gong et al. identify proanthocyanidins (OPC) as active compounds of grape seeds. OPC exhibits beneficial protection against cadmium-induced DN in multidimensional aspects by the regulation of oxidative-antioxidative status, metal-binding ability, mediation of the levels of essential elements, and activation of the p38 MAPK and Keap1/Nrf2 signaling pathways.New mechanisms of renal fibrosis and the protective effects of natural product have been investigated and uncovered. Fibrosis-related signaling pathways are the common therapeutic targets, especially TGF-\u03b2 pathway. Ma et al. prove that farrerol reverses oxidative stress, inflammation, and fibrosis in renal tubular epithelial cells by activating Nrf2 and subsequently increasing PINK/Parkin-mediated mitophagy and eliminating damaged mitochondria. Xiang et al. show that the restoration of PPAR\u03b1 activity delays diabetic nephropathy progression and attenuates lipid metabolism disorders by downregulating miR-21 expression to improve mitochondrial function. Li et al. report that maintaining the balance of mitochondrial dynamics exhibits renoprotection in kidney by inhibiting mitochondrial fission and promoting mitochondrial fusion via the downregulation of the primary mediator proteins of mitochondrial fission (Drp1 and Fis1) and the upregulation of fusion proteins (Opa1 and Mfn1). Zhang et al. carries out the serum metabonomics analysis of patients with diabetic kidney disease and shows the potential role of specific gut microbiota in the progression of renal fibrosis and diabetic kidney disease that involves the dysfunction of phenylalanine and tryptophan metabolisms. This study suggests the kidney-gut axis functions as a potential therapeutic target of renal fibrosis.Additionally, metabolic regulation and kidney-gut axis function as a promising therapeutic target against renal fibrosis. Shao et al. summarized five Chinese herbal medicines with sufficient clinical efficacy, high frequency of use, and well-studied mechanism, including Abelmoschus manihot and Huangkui capsule, Salvia miltiorrhiza and its components ; Rhizoma coptidis and its monomer berberine; Tripterygium wilfordii and its components ; Kudzu root Pueraria and its monomer Puerarin. The researches of these five Chinese herbal medicines set the study pattern for natural product against renal fibrosis, which are the promising candidate for widespread and standardized application.Since Chinese herbal medicine exhibits beneficial effects against renal fibrosis, the lack of randomized controlled trial and clear mechanism hinder natural product to pass modern assessments. Here, Dong et al. designed a multicenter, nonrandomized, single-arm clinical trial to explore the clinical effects of MFSD on idiopathic membranous nephropathy (MN), presenting an inspiring result that MFSD has significantly beneficial effects on idiopathic MN treatment, and has the same beneficial effects on patients with MN who are newly treated and who accepted with immunosuppressive therapy without remission. Further study from the same group by Gao et al. investigates the main active compounds of MFSD by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and more than 30 active compounds are identified. These active compounds alleviate podocyte injury by modulating autophagy-related protein and Wnt/\u03b2-catenin pathway, indicating autophagy and Wnt/\u03b2-catenin pathway as potential targets of MFSD for MN treatment. Zhang et al. demonstrate the anti-fibrotic and anti-inflammatory effects of Bupi Yishen Formula in vivo and in vitro by suppressing TLR4-mediated NF-\u03baB signaling.The study of Luo et al. reveals the anti-oxidant and anti-inflammatory ability of Shenkang injection (SKI) in kidney, and identifies chrysophanol, emodin, and rhein as active compounds against renal fibrosis via simultaneously targeting I\u03baB/NF-\u03baB and Keap1/Nrf2 signaling pathways. Jia et al. report TLYS decoction improves mitochondrial dynamics to attenuates renal fibrosis and renal function decline by suppressing oxidative stress and mitophagy. The comparative network pharmacology analysis is the alternative approach to explore the mechanisms of natural products with limited experiments. Chan et al. performed comparative network pharmacology to figure out the mechanism of Liu-wei-di-huang-wan. Liu-wei-di-huang-wan may ameliorate fibrosis, angiogenesis, inflammation, disease susceptibility, and oxidative stress via modulating TNF signaling pathway, which could be validated through clinical trials.Beyond to five Chinese herbal medicines, studies from the present issue provide the clinical evidences of natural products against renal fibrosis and explore underlying mechanisms. Mahuang Fuzi and Shenzhuo Decoction (MFSD), a Chinese herbal formula, is a promising candidate for renal fibrosis and CKD treatment in clinial. In conclusion, the collection of 25 articles in the Research Topic contributes to better understanding of natural products against renal fibrosis from the active compounds to underlying mechanisms and therapeutic targets. These studies provide promising and potential candidates against renal fibrosis by modulating novel pathways in clinical trial and animal experiment. Accompanying with the evolution of high throughput screening method and model, novel candidates and therapeutic targets will emerge to facilitate the drug discovery, which hold great potential for treatment with renal fibrosis."}
+{"text": "The implementation of sustainable food packaging solutions within future circular food supply chains is essential to protect customers and ensure food quality, safety, and optimal shelf-life. This will be improved by new innovative packaging materials and will contribute to reducing food waste. In this direction, it is important to employ lifecycle assessment (LCA) to define food supply chain impacts, taking into consideration food waste, global food industry environmental impacts, and shipping distances, with the aim of achieving consumer satisfaction. It is important to share data on (i) the consequences of specific food product\u2013package interactions, (ii) the consideration of the utilization of novel packaging biomaterials, and (iii) overall consumer behavior and satisfaction as a critical focus. The aim of this Special Issue was to bring the most updated information in the new era of sustainability and food packaging.D\u00f6rnyei et al.  proposedThe work of Wang et al.  presenteThe study of Shin et al.  showed tPleva et al.  investigChen et al.  developeSalmonella enterica via different contact materials (polypropylene from reusable plastic crates (RPCs), corrugated cardboard, and medium-density fiberboard (MDF) from wooden boxes). The survival of the pathogenic microorganism was studied in cauliflowers and the contact materials during storage. The LCA approach was used to evaluate the environmental impact of produce-handling containers fabricated from the different food-contact materials tested. The results showed a higher risk of cross-contamination via polypropylene compared with cardboard and MDF. Another outcome of the study was the potential of Salmonella surviving both in cross-contaminated produce and in contact materials under supply chain conditions. Regarding environmental sustainability, RPCs showed a lower environmental impact than single-use containers (cardboard and wooden boxes).L\u00f3pez-G\u00e1lvez et al.  assessedCruz et al.  presenteIn the article of Miller et al.  various The review from Krauter et al.  contextuBauer et al.\u2019s  study aiIn another study, Bauer et al.  presenteJunior et al.  presente"}
+{"text": "At present, cancers are described in both biological and clinical settings with static models that characterize tumors by the phenotypic and genotypic features observed at a given time point. However, cancers are highly dynamic processes that evolve based on specific genomic and epigenomic changes. Such dissonance between the model used to describe tumors and their true nature reverberates all the way from basic biological research to clinical practice. For instance, it is well established that anti-cancer treatments impose selective pressures leading to the emergence of resistant clones . This evHistorically, the first barrier to the characterization of the evolutionary properties of cancer was the limited amount of available data to accurately reflect tumor heterogeneity, which was traditionally based on a single tissue biopsy . Severala priori expectation when we proposed this research topic was to be confronted by a barrage of works focusing mainly on the genetic aspects of cancer evolution. Looking retrospectively at the collection of accepted manuscripts, however, we were surprised to observe some specific yet unexpected topics recurrently emerging.The articles in this research topic address important aspects of cancer evolution, encompassing models associated with a diversity of tumor types including renal cell carcinoma, glioblastoma, breast, colorectal, lung, ovarian, pancreatic and prostate cancer. Our Duic\u0103 et al.; Gao et al.; Qi et al.; Li et al.; Zheng et al.; Li et al.; Chen et al.; Zhao et al.). Duic\u0103 et al. presented a review of the role of miRNAs in cancer-relevant processes, focusing on gynecological malignancies . Another study  evaluated exosomal miRNAs as a mechanism of resistance in small cell lung cancer with particular elevation of exosomal miR-92b-3p that was associated with the PTEN/AKT pathway based on preclinical models . Importantly, this study also included a clinical cohort of 50 patients to help validate the authors\u2019 hypothesis that downregulation of this biomarker was associated with better clinical outcomes. Junchen Li et al., instead, focused on the anti-cancer mechanism of andrographolide in patients with luminal-like breast cancer through the inhibition of miR-21-5p . Similarly, Chen et al. investigated the role of circular RNA (circRNAs) in prostate cancer. The authors focused on the regulation, expression, and functional effects of circNOLC1 for in vitro and in vivo models, proposing circNOLC1 as a potential biomarker and target for prostate cancer treatment.Multiple articles within this collection focused on the role of non-coding RNA in cancer, including in particular microRNA (miRNA), circular RNA (circRNA) and long non-coding RNA (lncRNA) . Qi et al. evaluated lncRNAs as potential biomarkers to assess heterogeneity in metastasis for colon and rectal cancers. The analysis identified two biomarker lncRNAs, KCNQ1OT1 and SNHG1, associating with cancer initiation and metastatic potential. Interestingly, the authors proposed different mechanisms of actions of these two lncRNAs in colon and rectal cancers . Finally, Zheng et al. identified a panel of prognosis-associated lncRNAs that were significantly associated with survival in ovarian cancer across multiple independent cohorts, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The authors further selected and validated the expression of four lncRNAs in vitro on multiple ovarian cancer cell lines .Multiple studies focused on lncRNAs as well. Zheng et al. published a review on the communication between EMT and cancer stem cells (CSC). While this was once thought to be an unidirectional evolution, more recent studies suggest that this transition is bi-directional, stochastic, and mediated by the tumor microenvironment, ultimately showing how such \u201chybrid state\u201d or \u201cplasticity\u201d is linked to poor prognosis and resistance. Cui et al. studied the role of ENC1 in accelerating EMT processes in colorectal cancer, whereas the study by Shou et al. reported an inverse relation between tissue inhibitor matrix metalloproteinases 1 (TIMP1) and prognosis in samples from patients with renal cell carcinoma. The study evaluated TIMP1 as a biomarker to enhance metastasis via the EMT signaling pathway. Another study explored EMT-related genes using TCGA and local samples for pancreatic ductal adenocarcinoma . This study identified a 8-gene signature that impoved prediction compared to clinical variables alone, particularly to assess adjuvant treatment response, such as to immune checkpoint inhibitor therapy. In the future, evaluating therapies that target cells in this \u201chybrid\u201d EMT state may have specific applications to prevent seeding of metastatic sites.A second theme that was recurrent in our collection is the plasticity of the epithelial-mesenchymal transition (EMT). Within this collection, Lu et al. produced a review of Liquid\u2013liquid Phase Separation (LLPS) and protein/nucleic acid condensates. LLPS are a new paradigm in the study of cellular activities recently coming under more intense research focus. Recent progress has been made to understand the roles of LLPS in cancer. Additionally, Dai et al. published a review on RNA modifications and their role in cancer with a deep discussion on the YTH protein family of m6A readers, summarizing the recent advances in structure and biological function of YTH family proteins, and their roles in human cancer and therapy applications.Finally, it is worth mentioning two reviews on protein condensates and RNA modifications. This collection of articles highlights promises and challenges of characterizing the dynamic aspects of cancer. They nicely expose the critical need for multi-omics biomarkers to track cancer evolution in both research and clinical settings. Interestingly, we observed an emerging interest towards previously less studied molecular players, such as non-coding RNAs, condensates, and RNA modifications, both in the context of cancer cells and tumor microenvironment. We anticipate that the use of integrated models based on multiple biomarkers  will be necessary to capture the complexity of cancer evolution, especially in today\u2019s clinical settings dominated by a paradigm shift from monotherapy approaches towards combinations of chemotherapy, immune checkpoint inhibitors and targeted therapies."}
+{"text": "Cassia occidentalis Linn. stem using liquid chromatography tandem mass spectrometry: application to its pharmacokinetic studies\u2019 by Mohammed Riyazuddin et al., RSC Adv., 2020, 10, 4579\u20134588. DOI: 10.1039/C9RA07482ACorrection for \u2018Simultaneous quantification of five biomarkers in ethanolic extract of  The authors regret that the one of the affiliations (affiliation d) was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Considered a simple and versatile technique, electrospinning has emerged as a technology for developing 3D materials for a wide range of applications. Electrospun fibers ranging from nanometers to micrometers in diameter have been applied in many research areas including chemistry, materials science, engineering, and chemical engineering, as well as medicine, pharmacology, and pharmaceutics. Based on a large variety of polymers , types of collectors, and nozzle configurations, a vast and complex number of electrospun materials can be obtained, allowing those electrospun fibers to be applied for catalysis , separatBased on In their review entitled \u201cTunable Spun Fiber Constructs in Biomedicine: Influence of Processing Parameters in the Fibers\u2019 Architecture\u201d, Felgueiras et al. described how processing parameters can affect the architecture of electrospun fibers . In addiSt. John et al., in their review entitled \u201cAdvances in Electrospun Nerve Guidance Conduits for Engineering Neural Regeneration\u201d, reported the capability of the electrospun approach to fabricate fibers of various scales and which have a large surface area with a three-dimensional porous structure resembling the native extracellular matrix for regeneration of the nervous system . ConsideIn the third review published in this Special Issue\u2014\u201cOsteochondral Tissue Engineering: The Potential of Electrospinning and Additive Manufacturing\u201d by Costa et al.\u2014the most recent advances in osteochondral tissue engineering are summarized . The autIn two different research articles, Tawfik et al. reported the uses of coaxial electrospun fibers for as fast dissolving matrixes. In the paper entitled \u201cFabrication and Characterization of Fast-Dissolving Films Containing Escitalopram/Quetiapine for the Treatment of Major Depressive Disorder\u201d , authorsChen et al. demonstrated uses of aligned core-shell fiber for the delivery of docosahexaenoic acid and brain-derived neurotropic factor  . The cord,l)-lactide-co-glycolide (PLGA) nanofibers were loaded and spun on the metal stent. Electrospun fibers were characterized and the presence of drug on the material\u2019s surface was suggested based on water contact angle. The drug release was evaluated, in which the telmisartan was released over 30 days. In vitro and in vivo results of hybrid stent/PLGA nanofibers loaded with telmisartan indicated that this material can controllably release disease-relevant therapeutics, enhance the migration of endothelial progenitor cells, providing complete endothelial coverage and recovery, and reducing intimal hyperplasia.The research article \u201cTelmisartan Loaded Nanofibers Enhance Re-Endothelialization and Inhibit Neointimal Hyperplasia\u201d by Lee, Kuo, Liu and co-authors demonstrated the electrospun nanofibers loaded with telmisartan for sustained and local delivery of drug to injured arterial vessels . Poly evaluated the antibacterial activity of the fibers loaded with curcumin against polyresistant bacteria, using hyaluronic acid sodium as a polymer basis . Based ol-lactide-co-poly-\u03b5-caprolactone (PLA-PCL) electrospun tubular scaffold engineered with mesenchymal stem cells (MSCs), in order to promote and speed up the regeneration process, ensuring an adequate support to esophageal tissue reconstruction, avoiding the use of autologous conduits. They observed an interesting correlation between the asymmetrical shape of the scaffold and its p-MSCs cellularization process, which helped in keeping the scaffold\u2019s mechanical properties suitable for esophageal application. The authors also observed that the advantage of their pro-posed scaffold with hybrid composition (polymer combined to p-MSCs). Preliminary results collected after in vivo implantation in a porcine model were promising; but further studies are required to statistically validate the data.In terms of biologic applications, Pisani et al., in their research entitled \u201cEngineered Full Thickness Electrospun Scaffold for Esophageal Tissue Regeneration: From In Vitro to In Vivo Approach\u201d , developSteinberg et al.,  , developKim, D., Kim, S., and co-authors detailed in their article entitled Enhanced Differentiation Capacity and Transplantation Efficacy of Insulin-Producing Cell Clusters from Human iPSCs Using Permeable Nanofibrous Microwell-Arrayed Membrane for Diabetes Treatment  a biodegDean, Thomas, and co-authors detailed, in \u201cUni-Directionally Oriented Fibro-Porous PLLA/Fibrin Bio-Hybrid Scaffold: Mechano-Morphological and Cell Studies\u201d , a biohyCurrently, numerous polymers, blends and hybrid systems have been electrospun in order to improve these materials in biomedical applications. In addition to the several approaches in order to obtain electrospun fibers with a vast range of morphologies, including coaxial and side-by-side nozzles, and different collectors, combining this strategy with others microfabrication techniques has increased the applicability of these materials for different biological systems and chemical sciences."}
+{"text": "RSC Adv., 2018, 8, 18396\u201318399.Correction for \u2018Synthesis and optical properties of lead-free cesium germanium halide perovskite quantum rods\u2019 by Lin-Jer Chen,  The affiliation in the original article was incorrect. The correct affiliation is listed herein.RSC Advances article and their previous related paper published in Journal of Physical Chemical Letters, cited as ref. 21 in the original article.The author apologises that there are portions of text overlap between this In addition, there is an error in the \u2018Characterization and measurements\u2019 section of the ESI. The first sentence should be changed from \u201cThe as-prepared samples were characterized by X-ray powder diffraction (XRD), and transmission electron microscopy (TEM)\u201d to \u201cThe as-prepared samples were characterized by X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM)\u201d. There was no XRD data reported, therefore the ESI has been updated online to reflect this change.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The skin is comprised of multiple types of cells that serve as a protective barrier. Mutations in the genes that are responsible for protecting the functional integrity of the skin are often found in many inherited skin diseases, more commonly known as the Mendelian human skin disorders. Advances in molecular techniques and sequencing technologies have enabled identification of novel pathogenic variants, which helps to provide insight into genotype\u2013phenotype correlations and to define the genetic basis of these skin disorders. In this Research Topic, a total of ten articles are published, including those describing findings from case studies and original research, as well as a mini review of current genetic diagnosis strategies, novel gene variants, and genotype\u2013phenotype correlations in human Mendelian skin disorders.Xu et al. report on the use of WES in identifying a de novo pathogenic variant c.2T>C (p.M1T) in KLHL24 in Chinese twin boys with epidermolysis bullosa simplex. Similarly, Wang et al. demonstrate the detection using WES of a missense mutation, c.1156G > A (p.Ala386Thr) in DKC1, which leads to a benign form of dyskeratosis congenita syndrome with the mucocutaneous triad. In another article appearing in the Research Topic, WES analysis also reveals a heterozygous missense mutation c.293G>A in GJB3, which is associated with erythrokeratodermia variabilis, ichthyosis, and non-syndromic hearing loss Gao et al.Recent developments in genome-wide association studies (GWAS) and next-generation sequencing (NGS) techniques have resulted in an integrative approach to the use of functional genomics and expression data in deciphering the causative genetic variants of inherited skin diseases. Because most of the mutations identified in human Mendelian skin disorders reside in protein-coding genes, whole exome sequencing (WES) has been widely used in the identification of such pathogenic variants, and in the genetic diagnosis of Mendelian skin conditions with atypical or unique phenotypes. Wang et al. the genetic profiling of epidermolysis bullosa cases Alharthi et al. and the discovery of a novel CREBBP variant for genetic diagnosis of Rubinstein\u2013Taybi Syndrome Lee et al. Recent evidence from large-scale expression studies (using microarrays and RNA sequencing) has also revealed the roles played by non-coding RNA molecules, such as small non-coding RNAs or miRNAs, in the pathogenesis of several complex skin diseases  with a significant pathogenicity score. In addition, a novel homozygous missense mutation (p.L154R) in gene ABHD5 has been detected in a patient with Chanarin\u2013Dorfman syndrome, a rare autosomal recessively inherited genetic disease Liang et al. Finally, Wu et al. also report in this Research Topic on a new case of congenital poikiloderma with a novel missense mutation in the FAM111B gene c.1883G>A (rs587777238).Molecular genetic studies based on family case reports and large-scale regional profiling analyses often provide significant insight into novel pathogenic variants, thereby helping to extend the spectrum of the genetic profile, improve diagnosis, and establish an improved understanding of human Mendelian skin disorders. In this Research Topic, Xu et al. provide an initial description of their discovery of a c.2T>C pathogenic variant in KLHL24, affecting twins in China, and its correlation with epidermolysis bullosa simplex. Their research has identified correlations between phenotypes and genotypes in epidermolysis bullosa, in which KLHL24 pathogenic variants are associated with the mild phenotype. In contrast, the study by Liang et al. on genotype\u2013phenotype analysis in patients with reported Chanarin\u2013Dorfman syndrome reveals no correlation. Meanwhile, as indicated in a review by How et al. there is no significant genotype\u2013phenotype relation in incontinentia pigmenti, a rare type of X-linked dominant genetic disease characterized by ectodermal dysplastic disorder. However, the literature does suggest that variation in a combination of the types of mutations, functional domains affected, X-inactivation, and genomic background may lead to the variability observed in incontinentia pigmenti phenotypes How et al. The authors propose that a detailed understanding of the genotype\u2013phenotype correlation in incontinentia pigmenti will support further investigations concerning prognosis and future reproductive options. Meanwhile, a recent large cohort study involving investigation of genotype\u2013phenotype correlations in patients with autosomal recessive ichthyosis has provided new insights on and definitions of specific phenotypic clues for corresponding genetic mutations (Certain phenotypic features of inherited skin disorders may be associated with particular gene mutations, but paradigms for clinical genotype\u2013phenotype correlation remain unclear in many instances due to the highly variable phenotypic expressivity of the relevant mutations; these paradigms require further refinement. In this Research Topic, utations . In addiutations .In summary, this Research Topic enhances our knowledge of recent exciting progress in the field of genodermatosis, including molecular diagnostics protocols, novel pathogenetic variants, and genotype\u2013phenotype correlations. Together, these studies provide value in the form of greater diagnostic precision, a source of information for clinical assessments, and ways to improve clinical care and management."}
+{"text": "Cardiovascular and metabolic bone diseases are demanding health problems with high morbidity and mortality ,2. AlthoIn this context, the Special Issue (SI) \u201cDietary Bioactives: Their Role in the Prevention and Treatment of Cardiovascular and Metabolic Bone Diseases\u201d has published nine novel papers on this topic ,13,14,15The narrative review was published by Mandatori et al. (2021). The authors summarized the most relevant recent knowledge concerning the role of Vitamin K2, a bioactive compound with a key role in the \u201ccalcium paradox\u201d phenomenon, which involves both vascular and bone tissue . The chaLycii radicis cortex in a paper published by Park et al. (2021). Using an animal model of ovariectomized-induced osteoporotic mice, the authors identified scopolin as the candidate bioactive compound extracted from Lycii radicis cortex capable of preventing and treating osteoporosis [Cucurbita moschata leaves, a pumpkin cultivar in Western countries, were published by Lambertini et al. [Subsequently, the specific mechanism of Vitamin K2 in bone health was also addressed in an in vitro study . Specifioporosis . Finallyi et al. .Allium sativum extract in an ex vivo study on mouse heart samples exposed to E. coli lipopolysaccharide inflammatory stimulus [i) the capability of Sasa quelpaertensis to ameliorate metabolic dysfunction conditions including dyslipidemia, insulin resistance, and hepatic lipid accumulation, induce in rats by a high-fructose-diet [ii) the protective effects of Vitis labrusca on cardiovascular dysfunction due to hypertensive conditions\u2014employed the model of Spontaneously Hypertensive Rats [Regarding cardiovascular health, in this Special Issue, one in vitro, one ex vivo and two pre-clinical animal studies were published. Baldassare et al. (2021) reported the anti-inflammatory and anti-oxidative role of myo-inositol using a model of cultured human endothelial cells isolated from the umbilical cord vein of women affected by gestational diabetes . Indeed,stimulus . Additioose-diet  and (ii)ive Rats .Finally, in this SI, Esposito et al. (2021) published a cross-sectional analysis performed on a sub-cohort of 4592 subjects from the Moli-sani Study (2005\u20132010) which suggested that intake polyphenols, which contribute to slowing down the biological aging process, may exert protective effects on the long-term risk of cardiovascular and metabolic bone disease development .In conclusion, this SI allowed us to publish a number of encouraging scientific studies based on in vitro, ex vivo and in vivo approaches confirming the increasing interest of researchers in the discovery of new potential bioactive compounds for human health. However, future research must better understand the mechanisms of action of natural molecules and nutritional supplements for the management of cardiovascular and metabolic bone diseases."}
+{"text": "The article of Yamashita et al. illustrates the ability of in situ crystal growth to bypass kinetic barriers between phases, demonstrating the importance of this approach in phase discovery (Oswald et al., 2008Although chemically simple, the salt hydrates are very sensitive to external conditions, with complex energy landscapes containing multiple viable phases. However, transformations between solid phases are frequently kinetically hindered, and KCl\u00b7H"}
+{"text": "The innate immune system is the first line of defense against bacterial and viral infections and sterile inflammation through the recognition of pathogen-associated molecular patterns (PAMPs) as well as danger-associated molecular patterns (DAMPs) by pathogen-recognition receptors (PRRs), and produces proinflammatory and antiviral cytokines and chemokines . Cells is devoted to many aspects of innate immunity and gives an overview of different DAMPs, immune cells, special mechanisms, and therapeutic options for treating diseases related to chronic inflammation or infections.This Special Issue of One of the well-known DAMPs is the high-mobility group box 1 protein (HMGB1), which is either passively released by dying cells or actively secreted by immune and other cells and was described as implicated in both stimulating and inhibiting innate immunity. Andersson et al. reported that the pro- and anti-inflammatory activities of HMGB1 depend on post-translational modification of its disulfide bonds by binding to different extracellular cell surface receptors either directly or as a cofactor of PAMPs . Another DAMP, extracellular ribosomal RNA, which is released under pathological conditions from damaged tissue, acts synergistically with Toll-like receptor 2 ligands, inducing the release of cytokines in a nuclear factor kappa B-dependent manner in vitro as well as in vivo. Grote et al. suggest that extracellular RNA might sensitize Toll-like receptor 2 to enhance the immune response under pathological conditions and therefore might serve as a new target for the treatment of bacterial or viral infections .Arnholdt et al. demonstrate that cells related to innate immunity and influencing immunoregulatory and inflammatory processes, such as gamma delta T cells, play an important role in angiogenesis and tissue generation. By using a femoral artery ligation model in mice, depletion of this subset of T cells was demonstrated to impair angiogenesis, increase the number of leukocytes and inflammatory M1-like macrophages, and promote the formation of neutrophil extracellular traps (NETs) . The topic of autoinflammation is also covered in this Special Issue. The review of P. Georgel provides some examples of autoimmune/autoinflammatory diseases caused by the deregulated expression of type I interferons and interleukin-1\u03b2. The role of interleukin-1 and type I interferons and their crosstalk in autoinflammatory diseases such as rheumatic diseases are analyzed to reveal novel therapeutic opportunities .Gullet et al. discuss the key components of programmed cell death pathways and highlight the plasticity of pyroptosis, apoptosis, and necroptosis as well as significant crosstalk among these pathways. The concept of PANoptosis, an inflammatory cell death pathway that integrates components of different cell death pathways and is implicated in driving innate immune responses and inflammation, is explained . A review by Papendorf et al. provides a comprehensive overview of molecular pathogenesis disorders caused by proteostasis perturbations, and current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation is summarized .2+-binding protein [To investigate the crosstalk between coagulation and innate immunity, the effect of thrombin on macrophage polarization is investigated by Ukan et al. Results demonstrate that thrombin induces an anti-inflammatory phenotype in macrophages, which shows similarities to as well as differences from the classical M2 polarization states regarding the expression of secreted modular Ca protein .D. Suzuki third-instar larvae is described by Carrau et al. as a valuable tool for investigating hemocyte-derived effector mechanisms against pathogens, particularly for the formation of extracellular traps [To investigate insect innate immunity, the in vitro cultivation of primary hemocytes from ar traps . Drugs such as ganciclovir and its pro-drug valganciclovir are often used to treat viremic patients transfected with, e.g., human cytomegalovirus (HCMV). Results from Land\u00e1zuri now suggest that binding and signaling through endothelin receptor B (ETBR) is crucial for viral replication and that selected ETBR blockers inhibit HCMV infections .Lin et al. report that albumin attenuates chronic liver diseases (CLDs) via alleviating inflammation of Kupffer cells caused by bacterial products, which might provide a compelling rationale for albumin therapy in patients with CLDs ."}
+{"text": "Wang et al. develop a new iron cathode electro-Fenton process coupled with a pH-regulation divided electrolysis cell for p-nitrophenol degradation. In the electrochemical Fenton system, an iron plate was used as the cathode to inhibit the release of iron ions and promote the reduction of Fe3+ to Fe2+. Therefore, excellent electrocatalytic degradation performance towards organic pollutants was achieved. Wang and Wang synthesized a NiO modified BiVO4 nanocomposite by a hydrothermal and calcination method. The as-prepared nanocomposite showed enhanced photoelectrochemical performance due to the unique NiO lamellar structure that provided a large number of active sites.Numerous metals and metal oxides have been employed as electro- or photo-catalysts for energy conversion and pollutant degradation. Wang et al. used a sol-gel self-combustion method to prepare carboxylate-rich carbon-modified Fe3O4 magnetic catalysts for heterogeneous Fenton degradation of organic pollutants. The prepared Fe3O4-based catalysts displayed improved heterogeneous Fenton degradation performance due to the enhanced pollutant adsorption. Zhu et al. synthesized a CdS/microcrystalline cellulose nanocomposite photocatalyst using an ultrasonic-assisted method. The prepared nanocomposite photocatalyst displayed enhanced pollutant degradation performance under visible light due to the heterojunction formation that efficiently separates the photogenerated electrons and holes of the photocatalyst. Wang et al. prepared a Co3O4/Ti cathode by electrodeposition for electrocatalytic reduction of nitrate, in which the NO3\u2212 was reduced to N2 and NH4+ by the catalysis of Co3O4/Ti, and then NH4+ was selectively oxidized into N2 assisted by chloride ions and using IrO2-RuO2/Ti as the anode. Qiu et al. prepared Pt-modified TiO2 nanotubes as catalysts for photocatalytic degradation of Rhodamine B (RhB) under UV light. It was reported that the superoxide radical anions (O2\u2212\u2219), photogenerated hole (h+) and hydroxyl radical (OH\u2219) were the main active species contributing for RhB degradation.Bai et al. reported the Fischer\u2013Tropsch synthesis performance of Co-based catalysts supported on graphitized ordered mesoporous carbon. The high catalytic performance resulted from the highly crystallized graphitic structure of the mesoporous carbon and the uniform dispersion of CoO on the support. Dai et al. used ion-exchange, in situ modification and complexation-excessive impregnation modification methods to modify SAPO-11 molecular sieves with Ni. The Ni-modified SAPO-11 molecular sieves were supported by NiWS catalysts for hydroisomerization of n-Hexadecane. The complexation-excessive impregnation modification method led to the best hydroisomerization performance. Huang et al. studied the effect of Ga2O3 on the hydrodesulfurization performance of 4,6-dimethyldibenzothiophene catalyzed by the stepwise impregnation method. Ga2O3 promoted Ni and Mo species to disperse uniformly and doping of more Ni atoms into the MoS2 crystals, increasing the average stacking number and the length of MoS2. As a result, enhanced hydrodesulfurization performance was achieved due to the formation of more NiMoS active phases in the system.In addition, metal and metal oxide based or modified materials have also been used for other catalytic applications. Zhang et al. prepared a series of nanostructured Fe-Cu binary oxides for arsenic removal. The crystallinity and structure of the Fe-Cu binary oxides had a significant impact on the arsenic adsorption performance. The oxides with lower crystallinity showed higher surface hydroxyl density and better adsorption performance. Li et al. reviewed the preparation, classification and applications of templated materials, particularly adsorbents in wastewater treatment. The templating method can endow materials with high specific area and unique porous structures, thereby enhancing the material sorption performance towards aqueous pollutants. Wei et al. reviewed the composite adsorbents for fluoride removal, including the adsorbent types , preparation and sorption performance. The adsorption mechanisms for fluoride removal involving electrostatic attraction, ion exchange, complexation, and hydrogen bonding were also discussed.Adsorption is a simple but effective way for environmental decontamination . VariousYu et al. prepared new biochar from excess sludge, followed by acetic acid modification. The modified sludge-derived biochar displayed improved porosity and enriched\u2013COOH functional groups, thereby enhancing its adsorption performance to uranium. However, the catalytic performance of the sorbent was not discussed. Zeng et al. fabricated porous glass-ceramics based on coal fly ash without using pore forming agents by direct overfiring, in which borax was used to destroy the structure of quartz and amorphous vitreous body in coal fly ash and thus reduce the sintering temperature by the B-O bond. Chen et al. fabricated a non-sintered ceramsite from pyrite tailings for phosphorus removal. Both Plackett-Burman Design (PBD) and Box-Behnken Design (BBD) based response surface methodology were used to optimize the fabrication parameters.Recently, with the promotion of the circular economy, waste based materials have attracted growing interest for various applications, such as fertilizers , carbon Wang et al. reviewed the significant roles of surfactants in oriented immobilization of cellulase on nanocarriers as well as a surfactant reversed micelle system.Cellulase plays a key role in the production of fuel ethanol by enzymatic hydrolysis of lignocellulose, and immobilization of cellulase on the nanocarriers is an effective way to improve the hydrolysis efficiency. In summary, this Research Topic discussed various inorganic materials as catalysts or adsorbents with unique nanostructures and functionalities for energy conversion and environmental decontamination. In the future, inorganic materials will continue to play a vital role in addressing global energy and environmental challenges, such as climate change, energy shortages and environmental pollution. Engineering new high performance heterogeneous catalysts and understanding the limiting factors and their mechanisms in the catalytic reaction are two key research directions that should be paid more attention to."}
+{"text": "The rapidly growing industry of crop biostimulants leverages the application of plant growth promoting rhizobacteria (PGPR) to promote plant growth and health. However, introducing nonnative rhizobacteria may impact other aspects of ecosystem functioning and have legacy effects; these potential consequences are largely unexplored. Nontarget consequences of PGPR may include changes in resident microbiomes, nutrient cycling, pollinator services, functioning of other herbivores, disease suppression, and organic matter persistence. Importantly, we lack knowledge of whether these ecosystem effects may manifest in adjacent ecosystems. The introduced PGPR can leave a functional legacy whether they persist in the community or not. Legacy effects include shifts in resident microbiomes and their temporal dynamics, horizontal transfer of genes from the PGPR to resident taxa, and changes in resident functional groups and interaction networks. Ecosystem functions may be affected by legacies PGPR leave following niche construction, such as when PGPR alter soil pH that in turn alters biogeochemical cycling rates. Here, we highlight new research directions to elucidate how introduced PGPR impact resident microbiomes and ecosystem functions and their capacity for legacy effects. Like other introduced species, plant growth promoting rhizobacteria (PGPR) have unpredictable ecosystem consequences and legacy effects; these outcomes are a current knowledge gap. Commercially available crop biostimulants sometimes contain PGPR that directly or indirectly increase plant productivity or crop yield, stimulate nutrient uptake, improve nutrient cycling efficiency, reduce pathogen loads, and increase plant tolerance to abiotic stress . Interest in this research topic has expanded in recent years. Before 2015, fewer than 10 articles per year were published on this topic; the count jumped to 50+ per year since 2019. Despite increased interest in PGPR, only 12 of the 313 articles included the search term \u2018ecosystem\u2019 and one article included \u2018legacy\u2019. Here, we highlight potential effects of PGPR species introductions that may extend beyond the host plant to ecosystem functions that may persist longer than the PGPR populations , Box 1How do PGPR affect macronutrient and micronutrient cycling beyond host\u2013plant acquisition? PGPR may have traits to solubilize and mobilize macronutrients and micronutrients. Some research into nitrogen and potassium root acquisition and soil leaching currently exists. More research is needed into micronutrients important to plant productivity and organic matter persistence, such as iron and manganese.How do PGPR affect organic matter persistence? PGPR may shift relative abundance or activity of key players in the resident microbiome. These changes in microbe\u2013microbe interactions could cascade to changes in soil properties mediated by microbes such as pH, erodibility, porosity, and water holding capacity of soil. Experimental applications of PGPR under field conditions that quantify soil parameters are needed.What are the multi\u2010trophic consequences of introduced PGPR? PGPR are known to release volatile organic compounds (VOCs) that can deter herbivores. Some VOCs attract pollinators, but whether PGRP VOCs attract pollinators is unexplored. Indirect multitrophic interactions, mediated by changes in plant phenology like budbreak or flowering, may be spurred by PGPR and this remains a current knowledge gap. Additionally, PGPR may indirectly affect resident microbial abundances through antagonisms with bacterivores or fungivores.Do PGPR spread to other plant hosts in the ecosystem? Host specificity is low among biostimulant microbes due to their application across various crops. Thus, escape from crops to adjacent ecosystems has a high potential, although persistence may be negligible. Mitigating effects caused by the escape of biostimulant microbes is an area of active research  contains Bacillus velezensis GB03. Application is intended to reduce pathogens such as those causing blight , root rot (Pythium), and wilt (Fusarium). The hypothesized mechanism is that B.\u2009velezensis induces a systemic immune response across a wide range of plant hosts. Another potential mechanism is that the PGPR increases anti\u2010fungal indigenous taxa (Xiong et\u2009al., Another ecosystem consequence that affects crop yield is plant disease suppression. Many PGPR in biostimulants are added to crops for the purposes of reducing pathogen loads (Pieterse et\u2009al., et\u2009al., et\u2009al., et\u2009al., Microbial interactions affect organic matter persistence. Biostimulant PGPR may have indirect effects on ecosystem functions such as the accumulation and decomposition of organic matter through their interactions with the resident microbiome (Hellequin et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Introduction of new microbes could lead to genetic changes in the inoculant or community, yet the genetic impact of PGPR introductions remains largely unexplored. Any location with a high microbial density, such as the rhizosphere, can support rapid and pervasive horizontal gene transfer (Kent et\u2009al., et\u2009al., et\u2009al., et\u2009al., Legacy effects on resident microbial community structure can arise as PGPR establish and persist following introduction. Establishment and persistence can occur through at least two mechanisms: augmentation and displacement (Kurkjian et\u2009al., et\u2009al., Plant growth promoting rhizobacteria that persist following introduction can leave a legacy by altering their microenvironment to promote their own fitness, through a process known as \u2018niche construction\u2019 (Callahan et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., et\u2009al., Plant growth promoting rhizobacteria introductions that do not persist in the community may still leave legacy effects (Mallon et\u2009al., Introducing PGPR may have unintended effects that cascade throughout the resident microbiome, adjacent plant communities, and the whole ecosystem Box\u2009. We urgeJAMM wrote the initial draft of this manuscript and conceived original ideas. JAMM, PEA, JKM, WM and MAC contributed to idea refinement, writing, and revising the manuscript."}
+{"text": "Stroke stands as a major cause of death and disability with increasing prevalence. The absence of clinical improvement after either intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) represents a frequent concern in the setting of acute ischemic stroke (AIS). In an attempt to optimize overall stroke management, it is clinically valuable to provide important insight into functional outcomes after reperfusion therapy among patients presenting with AIS. The aim of the present review is to explore the predictive value of leukoaraiosis (LA) in terms of clinical response to revascularization poststroke. A literature research of two databases (MEDLINE and Scopus) was conducted in order to trace all relevant studies published between 1 January 2012 and 1 November 2022 that focused on the potential utility of LA severity regarding reperfusion status and clinical outcome after revascularization. A total of 37 articles have been traced and included in this review. LA burden assessment is indicative of functional outcome post-intervention and may be associated with hemorrhagic events\u2019 incidence among stroke individuals. Nevertheless, LA may not solely guide decision-making about treatment strategy poststroke. Overall, the evaluation of LA upon admission seems to have interesting prognostic potential and may substantially enhance individualized stroke care. Stroke represents not only the second leading cause of death but also the major cause of acquired disability among adult individuals, mostly accompanied by a considerable unfavorable effect on the long-term functional independence of stroke survivors ,2,3. TakThe beneficial effects of reperfusion therapy following stroke, either with intravenous thrombolysis (IVT) or mechanical thrombectomy (MT), have been well documented. IVT with recombinant tissue plasminogen activator (rt-PA) has emerged as a first-line treatment strategy for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset . IncreasGiven the fact that prompt forecasting of each patient\u2019s propensity for recovery substantially contributes to the decision-making in terms of poststroke treatment strategy, it becomes essential to be provided with an accurate and timely outcome prognosis . SeveralIntroduced by Hanchski in 1987 , the terConsidering the expected substantial increase in stroke patients with pre-existing LA undergoing reperfusion therapy, as stroke burden rises among the elderly and life expectancy continues to significantly expand in developed countries, it is of key importance to elucidate the potential contribution of LA on forecasting clinical response to IVT or MT poststroke. Thus, the objective of our study was to review all available literature published within the last decade dealing with baseline LA as a prognostic tool following stroke recanalization.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA registration number: CRD42022369840) were used to guide this study. Our study\u2019s methods were a priori designed. Two investigators conducted literature research on two databases (MEDLINE and Scopus) (SK and AS) to trace all relevant studies published between 1 January 2012, and 1 November 2022. Search terms were as follows: (\u201cleukoaraiosis\u201d OR \u201cwhite matter hyperintensities\u201d OR \u201cWMHs\u201d) AND (\u201cthrombolysis\u201d OR \u201cthrombectomy\u201d OR \u201cbrain revascularization\u201d OR \u201creperfusion\u201d). The retrieved articles were also hand-searched for any further potential eligible articles. Any disagreement regarding the screening, or selection process, was solved by a third investigator (KV) until a consensus was reached. Only full-text original articles published in the English language were included. Secondary analyses, reviews, guidelines, meeting summaries, comments, unpublished abstracts, or studies conducted in animals were excluded. There was no restriction on study design or sample characteristics.Data extraction was performed using a predefined data form created in Excel. We recorded the authors, year of publication, number of participants, follow-up time, method of leukoaraiosis assessment, time of computed tomography execution, time from symptom onset to recanalization, the scale used to examine stroke severity and clinical outcomes, and the main results of each study.No statistical analysis or meta-analysis was performed due to the high heterogeneity among studies. Thus, the data were only descriptively analyzed. Overall, 262 records were retrieved from the database search. Duplicates and irrelevant studies were excluded; hence, a total of 90 articles were selected. After screening the full text of the articles, 37 studies were eligible for inclusion .A total of 37 publications fulfilled our inclusion criteria, as shown in In total, 20 studies utilized the Fazekas score, 11 the van Swieten scale, three the Age-Related White Matter Change Scale, two differentiated between the presence or absence of LA, one used the CREDOS WMH visual rating scale, and four estimated WMH volume on imaging. In total, all the studies included in this review were longitudinal. They were either retrospective or prospective cohorts.The total number of stroke patients included in all studies ranges from n = 56  to n = 3In none of the 37 included studies, stroke patients are contrasted to demographically-matched healthy individuals and none of the studies include a disease-control group other than stroke patients.National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) have been simultaneously used in 30 studies. NIHSS was the only scale in three studies and mRS exclusively in one study. In two studies NIHSS was combined with the Fugl-Meyer rating scale (FMS) and in one study with the Oxford Handicap Scale (OHS).A literature review over the last decade was conducted in order to elucidate baseline LA prognostic value in AIS patients undergoing reperfusion therapy. A total of 37 full-text original articles dealing with the potential utility of LA evaluation in forecasting stroke survivors\u2019 clinical response to revascularization were identified and classified into three groups based on the implemented revascularization technique.With respect to poststroke outcome after EST, Zhang et al. , having Additionally, Liu et al.  further As far as the role of brain atrophy and LA in forecasting futile recanalization poststroke is concerned, Kaginele et al. , having With regard to clinical and radiographic variables able to act as predictors of futile recanalization among AIS patients undergoing MT, Gilberti et al. , having Regarding the relationship between both LA severity and time to successful reperfusion with 3-month functional outcome in an acute stroke setting, Milkati et al.  exploredWith respect to the occurrence of hemorrhagic transformation (HT), Shi et al.  investigApart from that, Lee et al.  reportedOn the contrary, Atchaneeyasakul et al. , having As for the prognostic utility of LA burden in patients presented with AIS due to large cerebral artery occlusion undergoing intra-arterial therapy (IAT), Giurgiutiu et al. , having With respect to the clinical response to IV rt-PA utilization in ischemic stroke patients in the setting of detectable LA on baseline CT scan, Huang et al.  examinedAdditionally, Zhong et al. , having As far as the role both early ischemic and pre-existing brain imaging signs are to play in terms of predicting clinical response to IVT in ischemic stroke patients, Delcourt et al.  observedConsidering that the assessment of the global burden of small vessel disease (SVD), as reflected by both white matter changes and pre-existing lacunar infarcts, may constitute a more precise marker with valuable prognostic potential in terms of clinical outcome and hemorrhagic complications following IVT among stroke patients, Arba et al.  investigConsidering the influence of pre-existing LA on CT scans of stroke patients admitted for IVT on 3-month functional outcome and risk of symptomatic ICH, Yang et al.  examinedDespite being associated with ICH occurrence and 3-month unfavorable outcome following IVT, LA severity was not reported as an independent prognostic marker of symptomatic ICH, mortality, or clinical outcome in a study conducted by Capuana et al.  within aWith respect to the prognostic significance of LA in terms of tPA-related bleeding events, Willer et al. , having Regarding the occurrence of remote post-thrombolytic hemorrhagic complications of IVT, Chen et al.  exploredAs far as the prognostic potential of LA burden among elderly stroke patients is concerned, Nighoghossian et al. , having Regarding the prognostic potential of endothelial dysfunction markers as the soluble tumor necrosis factor-like inducer of apoptosis (sTWEAK) in an acute ischemic stroke setting, da Silva-Candal et al.  exploredTaking everything into consideration, the present review provides evidence regarding the prognostic significance of LA severity, as evaluated on baseline head imaging within the early phase following stroke. Our findings suggest the significant role LA assessment may play in forecasting clinical response to reperfusion treatment strategy. LA burden, serving as a surrogate marker of biological age and consequently \u201cbrain frailty\u201d among stroke patients, appears to be able to yield additional information in terms of cerebral reserve and brain parenchyma resilience to emerging ischemia, thus reliably predicting both reperfusion status and clinical outcome after either IVT or MT. Determining the extent of pre-existing white matter abnormalities may properly guide the decision-making in a setting of acute stroke, as a greater degree of these lesions is usually coupled with unfavorable prognosis and poorer outcomes after the selected intervention is implemented. Additional data support the prognostic value of baseline LA on the potential development of adverse hemorrhagic events after IVT or MT, with a higher LA burden identified on admission head imaging being accompanied by an increased incidence of intervention-related ICH. Nevertheless, LA assessment should be interpreted in a clinical context and may constitute a more powerful tool when being paralleled with other clinical and neuroimaging biomarkers in an attempt to facilitate individualized stroke care. The aforementioned results highlight the need to further investigate LA as a promising imaging marker for clinical outcomes after IVT or MT to enhance patients\u2019 risk stratification and promote overall stroke management. Additional studies among stroke individuals on the linkage between LA burden and prognosis after stroke intervention are recommended in order to provide further insight into this clinically important relationship."}
+{"text": "Epigenetic mechanisms and post-translational modifications as novel therapeutic targets in cancer\u201d collected 11 articles on epigenetic mechanisms, post-translational modifications, cell cycle and signaling pathways related to tumorigenesis and development. Our aim is to provide new research directions for targeted cancer therapies and drug development.This Research Topic \u201cZhou et al. summarized the role and mechanism of the modification related enzymes \u201cWriters\u201d and \u201cErasers\u201d in cancer, providing a basis for the development of anti-tumor epigenetic drugs. Tang et al. assessed the causal relationship between smoking-related DNA methylation and breast cancer risk by Mendelian randomization. The results suggest that DNA methylation plays an important role in linking smoking to breast cancer, especially the subtype of ER+ breast cancer. Zeng et al. evaluated pyroptosis-related genes in esophageal adenocarcinoma and found that the expressions of GSDMB and ZBP1 were influenced by DNA methylation levels. Huo et al. focused on the role of RNA modification in cancer. They summarized the molecular mechanism of RNA modification in the occurrence and development of head and neck squamous cell carcinoma and discussed the related treatment options. Jing et al. demonstrated that hypoxia induced upregulation of ELFN1-AS1 expression in colorectal cancer cells. As a potential target of competing endogenous RNA, ELFN1-AS1 relieved the inhibition of TRIM14 by sponging miR-191-5p, thus promoting the proliferation and invasion of colorectal cancer cells. Lu et al. elucidated the role of acetylation modification in tumor immunity by focusing on histone acetyltransferases and deacetylases, and discussed the clinical application of acetylation-modified drugs in tumor therapy.Epigenetic modifications affect genetic expression without the sequence change of DNA, and its disorders are closely related to the occurrence and progression of cancer. Methylation is a widely studied form of epigenetic modification. Hou et al. provided evidence that low expression of USP47 in the primary colorectal cancer was associated with disease-free survival. USP47 deubiquitinated and stabilized the expression of transcription elongation factor A3 (TCEA3). Knockdown of UPS47 or TCEA3 can enhance doxorubicin-induced apoptosis and pyrotosis of colorectal cancer cells, which provides a potential target for the treatment of colorectal cancer.Post-translational modifications increase the protein diversity and play critical roles in regulating the protein activity, localization, and interaction with other molecules. Xia et al. identified aminoquinoline as a novel multi-kinase inhibitor of CDK4/6 and PI3K/AKT for the treatment of hepatocellular carcinoma. Zhao et al. revealed that lysophosphatidic acid induced transactivation of EGFR through MMP-dependent pathway, which upregulated geminin expression and promoted DNA replication in gastric cancer cells. Guo et al. found that a natural microbial product, Ilicicolin A, as a novel EZH2 antagonist, inhibited the EZH2-mediated signaling pathway to enhance the sensitivity of castration-resistant prostate cancer cells to enzalutamide. Yang et al. investigated the role of kinesin family member 2C (KIF2C) in cervical cancer. KIF2C expression was significantly upregulated in cervical cancer, promoted cervical cancer cells proliferation, invasion, and migration. Knockdown of KIF2C inhibited the development of cervical cancer by activating p53 signaling pathway, providing a new target for the treatment of cervical cancer.In normal cells, cell cycle and signal transduction are strictly regulated, and their dysregulation and abnormal activation lead to various diseases including cancer. Epigenetic mechanisms and post-translational modifications as novel therapeutic targets in cancer\u201d Research Topic emphasizes that epigenetic and post-translational modification provide new targets for the development of anti-cancer drugs and bring new strategies for treatment of cancer.In conclusion, the \u201c"}
+{"text": "It is challenging to conduct in-depth research of the molecular mechanisms associated specifically with human age-related diseases, and how internal and external factors are regulating these processes. For these reasons, research has focused on finding innovative therapies that increase the specificity of the treatment and reduce their drawbacks. This Research Topic on \u201cNLiu et al. offered insights into the heterogeneity of osteoarthritis, which provided in-depth understanding of the transcriptomic diversities within synovial tissue. This transcriptional heterogeneity may improve an understanding on osteoarthritis pathogenesis and provide potential molecular therapeutic targets for osteoarthritis. Zhao et al. investigated the aging-based diagnostic gene signature and molecular subtypes with diverse immune infiltrations in atherosclerosis. Huang et al. did comprehensive characterization of ageing-relevant subtypes associated with different tumorigenesis and tumor microenvironment in prostate cancer. The authors proposed that ageing-relevant molecular subtypes and gene signature might be of great significance to determine clinical outcomes and tumor microenvironment features as well as immunotherapeutic responses in prostate cancer. Song et al. identified reliable gene signatures through combination strategies of diverse feature selection methods, which facilitated the early detection of ischemic cardiomyopathy and revealed the underlying mechanisms. Liu et al. developed of a toll-like receptor (TLR)-based gene signature that can predict prognosis, tumor microenvironment, and chemotherapy response for hepatocellular carcinoma. They also proposed that this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients.This Research Topic described some high-throughput methods  for examining age-related molecular signatures. Lin et al. summarized the role of macrophage phenotypic diversity in the progression of the dynamic atherosclerotic plaque, and the possibility of treating atherosclerosis by targeting macrophage microenvironment. Wang et al. reviewed and concluded the AMPK as a potential therapeutic target for intervertebral disc degeneration. The role of sonic hedgehog pathway in the development of the central nervous system and aging-related neurodegenerative diseases was discussed by Yang et al.You at al. investigated the influence of anemia on postoperative cognitive function in patients undergo hysteromyoma surgery. The results from He et al. showed that secoisolariciresinol diglucoside (SDG) can significantly increase mitochondrial DNA copy number and slow down the process of telomere shortening. The authors also indicated that SDG could improve ovarian reserve by inhibiting oxidative stress. Qin et al. discovered that rational design and synthesis of 3-morpholine linked aromatic-imino-1H-indoles as novel Kv1.5 channel inhibitors sharing vasodilation effects. Du et al. found that the 4-methoxydalbergione could inhibit bladder cancer cell growth through inducing autophagy and inhibiting Akt/ERK signaling pathway. Wu et al. suggested that the sevoflurane could alleviate myocardial ischemia reperfusion injury via inhibiting P2X7-NLRP3 mediated pyroptosis. Jia et al. demonstrated that circulating LBX2-AS1 could be an underlying diagnostic marker in multiple myeloma (MM). Targeting LBX2-AS1 suppressed tumor progression by affecting mRNA stability of LBX2 in MM. Hence, LBX2-AS1 could be a novel therapeutic marker against MM. Lan et al. uncovered that the olfactory impairment could be an early indicator to guide early intervention for postoperative cognitive dysfunction.This Research Topic also discussed novel mechanistic insights and targeted therapies for a personalized treatment against various age-related diseases. Xing et al.Lu et al. reviewed the vitamin D and lipid profiles in postmenopausal women and concluded that the vitamin D administration in postmenopausal women could decrease the concentrations of triacylglycerol, and HDL-cholesterol, but have no effects on LDL-cholesterol and total cholesterol. Xu et al. summarized the recent progress in the functions and mechanisms of newly discovered circular RNAs in intervertebral disc degeneration. Zheng et al. stated that ginkgo biloba extract 80 could have cardioprotective properties through the activation of AKT/GSK3\u03b2/\u03b2-Catenin signaling pathway. Yin et al. investigated the cordyceps militaris-derived polysaccharide CM1 and demonstrated that it could alleviate atherosclerosis in LDLR (\u2212/\u2212) mice by improving hyperlipidemia. Zhou et al. revealed that propofol could ameliorate ox-LDL-induced endothelial damage by enhancing autophagy through PI3K/Akt/m-TOR pathway, which might offer a novel therapeutic strategy in atherosclerosis. A type I collagen-targeted MR imaging probe for staging fibrosis in Crohn\u2019s disease was conducted by Li et al. Their results demonstrates that targeted MRI probe (EP-3533) supplies a better enhanced effect compared to Gd-DTPA and could be a promising method to evaluate the progression and monitor the therapeutic response of bowel fibrosis. Yang et al. found that the sinomenine could suppress development of hepatocellular carcinoma cells through inhibiting MARCH1 and AMPK/STAT3 signaling pathways. This study provides a new support for SIN as a clinical anticancer drug and illustrates that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.New formulations or new therapeutic molecules useful for increasing anti-aging effectiveness and reducing toxicity are illustrated here. The atheroprotective effects and molecular mechanism of berberine were discussed by Wang et al. found that the aging-related gene signature was in relation to tumor immunity and stromal activation in rectal cancer, which might predict survival outcomes and immuno- and chemotherapy benefits. Li et al. stated that the miR-330\u20135p in small extracellular vesicles derived from plastrum testudinis-preconditioned bone mesenchymal stem cells could attenuate osteogenesis by modulating Wnt/\u03b2-Catenin signaling. Zeng et al. observed that knockdown of miR-615-5p reversed the suppression of circRNA_100146 silence on the proliferation and invasion of prostate cancer cells. The authors also stated that the tumor growth was also suppressed by silencing circRNA_100146 in vivo. Lu et al. identified two osteoarthritis-specific markers HTR2B and SLC5A3 and their knockdown ameliorated apoptosis and inflammation of Osteoarthritis synovial cells. Zhang et al. also discovered that mitomycin C could inhibit esophageal fibrosis by regulating cell apoptosis and autophagy via lncRNA-ATB and miR-200b.Finally, some genes and proteins involved in aging or anti-aging as well as substances that inhibit or rejuvenate aging are also presented in this Research Topic. We believe that researchers could find this Research Topic to be a useful Research Topic of articles on novel molecular mechanisms and innovative therapeutic approaches for age-associated diseases."}
+{"text": "Myeloid neoplasms (MN), namely myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemias (AML) are characterized by disrupted myelopoiesis encompassing increased apoptosis of bone marrow (BM) progenitors, differentiation arrest and increased proliferation . This reBarcellini and Fattizzo asked themselves the \u201cegg or chicken\u201d question as to whether immune phenomena comes before or after MN. They examined their epidemiological association, and discussed that autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance possibly resulting in tumor escape and infections. Alterations of the microbiota and of mesenchymal stem cells in MN are also discussed to highlight the importance of a permissive microenvironment for tumor growth. Finally, the authors highlight how novel therapies for MN (including checkpoint inhibitors and chimeric antigen receptor T-cells) may increase autoimmune phenomena.Cominal et al., focused on Philadelphia chromosome-negative MPN that display inflammatory alterations of BM niche. They studied BM soluble mediator signatures using a multiplex assay and found a distinctive profile in polycythemia vera with increased levels of chemokines, and growth factors compared to essential thrombocytopenia and primary myelofibrosis. Deregulation of soluble mediators was associated with abnormal blood counts, thrombosis, treatment status and risk stratification and this might represent a therapeutic target. Additionally, JAK inhibitors also affect the levels of inflammatory cytokines in MPN patients, as described by Cattaneo and Iurlo. They also discussed how these drugs affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells, resulting in a level of immune deficiency with increased infectious risk.Scium\u00e8 et al., focused on another rare \u201cproliferating\u201d condition: systemic mastocytosis. They described a KIT D816V mutated patient who evolved into MN with PDGFRA rearrangement and responded to imatinib therapy; they discuss how immunological mechanisms may play a role in promoting clonal prevalence of one entity (mastocytosis) over the other (MN).Bucelli et al., who described a large series of patients with co-occurrence of myeloid and lymphoid neoplasms. Patients mainly suffered from MPN with associated non-Hodgkin lymphomas; nearly a half required anti-lymphoma therapy and 1/3 experienced a high-grade infection that was significantly associated with mortality.The clinical and prognostic aspects of the concomitant presence of distinct hematological clonal entities was further addressed by Whether the myeloid and lymphoid clones share a common origin or develop autonomously is still debated, and another interesting example is the association of large granular lymphocyte (LGL) expansion with MN and BM failure syndromes. Our group performed a literature review and discussed how LGL clones, found in up to 1/3 of MN, are associated with deeper cytopenia (likely through immune mediated apoptosis) and good response to immunosuppression. Far from being innocent bystander, LGL clones may contribute to immunosurveillance, as their depletion after immunosuppression may favor leukemic escape.Li et al., developed and validated an innovative prognostic model based on a novel immune-17 signature derived from transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. They confirmed that immune biology processes and transcriptional dysregulations are critical factors in the development of AML. Interestingly, the incorporation of the immune-17 signature to the ELN2017 risk score improved patient stratification. This immune signature may be therapeutically exploited, as described by Sun Yao et al., that treated an AML patient with PD-1 blockade in combination with azacytidine after allogeneic hematopoietic stem cell transplantation; these strategies that reactivate anti-leukemic immune surveillance may in turn result in devastating autoimmune/autoinflammatory responses, as in the case described who developed fatal graft versus host disease.Focusing on AML, Razanamahery et al., described a case of Erdheim\u2013Chester disease (ECD), a rare histiocytosis, characterized by somatic mutations of MAP-kinase pathway in CD14+ monocytes. They found a correlation between disease activity and increased CD14++CD16\u2212 \u201cclassical monocyte\u201d and decreased CD14lowCD16++ \u201cnon-classical monocyte\u201d highlighting the contribution of a phenotype switch of innate immunity in this rare disease.Moving to innate immunity effectors, Giannotta et al., reported a patient with MPN who developed clinically overt PNH requiring anti-complement therapy. They discuss that the selection and expansion of PNH clones in MPN is likely to be ascribed to the same immunological bottlenecks described in BMF: autoimmunity against BM precursors, toxicity of therapies, and acquirement of cooperative somatic mutations.Another very rare condition associated with autoimmunity and MN is paroxysmal nocturnal hemoglobinuria (PNH). Caprioli et al., described how the use of single-cell technologies represent powerful tools to assess the cellular composition of the complex tumour ecosystem and its immune environment (Finally, ironment Figure\u00a01In conclusion, this Research Topic highlights the multifaceted immunologic aspects of pathogenesis, clinical course, and treatment of MN. This expanding field will increasingly benefit from sophisticated molecular tools to further identify druggable pathways/targets and optimize management of MN and other rare entities.All\u00a0authors\u00a0listed have made a substantial, direct, and intellectual\u00a0contribution\u00a0to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Aminul Islam et al., RSC Adv., 2022, 12, 7835\u20137849, DOI: 10.1039/D2RA00768A.Correction for \u2018Efficacy of surface-functionalized Mg The authors regret that the name of one of the authors (Md. Mahbubul Haque) was shown incorrectly in the original article. The corrected author list is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Due to demographic trends, the importance of optimal treatment of proximal femur fractures in elderly patients will undoubtedly continue to increase. The clinical outcome for this vulnerable patient group depends on many factors, some of which we as surgeons may influence . However, patient-specific factors  are also of upmost importance and may raise our suspicion for a complicative course.In this issue, several authors highlight different surgery-related and patient-specific factors that may influence the perioperative course of geriatric patients with proximal femur fractures.Kristen et al.  retrospeIn the context of surgical timing, Forssten et al.  investigIn addition to the above reported impact of timing, Weing\u00e4rtner et al.  highlighIn their randomized double-blinded trial, Zhang et al.  evaluateA retrospective, observational study evaluated whether beta-blockers therapy provided a survival benefit following hip fracture surgery . Ahl et Finally, Becker et al.  reviewedWe hope that this issue will provide you with useful information regarding your daily practice with this vulnerable patient group."}
+{"text": "Management of hemodialysis patients.\u201dChronic kidney disease (CKD) is a highly prevalent condition affecting >10% of the general population . Though Assessing the efficacy and safety of Juan Bi Tang for dialysis-related myofascial pain in the fistula arm: Study protocol for a randomized cross-over trial,\u201d Hsu et al. outline a protocol for randomizing HD patients to use of the Chinese herbal medicine Juan Bi Tang, to determine if this therapeutic strategy could alleviate dialysis-related myofascial pain. The authors note wide use of Juan Bi Tang in treatment of other musculoskeletal disorders, though efficacy in treatment of fistula-related pain has not been explored. The results of this study could provide a more effective strategy for managing access arm pain in HD patients.Patients who receive HD through an arteriovenous fistula may experience pain during or after dialysis treatments, which can be related to alterations in extremity perfusion . These sFlash glucose monitoring to assess glycemic control and variability in hemodialysis patients: The GIOTTO study\u201d, Mambelli et al. demonstrate the acceptability of flash glucose monitoring in patients on HD. Though further studies are warranted to validate its accuracy and precision in the setting of other comorbidities, the use of flash glucose monitoring in HD patients could provide an additional layer of safety in managing these vulnerable patients.Additionally, HD treatments can induce hyperglycemia and hypoglycemia in ESKD patients . In factKang et al., \u201cAssociation between alkaline phosphatase and muscle mass, strength, or physical performance in patients on maintenance hemodialysis,\u201d the authors found that high alkaline phosphatase levels were associated with poor physical performance in ESKD patients on HD, as assessed by several tests of muscle mass and function including handgrip strength and a 6-min walk test. High alkaline phosphatase levels in HD patients typically represent high-turnover bone disease, and have been shown to associate with increased risk of hospitalization and death  values are evaluated during HD treatments to predict short-term and long-term changes in PTH levels. This model would use blood and dialysate samples to guide management of mineral bone disease in HD patients, which is highly prevalent and contributes to significant morbidity. We anticipate that big data and mathematical modeling will continue to enable development of prediction models useful in management of HD patients.Given the massive amount of data collected and available from cohort studies such as the Dialysis Outcomes and Practice Patterns Study , advanceDialyzer classification and mortality in hemodialysis patients: A 3-year nationwide study cohort,\u201d Abe et al. report that protein-leaking dialyzers may be associated with a reduction in mortality. Compared to low-flux and high-flux dialyzers, protein-leaking dialyzers in a group of >250,000 patients on HD in Japan were associated with lower mortality , though the exact contributions of \u03b22-microglobulin removal were not evaluated. Further information is needed to clarify relationships between removal of variable dialyzable proteins and outcomes such as mortality (There are also several studies focusing on clinical endpoints in HD patients, such as mortality. Some risk of mortality may be related to HD treatments in themselves. In their study, \u201cortality .Tylicki et al., \u201cCOVID-19 vaccination reduces mortality in patients on maintenance hemodialysis\u201d, provides even more data to support the use of COVID-19 vaccination in patients on HD to reduce mortality.Finally, in the era of an ongoing pandemic, we must also acknowledge that non-dialysis related factors can significantly influence the outcomes of patients with ESKD. A study by Management of hemodialysis patients\u201d, contribute valuable information on assessing and treating some of the variable aspects of increased morbidity and mortality in ESKD patients on hemodialysis.In sum, the seven articles presented in this Research Topic, \u201cDP drafted the editorial. All authors contributed to editing and finalization of the manuscript."}
+{"text": "As the first evolutionary group that comprises of innate immunity and adaptive immunity, fish is considered as a supreme model for clarifying the evolutionary and regulatory mechanisms of vertebrate immunity. However, the types and characteristics of fish immune cells are still not quite clear. In this Research Topic, eight articles including six original research articles and two review articles highlight the advance of novel techniques to identify immune cell population in fish.Fei et\u00a0al. reviewed the reagents (including mAbs of surface markers and immune cells) available for the research of fish immunity. The authors further discussed the potential applications of fluorescence-activated cell sorting and droplet-based microfluidics in screening and identifying antigen-specific B lymphocytes with a high-throughput manner and suggested to incorporate the alternative technologies to promote the production of specific antibodies in a high-throughput and cost-effective way. Similarly, the review article by Chan et\u00a0al. summarized the protein marker and partial corresponding mAbs of teleost fish immune cells, and presented the interaction of fish T cells, B cells and dendritic cells via surface molecules for modulating adaptive immune response. More importantly, they further reviewed the advance for application of single-cell RNA sequencing (scRNA-seq) in teleost immunology and explored future directions of the methods developed for studying fish immunity at the cellular level. Mart\u00edn et\u00a0al. isolated two homologs of mammalian CD38 (CD38A and CD38B) from Rainbow trout (Oncorhynchus mykiss). By using the mAb against CD38A, CD38A+ populations among IgM+ B cells and IgM- leukocytes of head kidney (HK) were screened via flow cytometry. The IgM+ CD38A+ B cells increased post-inactivated Aeromonas salmonicida stimulation in vitro, which produced higher levels of IgM and enhanced B cell differentiation gene transcription than the cells lacking CD38A.The monoclonal antibody (mAb) specific for leukocyte surface markers is the classical approach to identify fish immune cells. Chan et\u00a0al., already applied to identify previously unknown cell markers of teleost immune cell populations. In anterior kidney (AK) of Nile tilapia (Oreochromis niloticus), Wu et\u00a0al. identified five distinct immune cell subsets including B cells, T cells, granulocytes, macrophages, and dendritic cells (DCs) and further uncovered different subsets of B-cell  and T cells  based on distinct transcriptional level of the transcription factors (TFs) and cytokines. Additionally, Huang et\u00a0al. analyzed scRNA-seq data of Orange-spotted grouper (Epinephelus coioides) with a full-length transcriptome as a reference, which was aimed to develop alternative approach for the fish samples without any published genome. In their study, four cell types including T cells, B cells, monocytes/macrophages (Mo/M\u03c6) and NCC (non-specific cytotoxic cells) were identified and two subsets of Mo/M\u03c6 (M1 and M2 type), as well as four subsets in B cells . Moreover, the finding of syngnathid fish, Syngnathus typhle (a fish species lacking the spleen and major histocompatibility class II (MHC II) pathway) by Parker et\u00a0al. indicated that the loss of CD4+ T cells accompanied the loss of the MHC II pathwapresencehe present of regulatory T cells and cytotoxic T cells.The scRNA-seq is a newly developed technique that, also reviewed by Smith et\u00a0al. examined the mRNA transcriptome profiles at different stage of Atlantic salmon  adherent head kidney leukocytes (HKLs) using microarray, and revealed that the adherent HKL cell population differentiates in vitro to become macrophage-like without exogenous stimulation, which might be regulated by miRNA and targeted differentially expressed genes (DEGs) associated with macrophage differentiation and function. Using transcriptome analysis, Park et\u00a0al. revealed that the macrophage heterogeneity in adherent intestinal cells (AIC) and adherent head kidney cells (AKC), as well as the functional characteristics of mucosal and systemic macrophages in Atlantic salmon. Their data also suggested that interaction of miRNA and mRNAs related to macrophages and epithelial cells were involved in macrophage activation and differentiation.Although the scRNA-seq technique develops rapidly and contributes to the research field of fish immune cell, the analysis of transcriptome profile is still a reliable method to clarify the activity and development of specific immune cell type in fish. In summary, all collected articles in this Research Topic exhibited recent novel works regarding fish immune cell identification and provided new strategy to better uncover the composition and function of teleost immune system, which can also help to expand our understanding for the evolution of the vertebrate immune system.All authors contributed to this editorial insight and approved the submitted version.This work was supported by National Natural Science Foundation of China , Natural Science Foundation of Guangxi (2020GXNSFAA297243), Technology Planning Project of Guangdong Province of China (grant no. 2015A020209181), National Key R&D Program of China (2018YFD0900501), Independent Project of Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang) (No. ZJW-2019-06), Special Foundation for \u201cAchieving the First Class\u201d of Guangdong Province , The Project of Guangxi Mangrove Coastal Wetland Ecological Protection and Sustainable Utilization Talent Highland (BGMRC202101), Guangdong South China Sea Key Laboratory of Aquaculture for Aquatic Economic Animals, Guangdong Ocean University (No. KFKT2019YB11), the Japan Society for the Promotion of Science KAKENHI Grants .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "K-edge HERFD-XANES is evaluated in mine waste samples and synthetically generated mixtures of reference compounds.The improvement in As speciation resulting from As  2O3), orpiment (As2S3), getchellite (AsSbS3), arsenopyrite (FeAsS), ka\u0148kite (FeAsO\u00ad4\u00b73.5H2O), scorodite (FeAsO4\u00b72H2O), sodium arsenate (Na3AsO4), and realgar (As4S4) were selected for their importance in mine waste systems. Statistical methods of principal component analysis and target transformation were employed to determine whether HERFD improves identification of the components in a dataset of mixtures of reference compounds. LCF was performed on HERFD- and total fluorescence yield (TFY)-XANES spectra collected from mine waste samples. Arsenopyrite, arsenolite, orpiment, and sodium arsenate were more accurately identified in the synthetic HERFD-XANES spectra compared with the transmission-XANES spectra. In mine waste samples containing arsenopyrite and either scorodite or ka\u0148kite, LCF with HERFD-XANES measurements resulted in fits with smaller R-factors than concurrently collected TFY measurements. The improved accuracy of HERFD-XANES analysis may provide enhanced delineation of As phases controlling biogeochemical reactions in mine wastes, contaminated soils, and remediation systems.High-energy-resolution fluorescence-detected (HERFD) X-ray absorption near-edge spectroscopy (XANES) is a spectroscopic method that allows for increased spectral feature resolution, and greater selectivity to decrease complex matrix effects compared with conventional XANES. XANES is an ideal tool for speciation of elements in solid-phase environmental samples. Accurate speciation of As in mine waste materials is important for understanding the mobility and toxicity of As in near-surface environments. In this study, linear combination fitting (LCF) was performed on synthetic spectra generated from mixtures of eight measured reference compounds for both HERFD-XANES and transmission-detected XANES to evaluate the improvement in quantitative speciation with HERFD-XANES spectra. The reference compounds arsenolite (As The oxidation of residual As-sulfide minerals or dissolution of As-bearing minerals in mine wastes releases dissolved As. Predicting the geochemical fate of As is important when designing remediation or prevention measures in mine wastes and other contaminated systems. Precipitation of stable and sparingly or insoluble minerals that incorporate or contain As promotes the attenuation of As. Understanding the mechanisms of As adsorption and mineralization processes, as well as the geochemical conditions that favour As attenuation, provides a foundation for the design of As remediation systems.et al., 1998et al., 2009et al., 2013et al., 2005et al., 2005et al., 2009et al., 2009et al., 2016et al., 2004et al., 2006et al., 2018et al., 2019et al., 2020et al., 2021et al., 2022et al., 2010et al., 2009et al., 2017et al., 2018et al., 2019Arsenic mobility in environmental systems has been extensively studied ; (2) low concentrations of elements of interest  wet chemical methods that rely on pre-treatments that convert the solid phase to a liquid- or gas-phase sample, et al., 2009et al., 2002et al., 2002et al., 2006et al., 2007et al., 2009et al., 2009et al., 2011et al., 2014et al., 2017et al., 2018et al., 2014et al., 2021K-edge  was developed to improve the detection limit, increase the resolution of the features in XANES spectra  and principal component analysis (PCA) techniques were employed to evaluate improved spectral-feature resolution in HERFD-XANES compared with transmission-detected XANES for standard compounds. Arsenic speciation analyses, HERFD-XANES, and total fluorescence yield (TFY)-XANES were conducted to determine the impact of detection mode on the quantification of As species in mine waste samples. The findings of this study will allow us to evaluate the benefits of HERFD-XANES over conventional detection modes for As speciation as applied to both standard compounds and environmental samples.2.2.1.2O\u00ad3) and sodium arsenate (Na3AsO4)  and mineral specimens of orpiment (As2S3), getchellite (AsSbS3), arsenopyrite (FeAsS), ka\u0148kite (FeAsO\u00ad4\u00b73.5H2O), scorodite (FeAsO4\u00b72H2O), and realgar (As4S4) . The mineral specimens contained a combination of host rock and the mineral of interest, which was visually identified and removed from the host rock with a fine-tipped diamond Dremel to avoid contamination. Environmental samples were collected from Long Lake Mine, an abandoned gold mine in Sudbury, ON, Canada, that operated intermittently from 1909 to 1939. Samples were collected in aluminium tubing using a piston-coring technique . Solid samples were then freeze-dried and stored at 4\u00b0C to preserve their mineralogical composition. All samples and reference compounds were finely ground with an agate mortar and pestle in an anaerobic chamber in preparation for analysis. Samples and reference compounds were transported in an anerobic canister and removed immediately prior to analysis.Arsenic reference compounds included reagent-grade arsenic trioxide  was performed to confirm the identities of the arsenic reference compounds. Ground reference compounds were loaded into Kapton capillaries and sealed at both ends with Locktite 454 ep\u00adoxy for PXRD analysis. Analyses were performed at CMCF-BM at the Canadian Light Source in Saskatoon, SK. Specifications of the beamline and endstation are fully described elsewhere  was used for further data processing, including diffractogram background subtraction and phase identification with the peak search and match algorithm using the COD-Inorg REV218120 2019.09.10 database .Diffraction images were background-subtracted, calibrated, and integrated using 2.3.Hephaetus . The energy resolution of the crystal analyzer is approximately 1\u2005eV. Normally, filters can be applied upstream of the sample to attenuate and lower the intensity of the incident beam to optimize the count rate for fluorescence yield (FY) detection; however, retaining the maximum signal intensity is critical for HERFD. When FY and HERFD were measured simultaneously, the FY count rate was optimized using aluminium foil to directly filter the signal before it entered the detector.All XAS measurements were performed at 20-ID-C at the Advanced Photon Source at the Argonne National Laboratory in Lemont, IL, USA, where monochromatic X-rays in the hard X-ray regime are produced by an insertion device and a monochromator (Si 311). Ground reference compounds were spread thinly on Kapton tape and layered to achieve the appropriate thickness for collection of transmission-detected XAS. The thickness, calculated for each reference mineral using 2.4.LARCH , orpiment (As2S3), getchellite (AsSbS3), arsenopyrite (FeAsS), ka\u0148kite (FeAsO4\u00b73.5H2O), scorodite (FeAsO4\u00b72H2O), sodium arsenate (Na3AsO4), and realgar (As4S4). Computer-generated spectra of mixtures were created with the spectra from each of the reference compounds, measured in both HERFD and transmission. All computer-generated mixtures were a combination of four reference compounds, each with a minimum contribution of 5% of the total mixture; these limitations were selected to represent speciation with a commonly acceptable number of fit components and detection limit. The computer-generated mixtures were analyzed with LCF and PCA. The datasets of mixtures were created with both HERFD and transmission reference compounds and each unique reference compound was included in 3500 synthetic spectra. A dataset was generated for each of the 70 combinations of four reference compounds to decrease sampling bias. A set of 100 random mixture ratios was generated using the NumPy module . LCF analysis on the mine waste samples was completed in Athena . A small shift of \u22120.5 to \u22121\u2005eV is observed in white-line energy in HERFD measurements compared with transmission measurements ; variations in set-up angles were minimized by the magnetically positioned sample holder and consistent sample mounting technique ensuring the sample surface position was unchanged between samples and references. This configuration allows comparison of measurements across samples and reference compounds.The resolution increases observed in the HERFD-XANES spectra are similar to other studies , scorodite , and sodium arsenate  reference spectra for both the HERFD and transmission data, but additional components did not further decrease the residual standard deviation. The synthetic mixtures of arsenopyrite, arsenolite, sodium arsenate, and scorodite were selected for PCA and target transformation because each had unique spectral features . The longer air-path to the area detector used for HERFD measurements could attenuate up to 56% of the As K\u03b1 fluorescence emission which would decrease the signal-to-noise ratio. A helium bag placed in the air-path would decrease the attenuation and improve the signal-to-noise ratio. However, improved speciation using HERFD-XANES was observed in samples of As-bearing mill tailings collected from the Long Lake mine, which were identified to have a binary mixture of arsenopyrite and scorodite or kankite  and arsenopyrite, scorodite and kankite are likely chemical components of the dataset  whereas getchellite, orpiment, realgar, arsenolite and sodium arsenate are unlikely to be chemical components of the dataset . On average, the LCF on HERFD-XANES spectra obtained from Long Lake samples with binary mixtures resulted in fits with significantly lower R2  than fits on FY XANES spectra obtained from the same samples  could be impacted by over-absorption (self-absorption) that dampens the amplitude of the XAFS oscillations  were not measured on the same samples used for XAS measurements. If over-absorption is present in the samples, the quality of the fits in both HERFD and TFY would be impacted.Sample spectra collected using FY detection were fit with reference compounds measured in transmission detection, which could be a source of misfit between the sample and standard spectra. Spectra collected in HERFD or TFY from thick samples containing high As concentrations (Table S3) showed no improvement in R2  with HERFD-XANES spectra. The lack of improved fit quality may be attributed to reference materials that do not exactly represent, but have similar molecular bonding environments to, the species present in the sample. Getchellite, orpiment and realgar are rare As-sulfide minerals that are not often identified as secondary minerals in oxidized mine waste environments; however, the spectra for these minerals are similar to arsenical pyrite  (arsenopyrite), As(III)\u2013S (getchellite), As(III)\u2013O (arsenolite) and As(V) (sodium arsenate) . Arsenopyrite was identified in some of the tailings samples with conventional XRD measurements, and Fe\u2013As\u2013O-containing phases were previously identified with SEM-EDS  and As(V) sorbed to various relevant iron oxides and iron hy\u00addroxy-sulfates, such as goethite, ferrihydrite, jarosite, and hematite. XANES and EXAFS studies show that As sorbs to and is incorporated into secondary precipitates .HERFD-XANES provides resolution of unique spectral features that may not be detectable with transmission-detection XAS analyses, and this additional resolution enhances LCF fitting when the appropriate standards are available. Slight improvements in spectral resolution are also expected when As is dilute or in a complex matrix, which is one of the main benefits of HERFD for environmental samples. Developing a database of environmentally relevant As reference compounds is vital to the application of LCF with HERFD-XANES to quantitatively determine the speciation of As in mine wastes and other haza\u00adrdous materials. Use of standard spectra from a HERFD-XANES database is critical with respect to the application of this technique (10.1107/S1600577522007068/ye5018sup1.pdfDetails on Datasets 1 and 2. Figures S1 to S15. Tables S1 to S3. DOI:"}
+{"text": "Vascular disease is now the leading cause of death worldwide, with cardiovascular and cerebrovascular diseases being the main contributors . HoweverYu et al. attempted to illustrate the association between plasma metabolic profiles and cerebral collateral circulation in patients with acute ischemic stroke (AIS). They found that the sphingosine-1-phosphate (S1P) level in plasma showed significant positive correlation with good collateral circulation and which might be a potential diagnostic biomarker for predicting collateral circulation status in patients with AIS. The paper by Xue et al. focused on excavating the potential biomarkers in lacrimal diabetic angiopathy and its potential mechanism. Hub genes App, F5, Fgg, and Gas6 related to the regulation of circulation and coagulation were identified. Meanwhile, certain small molecular compounds were considered that might reverse the altered differentially expressed genes. This study might empower the novel potential targets to treat lacrimal angiopathy and other diabetes-related diseases. The paper by Fan et al. found that myricanol could inhibit proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB by suppressing the platelet-derived growth factor receptor-\u03b2 and NF-kB p65 translocation. Furthermore, myricanol was found suppressing the intimal hyperplasia in mice with carotid stenosis. The paper by da Costa et al. found the events that HFD-fed leading decreased Nrf2 nuclear accumulation, decreased mRNA expression and activity of Nrf2-regulated enzymes  were prevented in castrated mice. The study indicate that testosterone would downregulate Nrf2, leading to oxidative stress and vascular dysfunction in HFD-fed obese mice.As the dominating part of this Topic, papers of basic research that we primarily collected have revealed some interesting relationships between metabolic abnormalities and vascular diseases. The paper by Hu et al. showed that there was no significant correlation between increased serum uric acid levels and the risk of first stroke in the Chinese adults with hypertension. Meanwhile, risk of the first stroke in patients with hyperuricemia less than 60 years old was significantly higher than control. The paper by Yu et al. was based on bioinformatic analysis of metabolomic and proteomic to reveal that the dysregulation of glutamate and glycine metabolism, upregulated glycolysis and fatty acid synthesis in the endothelial progenitor cells that treated with the oscillatory shear stress.However, papers of clinical research presented in this Topic have significant discoveries as well. The paper by Ning et al. with creative perspective summarized the potential mechanism underlying metabolic perturbation that type 2 diabetes mellitus (DM) affect the hypertension (HTN), what may be involved in the metabolism of insulin and angiotensin II, sympathetic nervous system as well as the energy reprogramming.Meanwhile, the Review paper by"}
+{"text": "In this Research Topic several studies have analysed the clinical and molecular profile related to cardiovascular disease (CVD) development in a range of inflammatory and systemic autoimmune diseases, including systemic lupus erythematosus (SLE), psoriatic arthritis, rheumatoid arthritis and spondylarthritis among others. Novel molecular mechanisms and biomarkers have been characterized along with clinical tools and approaches to manage this prevalent comorbidity.Quevedo-Abeledo et\u00a0al., studied the levels of three CVD molecules involved in the metabolism of triglycerides, such as lipoprotein lipase (LPL), angiopoietin-like protein 4 (ANGPLT4), and apolipoprotein C-III (ApoC3), in 185 patients with SLE and 162 healthy donors. Performing a multivariable analysis, they identified that the LPL, ANGPLT4 and ApoC3, axis is altered in SLE and associated with the disease damage score. Wang et\u00a0al., used public transcriptomic data to gain insight into the involvement of new players and pathways related to the development of atherosclerosis in SLE patients. They identified 5 hub genes  which might promote the monocytes differentiation into macrophages and the pathway of IL-17 signalling as potential mechanisms involved in the atherosclerotic process of SLE patients. Guzman-Martinez et\u00a0al., reviewed the association of the immune system with the pathogenesis of endothelial damage and atherosclerosis in SLE patients, including inflammatory mediators, specific circulating cell populations and autoantibodies. Additionally, they discussed the utility of the immune system as early CVD biomarkers and therapeutic targets in SLE.In the case of SLE, three studies have explored at the molecular level the underlaying mechanisms associated with CVD. Remuzgo-Mart\u00ednez et\u00a0al., analysed the role of the protein irisin as a serological and genetic biomarker of CV risk, disease severity and subclinical atherosclerosis in a cohort of 725 patients with axial spondylarthritis (axSpA). Their results suggested that low levels of irisin in the serum could be considered a marker of high CV risk, more severe disease and the presence of subclinical atherosclerosis, in axSpA patients. Furthermore, they found that irisin may also constitute a biomarker of disease activity in axSpA at the genetic level.On the other hand, Barbarroja et\u00a0al., reviewed the interplay of hepatic alterations and CVD, analysing different mechanisms where autoimmunity, chronic inflammation, metabolic deregulation and treatments seem to have an key role. They also discussed the latest controversies regarding the effects of anti-inflammatory therapies used in PsA and RA in the liver damage, such as biologics and DMARDs such as, leflunomide or methotrexate. Schwartz et\u00a0al., also analyzed in a cohort of PsA patients, the associations of metabolic dysregulation and systemic inflammation with coronary artery disease (CAD) measuring traditional CVD risk factors, serum markers of metabolic dysfunction, inflammatory cytokines and inflammation in specific tissues by using positron emission tomography-computed tomography (PET-CT). They identified metabolic and inflammatory players associated with subclinical CAD in PsA, including inflammation in adipose tissue which might be considered as novel target for CVD prevention and treatment in PsA.In the case of inflammatory arthritis like rheumatoid arthritis (RA) and psoriatic arthritis (PsA), Gao et al., using mendelian randomization and genome-wide association study (GWAS). The analysis suggested a potential causal link between CVD and psoriasis.The association between Psoriasis and the risk of CVD was also explored by Lastly, two studies in this issue evaluated the CV involvement in rare systemic autoimmune disorders.Zhou et\u00a0al., analyzed in anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM)//clinically amyopathic dermatomyositis (anti-MDA5 Ab+ DM/CADM) the myocardial involvement. Anti-MDA5 dermatomyositis is a rare autoimmune disease, with high prevalence in Japanese patients with clinically amyopathic dermatomyositis and progressive interstitial lung disease. It also shows systemic manifestations affecting skeletal muscle, skin, and other organs.In a cohort of seventy-six hospitalized patients suffering this disorder, this study identified twelve patients with MI (16%), associated with severe cardiovascular complications and adverse evolution of the disease. They concluded that myocardial involvement is an independent poor prognostic factor of patients with anti-MDA5 Ab+ DM/CADM.Huang et\u00a0al., investigated the efficacy of percutaneous transluminal pulmonary angioplasty (PTPA) in patients with Takayasu arteritis (TA) and pulmonary hypertension (PH) and pulmonary artery stenosis.Takayasu\u2019s arteritis is a rare chronic inflammatory autoimmune condition that impact the largest blood vessels in the body (aorta) and its branches, the supra-aortic trunks.Results of this study, analyzing 183 lesions from 79 surgeries carried out on 32 patients with TA and PH, indicated that PTPA improved clinical symptoms, hemodynamic parameters, and exercise tolerance, in patients with TA pulmonary artery stenosis and PH. Furthermore, reperfusion pulmonary edema was significantly reduced, and no patient died of PTPA-related complications with guidance from the pressure wire.Overall, these findings might be important for healthcare resource planning and preventive approaches. These 9 articles substantial CV-risk observed in autoimmune diseases patients, suggests that strategies to reduce CV-risk should become a routine part of the management of autoimmune disease patients. However, the causes of cardiovascular involvement associated with systemic autoimmune diseases, and their potential therapy, require further research.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Organisms respond and adapt to the internal and external environmental changes through various cell signaling. The abnormal alteration of cell-signaling pathways could disrupt cell homeostasis and cause diseases . For insCell Signaling Status Alteration in Development and Disease, we collected studies providing new insights into the roles of cell signaling in development and disease occurrence and progression. A total of 5 articles, including two reviews, two original researches and one method article, were published in this Research Topic. We summarize and discuss the main findings of these studies in this editorial.Although cell signaling can be measured through development of sequencing technologies and the application of effective bioinformatic tools , many quAbreu de Oliveira et al.). Yang et al. comprehensively reviewed the role of cyclic GMP-AMP synthase (cGAS)\u2014a stimulator of the interferon gene (STING) signaling pathway in various diseases, such as acute injury, pneumonopathy and kidney diseases, providing a theoretical basis for immunotherapy targeting the STING signal pathway . Ma et al. found that miR-654-5p overexpresses in activated human hepatic stellate cells and TGF\u03b2-treated human hepatic LX-2 cells augmented liver fibrosis in mice that were intraperitoneally injected with CCl4 by targeting the RXR\u03b1 receptor . Zhang et al. proposed a robust method to acquire finely resolved transcriptional programs with few cells from snap-frozen or RNAlater-treated clinical tissues that was sufficient enough to resolve even isoforms based on immunofluorescence-guided laser capture microdissection (immuno-LCM-RNAseq). With this method, the researchers were able to analyze transcriptional networks and signaling pathways during development, pathogenesis, and aging of specific cell types within native tissues . Lou et al. integrated both immune and hypoxia signaling to establish reliable prognostic signatures for lung adenocarcinoma (LUAD) across different omics data, and provided a robust prognosis predictor for the LUAD patients .Wnt signaling plays an important role in the mammary gland development and adult homeostasis in virtually all animal species. Willy et al. provided a systematic review on Wnt signaling involved in breast cancer and explored the impact of Wnt signaling alteration on the tumorigenesis and disease occurrence (The studies published in this Research Topic presented a diversity of intriguing and meaningful results covering a range of cell signals, which could facilitate our understanding of development and disease. We hope that this Research Topic will inspire researchers to systematically investigate development and disease progression from the perspective of cell signal in a systematic way."}
+{"text": "Insights in Cardiovascular Therapeutics: 2021\u201d has achieved great success and is attracting interest from the cardiovascular community. Here, we spotlight 12 studies published in our section that related to cell death and cardiovascular injuries, as well as some recent advances in the field that have tremendous potential in cardiovascular therapy. In addition, these highlights may serve as the foundation for some new developments in our Cardiovascular Therapeutics areas. In 2022, we will keep working to create a fantastic platform for cardiologists, translational cardiovascular scientists, and cardiovascular pharmacological scientists to share new results and data in clinical cardiology and translational cardiovascular therapeutics.With the effort and support of the authors, editorial office, and editorial team, the Frontiers in Cardiovascular Medicine, Cardiovascular Therapeutics Section-Research Topic \u201cWu et al., Liao et al., and Dash et al., atrial fibrillation reported by Lee et al. and Zheng Wang et al., refractory angina reported by Ambari et al., In-stent restenosis reported by Zhu et al., critical limb ischemia reported by Quiroz et al., protein conformational diseases reported by Zheng Song et al., mitochondrial dysfunction reported by Chen et al., and myocardial injury reported by Barbieri et al. and Cao et al.Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. An estimated 17.9 million people live with CVDs each year with no effective cures \u20134. In thIn recent decades, new mechanisms that orchestrate various cell death pathways have been discovered, and this field continues to expand. The current well-established forms of cell death pathways include intrinsic or extrinsic apoptosis, necroptosis, pyroptosis, ferroptosis, mitochondrial permeability transition (MPT)-driven necrosis, autophagic cell death (autosis), lysosome-dependent cell death, immunogenic cell death , cellula5 myocytes  production  pathway and has initially discovered in response to viral infections. Following infection with a virus such as influenza A virus (IAV), a master regulator of PANoptosis, Z-DNA-binding protein 1 (ZBP1)  , 42, int1 (ZBP1) . It is b1 (ZBP1) , resulti1 (ZBP1) . PANopto1 (ZBP1) . AlthougWu et al., Zheng et al., Wang et al., Liao et al., Dash et al., Lee et al., Ambari et al., Zhu et al., Quiroz et al., Zheng Song et al., Chen et al., Barbieri et al., and Cao et al. on our Research Topic to illustrate the cutting-edge treatments for different cardiovascular diseases. Readers could use Medical experts and scientists have long searched for potential cardiac disease treatments and surviving and improving patients' lives. The Frontiers in Cardiovascular Medicine -Cardiovascular Therapeutics section has provided a platform for distinguished scientists to communicate, inspire, and seek more potential therapeutic solutions , 47. In KX carried out literature collections, research analyses, and drafted the manuscript. MK, JY, NS, SW, RV-P, and HW provided editing input. XY supervised and edited the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by the National Institutes of Health Grants to XY , HW , JY (HL153599), MK (HL135177), and America Heart Association Award to KX (916828).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Pogostemon cablin ameliorates ethanol-induced acute liver injury in rats via inhibition of oxidative stress and lipid accumulation\u2019 by Qiong-Hui Huang et al., RSC Adv., 2018, 8, 24399\u201324410.Correction for \u2018Patchouli oil isolated from the leaves of  The authors regret that Corrected Fig. 1 caption: GC-MS analysis of patchouli oil. Numbers indicated on peaks correspond to those in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Mesenchymal stromal/stem cell (MSC) therapies are increasingly explored as novel regenerative and immunomodulatory approaches to treat or prevent diseases  is the only curative option available today for several hematological and non-hematological diseases. However, HSCT is associated with several early and late complications, such as low HSPC engraftment and impaired hematopoietic recovery, immune-mediated graft rejection, and GvHD in the case of allotransplantation : a potential game changer for the COVID-19 crisis,\u201d to employ their immunomodulatory and regenerative properties for lung repair. In turn, Yang et al. from the \u201cCenter for Respiratory Medicine\u201d at the China-Japan Friendship Hospital in Beijing, China, review \u201cTherapeutic applications of MSCs in IPF.\u201d The authors present an in-depth analysis of relevant factors for the optimization of MSC treatment, including the use of MSCs from different sources for lung repair, different administration routes, timing, dosing, frequency, and potential pretreatment of the clinical MSC products, to guide the design of future clinical research and to identify novel therapeutic options for these complex diseases.Due to the perivascular nature of MSCs surrounding and maintaining the integrity and function of blood vessels : a liver-derived MSC-like population with pro-regenerative properties.\u201d These HLSCs were first described in 2006 as a new stem cell population obtained from the highly vascularized healthy human livers . The most studied MSC types were isolated from umbilical cord (UC-MSCs), adipose tissue (AT-MSCs) and bone marrow (BM-MSCs). The most studied diseases were wounds, ulcers, burns and psoriasis. Montero-Vilchez et al. report in their article \u201cMSC-conditioned medium for skin diseases: a systematic review\u201d that MSC-CCM improved wound healing, hair restoration, skin rejuvenation, atopic dermatitis, and psoriasis, in both animal models and humans, and decreased hypertrophic scars and flap ischemia in animal models, with further studies needed to standardize CCM manufacturing. In addition, Qui\u00f1ones-Vico et al. reviewed \u201cThe role of exosomes derived from MSCs in dermatology\u201d for both in vitro and in vivo models of different skin conditions.The skin is the largest organ of the human body and skin injuries can damage this important barrier. Three review articles were contributed to our topic from researchers at the \u201cAndalusian Network of Design and Translation of Advanced Therapies\u201d at \u201cVirgen de las Nieves University Hospital\u201d in Granada, Spain. These reviews give an excellent overview on the treatment of skin disease with \u201ccell products\u201d  and \u201ccell-conditioned\u201d media (CCM), as well as \u201cMSC-derived exosomes\u201d in dermatology. Khan et al. from \u201cThe Interdisciplinary Stem Cell Institute\u201d at the University of Miami share their experiences in their article: \u201cThe Interdisciplinary Stem Cell Institute's Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases.\u201dIn some cases, patients present a life-threatening condition or serious disease that requires the urgent access to investigational medical product . For those cases, the U.S. Food and Drug Administration (FDA) may authorize expanded access, to gain access to an investigational medical product for treatment outside of clinical trials. An in-depth understanding of the molecular mechanisms underlying MSCs' beneficial therapeutic effects in different clinical indications is essential to manufacture safe and effective therapies tailored to the individual patient need  and endothelial progenitor cells (EPCs) -MSC-derived EVs, thus suggesting that the EVs confer neuroprotection to the damaged hippocampus. De Luna et al. reviewed the role of \u201cMSC-derived EVs as silver linings for cartilage regeneration.\u201d Ghafouri-Fard et al. summarize \u201cThe emerging role of exosomes in the treatment of human disorders with a special focus on MSC-derived Exosomes.\u201d Zhong et al. review \u201cThe emerging potential of exosomes on adipogenic differentiation MSCs\u201d. Zhang J. et al. review the \u201cPotential networks regulated by MSCs in acute-on-chronic liver failure (ACLF): exosomal miRNAs and intracellular target genes,\u201d identifying beneficial effects of MSC-derived exosomes. Zhang Y. et al. investigated the therapeutic potential of exosomes derived from amniotic fluid stem cells in a rat model of skin wound repair. They found accelerated wound healing and improved regeneration of hair follicles, nerves, vessels, and increased proliferation of cutaneous cells, and more natural distribution of collagen during wound healing, while preventing excessive aggregation of myofibroblasts and the extracellular matrix. Lai et al. found that AT-MSC-derived exosomes decreased cardiomyocyte apoptosis and hypertrophy in the heart of mice with myocardial ischemia/reperfusion injury, concluding that they act as potent cardioprotectors.The production and release of EVs, including exosomes, from MSCs is perceived to be a major mediator of their therapeutic effects for several pathological conditions  influence the secretome of MSCs and their interaction with monocytes from stroke patients to promote the beneficial antiinflammatory effect of MSCs. In turn, Maisonneuve et al. shed light on how human dental pulp derived stromal cells (DPSCs) react toward interaction with Streptococcus mutans, which is involved in dental pulp necrosis and cardiovascular tissue infections. In response to infection, DPSCs adopted a proinflammatory profile, strengthening the establishment of the dental pulp inflammation.in vivo characterization and cell sorting, preconditioning of MSCs, cellular engineering and the use of structural supports/3D systems.Recent research efforts focus on strategies for further improving the therapeutic efficacy and safety of MSCs and their products, thus helping to achieve better treatment outcomes. These entail amongst others improved Valiuliene et al. from the \u201cLife Sciences Center\u201d at Vilnius University in Lithuania studied the \u201cMetabolic profile and neurogenic potential of human amniotic fluid MSC-like stem cells from normal versus fetus-affected gestations.\u201d The authors found some characteristic differences in surface markers, phosphorylation rate, ATP, ROS, and cytokine secretion between the two groups, which may indicate metabolic and phenotypic differences that need to be considered in their clinical use. Xie et al. from Sun Yat-sen University in Guangzhou, China, studied how \u201cCardiac-derived CD51-positive MSCs enhance cardiac repair through SCF-mediated angiogenesis in mice with myocardial infarction.\u201d Most vascularized tissues contain resident MSCs, but there is no typical marker to identify resident cardiac MSCs, and the authors here identify CD51 as a novel marker for cardiac resident MSCs.Zhao et al. demonstrate that hypoxic culture preconditioning may constitute a promising strategy to enhance cellular viability and angiogenesis of transplanted AT-MSCs. Lucciola et al. have studied the \u201cImpact of sustained TGF-\u03b2-receptor inhibition on chromatin accessibility and gene expression in culture human endometrial EM-MSCs.\u201d The authors found that A83-01, a selective TGF-\u03b2-receptor inhibitor, promotes the expansion of EM-MSCs in culture by blocking differentiation and senescence, with in-depth analysis of the underlying gene networks and genome-wide chromatin changes. Bai et al. report how \u201cGlycyrrhizic acid promotes osteogenic differentiation of human BM-MSCs by activating the Wnt/\u03b2-catenin signaling pathway,\u201d thus indicating the potential of pharmacological pretreatment for improvements in bone repair. Preconditioning of MSCs also modifies the content and secretion of EVs. Peltzer et al. present that \u201cIFN-\u03b3 and hypoxia priming have limited effect on the miRNA landscape of human MSC-derived EVs.\u201d Li et al. found that \u201cmiRNA-27a-5p is abundant in small EVs derived from epimedium (EPI)-pre-conditioned BM-MSCs stimulate osteogenesis by targeting Atg4B-mediated autophagy.\u201d Feng et al. reviewed the \u201cEffect of melatonin for regulating MSCs and their EVs\u201d in preclinical and clinical studies.An injured tissue constitutes an ischemic and hypoxic environment that damages the implanted therapeutic cells, leading to apoptosis and thus compromising their capacity in the early stages of cell transplantation. Garcia-Bernal et al. from Murcia in Spain studied how \u201cExofucosylation of AT-MSCs alters their secretome profile.\u201d The authors found that the exofucosylation modification that improves MSC in vivo trafficking also improved their secretome to promote their antiinflammatory properties, which could be beneficial in treatment of autoimmune, inflammatory, and degenerative diseases. Pawitan et al. reviewed the \u201cEnhancement of the therapeutic capacity of MSCs by genetic modification.\u201d Of the 85 articles reviewed, 51 studies focused tumor/cancer/metastasis, while 34 studies focused on non-cancerous pathologies. In line, Han et al. studied how \u201cKnockdown of POSTN inhibits osteogenic differentiation of MSCs from patients with steroid-induced osteonecrosis,\u201d while Zhang W. et al. studied how \u201cUpregulation of PARKIN accelerates osteoblastic differentiation of BM-MSCs and bone regeneration by enhancing autophagy and \u03b2-catenin signaling.\u201dLin et al. from \u201cTsing Hua University\u201d in Taiwan demonstrate how \u201c3D-spheroids of UC-MSC-derived Schwann Cells (SCs) promote peripheral nerve regeneration.\u201d The authors used a well-defined non-genetic approach to phenotypically, epigenetically, and functionally convert UC-MSCs into SC-like cells that simulated sprouting of neurites from neuronal cells. To enhance their therapeutic effectiveness, the authors assembled the cells in 3D spheroids with a marked increase in their neurotropic, proangiogenic and anti-apoptotic profile. Marinaro et al. from C\u00e1ceres in Spain tested \u201cLaparoscopy for the treatment of congenital hernia: Use of surgical meshes and MSCs in a clinically relevant animal model.\u201d The authors combined laparoscopy and stem cells incorporated into a mesh by using a fibrin-sealant solution for the treatment of hernia in a swine model, with improved in vivo performance in the MSC containing group compared to cell-free mesh.Among the strategies to preserve MSC biological functions are those mimicking the natural habitat of MSCs during cell therapy. This multidisciplinary Research Topic has brought together specialists in Stem Cells, Immunology, Bioengineering, and Cellular Neuroscience, to share their knowledge on current therapeutic strategies and the mechanisms underlying the immune modulation and tissue regeneration that are orchestrated by MSCs. The different articles contained in this Research Topic reflect the great interest, knowledge and innovation in these fields. Here, we have given a summary on the latest clinical developments, efforts to refine the understanding on the MoA of MSC therapeutics, and introduced novel strategies to enhance the efficacy of MSCs and their derived products. Importantly, inflammation and the regulation thereof is an essential part of the healing and regenerative cascades in the human body. The modulation of inflammation is an important aspect of MSCs beneficial properties in the healing of tissue injury or suppression of tissue damage. The many studies contained in this Research Topic indicate that MSCs employ a host of mediators and mechanisms to achieve this goal, with great promise for clinical use.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.VC-G receives support of the Consejer\u00eda de Transformaci\u00f3n Econ\u00f3mica, Industria, Conocimiento y Universidades co-funded by Fondos FEDER (PY20/00481), the Institute of Health Carlos III co-funded by Fondos FEDER (CP19/00046 and PI20/00341), the Fundaci\u00f3n Cient\u00edfica de la Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer (IDEAS20051CAPI), and the Asociaci\u00f3n Pablo Ugarte (+VIDA project). VH-P receives funding from the Spanish Ministry of Science, Innovation and Universities (PCI2018-093062) and the Valencian Council for Innovation, Universities Science and Digital Society (PROMETEO/2019/075). Contributions from GM were made possible by the German Research Foundation (DFG) and the German Federal Ministry of Education and Research (BMBF) through the BSRT (GSC203) and BCRT, respectively, and in part supported by the European Union's Horizon 2020 Research and Innovation Program (Horizon 2020 Framework Program) under the Grant Agreements No. 733006 (PACE) and No. 779293 (HIPGEN).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The literature demonstrates that infections like Borrelia and Lyme, as well as other infections like group A beta-hemolytic streptococcal (GABHS), can cause an autoimmune reaction and associated antibodies target dopaminergic loci in the mesolimbic region of the brain, which interferes with brain function and potentially causes RDS-like symptoms/behaviors. The treatment of PANDAS remains controversial, especially since there have been limited efficacy studies to date. We propose an innovative potential treatment for PANDAS based on previous clinical trials using a pro-dopamine regulator known as KB220 variants. Our ongoing research suggests that achieving \u201cdopamine homeostasis\u201d by precision-guided DNA testing and pro-dopamine modulation could result in improved therapeutic outcomes.Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, or obsessive-compulsive disorder (OCD), whose symptoms are exacerbated by group A streptococcal (GAS) infection. PANDAS has been known to cause a sudden onset of reward deficiency syndrome (RDS). RDS includes multiple disorders that are characterized by dopaminergic signaling dysfunction in the brain reward cascade (BRC), which may result in addiction, depression, avoidant behaviors, anxiety, tic disorders, and/or OCD. According to research by Blum  Th. Thi.e.,s of RDS .Group A beta-hemolytic streptococcal (GABHS) infections are thought to be the root cause of RDS and a variety of aggressive and depressive behaviors . CumulatThe original concept of PANDAS can be traced back to a clinical trial that was conducted at the National Institutes of Health (NIH) in the US . The nos2.It is currently believed that PANDAS is an autoimmune reaction that, in part, mimics rheumatic fever and differs from the etiological links associated with spectrum disorders  or RDS. As a result, rheumatic fever can be thought of as an autoimmune disorder caused by streptococcal infections in which antibodies affect the brain and induce neuropsychiatric conditions. In their article on Tourette\u2019s Syndrome and OCD, Lombroso & Scahill introduced the idea of \u201cmolecular mimicry\u201d as a potential explanation for PANDAS . Accordiet al. in 1998 ..et al. iet al. conducted a study involving 311 subjects  who self-reported neuropsychiatric symptoms and also had concurrent group A streptococcal infection status ..et al. a3.et al. came to the conclusion in 2018 that rigorously conducted research regarding treatments for PANDAS is scarce, and published studies have a significant risk of bias  and other anti-dopaminergic reward gene risk polymorphisms as measured by genetic risk assessment at the DNA level in compromised pre- and post-adolescence children with PANDAS/CANS. Our ongoing work posits a potential positive clinical outcome as a function of the induction of \u201cdopamine homeostasis\u201d with precision-guided DNA testing and pro-dopamine regulation ."}
+{"text": "SARS-CoV-2 spike protein comprises a conserved hydrophobic pocket that binds linoleic acid (LA). LA supplementation interferes with viral entry into the cell and replication, and thus could be used as an antiviral. The COVID-19 pandemic and concomitant lockdowns presented a global health challenge and triggered unprecedented research efforts to elucidate the molecular mechanisms and pathogenicity of SARS-CoV-2. The spike glyco\u00adprotein decorating the surface of SARS-CoV-2 virions is a prime target for vaccine development, antibody therapy and serology as it binds the host cell receptor and is central for viral cell entry. The electron cryo-microscopy structure of the spike protein revealed a hydrophobic pocket in the receptor-binding domain that is occupied by an essential fatty acid, linoleic acid (LA). The LA-bound spike protein adopts a non-infectious locked conformation which is more stable than the infectious form and shields important immunogenic epitopes. Here, the impact of LA binding on viral infectivity and replication, and the evolutionary conservation of the pocket in other highly pathogenic coronaviruses, including SARS-CoV-2 variants of concern (VOCs), are reviewed. The importance of LA metabolic products, the eicosanoids, in regulating the human immune response and inflammation is highlighted. Lipid and fatty-acid binding to a hydrophobic pocket in proteins on the virion surface appears to be a broader strategy employed by viruses, including picornaviruses and Zika virus. Ligand binding stabilizes their protein structure and assembly, and downregulates infectivity. In the case of rhinoviruses, this has been exploited to develop small-molecule antiviral drugs that bind to the hydrophobic pocket. The results suggest a COVID-19 antiviral treatment based on the LA-binding pocket. Spike makes the first contact with the receptor on the host cell, human angiotensin-converting enzyme 2 (ACE2), and mediates infection by virus\u2013host cell membrane fusion . The furin-cleavage site in spike is key to the increased pathogenicity of SARS-CoV-2 . S2 comprises the membrane-fusion machinery, including the fusion peptide (FP), the fusion peptide-proximal region, heptad repeat (HP) 1, a central helix region (CH), HP2, a transmembrane anchor and a cytoplasmic C-terminal tail . The central helices of spike form a coiled-coil trimeric core. When spike interacts with ACE2, the S2 core and a second proteolytic site (S2\u2032) become exposed  leading to an elongated coiled-coil structure formed by HP1, the central helix and HP2 which positions the N-terminal fusion peptide close to the host cell membrane . In the closed conformation of spike the RBDs are all \u2018down\u2019, resulting in threefold symmetry. Importantly, the closed conformation of spike is considered to be a non-infectious form because the RBM is inaccessible. ACE2 interacts with spike in open states with one, two or all three RBDs pointing \u2018up\u2019 , and it has been suggested that ACE2 interaction enhances the opening of the RBDs  of the RBD is accessible Fig. 1b. In thp\u2019 Fig. 1b, and i2.et al., 2016et al., 2016et al., 2020et al., 2006et al., 2020et al., 2021et al., 2021et al., 2020et al., 2020C3-symmetrized structure reached a resolution of 2.85\u2005\u00c5. Surprisingly, the RBDs moved closer to each other compared with available atomic models. In a pocket of the RBD, additional tube-shaped density was identified which could not be attributed to protein  and LC-MS-MS, the ligand in the RBD was confirmed to be LA  in mammalian cells and stabilization of the spike trimer by a trimerization domain . Notably, the RBM is completely structured, which is not the case in the LA-free closed conformation, where regions including the RBM were disordered. In the presence of LA, the RBM is tucked away between the RBDs and is inaccessible for ACE2 binding , resulting in increased release of LA from the membranes and increased intracellular LA concentration , including LA. The media used for insect-cell culture contain FFAs as additives, thus mimicking the host environment. Secondly, the transfection of a plasmid encoding spike protein into mammalian cells does not faithfully recapitulate SARS-CoV-2 viral infection. The latter causes extensive membrane and lipidome remodelling and cPLA2.1.et al., 2020et al., 2022et al., 2022et al., 2017et al., 2022et al., 2019et al., 2022et al., 2021Sequence alignments of spike proteins of the other human betacoronaviruses SARS-CoV, MERS-CoV, HKU1-hCoV and OC43-hCoV indicated that the hydrophobic pocket in the RBD (named the B domain in HKU1-hCoV and OC43-hCoV) is conserved  application of the force resulted in an opening of the closed spike in the absence of LA. In contrast, only 14% of the LA-bound spikes opened on the application of the same force. This demonstrates that LA binding stabilizes the locked state of spike, increasing the energy required to raise a single RBD and reach an open conformation  simulations were performed to assess the relative stability of the closed and LA-bound locked spike proteins  which coordinates the carboxy headgroup of LA  spike was found to contain a lysine-to-asparagine mutation (K417N) leading to loss of a positive charge at the RBD\u2013RBD interface. This may affect the intersubunit LA\u2013RBD interaction and weaken the stabilization effect of LA in this VOC spike , significantly reduced attachment to human cells was observed compared with mini-virions with apo spike devoid of LA. Importantly, saturated fatty acids such as palmitic acid (PA) did not show this inhibitory effect, and the mini-virions bound with similar efficiency as mini-virions with apo spike , an enzyme target for antiviral drug development  in a negative-feedback mechanism  of SARS-CoV-2 spike (Wuhan) has been shown to bind the heme metabolites bilirubin and biliverdin . Receptor binding to the canyon displaces a hydrophobic \u2018pocket factor\u2019 from a pocket in VP1 below the canyon . This \u2018pocket factor\u2019 in the VP1 pocket has been suggested to stabilize picornavirus assembly. Receptor recognition and concomitant loss of the \u2018pocket factor\u2019 destabilizes the capsid and helps to release the picornavirus RNA genome during infection  and vitamin A were shown to have antiviral activity against SARS-CoV-2.\u2005A recent cryo-EM structure reveals that ATRA indeed binds to the hydrophobic pocket of SARS-CoV-2 spike protein . Importantly, ATRA inhibits the entry of SARS-CoV and MERS-CoV pseudoviruses into human cells, confirming the conservation of the hydrophobic pocket  by desaturation and elongation (Hanna & Hafez, 2018M (Richieri & Kleinfeld, 1995M in a so-called fatty acid\u2013lipid storm (Yan et al., 2019et al., 2021et al., 2022et al., 2022et al., 2020et al., 2021et al., 20202s releasing long-chain PUFAs from host cell membranes has been implicated in severe COVID-19 (Barberis et al., 2020et al., 2021et al., 2020et al., 2020Under physiological conditions, the levels of unsaturated FFA are maintained below 0.1\u2005\u00b52 activation and lipid metabolome remodelling, which are both common elements of viral infection (Goodwin et al., 2015et al., 2019et al., 2019et al., 2015et al., 2015et al., 2020et al., 2020et al., 2001The dysregulation of FFA levels during COVID-19 is suggested to result from cPLA4.2 and lipid remodelling, allowing the formation of viral replication compartments. LA release from the membranes contributes to the later-stage fatty acid\u2013lipid storm caused by pro-inflammatory eicosanoids. Release of PUFAs, including LA, from the membrane by cPLA2 changes the fluidity of the cellular membranes and contributes to pulmonary and cardiovascular disease. Taken together, this suggests that early-stage supplementation of LA, i.e. while the viral infection is localized in the upper airways, may be beneficial to interfere early with SARS-CoV-2 infection, replication and viral transmission. Current insights into the mechanism of SARS-CoV-2 infection further provide a rationale for the development of intranasal, pulmonary or oropharyngeal drug-delivery systems for self-administration, targeting mucosal epithelial cells with high ACE2 concentration. Given worldwide persisting SARS-CoV-2 infections and the conservation of the pocket in spike protein, LA delivery could present a novel and sustainable strategy for early COVID-19 treatment and prophylaxis.LA binding to an evolutionarily conserved hydrophobic pocket of the RBD of SARS-CoV-2 spike protein was discovered in the spike cryo-EM structure and substantiated by LC-MS-MS. LA impacts viral infection and disease progression by several mechanisms. LA stabilizes spike protein in a non-infectious locked conformation, avoiding premature S2\u2032 cleavage and dissociation of the S1 subunit of spike. Important immunogenic epitopes in the RBD of spike, including the RBM, evade immune recognition in the LA-stabilized locked conformation. In the human host cell, LA binding to spike and viral membranes contributes to hyperactivation of cPLA"}
+{"text": "Prediction and Explanation in Biomedicine using Network-Based Approaches\u201d putting together \u201cprediction\u201d  and \u201cexplanation\u201d . Scientific methodology is aware of the different, albeit related, status of the two perspectives since long time , gene expression correlation  and protein-protein interaction networks . In particular, Uversky and Giuliani review the most recent results in terms of hierarchical organization of complex biological systems, remarking the benefits of analyzing such systems in a multi-level fashion, hence going beyond the standard causative model where events originate at molecular level and then show up at the \u2018top\u2019 of the hierarchy . Causality is also the key in , where the authors review how causality can help in shaping disease networks, shedding light on using also functional information alongside physical proximity  for a thoughtful modelling. In Tran et al., the authors question the suitability of MCF-7 cell line for in vitro breast cancer research. They use a network-based approach to compare two MCF-7 datasets against a human breast invasive ductal carcinoma dataset taken from The Cancer Genome Atlas (TGCA), showing how they have only minimal similarity in biological processes, hence concluding that using MCF-7 to study breast cancer can hide important gene targets. Finally, TGCA plays an important role also in , where the authors use a network-based approach to find hub genes related to acute lymphoblastic leukemia.Biological systems are the most evident paradigm of complexity, and this is why it is much more productive to focus on the dynamics of their correlation structure with respect to an in-depth analysis of isolated features. In this Research Topic, this point is made evident by papers exploring correlation structures located at different organization layers: contacts between amino-acid residues of a protein molecule  motivated by the solution of relevant biomedical problems. Specifically, Kuznetsov et al. use a variational autoencoder to generate a synthetic 1-cycle ECG which not only looks quite natural, but can also be generated starting from just 25 features automatically learned by the autoencoder. As instead, Nazarenko et al. show an interesting network-based approach based on parenclitic and synolytic networks to describe multidimensional data via a suitable graph that makes the data easier to inspect, visualize and analyze. Tests on synthetic and benchmark data corroborate the competitiveness of using parenclitic and synolytic networks against common machine learning approaches.It is important not to confuse the integration of data analysis and explanatory perspectives with the too-often repeated statement of the substantial irrelevance of the hypothesis-driven approach when in presence of massive amount of data ; the sitChen et al.; Jung et al.; Luo et al.; Thomas et al.), that give us the strong impression that network-based approaches are here to stay. In detail, Thomas et al. review how network biology can help in understanding inflammatory bowel disease by discussing different network modelling , with some examples also on multi-layered networks. Chen et al. build a predictive model based on network analysis and circular miRNA to address recurrent implantation failure (RIF). Luo et al. also aim at characterizing RIF, but the authors exploit network-based approaches (protein-protein interaction and circRNA\u2013miRNA\u2013mRNA networks) to highlight four hub genes that may be involved in the development of RIF. Finally, Jung et al. briefly review computational models based on machine learning, network modelling and genome-scale metabolic models to characterize drug-resistant cancer cells.In this Research Topic, the application potential to biomedical practice of network-based approaches is explored in (After all, this is not surprising at all, \u201cnetwork biology\u201d is nothing else than \u201cbiology as such\u201d given any biological system derives its peculiar behaviour from the interaction of many different element players at different organization layers with no privileged causal layer of explanation . This is"}
+{"text": "More than 50 million individuals worldwide suffer from dementia with ~60\u201370% affected by Alzheimer's disease (AD). As a progressive and neurodegenerative disorder and the leading cause of dementia in the elderly, AD lacks effective treatments to modify or stop disease progression. Over the past years, studies have identified new molecular mechanisms and modifiable risk factors of AD. Accumulating data suggest that advancing the understanding of AD mechanisms and risk factors may allow the development of targeted interventions to potentially prevent or cure the disease. There are an increasing number of preclinical studies focusing on mechanism-driven therapies, which need to be further characterized before introducing into clinical trials to determine their efficacy.Progress of Translational Medicine in Alzheimer's Disease\u201d in Frontiers in Aging Neuroscience includes a series of 13 articles that discuss recent advances in the field of translational studies in AD and highlight current challenges and outstanding questions requiring further study in order to advance research in this domain. These articles are discussed based on two main specific themes, noted below.Here, the Research Topic \u201cXing et al. have completed a meta-analysis, combing through discoveries which describe the diagnostic values of exosome-derived biomarkers in AD and MCI (Mild Cognitive Impairment). The meta-analysis includes 19 eligible studies involving 3,742 subjects and supports the potential diagnostic value of exosome-derived biomarkers in AD and MCI, and lays a foundation for future research to further confirm this finding.Emerging evidence has shown that exosome-derived biomarkers are potentially related to early occurrence and development of AD, which requires a consolidated analysis. Vogrinc et al. summarize more than 100 AD risk loci, with many of them potentially serving as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, the analysis of GWAS data has led to identification of key pathways underlying AD pathogenesis, including cellular and metabolic processes, biological regulation, localization, transport, regulation of cellular activities, and neurological system processes. Thus, gene clustering into molecular pathways may help identify novel molecular targets and support the development of more tailored and personalized intervention of AD.Over the past decade, numerous genome-wide association studies (GWAS) have identified significant genes associated with increased risk of AD, for which a systemic review to identify potential molecular mechanisms was overdue. In a review article, Homann et al. conduct an analysis of GWAS on AD brain imaging biomarkers and neuropsychological phenotypes using the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset (EMIF-AD MBD). Their results highlight the power of using quantitative end phenotypes as outcome traits in AD-related GWAS analyses and nominates new loci underlying cognitive decline.Next, Shi et al. investigate plasma proteomic biomarkers associated with AD through a meta-analysis. The study assesses the diagnostic performance of their own group's previously identified blood biomarkers, and identifies proteins significantly associated with AD, including alpha-2-macroglobulin (A2M), ficolin-2 (FCN2) and fibrinogen gamma chain (FGG).Although plasma biomarkers for the diagnosis and stratification of AD have been intensively analyzed, no plasma markers have so far been well-established and confirmed for AD diagnosis. To this end, Logan et al. explore convolutional neural networks (CNN), a class of deep learning algorithms, for classifying multi-modal neuroimaging data such as magnetic resonance imaging (MRI) and positron emission tomography (PET). These networks may successfully enable early detection of AD and provide insight into AD classification using 3D architectures for multi-modal PET/MRI data.Presently, another challenging barrier to understanding AD and related dementias is availbility of suitable artificial intelligence (AI) methodologies for analyzing massive AD datasets. In a comprehensive review, Wu et al. summarize recent findings involving altered gut microbiota of patients with AD, and discuss pathogenetic mechanisms of gut microbiota in AD, suggesting gut microbiota\u2013targeted therapies for AD.Recently, increasing evidence has suggested the involvement of gut microbiota dysbiosis in association with AD. In a through review, Mee Hayes et al. discusses recent progress and potential mechanisms for targeting aggregates with proteasomes and disaggregases in liquid droplets.Despite the long-standing and established findings supporting insoluble protein deposition as pathological hallmarks of AD and other neurodegenerative disorders, studying the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. A timely review by Stonebarger et al. present an article challenging a major obstacle in understanding the etiology of normative and pathological aged brains in AD\u2014the availability of suitable animal models. This article highlights our current knowledge in the area and examines the use of the rhesus macaque monkey as a pragmatic translational animal model to progress future research in this area.Furthermore, Morgan et al. have performed text-mining and generated an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. The results of this research may be applicable to the context of the broader AD literature corpus.The issues surrounding the large number of poorly understood underlying functional mechanisms is a major stumbling block in AD research today. Blevins et al. present a review article looking into the AD-related NLRP3 inflammasome, a multiprotein complex that plays a common and pivotal role in regulating innate immunity and inflammation underlying human pathophysiology.Finally, Zhong et al. focusing on D-penicillamine (D-Pen), a water-soluble metal chelator that can reduce A\u03b2 aggregation. The authors report that D-Pen significantly improves the cognitive functions of APP/PS1 mice and reduces A\u03b2 generation with an associated increase in ADAM10 via the non-amyloidogenic processing pathway.The first article that addresses potential therapies for AD is a study by Ma et al. present the results of their study describing the effects and molecular mechanisms of cornel iridoid glycoside (CIG), an active ingredient of the traditional Chinese herb Cornus officinalis, in pathological tau P301S transgenic mice. The data support CIG as a promising molecule for potentially treating AD-related tauopathy.Next, Carranza-Naval et al. analyze liraglutide (LRGT), a glucagon-like peptide-1 agonist, for its effects on reducing pathological changes in the brain of a mixed murine model of AD and T2D (APP/PS1 x db/db mice). These results support the potential for LRGT therapy to reduce AD-associated brain complications.Because type 2 diabetes (T2D) is a major contributor to the development of AD and AD patients with co-occurrence of T2D are regularly observed in the clinical arena, In closing, we would like to thank all the contributing authors and reviewers for their valuable expertise and effort toward successfully compiling this series of research focusing on translational medicine for AD. We realize that although these selected articles cover a good number of studies reporting up to date research findings, future studies will be necessary to better understand the \u201celephant in the room:\u201d the etiology of AD, which is our primary goal in developing this Research Topic. We sincerely hope that this Research Topic of articles will provide a useful point of reference and stimulate future studies committed to ultimately understanding the complex pathogenesis of AD and advancing the development of useful therapeutics for AD.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.EF has CRADA arrangement with ChromaDex and is consultant to Aladdin Healthcare Technologies, Vancouver Dementia Prevention Center, and Intellectual Labs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Formulations from nanotechnology platform promote therapeutic drug delivery and offer various advantages such as biocompatibility, non-inflammatory effects, high therapeutic output, biodegradability, non-toxicity, and biocompatibility in comparison with free drug delivery. Due to inherent shortcomings of conventional drug delivery to cancerous tissues, alternative nanotechnological-based approaches have been developed for such ailments. Ovarian cancer is the leading gynecological cancer with higher mortality rates due to its reoccurrence and late diagnosis. In recent years, the field of medical nanotechnology has witnessed significant progress in addressing existing problems and improving the diagnosis and therapy of various diseases including cancer. Nevertheless, the literature and current reviews on nanotechnology are mainly focused on its applications in other cancers or diseases. In this review, we focused on the nanoscale drug delivery systems for ovarian cancer targeted therapy and diagnosis, and different nanocarriers systems including dendrimers, nanoparticles, liposomes, nanocapsules, and nanomicelles for ovarian cancer have been discussed. In comparison to non-functionalized counterparts of nanoformulations, the therapeutic potential and preferential targeting of ovarian cancer through ligand functionalized nanoformulations\u2019 development has been reviewed. Furthermore, numerous biomarkers such as prostatic, mucin 1, CA-125, apoptosis repeat baculoviral inhibitor-5, human epididymis protein-4, and e-cadherin have been identified and elucidated in this review for the assessment of ovarian cancer. Nanomaterial biosensor-based tumor markers and their various types for ovarian cancer diagnosis are explained in this article. In association, different nanocarrier approaches for the ovarian cancer therapy have also been underpinned. To ensure ovarian cancer control and efficient detection, there is an urgent need for faster and less costly medical tools in the arena of oncology. Then extracellular matrix gets degrade and the dissociation of cells takes place from primary cancer. The dissociated cells become abdominal free-floating cells or clumps together that forms multicellular aggregates.In the context of patient survival, chemotherapy and radiation therapy is under clinical trials to evaluate the ovarian cancer initial stage and approach the benefits of survival (Boev\u00e9 et al., In the early phase ovarian cancer detection, the current treatment and diagnostic methods are not enough efficient and sensitive as well. Furthermore, delayed diagnosis has been observed as a virtue of non-specified detection and high costs of the applied methods. Recently, nanotechnology is emerged as a growing field in the treatment and diagnosis of ovarian cancer that offers the development of novel and potential strategies to overcome ovarian cancer (Zhou et al., Liposomes exhibit a lipid bilayer that holding hydrophobic interface that enables the attachment of therapeutic and diagnostic agents of both hydrophilic and hydrophobic nature to the geometry of liposomes. The core region of dendrimers is closer to the hydrophobic component and hydrophilic termini that helps in the delivery of hydrophobic payloads within water insoluble domain. On another hand chemical conjugation of moieties with the exterior is take place for its delivery. Adsorption of carbon nanotubes to various agents is take place for consecutive delivery. Micelle provides delivery platform for hydrophobic anticancer drugs with prolong circulation.2.In recent years, ovarian cancer is globally classified as deadly gynecological cancer (Boitano et al., Biomarkers manifest versatile class of biomolecules that indicates a specific disorder or biological function Ueland, . In the 2.1.Optical biosensor utilizes an optical transducer system with sensing features that are used for analysis purposes. It senses and transmits those signals that are directly proportional to the biomarker . These bTo improve the surface glycosylation visibility of sample cells an accelerating technique was used that showed efficient results. During the technique the MUC1 precise glycosylation on the cancer cell surface was pictured through a quantum dots label using the strategy of RMC magnification. This study offers a sort of suggested scheme for protein-specific glycosylation and thus indicates the mentioned technique as a feasible strategy (Yang et al., 2.2.Electrochemical nanosensors have shown potential methodology and role for the precise detection of biomarkers in ovarian cancer and usually have the detection power in minute quantities of biomarkers and other analytes (Parmin et al., Another research group worked on the CA-125, biomarker identification through the development of immuno-based electrochemical nanosensor. The developed nanosensor was composed of multiwall carbon nanotubes, gold nanoparticles and 3D reduced graphene oxide composite. The developed system displayed an excellent detection limit i.e. 6 \u00b5U/mL .2.3.Micro fluidic laboratory-on-chip nanosensor integrates easily the various features of multiple sensing systems with less sampling rate and thus pose it a versatile miniaturized system (Jamshaid et al., 2.4.Within a portable system, it is the unique feature of giant magnetoresistive biosensors that it measures multiple biomarkers all together. In addition, other advantages include integrated circuit connectivity, high accuracy and easy biomolecular detection (Xuan et al., 3.In the recent years, many nanoconjugates and nanoformulations as a drug delivery system have been developed and they have improved the therapeutic drug delivery to the target side due to unique features such as biocompatibility, high therapeutic efficacy as compared to free drug, non-toxicity, biodegradability, off-target side effects and ease of manufacturing scale-up (Larra\u00f1eta et al., 3.1.Liposomes are nontoxic phospholipids-based sphere-shaped small vesicle ranges in size from 400\u2009nm to 2.5\u2009mm. Liposomes are extensively employed renowned clinically delivered nanosystems with biodegradable nature and have the capability to entrap hydrophobic and hydrophilic biomacromolecules, i.e. RNAs, peptides and proteins without modification in their inherent properties (Sun et al., The co-loading of two chemotherapy agents into a single liposome in clinical trials has shown many advantages but the loading of two chemotherapeutic drugs into a single liposome is quite challenging. In this context, irinotecan and doxorubicin were encapsulated and loaded into liposomal nanoformulations to treat ovarian cancer xenograft. Various ratios between drugs to the drug were used during loading into the liposome. The encapsulation efficiency was 80%, and it was found that after storage for 6 months the liposomal stability attributes significantly influenced the drug encapsulation. After the administration of developed nanosystem via intraperitoneal route considerably enhanced the survival of the animals with tumor, which was attributed to increased exposure of liposomal nanoformulations to the systemic circulation (Shaikh et al., 3.2.Several nano-sized drug delivery systems have been tested in cancer treatment to reduce the side effects of traditional anticancer drugs while increasing the antitumor efficacy of target therapy (Mohammadzadeh et al., In addition to metal nanoparticles, biomacromolecules such as vitamins, nutrients, hydrophobic drugs and phenolic compounds were immensely delivered to multifaceted biological systems using chitosan nanoparticles. Chitosan-a chitin-deacylated biopolymer of natural origin that exhibit useful features such as inertness, biodegradability, biocompatibility and the presence of hydroxyl and amino group that make it a suitable candidate for the drug delivery (Muddineti et al., In another research study, cannabidiol-loaded polymeric nanoparticles were developed and evaluated in ovarian cancer cell for growth inhibition potential. The encapsulation efficiency found was 95% with 240\u2009nm size nanoparticles and displayed controlled release kinetics for cannabidiol after internalization to SKOV-3 ovarian cancer cells for an extended period of 96\u2009hours. After encapsulation, the antiproliferative effect of cannabidiol was found excellent against the SKOV-3 cells. Apoptosis was also induced by the applied drug-loaded nanosystem that was confirmed when PARP protein was found provoked. Importantly, the ovarian tumor growth inhibition was slightly higher for cannabidiol-loaded nanoparticle as compared to free cannabidiol (Fraguas-S\u00e1nchez et al., In the arena of ovarian cancer targeted drug delivery epigallocatechin gallate-loaded chitosan base mesoporous silica nanoparticles were developed and evaluated. Furthermore, the fabricated system was attached with AS1411 aptamer through conjugation with the amine group present in the chitosan using electrostatic attraction. The aptamer functionalized nanosystem followed macro-pinocytosis and displayed efficient internalization potential in SKOV-3 cell lines. Consequently, it resulted in an augmented cytotoxic effect in 93% of ovarian cancer cells along with G1 cell cycle arrest and down-regulation of ERK2 expression level (Alizadeh et al., 3.3.Solid-lipid nanoparticles are made up of surfactants, lipids and therapeutic drugs enclosed in spherical shape colloidal nanocarriers exhibiting 50\u20131000\u2009nm diameters. The lipid core and nano size range of solid-lipid nanoparticles make them versatile drug delivery carriers from nanotechnology platforms. Such nanocarriers have attained greater interest also due to their considerable biocompatibility, excellent circulation time and marked accumulation at the target site (Radhakrishnan et al., 3.4.l-buthionine sulfoximine\u2014a \u03b3-glutamylcysteine ligase inhibitor, the glutathione synthesis was hampered significantly. Systemic toxicity consideration in this context helped in overcoming the issue of carboplatin resistance by using polyurea-based dendrimer formulations (Cruz et al., Dendrimers are spherical nano size, regularly branched, three-dimensional tree-like architectures of high molecular weight in which the branch lengths are stearic limited exhibiting an inner core. The inner microenvironment and surface of dendrimers are composed of functional moieties that help in the attachment of delivering cargoes (Mishra et al., 3.5.Among nanostructured materials micelles represent an intriguing class of nanoarchitecture in which amphiphilic molecules above critical micelle concentration aggregates to form such a versatile class of nanocarriers (Karayianni & Pispas, 3.6.Nanocapsules manifest a nanoscale vesicular system that is composed of central cavity that gives space to the drugs of interest. In addition, an outer polymeric shell is also there surrounding inner core and it helps in the attachment of various targeting ligands and moieties during surface functionalization (Li et al., A summary of various nanosystems is provided in 4.The knowledge and research on nanotechnology-based formulations has bloomed in recent years, however, only few formulations have made their way successfully to clinics. Most of such formulations fail to demonstrate similar results when tested in vivo and halt their progress to clinical trials. For clinical translation, every nanoformulation has particular challenges, however, most of them confront biological, technological, and study-design-related challenges.Biological challenges include lack of routes of administration, tempering biodistribution, hannelling nanosystems across biological barriers, toxicity and degradation (Lv et al., Controlling nanoparticle\u2019s biological fate is difficult and requires focus. There is a possibility of liver, lung, and kidney damage, despite the fact that nanoparticles are made of biosafety materials. Surface area, shape, solubility, particle size and agglomeration are the factors that are reported to cause toxicity (Jia et al., Technological challenges of nanosystems include equal optimization, performance predictions and scale-up synthesis. Most nanoparticles used are produced in small batches, and scaling up is not always possible due to instrumentation and other factors. In animal models, the best lead clinical candidates are not always systematically designed and optimized. To circumvent this, we can employ specific methods that permit the testing of numerous nanoformulation and the selection of a single optimized formulation via selective iterations (Dobrovolskaia et al., N\u2009=\u20091 clinical studies will be needed for personalized medicine. This includes genetic, environmental, and medical history factors (Love et al., Study-design challenges such as study size, intent, and timing of nanoparticle therapies during therapy have a significant impact on clinical studies. The majority of research is based on \u201ccell and animal models,\u201d which may not translate to human trials. Therefore, it is challenging to mimic natural human body reactions using a single model. Metastasis is an important attribute of cancer, so \u201cmodels of cancer metastasis\u201d should be researched. Nanotechnology enables personalized oncology, in which cancer therapy and diagnosis are tailored to each patient\u2019s tumor molecular profile, and predictive oncology, in which genetic and/or molecular markers predict development and progression of disease and clinical outcomes. The National Cancer Institute in the US has recently allocated funds to eight national Centers of Cancer Nanotechnology Excellence due to its potential impact on cancer research (Misra et al., 5.The precise delivery of therapeutic cargoes into ovarian tumor cells through novel engineered carriers from nano scaffolds has been widely explored in recent years. In the diagnosis and treatment of ovarian cancer, the chemotherapeutic drugs\u2019 adverse effects were significantly curtailed, the site-specific delivery was augmented and solubility issue of hydrophobic cargoes was resolved using numerous nanotechnology-based carrier systems. In ovarian cancer, nanotechnology from nanoscience domain addresses the site-specific delivery and provides new-enhanced and targeted therapy possibilities. Several formulations show interesting results but only a few will make their way to clinical trials and clinics because the progress of most of them is halted in pre-clinical stages due to a number of factors. Regarding clinical translation, each nanoformulation has particular challenges related to either biological, study-design, or technology related. In addition, the toxicity, biotransformation and excretion of nanocarriers-based systems for ovarian cancer will also be a challenging aspect. Therefore, in the design stages, such considerations should be kept in mind for developing biocompatible and nontoxic carrier systems. Numerous nanotechnology-based biosensors have been proposed and tested in recent years for the diagnosis of ovarian cancer. The associated concerns with ovarian cancer diagnosis and treatment could be resolved through these nanomaterials based biosensors due to their high sensitivity and selectivity. However, the development of nanosensors is a time-consuming and complex process and thus often fails in the critical evaluation of biomarkers. Importantly, in the identification of ovarian cancer biomarkers, the demand of portable nanosensors that could be used to rescue subjects outside the clinical settings is of much value. In the scenario of ovarian cancer diagnosis, microfluidic and paper-based nanosensors fabrication offers feasible prospect for biosensors\u2019 commercialization. In a nutshell, in the near future thrilling developments are required for sensing procedure scale-down using nanotechnology platform that hopefully would enable the patients to check their health easily and indeed would open new avenues in the diagnosis and treatment of ovarian cancer."}
+{"text": "Dementia-related continuing education opportunities are important for rural primary health care (PHC) professionals given scarce specialized resources. This report explores the initial perceptions and continuing education needs of rural interprofessional memory clinic team members and other PHC professionals related to a short series of dementia-related education webinars. Three webinars on separate topics were delivered over an 8-month period in 2020 in Saskatchewan, Canada. The research design involved analysis of webinar comments and post-webinar survey data. Sixty-eight individuals participated in at least one webinar, and 46 surveys were completed. Rural memory clinic team members accounted for a minority of webinar participants and a majority of survey respondents. Initial perceptions were positive, with webinar topics and interactivity identified as the most effective aspects. Continuing education needs were mainly aligned with professional roles; however, some overlap of interests occurred. Future webinars will further explore learning needs within an interprofessional environment. Meant tet al., et al., et al., et al., et al., IPE in primary care that promotes interaction and learning between different professional groups is important for strengthening collaboration skills and behaviours and fostering collaboration within teams  team members and the developer (DS) of the Primary Care Dementia Assessment and Treatment Algorithm (PC-DATA\u2122), which has been adapted and integrated into the clinic model. Prior to 2020, continuing education was offered periodically to one team at a time, delivered by clinical specialists and other experts via telehealth videoconference. Teams suggested topics in which they were keen to receive further training, which included differential diagnosis, capacity and competency, medication for dementia, and driving assessment. More teams were invited to take part in the sessions as the model spread to other communities. In a recent process evaluation, teams indicated participation in training and continuing education improved self-confidence in abilities and supported implementation of memory clinics (Morgan 1). Each webinar began with a 30\u201345 minute presentation followed by 30\u201345 minutes of discussion. Team members had the flexibility to join remotely with their chosen device since they often travel between settings and communities. During the webinars, the presenter\u2019s camera and audio were live and participants could offer written or oral comments at any time; however, participant\u2019s cameras were turned off.In February 2020, the researchers introduced a cross-team dementia-related continuing education series delivered via WebEx. Three webinars were delivered in 2020 on topics suggested by the teams and are included in this analysis .2). Six Likert items and two open-ended questions were adapted from previous evaluations of dementia-related continuing education sessions for health professionals . Regarding webinar content, the majority agreed the sessions were appropriate for their professional needs and new information was learned (96%). Most found the interactive format and webinar environment effective for learning (96%). A majority also intended to apply the information in their practice and appreciated the participation of other PHC teams and professionals; however, these particular items were endorsed by fewer participants (<90%).Among survey respondents across the webinars, overall satisfaction was high (94%)  (data not shown in table). Regarding the first two webinars which were more medication-focused than the third session, some AHPs found themselves engaged although they were not in a prescribing role and did not feel highly knowledgeable about the topic . Illustrative quotations of themes are provided in Supplemental Table\u00a0This study explored the perceptions and continuing education needs of rural memory clinic team members and other PHC professionals participating in interprofessional dementia-focused webinars. Findings from post-webinar survey evaluations indicated positive initial perceptions of webinar content and format, and education suggestions that mainly corresponded to professional roles.et al., et al., et al., et al., et al., Our findings are consistent with research showing rural health professionals react positively to dementia care learning opportunities delivered remotely . To help improve management capacity, the rural memory clinic model and other task-sharing approaches collaborate with highly qualified and experienced dementia specialists to further train and support PHC professionals (Canadian Academy of Health Sciences, et al., et al., et al., Suggestions by survey respondents for future education topics generally aligned with professional roles. The mutual interest of AHPs and FP/NPs in pharmacological and non-pharmacological management, and emphasis by FP/NPs on management interventions, underscores the challenge of these issues in primary care. Interest in medication-related topics is consistent with recent research showing potentially inappropriate prescribing is associated with higher levels of comorbidity among people living with dementia (Delgado Limitations of this study should be considered. Survey items focused only on a few selected perceptions of webinar content and format. Other measures of content and format, and other domains, may have been pertinent to participant experience but were not included. Survey participation was voluntary; therefore, the results are subject to non-response bias. Respondents may also have tended to agree rather than disagree with statements, reflecting acquiescence bias. Furthermore, the initial findings from a small sample of professionals from one geographic area limit the generalizability of the findings.There have been few published studies of initiatives that offer dementia-related continuing education in an interprofessional setting to PHC professionals. Initial results from this study indicate favourable feedback from rural participants of a short series of interprofessional dementia-related education webinars. The findings also revealed opportunities to seek further input on varying education needs within teams, to inform future webinars and research."}
+{"text": "For patients with a variety of severe diseases, including primarily hematopoietic malignancies, immunodeficiency syndromes, and genetic disorders, allogeneic hematopoietic stem cell transplantation (aHSCT) represents a potentially curative therapeutic approach. In this context, despite significant progress in the optimization of aHSCT, the development of graft-versus-host disease (GVHD) remains a challenge to long-term transplant success after aHSCT. It is associated with significant morbidity and mortality and is the major cause of non-relapse mortality.GVHD occurs when donor T cells are primed by recipient antigens subsequently eliciting an inflammatory response against the host. Clinically, two types of GVHD are distinguishable: an acute form (aGVHD), and a chronic form (cGVHD). In brief, the main characteristics: aGVHD occurs in 30-50% of aHSCTs and is a multi-organ disorder resulting from inflammatory cytokines and donor T cells which primarily damage skin, liver, gastrointestinal tract, and eye. cGVHD, with a prevalence of 30-70% of aHSCTs, is induced by T and B cells resulting in a heterogeneous immunological complication affecting virtually every organ.Traditionally, broad immune-suppressive drugs (with considerable toxicities) including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus), together with methotrexate or mycophenolate mofetil (MMF), and mTOR inhibitors (Sirolimus/Rapamycin) are used as GVHD prophylaxis. But despite first success reports, significant GVHD still occurs with these drugs. Other prophylaxis strategies like pre-transplant anti-thymocyte globulin (ATG) are effective in reducing severe GVHD but have no survival benefits and steroids have serious side effects.One of the most critical challenges in aHSCT is the development of less toxic and more targeted therapies that maintain the graft-versus-leukemia/tumor (GVL/T) effect but suppress GVHD while facilitating enhanced immune reconstitution relative to existing strategies. Recently, several prophylaxis strategies for GVHD have been developed and others are currently in development, including, for example in the case of haploidentical HSCT, post-transplant cyclophosphamide (PTCy), which seem to be very promising.In the frame of this specific Research Topic, we aimed to collect recent developments of innovative methods for both prevention and treatment of GVHD, without impairment of GVL. In 8 original research articles and 4 reviews, this edition provides a deep insight into the role of the microbiome and metabolism as well as recent advances of small molecule and cell therapy development.Mohamed et\u00a0al., summarize metabolic pathways contributing to GVHD and discuss metabolic targets for acute and chronic GVHD in immune and non-immune cell as well as the immunomodulatory function of microbial metabolites. Furthermore, they examine the metabolic effects of co-inhibitory pathway blockade (PD-1) and cellular therapies (Tregs/MSCs/Bregs) in aHSCT. The mini review by Karl et\u00a0al., provides an overview of metabolic T cell alterations in GVHD and illustrates the impact of conventional GVHD therapy on T cell metabolism.We are glad, that experts in the field highlight the recent progress in the broad field of immune cell metabolism with two comprehensive reviews. Ghimire et\u00a0al., investigates the role of G-protein coupled receptors (GPR43 and GPR109A) which engage microbial derived metabolites, like short chain fatty acids, in the mitigation of GVHD in intestinal biopsies from patients after allo-HSCT. A second study by Heidrich et\u00a0al., describes an association of dental biofilm microbiota dysbiosis with the risk of aGVHD.Recent studies have shown the association of microbiome dysbiosis and aGVHD. Here, primary research by Campe and Ullrich. Moreover, Agbogan et\u00a0al., explore the immunomodulatory effect of adoptively transferred CpG-activated B cell progenitors to alleviate GVHD symptoms. In addition, Scheurer et\u00a0al., describe an in vitro generated sub-population of CD11b+CD11c+ myeloid-derived suppressor cells (MDSCs) as potent immune modulators leading to the prevention of GVHD without negatively affecting tumor cytotoxicity. Another innovative and attractive strategy using CRISPR/Cas9 has been described by Majumder et\u00a0al., for genetical engineering of na\u00efve T cells pre transplant as a method for GVHD prevention in a major murine mismatch model.In the context of cell therapy development, the biological relevance of T helper cell lineage defining transcription factors as potential targets for GVHD therapy has been delineated in a review article by Braun and Zeiser thoroughly review the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT. Thangavelu et\u00a0al., evaluate the efficacy of a novel agonist of the retinoic X receptor (RXR), IRX4204, to treat cGVHD in two complementary murine models with bronchiolitis obliterans or sclerodermatous manifestations. Primary research by Matos et\u00a0al., analyzes a possible association of anti-thymocyte globulin (ATG) treatment and serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in 4 HSCT cohorts with different vitamin D3 supplementation. Lastly, Hadjis et\u00a0al., characterize post-transplant cyclophosphamide as superior in ameliorating pre-clinical GVHD compared to five other optimally dosed chemotherapeutics  that vary in mechanisms of action and drug resistance.In addition, the recent therapeutic advances in the area of drug development, e.g. small molecules and antibodies, are also addressed. Finally, this Research Topic makes us again aware of how complex the regulation of GVDH is and in which fragile balance between GVHD and GVL patients after aHSCT find themselves. We are aware that this issue can only compile a first selection of innovative findings and treatment strategies that are currently being developed for the prevention and treatment of GVHD.GVHD biology and treatment remains a field that is always influenced by current research developments and new advances can be expected in a short time. Therefore, we will continue to monitor the field and provide updates to the authorship of Frontiers in Immunology.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.EU is a member of Phialogics and receives research support from BMS and Gilead. AB is a scientific cofounder of Aamuthera Biotech GmBH and Dualyx NV.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Fossil-based heteroatom-containing compounds are crucial core scaffolds or key intermediates in a wide range of pharmaceutical molecules, fiber dyes and printing ink , which cLiu et al., Zhu et al., Liu et al., Zhang et al., Sun et al., Yao et al., Zhou et al., Zhao et al., Yang et al., and Zhou et al.), biodiesel production , and green synthesis of heteroatom-containing bioactive compounds and functional materials . Also, the Research Topic provides interesting insights into the green photocatalysis of organic pollutants .This Research Topic is Volume II of a series, and here we present a collection of original research and review articles  with topics on green and sustainable chemistry, including catalytic conversion of biomass feedstocks . Zhang et al. use glycerol waste to comparatively evaluate the ameliorative effect on lignocellulose under microwave or conventional heating method. During fast pyrolysis, levoglucosan produced from microwave-treated samples (32.9%) was far more selective than the conventional heating group (18.8%), and the content of aldehydes (high toxicity to the downstream fermentation) after glycerol waste and microwave pretreatment was decreased by 2.5 times compared with the untreated counterpart. In addition to directly using raw biomass resources, simple sugars like fructose can be efficiently converted to 5-hydroxymethylfurfural (up to 82% yield) by dehydration over a stable Ti-doped SBA-15 catalyst in DMSO at 140\u00b0C for 1\u00a0h , or to 5-ethoxymethylfurfural (80.4% yield) by cascade dehydration-etherification using a UIO-66-SO3H catalyst in ethanol under the same thermal conditions . Zhang et al. manufacture a biomass-based solid acid catalyst (SiO2@Cs-SO3H) with a large specific surface area (21.82\u00a0m2/g) and acidity (3.47\u00a0mmol/g) using renewable chitosan as raw material through sulfonation procedure under relatively mild conditions, which is active for esterification of oleic acid and methanol to produce biodiesel (98.2% yield).Original research paper of Chen et al. reports an unprecedented inactivation process of the indanol-derived NHC catalysts bearing N-C6F5 groups, giving an unexpected multi-cyclic complex product from the 3-component reaction with 1-methylcyclopropyl-carbaldehyde, 2,2,2-trifluoroacetophenone and the NHC catalyst. Pan et al. develop an acid-catalyzed 2-alkylation of indole molecules catalyzed by traceless HI, and 2,3-disubstituted indole molecules bearing congested tertiary carbon centers are obtained in moderate to good yields. Some functional catalytic materials such as hierarchical porous SAPO-34 , bimetallic Zn-Zr metal-organic framework , and graphene oxide-silver nanoparticles composite  are prepared in sustainable ways, and found to be efficient for the synthesis of value-added chemicals  or degradation of organic pollutants.The work of Liu et al., Sun et al., Zhou et al., Yang et al., Yao et al., Liu et al., Wu et al., Liu et al., Pan et al., and Zhang et al.). Liu et al. review the application of recyclable heterogeneous non-noble Zr/Hf-containing catalysts  with acid-base bifunctionality for catalytic transfer hydrogenation using the safe liquid hydrogen donor, with emphasis on evaluating the reaction mechanisms and conversion pathways. In a more detailed manner, the research progress of catalytic synthesis of \u03b3-valerolactone from furfural by Zr/Hf-based catalysts is reviewed by Sun et al., and the effects and regulation approaches of Lewis acid-base and Br\u00f8nsted acid sites in the catalysts on each steps in the reaction process are discussed. Zhou et al. reveal the significance and potential of using titanate nanotubes-based materials as sustainable and environmentally benign solid catalysts/supports for synthesis of various bio-based chemicals, such as glycerol-derived solketal, jet fuel range alkanes precursors, biomass-derived esters, aldehydes, and aromatic compounds. Yang et al. propose the research development trend for improving the institutional mechanism of the utilization of crop straw resources, strengthening technology research and development, exploring the economic model of green cycle agriculture, accelerating the construction of the industrial system, and designing new paths of resource utilization in multiple ways. Yao et al. mainly review some latest studies about the conversion of cellulose to 5-hydroxymethylfurfural catalyzed by solid acids with Br\u00f8nsted and/or Lewis acidic sites, such as sulfonated solid acids, carbon-based acids, and zeolites. Liu et al. summarize the mechanisms of several important processes of producing 5-ethoxymethylfurfural from lignocellulosic biomass-derived sugars and the research progress of the developed acid catalysts. In addition, advancements in tobacco (Nicotiana tabacum L.) seed oils  and lipid extraction from microalgae using green solvents  for biodiesel production are also collected. For some structurally somplex natural products such as sex pheromones , and momilactones and related 9\u03b2-H pimarane skeleton , the recent advances in their synthetic strategies with the involved challenges are overviewed.This Research Topic features several review articles with distinct scopes (We wish this Research Topic attracts interested colleagues, enlightening more eco-friendly and sustainable synthetic procedures, shedding light on renewed catalytic strategies and routes developed for the production of bio-based heteroatom-containing compounds, and providing enthusiasm in research and studies. Enjoy its reading!"}
+{"text": "Back in 2010, when we first published data on the in vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet [Research is growing at a fast pace, acknowledging that gene\u2013diet interactions play an enormous role in human health and are typically only partially assessed. Healthcare providers, on the other hand, receive scarce knowledge of these interactions, thus jeopardizing the application of precision nutrition ,3. At thThis Special Issue on the effects of gene\u2013diet interactions in human health includes six original research articles showing data that will bring readers closer to the state-of-the-art developments in the field of nutritional genomics. From human intervention studies in Spain and Latin America to large-scale genome-wide association studies (GWAS), such as the UK Biobank, and the study of molecular mechanisms in Drosophila melanogaster, this issue includes the latest advances driving our understanding of gene\u2013diet interactions.A genetic correlation and two-sample mendelian randomization study was performed by Xu et al.  assessinGranado-Serrano et al.  studied Rivera-I\u00f1iqguez et al.  studied A high polygenic risk score for Type 2 diabetes mellitus was used by Lopez-Portillo et al.  to assesDu et al.  used DroGene\u2013diet interactions, once fully incorporated into clinical practice, hold great promise as a precise tool to improve quality of life, health span, and reduce healthcare costs. This special issue added a piece of knowledge in that direction with more precise data and analysis."}
+{"text": "Polasa et al. use an extensive set of equilibrium and non-equilibrium molecular dynamics simulations to describe the conformational changes in the YidC during membrane insertion . Similarly, Li et al. consider the effect of cholesterol and membrane composition on C99 dimerization with ramifications in Alzheimer\u2019s disease . Be it atomistic or coarse-grained, molecular dynamics uses a physics-based approach to explicitly describe the interaction between molecular moieties of interest with an outstanding resolution. Aslam and Alvi present a different computational approach based on systems biology. Their mathematical modeling allowed the complete exploration of a novel postsynaptic channel for glutamatergic synaptic transmission and its effector molecules composed of ions, diacylglycerides, and protein kinases (Aslam and Alvi). Unlike molecular dynamics, systems biology works at much larger scales and aims to characterize emergent phenomena from complex and interdependent processes and interactions in biological systems. Advancing our knowledge of membrane-related processes depends on experimental methods as well. The Research Topic includes the purely experimental work by Kurakin et al., who studied lipid vesicle and divalent ion interactions . This process is of paramount importance in signaling and membrane structure. Overall, we show that advancement in membrane research requires synergies from widespread techniques.Our knowledge of cellular membranes and their components\u2019 critical role is recent and so far, unfinished. Bilayers of lipids were proposed less than 100\u00a0years ago . \u201cFluid"}
+{"text": "Resco de Dios et al. Nature Communications 10.1038/s41467-022-32013-9 (2022)In their letter, Resco de Dios et al. discuss fire regimes in China using a dataset of annual area burned from a satellite product, i.e., the Moderate Resolution Imaging Spectroradiometer (MODIS) Collection 6 (C6) MCD 64 A1. They suggest that: (1) the fraction of burned area in China\u2019s subtropics is low, (2) no dipole pattern exists between the burned area in western and eastern subtropical China, (3) the El Ni\u00f1o-Southern Oscillation (ENSO) has only weak effects on area burned in subtropical China, and (4) the fire suppression policy has little effect on fire activity in subtropical China. Their analysis of satellite-derived annual area burned raises some interesting issues that deserve further discussion.1. Even though MODIS-derived fire products, such as active fires and area burned, have much improved in recent years2, biases still remain in these products because of surface topography, fast vegetation growth rates, and clouds2. In addition to these biases, crop data gaps due to clouds occur in these fire products2 and this is especially the case in cloudy subtropical China. As a result, fire patterns in southwestern China have been found to be inconsistent between MODIS fire products and ground observations3. To address these biases, we calculated fire occurrences from MODIS fire points4 and further distinguished between wildfire and crop fire in the fire occurrence dataset. We find a high fraction of crop fires in the MODIS fire data in northern China, particularly in the North and Northeast China Plains  and Resco de Dios et al. may be the primary reason for the discrepancies between the two studies. We developed the Wildfire Atlas of China (WFAC), a robust ground-truthed fire occurrence dataset, in which fire occurrences were detected by multiple satellites (including MODIS) and carefully validated through surface observations by local forestry departments and Resc1. To support our previous findings, we have now implemented empirical orthogonal function (EOF) analyses on the WFAC field only (Fig.\u00a0Based on their analysis of the annual area burned, Resco de Dios et al. argue the lack of a dipole pattern in fire activity between western and eastern subtropical China suggested in our study. We detected this pattern based on the co-varying patterns between the coupled fields of fires in WFAC and sea surface temperaturenly Fig.\u00a0. The firResco de Dios et al. claim that the modulation of ENSO on fire in China is weak. They base their claim on the insignificant correlations they find between gridded area and ENSO indices on individual grid points in China. Unlike their analysis of individual grid points, our analyses were based on the covariance of data on these grid points. Combining all grid points, our correlation analysis increases the degree of freedom, raises the likelihood of a significance test, and therefore is reliable and robust. Fire in individual grid points can be noisy on a local scale, while climate plays a more critical role in modulating large-scale fires.8. Resco de Dios et al. stated that the ENSO could only influence the ignitions and thus has little effect on fire activity. In fact, fuel availability and flammability are also key factors in fire occurrence, particularly for large-scale fires9. This is evidenced by the strong correlations between fire occurrence and interannual climate variability.Many previous studies revealed the dominant impacts of ENSO in different regions of China10.China\u2019s fire policy not only suppresses existing fires but also prevents human-ignited fire occurrences. As revealed in previous studies, the fire suppression policy since 1987 decreased not only burnt areas but also fire occurrencesThe study by Resco de Dios et al. was based on MODIS-derived annual area burned, which differs from our ground-truthed WFAC fire occurrence dataset. The MODIS cannot sufficiently distinguish the wildfire from the frequent crop fires and thus vastly misinterrupt the crop fires as wildfire, especially over the northern plains where forests are rare. Here, we show that the EOF analyses of the WFAC can also reveal the dipole fire pattern between southwestern and southeastern China. We highlight that the dipole fire pattern and ENSO modulation are on large scales. The fire control policy not only suppresses existing fires but also prevents human-ignited fire occurrences, and thus plays an effective role in reducing five activities in China."}
+{"text": "Aboo Shuhailath et al., RSC Adv., 2016, 6, 54357\u201354370, DOI: 10.1039/C6RA07836B.Correction for \u2018Photoactive, antimicrobial CeO The corrected list of affiliations is as shown above.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Epithelial-mesenchymal transition (EMT) is a core cellular program in vertebrate embryonic development where the expression of key junctional and cytoskeletal proteins such as E-Cadherin and Vimentin orchestrate stages of embryogenesis such as gastrulation or morphogenesis . In 2003When epithelial tumors progress, they lose cell\u2013cell contacts and apico\u2013basal polarity, transforming into spindle-shaped mesenchymal structures. Such cells also gain capabilities of motility and invasiveness for metastasis . At metaVuletic et al.). EMT-associated gain of NK cell ligands in cancer cells may enhance NK cell mediated cytotoxicity, whereas an immune suppressive tumor microenvironment (TME) may activate enzymes that lead to a loss of ligands. He et al. show that the expression of PSMC5 altered the type of immune cells in the TME of CRC by suppressing the infiltration of CD8+ T cells and enhancing the infiltration of innate immune cells such as macrophages and neutrophils and was associated with EMT .EMT proteins can have various non-EMT related functions and act in a tissue-specific manner such as acquisition of immunosuppression and cancer stem cell (CSC)-like features . The tumYu et al.). Song et al. show that expression of \u03b2-arrestin1 enhanced the motility of CRC cells via the activation of Wingless/integration-1 (Wnt)/\u03b2-catenin signaling .EMT may enhance chemoresistance with evidence for enhanced drug efflux, slower cell proliferation and avoiding apoptosis signaling pathways. Slug was implicated in the development of partial EMT and resistance to doxorubicin via upregulation of drug efflux transporters and stemness in liver cancer cell lines . Yu et aReliance on one or two genes to evaluate a process as complex as EMT as well as the use of acute tumor models may not be sufficient to recapitulate the heterogeneity, metabolic idiosyncrasies, and growth pattern of a slow growing tumor . Over thJia et al.). Moreover, modeling experiments suggest that partial EMT can facilitate hybrid metabolic states with combination of glycolysis and oxidative phosphorylation, contrary to primary tumors that mostly rely on glycolysis . The results reported provide new insights into EMT plasticity and its implications in CRC."}
+{"text": "For a comprehensive understanding of protein function and dynamics, it is crucial to study their mechanical properties ,9,10,11.Recent progress regarding theoretical AI-based approaches for the prediction of 3D structures  has creaVan der Sleen and Tych  reviewedGala and \u017dold\u00e1k  applied Single-molecule force experiments can explore protein folding and unfolding under mechanical force. However, such experiments are challenging, cost-demanding and require many years of highly specialized expertise. Bauer and \u017dold\u00e1k  describeAtomic force spectroscopy was used to examine the mechanical properties of two peptides on the surfaces of gold nanoclusters (Au NCs) as small as 2 nm . Such smNon-equilibrium pulling data and derived force-dependent kinetic rates measurements show a systematic discrepancy between the total distance between the native (N) and the unfolded state (U) from elastic models and the sum of the measured distances for folding and unfolding kinetics. Rico-Pasto et al.  performeSziklai et al.  applied Microtubule disassembly and protein degradation are essential processes in the cell, which are mediated by highly specialized hexameric nanomachines. Varikoti et al.  conducteTo summarize, as shown by the research articles in this Special Issue, protein nanomechanics is a fruitful emerging concept which describes the internal dynamics of highly mechanically anisotropic proteins. The further development of experimental methods and bioconjugation strategies will strongly contribute to developing our fundamental understanding of complex protein nanomachines and protein behavior at solid interfaces. Based on our knowledge of protein mechanics, we should be able to design and develop nanomachines and proteinaceous surfaces with tailored-made functional and elastic properties."}
+{"text": "Studies have identified high rates of mental disorders in refugees, but most used self-report measures of psychiatric symptoms. In this study, we examined the percentages of adult refugees and asylum seekers meeting diagnostic criteria for major depressive disorder (MDD), post-traumatic stress disorder, bipolar disorder (BPD), and psychosis.A systematic literature search in three databases was conducted. We included studies examining the prevalence of MDD, post-traumatic stress disorder, BPD, and psychosis in adult refugees according to a clinical diagnosis. To estimate the pooled prevalence rates, we performed a meta-analysis using the Meta-prop package in Stata (PROSPERO: CRD42018111778).I2= 99%) for MDD, 31%  for post-traumatic stress disorder, 5%  for BPD, and 1%  for psychosis. Subgroup analyses showed significantly higher prevalence rates of MDD in studies conducted in low-middle income countries  than high-income countries studies , and in studies which used the Mini-International Neuropsychiatric Interview  compared to other diagnostic interviews . Studies among convenience samples reported significant (p = 0.001) higher prevalence rates of MDD  and PTSD  than studies among probability-based samples .We identified 7048 records and 40 studies (11 053 participants) were included. The estimated pooled prevalence rates were 32% (95% CI 26\u201339%; This meta-analysis has shown a markedly high prevalence of mental disorders among refugees. Our results underline the devastating effects of war and violence, and the necessity to provide mental health intervention to address mental disorders among refugees. The results should be cautiously interpreted due to the high heterogeneity. In 2020et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., During the last years, several studies have examined the prevalence of mental disorders in refugees and asylum seekers. However, the resulting prevalence rates in this population present great variability , and psychosis] in refugees and asylum seekers from conflict-affected areas. Serious mental disorders are conditions resulting in serious functional impairment, which interferes with major life activities NIH, . Other det al., et al., v. high-income countries, and among different kind of population sample (convenience samples v. probability-based samples).Similar to previous studies (Fazel www.prisma-statement.org)  statement  from inception to June 4, 2020, by a medical librarian. Search terms included controlled terms  as well as free text terms. The following terms were used (including synonyms and closely related words) as index terms or free-text words: \u2018refugees\u2019 and \u2018mental illnesses\u2019. A search filter was used to limit the results to adults. The search was performed without date or language restrictions. Duplicate articles were excluded. The full search strategies for all databases can be found in the online Supplementary materials.et al., et al., Studies were considered eligible for this meta-analysis if they examined (a) the prevalence of serious mental disorders , (b) in an adult (\u2a7e18 years) population of refugees and asylum seekers who had to cross their country borders, (c) according to the criteria of Diagnostic and Statistical Manual of Mental Disorders  or International Classification of Diseases (ICD 9 or10) (d) assessed with a structured or semi-structured clinical interview, such as the Structured Clinical Interview \u2013 SCID, Mini-International Neuropsychiatric Interview \u2013 MINI, or Composite International Diagnostic Interview \u2013 CIDI. No cut-off has been considered to evaluate the diagnosis' severity. Disorders have been evaluated serious according with the National Institute of Mental Health (NIH) and GBD considerations  and asylum seekers (a person who seeks protection from persecution or serious harm in a country other than their own) were in agreement with the UNHCR Master Glossary of Terms UNHCR,  and AsylAll title and abstracts were screened by two researchers independently (MP/MS or SG). We retrieved the full texts of all abstracts that seemed eligible for inclusion. Subsequently, we performed a full-text selection according to our pre-specified eligibility criteria. Disagreements between the reviewers were resolved by discussion.For every eligible study, two reviewers independently (MP/MS or SG) extracted data related to the year of publication, the country of data collection, the country of the refugees' origins, the sample size of the population, the age, the gender, the time elapsed as refugees or asylum seekers, the diagnostic tool used. Finally, we extracted the prevalence rates of MDD (current episode and recurrent), PTSD, BPD and psychotic disorder. In the absence of absolute numbers and if allowed by the data reported, the percentages of prevalence rates were converted into numbers. The time since displacement was reported in three different categories: (1) people who have spent more than five years as refugees or asylum seekers (\u2a7e5), (2) people who have spent between 5 years and 1 year as refugees or asylum seekers (>1\u00a0<\u00a05) and (3) people who have spent less then 1 year as refugees or asylum seekers. Countries were categorised as low-, middle- (LMIC) and in high-income (HIC) based on the World Bank list of economies 2020  evaluated the assessment of the methodological quality of individual studies using a modified version of the Joanna Briggs tool \u2013 JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data . Prevalence rates were calculated per each disorder separately. Pooled rates for subgroups were indicated, when at least three studies were present for each disorder. All statistical analyses were conducted using Meta-prop package in STATA/SE 16.1 for Mac       of MDD between studies conducted in refugees resettled in LMICs  higher prevalence rate of MDD  has been reported in studies  higher prevalence of MDD and PTSD  than studies . The other analyses of the MDD, reMDD and PTSD subgroups, showed no significant differences among prevalence rates and high heterogeneity , followed by PTSD (31%), recurrent episode of MDD (16%), and BPD (5%). The prevalence of psychotic disorders was 1%. Subgroup analyses showed that MDD appeared to be more prevalent (47%) among studies conducted in LMICs than in HICs (28%), and when the MINI (37%) has been used, compared to other diagnostic instruments (26%). PTSD and MDD showed higher prevalence rates (34% and 35% respectively) in studies where participants were from convenience samples in comparison to studies that used probability-based samples. PTSD and MDD were the most frequently evaluated disorders with 36 studies and 32 studies respectively, as opposed to BPD and psychosis of which we had only a few studies.et al., et al., et al., et al., et al., et al., et al., According to previous studies, the world-wide prevalence rate reported for MDD is 4.4% WHO, , the lifet al., et al., et al., et al., Our results are in line with the prevalence rates of the Blackmore and colleagues , and that its administration is shorter and its outcomes therefore potentially less precise.Despite the high heterogeneity and methodological limitations of included studies, a high prevalence of serious mental disorders was found in refugees and asylum seekers diagnosed through structured clinical interviews. However, specific instruments culturally adapted for use across different local cultures and contexts for refugees would be advisable, since no one of the diagnostic instruments currently in use has been developed for the non-western populations, who represent the highest sample of refugees. For this reason, to reduce the high heterogeneity, more rigorous studies, using representative samples and culturally adapted instruments, to measure cultural concepts of distress would be recommended. Moreover, to strengthen the evidence base concerning the more serious mental disorders, further research on the prevalence of psychosis and BPD is imperative. To follow this goal, international and government investments in mental health research, population screening, and specific interventions on asylum seekers and refugees are warranted. However, until we have more rigorous studies and adequate diagnostic tools, due to the high heterogeneity between these studies, our results should be considered with caution.In sum, our systematic review and meta-analysis show that it is imperative that governments and actors across the world acknowledge the devastating effect of war and prosecution on individuals' mental health. In order to prevent cycles of violence and victimisation, effective public mental health responses may be put in place to address worldwide suffering.All the data involved have been included in Tables and Figures of this paper, including online Supplementary materials."}
+{"text": "Image and video processing operatons are significant in our life as most electronic devices, such as PCs and mobiles, are all developed by signal processing. Therefore, signal processing can be considered as a part of computer science. Information entropy is very important in signal processing, and it was developed by Claude Shannon and Harry Nyquist who defined data representations of the physical world. Nowadays, deep learning is widely used in signal processing due to its good performance. This Special Issue calls for current studies on several signal (including image and video) processing approaches that are based on information entropy and machine learning. Papers that were both applicative and theoretical in nature were welcomed (both research papers and reviews), and contributions regarding new signal processing tools for the entropy research community were also welcome. Finally, six papers were selected for this Special Issue.In the contribution by Jia et al., \u201cChaotic Mapping-Based Anti-Sorting Radio Frequency Stealth Signals and Compressed Sensing-Based Echo Signal Processing Technology,\u201d the signal-generating design principle of anti-sequential difference histogram (SDIF) arrangements was studied for the principal arrangement approach of the SDIF . In addiIn the contribution by Bao et al., \u201cPCQNet: A Trainable Feedback Scheme of Precoder for the Uplink Multi-User MIMO Systems,\u201d the authors presented a CNN-based compression network titled PCQNet to minimalize the feedback\u2019s overhead . The autThe contribution by Wang et al., \u201cEfficient Entropic Security with Joint Compression and Encryption Approach Based on Compressed Sensing with Multiple Chaotic Systems\u201d, focused on a novel approach that uses compressed sensing for image compression and encryption concurrently . In thisIn the contribution by Zhao et al., \u201cA Complex-Valued Self-Supervised Learning-Based Method for Specific Emitter Identification,\u201d the authors present a complex self-supervised learning approach to fully examine the unlabeled examples . In the In the contribution by Liu et al., \u201cMulti-Scale Mixed Attention Network for CT and MRI Image Fusion,\u201d the authors present a CNN-based CT and MRI image fusion approach, which uses a pictorial saliency-based plan to reserve more valuable information . In thisIn the contribution by Sun et al., \u201cOn Architecture Selection for Linear Inverse Problems with Untrained Neural Networks,\u201d the authors attempted to broaden the application and understanding of untrained neural network priors by exploring the interaction between the choice of architecture and measurement models . The aut"}
+{"text": "To the Editor: We read with great interest the article by Lima et al. (Melioidosis is not a notifiable disease in India. Even so, from a single tertiary-care teaching hospital at Odisha, we have reported >100 cases of culture-confirmed cases during 2016\u20132021 (Clinical severity of melioidosis is predominantly a function of host immunity ("}
+{"text": "Li et al.; Sequencing technologies including bulk and single-cell approaches have been employed broadly to investigate molecular changes and the underlying mechanisms of cancer development, progression, and metastasis . For insThe Application of Sequencing Technologies and Bioinformatics Methods in Cancer Biology, we aimed to collect novel findings and methods in the field of cancer biology related to mining bulk and single-cell sequencing data with bioinformatics approaches for illuminating different types of tumors  and immune checkpoint expression or tumor mutation burden was an effective prognostic biomarker for immunotherapy. Their findings highlighted that SRS could regulate the immune microenvironment of LUAD.Zhou et al. explored the immune-oncology profile of LUAD and identified a set of immune genes significantly correlated with progression-free survival. They also found that the risk signature based on several of these immune genes was associated with neutrophil infiltration. Therefore, these three studies screened out different types of prognostic biomarkers for LUAD patients, which could be useful and promising for survival analysis.Three studies on this Research Topic dissected lung adenocarcinoma (LUAD) from different perspectives and identified a number of potential prognostic biomarkers. For example, Liu et al. identified five CRC survival-related genes  based on hub gene analysis of co-expression and protein-protein interaction networks. They also constructed a promising risk model using three  of them for prognostic prediction. Their results indicated that these hub genes could be correlated with CRC development and the survival of patients. Wang et al. constructed a scoring model based on four necroptosis-related genes , which can effectively predict the prognosis and response of colon cancer patients to chemotherapy and immunotherapy. They also found that the activation of necroptosis-related genes could promote the metastasis of colon cancer. Unlike these two studies, Bartlett et al. investigated the association between miRNAs and immune checkpoint blockade for CRC. They detected a number of miRNAs that were correlated with mutation burden, microsatellite instability, or PD-L1 expression. Among them, three miRNAs  were related to the M1 macrophage polarization state and their targets had the potential to impact the TGF-\u03b2 pathway.For colorectal cancer (CRC), three studies discovered potential prognostic biomarkers or treatment preditors by analyzing large-scale datasets. For instance, Zhao et al. discovered that loss of ARID1A was strongly correlated with the high expression of CD47 in gastric cancer. They identified CD47 as a potential direct downstream target of ARID1A, while the combination of ARID1A and CD47 would be a promising prognostic biomarker. Pan et al. examined the landscape of papillary thyroid cancer (PTC) at single-cell resolution and detected molecular signatures correlated with the disease-free survival of patients. They also found that dendritic cells and B cells could play critical functions in preventing PTC progression. identified GPX1 as a promising prognostic biomarker for breast cancer  based on whole-exome sequencing and single-cell RNA-seq data. They found that RUNX3 could be a potential driver and therapeutic target for RRMM. Wu et al. detected KIF23 as an effective prognostic biomarker for clear cell renal cell carcinoma (ccRCC). They also revealed that KIF23 could promote the nuclear translocation of \u03b2-catenin, while the knockdown of KIF23 would reduce the proliferation, migration, and invasion of ccRCC. For liver cancer, Wu et al. showed that up-regulated expression of POSTN, LAYN, and HTRA3, and down-regulated expression of AANAT and AFM were associated with poorer overall survival of patients. They also found that the gut microbial metabolites of trimethylamine N-oxide TMAO and POSTN were potential targets for liver cancer treatment. Jiang et al. revealed that TMEM176B could be a diagnostic and prognostic biomarker for skin cutaneous melanoma. The expression of TMEM176B was shown to be correlated with tumor-infiltrating lymphocytes, pathological stage, therapy sensitivity to radiation, as well as tumor ulceration.In addition to biomarker exploration articles in lung and colorectal cancer, we received articles that explored biomarkers in gastric, thyroid, breast, and other tumor types. For example, t cancer . They obWu et al. systematically analyzed AP3S1 in diverse tumor types and found that its expression was widely associated with the immunosuppressive microenvironment. They also demonstrated that AP3S1 could be a pan-cancer biomarker for prognosis and immunotherapy. The other study explored the gene expression profiles of 988 cell lines from 20 distinct cancers by employing several computational methods Ding et al. They identified robust pan-cancer biomarkers for differentiating a variety of cancer types. Overall, the aforementioned studies discovered different types of potential biomarkers for diverse tumors, which could be useful for the diagnosis, prognosis, or treatment of corresponding cancers.Another two studies conducted pan-cancer analyses and detected potential biomarkers for the clinical management of cancers. For example, Dai et al. developed a novel model based on the score of cell type compositions (CTCs) for improving the prognostic analysis of acute myeloid leukemia patients (AML). They further showed that the CTC score could potentially benefit the individualized treatment of AML patients. Chen et al. systematically investigated the chromosome instability (CIN) profile of 280 patients with bone metastatic cancer based on the copy number variations inferred from cell-free DNA (cfDNA) sequencing data. They revealed that CIN quantification with cfDNA provided an effective and non-invasive method for predicting the survival of spine metastasis patients. Yuan et al. developed a scoring approach based on 15-DNA repair gene signatures for effectively predicting the prognosis of gastric cancer patients who received immunotherapies. The scoring system developed by them may benefit the tailored immunotherapy of gastric cancers. Chen et al. proposed an efficient strategy for identifying the circular RNAs (circRNAs) with protein-coding potential in CRC. They also suggested that those circRNAs might be functional in promoting proliferation and invasion ability, while the peptides derived from circRNAs could be potential targets for CRC therapy or diagnosis. Hu et al. designed a panel based on 28 breast cancer-related genes for long-read sequencing . They demonstrated that this approach can effectively detect structural variations in breast cancer patients, which could be used in related clinical investigations. Shi et al. systematically evaluated a gene panel containing \u223c1,300 key immuno-oncology genes designed for characterizing tumor microenvironments. Based on the analysis of >1,200 formalin-fixed paraffin-embedded tumor samples, they showed that this panel was comparable with orthogonal platforms . The computational strategies developed in these studies were useful and promising for exploring and characterizing various aspects of different cancers.Besides biomarker investigation, several studies on this Research Topic developed new computational strategies for profiling tumors from different aspects. For instance, Taken together, the studies published in this Research Topic presented a diversity of interesting and meaningful results for a range of different cancers, which could facilitate our understanding of cancer biology. It is well known that bulk and single-cell sequencing technologies can respectively obtain whole-system and cellular views of tumors. Multi-omics and multimodal strategies are superior to single-omics methods for dissecting cancers since different types of data could be complementary . Third-g"}
+{"text": "Micro and nano molding technologies are continuously being developed due to enduring trends such as increasing miniaturization and the higher functional integration of products, devices and systems. Furthermore, with the introduction of high-engineering-performance polymers, feedstocks and composites, new opportunities in terms of materials properties can be exploited, and consequently, more micro product and micro/nano structured surfaces are currently being designed and manufactured.Innovations in micro and nano molding techniques are seen in different processes employed in production ; in the use of new and functional materials including, e.g., nanocomposites; for an ever-increasing number of applications ; in several key enabling technologies that support the successful realization of micro and nano molding processes  and their integration into new manufacturing process chains.Accordingly, this Special Issue seeks to showcase research papers focusing on the latest developments in micro and nano scale manufacturing using molding techniques as well as their related key enabling technologies to produce both micro products and micro/nano structured surfaces.The Special Issues consists of 10 original research papers and 2 review papers, which cover fundamental molding process technology development, key enabling technologies, as well as the design and application of these technologies for the fabrication of micro/nano devices and micro structured components.The papers included in the Special Issue address research, development and recent advancements in four main domains of micro/nano molding: (1) process technology developments and characterization; (2) modeling and simulation; (3) tooling technologies and micro tool design; (4) applications.(1)Process technology developments and characterization. Calaon et al.  analyzed(2)Modeling and simulation. Weng et al.  modeled (3)Tooling technologies and micro tool design. Wang et al.  develope(4)Applications. Kim et al.  presenteWe wish to thank all of the authors who submitted their papers to this Special Issue, entitled \u201cLatest Advancements in Micro Nano Molding Technologies\u2014Process Developments and Optimization, Materials, Applications, Key Enabling Technologies\u201d. We would also like to acknowledge all of the reviewers whose careful and timely reviews ensured the high quality of this Special Issue.http://www.prosurf-project.eu/, accessed on 5 April 2022, 2018\u20132021, Project ID: 767589), as well as the Marie Sk\u0142odowska-Curie Action Innovative Training Networks MICROMAN  and DIGIMAN4.0 , is acknowledged. The support and funding from the Danish Innovation Fund , through the research projects MADE DIGITAL, Manufacturing Academy of Denmark , Work Package WP3 \u201cDigital manufacturing processes\u201d and QRprod  is acknowledged.The support and funding from the European Commission Horizon2020 Framework Programme for Research and Innovation through the ProSurf project (\u201cHigh Precision Process Chains for the Mass Production of Functional Structured Surfaces\u201d,"}
+{"text": "Development of a risk assessment profile tool to determine appropriate use of SARS-CoV-2 rapid antigen detection tests for different activities and events in Ireland, since October 2021\u2019 by Mallon et al., published on 20 January 2022, the name of author Aileen Conway was corrected . This change was made on request of the authors on 4 February 2022.In the article \u2018"}
+{"text": "Lane CA, Barnes J, Nicholas JM, et al. Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study. Lancet Neurol 18: 942\u2013522019; \u2014The appendix of this Article has been corrected as of June 17, 2020."}
+{"text": "Aberrations in epigenetic regulation at various levels, including DNA methylation, chromatin architecture, and regulatory RNAs, are often associated with, and significantly contribute in most carcinogenesis . TranscrParrello et al. discussed the possibility of targeting factors that control global transcriptional regulation. Li et al. discussed the dual roles of CBX7, a component of polycomb repressive complex, in cancer where it can either help in cancer progression by downregulating tumor suppressor genes or help cancer suppression by modulating cell cycle related proteins. CBX7 interacts with various regulatory RNAs, including micro RNAs, long non-coding RNAs, circular RNAs. Regulatory RNAs play a significant role in carcinogenesis, including chemo-resistance . Sun et al. showed that plasma-derived exosomal micro RNA, miR-2276-5p in glioma patients could serve as a potential diagnostic and prognostic marker. Transcriptomics based gene signatures are emerging as promising biomarkers in cancer .Genome-wide transcriptional control is often dysregulated in cancer. In this research topic, Fatima et al. and Raina et al.). Abbas et al. reported that maternal diet rich in omega-3 fatty acid can reprogram epigenetic and transcriptomic landscapes in F1 generation mice and provide resistance to breast cancer development. Pu et al. reported that methylation profiles of zinc finger genes, specially ESR1 and ZNF132, could be potential biomarkers for the early diagnosis of colorectal cancer patients carrying KRAS mutations. Another study by Gua et al. showed that APOA1 gene is downregulated by DNA methylation in hepatocellular carcinoma that could be a potential biomarker to predict survival. Role of NTPCR in epithelial ovarian cancer  and FGFR1\u2013GLI1 axis as a potential therapeutic target in breast cancer  were also reported.Epigenetic landscape is altered in cancer cells that results in transcriptional dysregulation. Various dietary components have ability to modulate epigenetic aberration (Gazova et al. used CRISPR-Cas9 to generate homozygous inactivating mutation in USP16 gene using leukemia cell line and studied how these cells adapt to the extreme selection pressure through compensatory pathways. Authors also cautioned targeting USP16 in leukemia as cancer could develop resistant to USP16 inhibitors. A timely review by Amir et al. discussed the usefulness of combination therapy of tyrosine kinase inhibitors with epigenetic drugs in chronic myeloid leukemia. Leszczynska et al. reviewed the emerging therapeutic approaches against pediatric high-grade gliomas, particularly those having mutations in genes coding for histone 3 variants that result in substitution of lysine at 27 to methionine.In conclusion, epigenetic aberration and transcriptional homeostasis disruptions are associated with cancer. In-depth understanding of these processes and their interdependencies is needed to better understand carcinogenesis and to develop novel and effective therapeutic approaches."}
+{"text": "L\u00fcke et al.).The aim of anakoinosis is \u201ctissue editing,\u201d meaning that bioactive, regulatory acting principles are combined to re-establish tissue homeostasis at primary and metastatic tumor sites by communicatively reprogramming tumor tissue and cell recruitment . Pro-anaL\u00fcke et al.; L\u00fcke et al.; Heudobler et al.). The clinical responses outline the possibility to specifically activate unique tumor tissue dynamics in response to pro-anakoinotic effectors, either by combining differently acting biomodulatory drugs, or associating DNA damage with fungal infection.This Research Topic highlights differential clinical outcome characteristics in three histologically completely different neoplasia as a response to \u201ctissue editing\u201d when treated either with pro-anakoinotic approaches  or accidentally initiated by severe fungal infection and reduced intensity induction chemotherapy in acute lymphoblastic leukemia (ALL) .DNA damage response following \u201cone shot\u201d chemotherapy in ALL seems to serve as a homeostatic trigger in the case of parallel fungal infection, presumably supervising and amplifying immunological response by the innate immune system, thereby preventing both early relapse and persistence of minimal residual disease, as indicated by long-term continuous complete remission in both described ALL cases .In r/r NSCLC, explorative studies of the randomized trial provide strong hints that pre-treatment with combined biomodulatory therapy may be the basis for successful consecutive immune checkpoint inhibitor (ICPi) therapy: even though the progression-free survival rate of the biomodulatory treatment arm is significantly inferior to that of the ICPi arm, it, however, exerts tissue modifications that render successive ICPi more efficacious. These results stimulate the hypothesis that the addition of ICPi to the biomodulation could be beneficial .The immune-modulatory acting MEPED schedule for r/r cHL resulted in pivotal outcomes in six cases. Whether a patient is frail and does not respond to reduced standard first-line therapy, or patients are r/r after autologous hematopoietic-stem-cell transplant (autoHSCT), or even allogeneic hematopoietic-stem-cell transplant , MEPED may induce complete PET negative remission. The remissions could be maintained by alloHSCT. But even after discontinuation of MEPED in a frail patient, CR continued without any HSCT. Like in NSCLC, a possible beneficial supplementation of the immune-modulatory schedule could be ICPi therapy  has been given by the group of dulators .Favero et al.; L\u00fcke et al.; L\u00fcke et al.; Heudobler et al.). In vitro studies by Del Favero identify novel biological paths induced by bio-physical circumstances, such as shear stress, and give a first hint on how to target respective biologic structures for reprogramming tumor functions. Drugs used in pro-anakoinotic schedules, like mTOR inhibitors, e.g., in cHL, may reprogram a response to shear stress, as experimentally shown .Besides therapeutic modulation of cell metabolism, immune response, or tumor-associated inflammation in neoplasia, as exemplified in cHL, NSCLC, and ALL or GVHD, reprogramming the mechanical properties of tumor and adjacent stromal cells may be an important new therapeutical direction . The ALL studies highlight that clinical courses of malignant diseases may cause tissue alterations that render therapeutically accessible homeostatic disbalances previously hidden .For successful development of combination therapies in the field of anakoinosis, the detailed description of complex tissue functions supporting disease-related, pathophysiologically dysbalanced homeostasis is necessary. This message clearly emerges from the contributions on GVHD, and from the mechanistic analysis of how T24 bladder cancer cells cope with fluid shear stress by modifying their shape .Development and evaluation of biomodulatory drugs is already ongoing .A novel technology for the evaluation of systems biological drug interactions, relevant for anakoinosis research, has been presented by Liao et al.).Gold nanorods, currently studied as potential therapeutics in photothermal therapies, may also contribute to evaluating pathophysiology in tumor tissues, and as such the impact on tissue homeostasis, by identifying specific binding sites of gold nanorods in single-cell compartments (in vitro test systems, as indicated by the Research Topic, may promote the exploration of biomodulatory drugs derived from different pharmacological tools for designing pro-anakoinotically acting combination therapies, particularly for overcoming therapeutic problems with refractory neoplasia and complex non-malignant diseases associated with tissue dysregulated homeostasis (Kumari et al.; L\u00fcke et al.; L\u00fcke et al.; Heudobler et al.; In summary, this research topic provides a novel clinical collection of pro-anakoinotic approaches modifying dysregulated homeostasis in quite different ways for long-term tumor control or even healing of refractory tumor disease. Hopefully, pre-clinical"}
+{"text": "With interest, we read the recent article by Wang et al. in which their logistic regression analysis identified the use of vasopressor agents, the presence of a neurological disease, high APACHE II and SOFA scores, an acute gastrointestinal injury (AGI)\u2009\u2265\u2009grade II, and the use of mechanical ventilation or continuous renal replacement therapy (CRRT) as independent risk factors influencing the success rate of placement of a naso-jejunal tube (NJT) . The imp"}
+{"text": "Cancer is a genetic disease associated with the rapid growth of abnormal cells, which provoked the death of almost 10 million people worldwide during 2020 , placingSanit\u00e0 et al. reviewed the most recent techniques for surface modification and functionalization of nanoparticles in order to improve their biocompatibility and cellular uptake behavior. Similarly, Cheng et al. summarized and analyzed the current research progresses and challenges in tumor microenvironment-responsive shrink-sized drug delivery nanosystems. Cheng et al. also discussed the current implications and knowledge for promoting deep penetration into tumors using nanoparticles. Meanwhile, Chen et al. used two novel HLA-A2-restricted cytotoxic T lymphocyte epitopes (SV95\u20136 and SV95\u20137 peptides) derived from survivin , and were then loaded into human dendritic cell/poly(lactic-co-glycolic) acid-based nanoparticles, thus obtaining advanced materials specific against cancer cells. It should also be noted that Chen et al. carried out major histocompatibility complex peptide binding algorithms to predict a range of modified SV95 decamers (from SV95\u20132 to SV95\u201310) based on the natural SV95\u2013104 peptide sequence of ELTLGEFLKL. On the other hand, Sharifiaghdam et al. designed and synthesized new layer-by-layer selenium-based nanocomplexes as carriers of small interfering RNA with improved stability and a dual mode of action against tumors: gene silencing and apoptosis induction in cancer cells. To close this research topic, Shah et al. reported theranostic optical imaging probes based on shortwave infrared (SWIR)-emitting rare earth-doped nanoparticles encapsulated with human serum albumin (ReANCs), which demonstrated superior surveillance ability for detecting micro-lesions at depths of 1\u00a0cm in an animal models of breast cancer metastasis, thereby promising an ability for follow-up therapy based on SWIR fluorescence measurements from tumor-targeted ReANCs.Traditional cancer treatments have shown several limitations. Nonetheless, diverse technologies based on nanotechnology have shown significant advances with the aim of obtaining a more efficient and safe cancer therapy. Despite this, several key obstacles related to the use of nanoparticles for cancer therapy such as the complexity and heterogeneity of tumor biology, a lack of understanding of nano-bio interactions, as well as chemical, manufacturing and control challenges must be further studied for clinical success. This research topic addresses some novel aspects of engineering that take advantage of our growing understanding of bionano behaviors and interactions to develop more efficient nanotherapies for cancer patients. Keeping this in mind, in this research topic, The role of nanotechnology in cancer research has grown dramatically in recent years. However, only a few dozen nano-based technologies have reached the market so far, primarily cell-scale targeted bionanosystems, and controlled and sustained carries of desired biomolecules. To change this, we must reconsider traditional views and rethink how we conduct translational cancer nanomedicine research."}
+{"text": "Editorial on the Research TopicHearing Loss: Mechanisms and PreventionHearing Loss: Mechanisms and Prevention has encompassed 34 contributions from experts who are dedicated to recent advances in the mechanisms and prevention of hearing loss in ways of hair cell damage and prevention, spiral ganglion cell development and inherited hearing loss in animal models and patients, as well as a range of novel treatment approaches for hearing loss.Hearing loss, which is often referred as an \u201cinvisible disability,\u201d is one of the most common sensory impairments worldwide. The prevalence of hearing loss is high and it is estimated that 20 percent of the world\u2019s population is affected by hearing loss to some degree in 2021 according to the WHO report. The resulting consequences are significant burdens to the economy and society. There are numerous contributing factors to hearing loss, such as noise exposure, congenital, infectious, traumatic, and immune-mediated causes and the severity of hearing loss is always related with age. To develop preventative and treatment strategies specific to the underlying causes, it is crucial to understand the pathophysiology of these contributing factors. This Frontiers Research Topic entitled Sun et al. identified that the G protein-coupled receptor 125 is expressed in multiple cell types dynamically in the developing and mature cochlea in mice. Stereocilia play an important role in hearing and balancing sensation. Du et al. investigated the role of the Rho GTPase cell division cycle 42 in mice and reported it as a vital regulator in stereocilia development of cochlear hair cells. In recent decades, new technologies have emerged in inner ear research which help researchers reveal the development of hair cells. As such, single-cell sequencing technology is a powerful tool for analyzing gene expression variations across different cell types, and it has also been proven to be useful in inner ear research. Wu et al. reviewed recent applications of single-cell sequencing in inner ear research, covering from identifying unknown cell subtypes, discovering novel cell markers, to revealing dynamic signaling pathways during development. Meanwhile, by using single-cell RNA sequencing analysis, Chen et al. Identified different cell subtypes in the greater epithelial ridge cells in the cochlear duct related to their degeneration during postnatal development in rats. During P1 and P7 rats, five cell clusters reduced significantly while four clusters, enriched with genes associated with the degeneration of the greater epithelial ridge cells, had high similarity in gene expression patterns and biological properties. Besides utilizing single-cell sequencing technique, Wu et al. from a different group developed a 3D imaging technique for the three-dimensional examination of the microstructure of the full thickness of the tympanic membranes in mice. With this imaging technique, they discovered the 3D form of the elastic and collagen network, as well as the close spatial relationships between the elastic fibers and the elongated fibroblasts in the tympanic membranes, which provides important information for hair cell development.Hair cells are most important part in sound conduction and balancing sensation. Their development is tightly correlated with the function of cochlea. To reveal cochlear development and hearing, Liu et al. reported excessive accumulation of calcium due to acoustic overexpression and slow clearance around the presynaptic ribbon might lead to disruption of calcium homeostasis by compared the consequences of noise-induced cochlea synaptopathy of C57BL/6J and CBA/CaJ mice. The susceptibility of noise-induced cochlear synaptopathy in CBA mice is caused by mitochondrial dysfunction of inner hair cells. Xiao et al. investigated the molecular behavior of high-mobility group box 1 (HMGB1) in the cochlea following noise exposure both in mice and in vitro and reported that HMGB1 has a possible negative effect on cellular lifespan indicated by the higher cell viability observed in the HMGB1 knocked-down mice after stimulation with H2O2. In addition to resolving the intrinsic cause of noise-induced hearing loss, researchers are also working on the approaches to protecting noise-induced damge. The use of FK506 (tacrolimus) to treat noise-induced hair cell loss and noise-induced hearing loss (NIHL) has been applied clinically and He et al. identified the downstream mechanisms of FK506-attenuated NIHL. They found that FK506 treatment not only inhibits calcineurin activity to attenuate moderate-noise-induced outer hair cell loss and hearing loss, but also inhibits reactive oxygen species and activates autophagy. Badash et al. demonstrated that endolympahtic hydrops are correlated with noise-induced cochlear synaptopathy by exposing live CBA/CaJ mice to various noise intensities and using optical coherence tomography to measure endolymph volume. Liang et al. also found a positive role sirtuin-3 in protecting cochlear hair cells against noise-induced damage via the superoxide dismutase 2/reactive oxygen species signaling pathway. Many different factors are also involved in the development of hair cells and contribute to hearing loss. Ding et al. identified that the ototoxicity of 2-hydoxypropyl-beta-cyclodextrin (HP\u03b2CD) spread from the high-frequency base towords the low-frequency apex of the cochlea from P3 to P28 and the HP\u03b2CD-induced outer hair cell (OHC) death is correlated with the upregulation of prestin in OHCs. In addition, 4\u20136\u00a0weeks post-HP\u03b2CD treatment, there is a second, massive wave of degeneration involving inner hair cells, pillar cells, auditory nerve fibers and spiral ganglion neurons. An interesting effect of caffeine in cochlear hair cells was identified by Tang et al. They showed that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1\u0251 pathway, which suggests overdoes of caffeine may lead to hearing impairment. Gong et al. described the importance of claudin h in morphogenesis and auditory function of the hair cells. Zebrafish with deficiency of claudin h have significant reduction of otic vesicle size and loss of utricle otolith and loss of hair cells in neuromasts caused by the deficiency of claudin h can be rescued by claudin h mRNA in zebrafish. Tu et al. demonstrated that the deficiency of small muscle protein, x-linked (SMPX) causes stereocilia degeneration in cochlea and progressive hearing loss using an Smpx null mouse model by CRISPR-Cas9 technique. Kwesi et al. presented a study of effect of high jugular bulb (HJB) on the hearing loss in patients with large vestibular aqueduct syndrome (LVAS). LVAS patients with concurrent HJB show higher air conduction thresholds.A great effort has been made to study the cause of hair cell damage and the approaches to protecting them. Noise can induce cochlear hair cell damage and it is the most common cause of hearing impairment. Noise-induced hearing loss involves different mechanisms and pathways. Li et al. Although hearing loss can be caused by various factors, new approaches to treating hearing loss are emerging. Dong et al. revealed the positive function of optic atrophy1 (OPA1) in hearing by examining the ability of OPA1 to protect against cisplatin-induced cochlear cell death both in vitro and in vivo. They showed overexpression of OPA1 prevented cisplatin-induced ototxicity, which suggests a possible role of OPA in ototoxicity and/or mitochondria-associated cochlear damage. It has been demonstrated before that neither N-acetylcysteine nor dexamethasone can protect hair cells from oxidative stress when at ineffective concentrations, but Bai et al. reported when these two drugs combine together, they show a better therapeutic effect both ex vivo and in clinical patients. Chen et al. developed a stable and effective to deliver dexamethasone (DEX) via an electrode coated with polycaprolactone. This device maintains stabilityof DEX concentration for more than 9\u00a0months and shows promising application in cochlear implantation. New technologies are also making contributions to treatment of hearing loss, such as stem cell-based therapies as reviewed in He et al. and nanoparticle treatment as reviewed by Huang et al. In the prior review, they fully described the ways of inducing the differentiation of stem cells, the implantation operation and regulation of exogenous stem cells after implanted into the inner ear, and elaborated the relevant inner ear signal pathways and the clinical applications of new materials. In the latter review, they summarized recent developments challenges of nanoparticles in diagnostics and treatment of hearing loss.Apart from cochlear hair cell damage, hearing loss can also relate several neurological disorders, such as Alzheimer\u2019s disease, Parkinson\u2019s disease, Huntington\u2019s disease and autism spectrum disorder, as thoroughly reviewed in Sun et al. explored the regulatory mechanisms of atrial natriuretic peptide (ANP) underlying functional properties of auditory neurons in vitro and reported that ANP could support and attract neurite outgrowth of sprial ganglion neurons (SGN) and possesses a high capacity to improve neuronal survival of SGNs against glutamate-induced excitotoxicity via triggering the natrieretic peptide receptors-A/cGMP/PKG pathway. Ma et al. indicated that the expression levels of vesicle transporter protein 3, glutamate/aspartate transporter protein, and Na+/K+-ATPase \u02511 are disrupted in spiral ganglion cells in mice after noise exposure, suggesting that disruption of glutamate release and uptake-related protein expression may exacerbate the occurrence of synaptopathy. Some gene mutations are also participated in the development of spiral ganglion neurons. Qiu et al. investigated the pathological role of mutant ATP6V1B2 in the auditory system with transgenic mice carrying c.1516 C > T (p.Arg506\u2217) in Atp6v1b2, Atp6v1b2Arg506\u2217/Arg506\u2217. They showed the transgenic mice have hidden hearing loss at early stages and developed late-onset hearing loss. The degeneration of spiral ganglion neurons are induced by apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux, which then further impairs the hearing. Meanwhile, scientists are searching for potential approaches to protecting spiral ganglion neurons. Wang et al. described a transgenic mice with tumor necrosis factor 2/4 double knockout show the attenuation of spiral ganglion neuron degeneration by the differential regulation of some core molecules. Chen et al. explored a way to reprogram cochlear Sox2+ glial cells into functional spiral ganglion neurons by induction of small molecules. In the field of regeneration research of spiral ganglion neurons in the inner ear, utilization of specific genetic tool of animal models is a common research approach. For example, a specific spiral ganglion neuron damage approach is described by Hu et al. They generated a strain of transgenic mice exhibiting inducible SGN-specific Cre activity in the inner ear which may serve as a valuable SGN damage model.Spiral ganglion neurons are bipolar neurons connecting the primary auditory receptor cells, the hair cells, with the auditory brain stem. Their development and protection are highly linked with the auditory system. Xu et al. identified a spontaneous mutation of coiled-coil domain-containing 154 gene as a new osteopetrosis-related gene can induce congenital deafness. In porcrine model, Ren et al. studied the population statistics, hearing phenotype, and pathological changes of congenital single-sided deafness (CSSD) which is highly resembled with human non-syndromic CSSD disease. The deaf cochlear of this strain show cochlear-saccular degeneration. In vitro, Wen et al. investigated the mechanisms of Waardenburg syndrome (WS) by inducing an iPSC line derived from a WS patient with SOX10 mutation. The induced cells differentiated into neural crest cells (NCCs) and SOX10 deficiency had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. In children, Liang et al. identified 18 new potential genes associated with congenital deafness and 87 potential new genes associated with otitis media by using a network-based method incorporating a random walk with restart algorithm, as well as a protein-protein interaction framework. In patients, Wang et al. reported a phenotypic heterogeneity of post-lingual and/or milder hearing loss with the GJB2 c.235delC homozygous mutation. Zhu et al. reported a compound heterozygous variant of the OTOF gene in familial temperature-sensitive auditory neuropathy and the auditory neuropathy can be diagnosed by the presence of cochlear microphonics with absent or markedly abnormal auditory brainstem responses (ABRs). Wang et al. further demonstrated the significance of genetic testing for auditory neuropathy patients with p.E818K in the ATP1A3 gene. All these findings have made contributions to a genetic understanding of inherited deafness and provide novel biomarkers for clinical screening.Although various environmental insults can cause damage to hair cells and spiral ganglion neurons, inherited factors will also lead to hearing loss verified both in animal models and clinical patients. In mice, In conclusion, the collection of research articles and reviews presented in this Research Topic provides a comprehensive set of information on the factors attributing to hair cell development, the mechanisms of hair cell damage and the approaches to protect them, as well as spiral ganglion neuron development and protection and genes involved in the inherited hearing loss. Most importantly, there are various new potential treatment approaches to hearing loss. Together, the achievements included in this Research Topic make huge contributions to further understand the underlying causes of hearing loss and may facilitate the development of novel therapies to treat hearing loss in the near future."}
+{"text": "Following publication of the original article  phenotype which means the mutant was not able to grow at ambient CO2 level  to LC  condition , an efficient inhibitor for both CCMs and the GlyDH (glycolate dehydrogenase) in C2 cycle (Taubert et al. Synechocystis, nor in mutant with HCR phenotype (Eisenhut et al. 2 level, without displaying the HCR phenotype. It is worthy to further investigate the underlying mechanism of glycolate excretion of strain WT-\u0394glcD.Additionally, inactivation of glycolate metabolism was reported to render a high-CO"}
+{"text": "Escherichia coli and Saccharomyces cerevisiae, over the past few years, oleaginous yeasts that naturally accumulate high-content lipids have been directly used or genetically modified for producing diverse bioproducts, although early trials on the commercial production of microbial oil date back to World War I. This Research Topic concentrates on the advancement of bioengineering of oleaginous yeasts, including Yarrowia lipolytica and Rhodosporidium (Rhodotorula) toruloides, for producing biofuels and bioproducts, with particular emphasis on the establishment of synthetic biology tools and novel engineering strategies.The current Research Topic provides an effective communication platform, collecting both original research articles and review papers examining explorations of the mechanism for lipid accumulation, biotechnological applications, and metabolic engineering efforts related to oleaginous fungi including the non-conventional yeasts. Microbes have been harnessed for the production of hydrocarbon with a high-energy density as \u201cdrop-in\u201d fuels, renewable chemicals, and value-added compounds. In addition to the commonly used model organisms such as Y. lipolytica   biological engineering cycle for strains development and improvement. The sets of molecular biology toolbox have been established for the genetic manipulation of non-conventional yeasts Y. lipolytica has been engineered for producing microbial lipid with a titer of 99 g L\u22121 and a rate of 1.2 g/L/ h , the oleaginous yeast Y. lipolytica, NADPH to support lipid biosynthesis was primarily generated from the oxidative pentose phosphate pathway (PPP) when glucose was used as a carbon source, this resulted in carbon loss as released CO2 for the biosynthesis of the end product (Wasylenko et al., Y. lipolytica, different synthetic pathways were engineered in yeast cytosol to convert glycolytic NADH into NADPH (Qiao et al., Y. lipolytica (Markham et al., Y. lipolytica (Xu et al., Aspergillus terreus in Y. lipolytica (Zhao et al., Y. lipolytica (Larroude et al., To construct the productive cell factories of oleaginous microorganisms, some novel metabolic engineering strategies including engineering central carbon metabolism and pathway compartmentalization have been employed. In the oleaginous yeast XX wrote the manuscript. YX and JQ provided comments and helped with the revision of the manuscript. All the authors approved the submission of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The interest in utilizing food-derived compounds therapeutically has been rising. With the growing prevalence of systematic chronic inflammation (SCI), efforts to find treatments that do not result in the side effects of current anti-inflammatory drugs are underway. Bioactive peptides (BAPs) are a particularly promising class of compounds for the treatment of SCI, and the abundance of high-quality seafood processing byproducts (SPB) makes it a favorable material to derive anti-inflammatory BAPs. Recent research into the structural properties of anti-inflammatory BAPs has found a few key tendencies including they tend to be short and of low molecular weight (LMW), have an overall positive charge, contain hydrophobic amino acids (AAs), and be rich in radical scavenging AAs. SPB-derived anti-inflammatory BAPs have been observed to work via inhibition of the NF-\u03baB and MAPK pathways by disrupting the phosphorylation of I\u03baB\u03b1 and one or more kinases , respectively. Radical scavenging capacity has also been shown to play a significant role in the efficacy of SPB-derived anti-inflammatory BAPs. To determine if SPB-derived BAPs can serve as an effective treatment for SCI it will be important to understand their properties and mechanisms of action, and this review highlights such findings in recent research. Food has been used as a therapeutic treatment of diseases for millennia, however the discourse surrounding the role that food and food-derived compounds play in human health has been reinvigorated of late . Recent Systemic chronic inflammation (SCI) is one of the greatest challenges to human health and wellbeing in the 21st century . SCI proSeafood processing byproducts (SPB) are an ideal candidate to derive useful biomolecules and have already garnered attention in the fields of nutrition, medicine, and cosmetics ,11. A laBAPs are small, liberated protein fragments, around 2-20 amino acid (AA) bases long. The small size and exposed AA side chains of BAPs enable ready interaction with other molecules ,21,22. BThe properties of anti-inflammatory protein products and the mechanisms by which they act are intrinsically linked. A better understanding of how BAPs structural properties and mechanisms are connected will be required to harness their potential in the coming years. This review provides a resource in which properties and mechanisms of fish- and shellfish-derived anti-inflammatory protein products are discussed based on the recent evidence. Previous work by Chakrabarti et al., Bechaux et al., Venkatraman et al., Cal et al., Chalamaiah et al., Olsen et al., Daliri et al., La Manna et al., Zamora-Sillero et al., Nongonierma et al., Urakova et al., Guha et al., and Zhu et al. have expounded on aspects of marine-derived bioactive compounds ,32,33,34Inflammation is an important biological mechanism that promotes healing and resolution in cases of infection and injury . FurtherPancreatic cancer, for instance, can be initiated by DNA damage resulting from inflammation and the associated increase in reactive oxygen and nitrogen species . SCI proNSAIDs are a common treatment for inflammation, both chronic and acute. While NSAIDs are an invaluable tool in combating inflammation, problems arise when used to treat chronic inflammation over long periods of time, the risk of associated gastric bleeding, ulceration, renal failure, and a myriad of other side effects can occur ,25,40. AA number of broad trends have been observed in the structure of anti-inflammatory peptides. Anti-inflammatory BAPs tend to be positively charged, have hydrophobic AA residues, be rich in antioxidative AAs, and be short, of low molecular weight (LMW) peptides  34]. N-. N-34]. Anti-inflammatory peptides tend to have an overall positive charge, and contain an abundance of positively charged AAs such as arginine, lysine, and histidine, particularly in the N- and/or C-terminal positions ,44,45,462+ signaling, which plays a central role in NF-\u03baB signaling and cytokine production . NS. NS43]. NF-\u03baB is a family of inducible transcription factors that contribute to an immune and inflammatory response. NF-\u03baB is a large biochemical pathway that stimulates the production of numerous cytokines and chemokines that can be easily measured via a multitude of methods, both in vivo and in vitro . NF-\u03baB iThe canonical pathway for NF-\u03baB activation relies upon the phosphorylation and subsequent degradation of the subunit I\u03baB\u03b1 by I\u03baB, which then allows for nuclear translocation of NF-\u03baB ,61,63. ACOX-2 stimulates the conversion of arachidonic acid into prostaglandins, and is the target of most NSAIDs . ProstagIL-1\u03b2 and IL-6 are cytokines that are upregulated during inflammation. IL-1\u03b2 deregulation is implicated in inflammation related pain as well as many of the numerous chronic inflammation-related diseases previously mentioned . IL-6 upActivation of MAPK is another notable cellular process under inflammation. MAPK is a highly conserved pathway integral to numerous cellular functions including cell proliferation, differentiation, and inflammatory response ,79. MAPKTNF-\u03b1 is cytokine produced by macrophage cells during inflammation and is both an activator of inflammatory pathways and a product of inflammation. TNF-\u03b1 expression is regulated by both MAPK and NF-\u03baB pathways. Research by Gao et al.  indicateOxidative stress and inflammation are intimately connected. Reactive oxygen species and reactive nitrogen species (RNS) are ubiquitous in the body and regulate cellular function when at healthy levels ,70. HoweChronic inflammation is one of the preeminent threats to the human health in the 21st century, in fact over 50% of deaths worldwide are attributable to diseases associated with chronic inflammation . It is i"}
+{"text": "Circular RNA (circRNA) is a novel class of single-stranded RNAs with a closed loop structure. The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing. Their expression is dynamically regulated and shows spatiotemporal patterns among cell types, tissues and developmental stages. CircRNAs have important biological functions in many physiological processes, and their aberrant expression is implicated in many human diseases. Due to their high stability, circRNAs are becoming promising biomarkers in many human diseases, such as cardiovascular diseases, autoimmune diseases and human cancers. In this review, we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases. We highlight their abundant expression, essential biological functions and significant correlations to human diseases in various components of peripheral blood, including whole blood, blood cells and extracellular vesicles. In addition, we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis. EGFR) gene was used to guide the response of EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients, which was approved by the FDA in clinical practice  are a group of endogenous noncoding RNA molecules Chen, . They weDue to the importance of liquid biopsy biomarkers in precision medicine  is covalently joined with an upstream 3-prime ss Fig.  Li et a. There aWith the rapid application of high-throughput RNA-sequencing (RNA-seq) technology  , is the first circRNA that was discovered to function as an RBP sponge  at the promoter region of their parental genes and enhances their transcription  and cyclin-dependent kinase inhibitor 1 (p21), which facilitates the inhibition of CDK2 by p21, thus blocking cell cycle progression  modification of circRNAs , such as BodyMap dataset, we observed tissue-specific circRNA expression in all 11 rat tissues, which may be closely related to the physiological functions of those tissues  patients after surgery  in adipose-secreted exosomes was found to regulate deubiquitination via the suppression of miR-34a and the activation of deubiquitination-related USP7 in plasma samples of hepatocellular carcinoma (HCC) patients, which could reduce DNA damage and promote HCC cell growth  patients and 55 normal subjects. They found that serum exosomal circFLI1 levels were significantly higher in SCLC patients, especially in SCLC patients with distant metastasis  under normal conditions  and identified circRasGEF1B as a conserved positive regulator of the LPS response  and lung cancer patients (Huang et al., hsa_circ_001937 had good discriminative power with an AUC of 0.873. After anti-TB treatment, the expression level of hsa_circ_001937 was significantly decreased compared to that of healthy controls. These results suggest that PBMC hsa_circ_001937 may be a TB diagnostic biomarker (Huang et al., circ_0000798 expression in PBMCs of HCC patients, which was associated with poor overall survival (Lei et al., circ_0000798 expression could distinguish HCC patients from healthy controls with an AUC of up to 0.703. The authors suggested that PBMC circ_0000798 has potential as a blood biomarker for HCC diagnosis and prognosis (Lei et al., , hsa_circ_0057762 and hsa_circ_0003090, that can differentiate children with SLE from healthy controls (Li et al., hsa_circ_0054633 in peripheral whole blood as a sensitive and specific diagnostic biomarker for prediabetes and T2DM (Zhao et al., With increasing knowledge of blood cell circRNAs and their function, many circRNAs in blood cells or whole blood have been proposed as liquid biopsy biomarkers for human diseases Fig. C Aufier. For insThe high stability, abundance and spatiotemporal specific expression of blood circRNAs make them ideal biomarkers for liquid biopsy. In the past several years, many studies have shown that blood circRNAs, both cell-free blood circRNAs and circRNAs in blood cells, have great potential as biomarkers of many human diseases in liquid biopsy. A biomarker with broad clinical application must have demonstrated analytical validity, clinical validity and clinical utility (Byron et al.,"}
+{"text": "N- and N,N\u2032-alkyl indigo derivatives\u2019 by Daniela Pinheiro et al., Chem. Sci., 2020, DOI: 10.1039/d0sc04958a.Correction for \u2018Deep in blue with green chemistry: influence of solvent and chain length on the behaviour of  The authors regret that incorrect compound names and values are reported in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "We have read the study by Jerjes-S\u00e1nchez et al with interestCould you detail how many of your PA-VTE developed left-sided extensive iliofemoral DVTs?Chan et al performed a systematic review in 124 patients with PA-DVT in which 84 (88%) of the known 96 patients, for which the side was known to be affected, were reported to have left-sided DVT; 87 (71%) of the 122 DVTs were restricted to the proximal veins, without distal calf vein involvement, and 64% 56/87) were iliofemoral DVTs, concluding that if larger studies confirmed such findings, these could positively impact our understanding of pathophysiology and derivation of diagnostic algorithms in PA-VTE.6/87 wereWax et al performed a retrospective care series in four women with MTS, describing diverse clinical scenarios; previous ischemic stroke from presumed paradoxical emboli, chronic LE venous congestion treated prepregnancy with stenting, previous history of iliofemoral DVT treated with catheter-directed thrombolysis, anticoagulation and stenting, and active third trimester acute iliofemoral DVT. The first three patients received thromboprophylaxis doses of anticoagulation, while the fourth one was fully anticoagulated.DeStephano et al described successful pharmacomechanical percutaneous thrombectomies in three patients with extensive iliac DVTs in pregnancy from MTS, concluding that endovascular interventions may play an important role in carefully selected patients, reducing thrombotic burden, and decreasing long-term complications like postthrombotic syndrome.Regarding MTS and pregnancy, evidence suggests that MTS confers an anatomic predisposition to DVTs as vein compression leads to endothelial damage and subsequent buildup of elastin and collagen and stagnant blood flow.Should societal clinical practice guidelines  consider including MTS as a strong preexisting risk factor for the development of PA-VTE?Given the paucity of data regarding MTS during pregnancy and postpartum in the form of case reports and case series,"}
+{"text": "Imaging technology is being recognized as an important tool for breaking through the bottleneck of drug development as it is able to provide great insights into the morphology or functionality of pharmacological models, including cell, tissue, and animal. Imaging has several advantages compared to traditional evaluation methods, which include high spatiotemporal resolution, imaging sensitivity, and tissue specificity. In addition, imaging can be utilized to determine the gene expression, metabolism of various substances, cancer detection, drug development, as well as other fields.Imaging technology includes both microscopic and macroscopic imaging scales, and encompasses fluorescence-based microscopy , Raman-bFang et al. systemically summarized the recent advances that have been made in the development of noninvasive imaging and radiotherapy agents for the different molecular subtypes of breast cancer in preclinical studies in their study, \u201cTheranostics for the different molecular subtypes of breast cancer.\u201d The researchers provided a conceptual examination of recent or current original articles that were published within the last decade in the field of preclinical breast cancer nuclear imaging. Data were extracted from the PubMed database and filtered according to the key words \u201cbreast cancer,\u201d \u201cpreclinical,\u201d \u201cPET/SPECT,\u201d and \u201ctargeted imaging.\u201d In order to help guide future investigations of novel theranostic agents, they listed different imaging agents and cell lines that were tested in preclinical studies. They think molecular imaging can help with diagnosis, staging, guiding treatment, and predicting response to corresponding targeted therapy. The review of Zeng et al. which was titled \u201cTreatment coherent Raman scattering microscopy in oncology pharmacokinetic research\u201d highlighted coherent Raman scattering (CRS) microscopy as a novel emerging platform to facilitate oncology pharmacokinetic research. It would be of great importance to develop label-free optical microscopy that is able to assess stability and dissolution of drugs in the solid state, and uptake, distribution, interaction, and excretion of anticancer drug nanocarriers in a biological environment. Therefore, they summarized the recent technical advances and applications of CRS microscopy in the field of anticancer drug pharmacokinetics at the single cell level, drug stability and dissolution in the solid state, as well as the activities of anticancer drug nanocarriers in single cells. According to their review, there are several reasons to believe that CRS microscopy with label-free, chemically selective, high temporospatial resolution, and highly sensitive imaging can offer novel opportunities for investigation of anticancer drugs.Two review articles demonstrated the role of one imaging technology in the treatment of cancer. in vitro studies. Zhang et al. in the article \u201cMetabolic reprogramming of sulfur in hepatocellular carcinoma and sulfane sulfur-triggered anti-cancer strategy\u201d uncovered reprogramming of sulfur metabolism in hepatocellular carcinoma (HCC) and were able to provide a potential therapeutic strategy for HCC by donating sulfane sulfurs. Herein, the cell imaging assay was carried out to support their hypothesis. Their findings suggest that application of sulfane sulfurs may be an effective therapeutic strategy, particularly for HCC tumor cells that have reprogrammed the sulfur metabolism. Jin et al. in their article \u201cHirsutella sinensis fungus regulates CD8 + T cell exhaustion through involvement of T-Bet/Eomes in the tumor microenvironment\u201d have provided insights into the application of Hirsutella sinensis fungus (HSF) in a tumor immune treatment. Their study demonstrated that HSF exerts antitumor effects mainly by reducing the expression of immune checkpoints by inhibiting T-bet in T cells, which lowers Tex cell production in the tumor microenvironment. Additionally, HSF could promote the Eomes expression in order to enhance T cell function. In vivo imaging technology was utilized to evaluate the effects of HSF on various tumor mouse models. Their findings were able to provide novel insights into the effect of HSF on tumor immune responses.In order to explore a novel strategy of cancer treatment, imaging technology can be applied across several in vivo evaluation of drugs. Xu et al. in their article \u201cBioluminescence imaging-based assessment of the anti-triple-negative breast cancer and NF-Kappa B pathway inhibition activity of britanin\u201d were able to evaluate the anti\u2013breast cancer activity of britanin. Their results demonstrated that britanin induces apoptosis via inhibition of the NF-\u03baB pathways. The bioluminescence imaging screening system is useful for accelerating application of britanin in the antitumor field, which provides a useful tool for evaluating the efficacy of phytochemicals in inhibiting cancer cell proliferation in animal models. Zhan et al. in their article \u201cin vivo improvement of synergistic chemotherapy in esophageal cancerConstruction of biocompatible dual-drug loaded complicated nanoparticles for \u201d developed a doxorubicin and \u03b2-elemene\u2013loaded mesoporous silica nanoparticle system to exert inhibitory effects in esophageal cancer treatment. Fluorescence images were applied in order to validate efficacy of the combination therapy in vivo. Zhang et al. in their article \u201cTerphenyllin suppresses orthotopic pancreatic tumor growth and prevents metastasis in mice\u201d reported a novel marine-derived natural product terphenyllin with potent anti-pancreatic cancer (PC) activity. Herein, terphenyllin was found to significantly suppress PC cell growth and metastasis in vitro and in vivo. Terphenyllin induced PC cell apoptosis by increasing the expression of proapoptotic proteins and decreasing the expression of antiapoptotic proteins. The Panc1-Luc cell lines were utilized to develop an orthotopic mouse model, which may be able to closely mimic the original situation in human PC patients and may be better able to predict the therapeutic efficacy of the test compound. The in vivo imaging technique demonstrated significant inhibitory effects of terphenyllin on tumor growth. Their results reveal the therapeutic potential of terphenyllin in PC, which can help provide a basis for further developing this natural compound as an anticancer therapeutic agent.Imaging technology was a powerful tool for the Li et al.\u2019s \u201cManganese-based targeted nanoparticles for postoperative gastric cancer monitoring via magnetic resonance imaging,\u201d an Mn-based contrast agent for MRI was synthesized to provide accurate evaluation of therapeutic effects and guide treatment strategy adjustment over time. A series of in vitro and in vivo imaging experiments were employed to assess the characters of Mn3O4@PEG-RGD NPs. Their results indicated that Mn3O4@PEG-RGD NPs likely have a great potential for the MRI postoperative monitoring of gastric cancer and give an appropriate strategy for following chemotherapy. Xu et al. in their research \u201cin vitro anticancer activity of fullerenol-foxorubicin conjugates alpha 3 function by colchicineSynthesis, characterization, cellular uptake, and s\u201d designed and synthesized the fuller enol (FU)-DOX conjugates and folic acid (FA)-grafted FU-DOX conjugates in order to improve the selectivity and activity of DOX in cancer cells. They synthesized DOX and FU conjugates (FU-DOX) through the use of the acid-sensitive hydrazone bond and were further modified by FA in order to obtain FA-FU-DOX conjugates for improving tumor-targeting effects. In their study, fluorescent microscopy was utilized to monitor cellular uptake. Indeed, FA-FU-DOX conjugates may optimize the safety and efficacy profile of DOX. Zhou et al. also wrote another review article \u201cpH-Sensitive and long-circulation nanoparticles for near-infrared fluorescence imaging-monitored and chemo-photothermal synergistic treatment against gastric cancer\u201d which reported photothermal\u2013chemotherapy combined nanoparticles (PCC NPs) that have functions of chemo-photothermal synergistic therapy and continuous imaging for gastric cancer. The PCC NPs consisted of dopamine, poloxamer, DOX, and IR-820 via \u03c0\u2013\u03c0 stacking and demonstrated good biocompatibility both in vitro and in vivo. Their study can offer a novel postoperative treatment for gastric cancer.The integrated diagnosis and treatment of nanoparticles will provide precise information for a cancer treatment strategy. In Zhao et al. in their article \u201cAccuracy of endoscopic diagnosis of helicobacter pylori based on the Kyoto classification of gastritis: a multicenter study\u201d provided evidence of clinical accuracy and robustness of the Kyoto classification of gastritis in the Chinese population. Furthermore, they discovered that the reappearance of two indicators (unclear atrophy boundary and unclear atrophy boundary) in atrophic mucosa could help sufficiently determine the presence of Helicobacter pylori (H. pylori) infection on an endoscopic basis. Their prospective and multicenter study was based on 650 Chinese patients. In order to prevent the occurrence and development of gastric cancer (GC) early on, their study offered an important novel finding for screening of early GC based on the close relationship between H. pylori and GC.Moreover, imaging technology also plays a significant role in a clinical anticancer medication strategy. in vitro, evaluating in vivo anticancer effects, and benefiting the clinical diagnosis. These articles provide deep insights into methodology and applications of imaging technology. We believe that imaging technology would be increasingly welcome in oncology pharmacological research.In conclusion, a collection of 11 articles contributed to this research topic, which covers two reviews and nine research articles. It is important to note that these published articles cover a wide spectrum of applications of imaging technology in oncology pharmacological research, which includes exploring a novel anticancer chemotherapy strategy"}
+{"text": "Matricaria chamomilla, commonly known as chamomile, and one of the most popular medicinal plants in the world. Thanks to a high content of phenolic compounds and essential oils, preparations from chamomile flowers demonstrate a number of pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and sedative actions as well as improving gastrointestinal function. Several recent studies have shown certain positive effects of chamomile preparations in the prevention of obesity and complications of diabetes. These effects were associated with modulation of signaling pathways involving the AMP-activated protein kinase, NF-\u03baB, Nrf2 and PPAR\u03b3 transcription factors. However, the potential of chamomile in the management of obesity seems to be underestimated. This review summarizes current data on the use of chamomile and its individual components  to treat obesity and related metabolic disorders in cell and animal models and in human studies. Special attention is paid to molecular mechanisms that can be involved in the anti-obesity effects of chamomile preparations. Limitation of chamomile usage is also analyzed. Obesity is an increasing health concern related to many metabolic disorders, including metabolic syndrome, diabetes type 2 and cardiovascular diseases. Many studies suggest that herbal products can be useful dietary supplements for weight management due to the presence of numerous biologically active compounds, including antioxidant polyphenols that can counteract obesity-related oxidative stress. In this review we focus on  AMPK 5' adenosine monophosphate-activated protein kinaseAP-1 activator protein-1FOXO1 forkhead box O protein 1GLUT-4 glucose transporter type 4HFD high fat dietFFAs free fatty acidsLDL low density lipoproteinsNF-\u03baB nuclear factor-\u03baBNrf2 nuclear factor erythroid 2 related factor 2PPAR\u03b3 peroxisome proliferator-activated receptor gammaROS reactive oxygen speciesSTZ streptozotocinTAG triacylglyceridesTNF\u03b1 tumor necrosis factor alphast century . Intensal., 2017; Kanda eal., 2017; Matsudaal., 2017; Catryssal., 2017; Bayliakal., 2017). Metaboal., 2017; Laclausal., 2017; Saklayeal., 2017). Global anti-obesity strategies are focused on dietary and lifestyle changes, i.e., change the energy balance so that calories spent prevail over calories consumed along with an increase in physical activity . NaturaMatricaria chamomilla (synonym: Matricaria recutita), commonly known as chamomile, is one of the most popular medicinal plants in the world  and phenolic compounds - phenolic acids, coumarins and flavonoids . Preparal., 2011; Europeaal., 2011), and coal., 2000; McKay aal., 2000; Haghi eal., 2000). In vitro and in vivo studies have shown that polyphenols have protective effects against oxidative stress-related diseases, including metabolic syndrome and obesity . In linal., 2006, 2020) an) an(7) Anta, 2012). It seeSeveral human clinical trials have confirmed the effectiveness of chamomile tea in the improvement of inflammatory markers, lipid profile and insulin resistance in patients with type 2 diabetes , and thgenerally recognized as safe) list of the United States Food and Drug Administration (FDA), which means a substance added to food is considered safe by experts . Howeveal., 2010; Benito al., 2010; Europeaal., 2010), and thal., 2001; Paulsenal., 2001). Chamomal., 2001), rhinital., 2001) and eyeal., 2001). In addal., 2001; Europeaal., 2001; Nakagawal., 2001). Peopleal., 2001). Sesquial., 2001) and coual., 2001) are conal., 2001). Due to chamomile mild sedative effects , long-tSince chamomile essential oils and phenolic compounds possess a strong antibacterial activity, the oral consumption of chamomile preparations at high concentrations can affect gut microbiota composition. In this, context, both beneficial and undesirable gut bacteria can undergo qualitative and quantitative changes resulting in health adverse effects such as gastrointestinal problems. However, future clinical studies on this issue are needed. At high concentrations, plant phenols exert pro-oxidant activity ; therefChamomile flowers contain a wide range of polyphenolic compounds and essential oils that possess various biological activities including antioxidant, anti-inflammatory and energy metabolism modulating effects. Due to these properties chamomile preparations can be effectively used for obesity prevention and treatment. Whole chamomile extract seems to be more effective than isolated individual components since the latter show some differences in cellular and protein targets and together may demonstrate synergetic effects. More research is needed to establish the molecular mechanisms of action of chamomile preparations. In particular, there is a need to further explore the involvement of PPAR\u03b3 and Nrf2 signaling pathways because these were found to play dual roles in obesity demonstrating both anti-obesity and obesity-promoting effects  to VIL and a grant from National Research Foundation of Ukraine (#2020.02/0118) to MMB.The authors declare that they have no conflict of interest.Maria M. Bayliak provided idea and design of the article, prepared figures and tables, performed review and editing; provided funding acquisition; Tetiana R. Dmytriv collected literature, wrote the original draft and prepared figures; Antonina V. Melnychuk and Nadia V. Strilets collected literature and wrote the original draft; Kenneth B. Storey performed review and editing and provided valuable discussion; Volodymyr I. Lushchak performed analysis, review and editing the manuscript, provided funding acquisition. All authors read and approved the final manuscript."}
+{"text": "Endogen (DAMPs) . Upon PA et al.) .Nucleic Acid-Associated Inflammation\u201d by Roca Suarez et al., as well as Xu et al.Given the central role of PRRs in the control of invading pathogens and endogenous threats, it is not surprising that genetic or etiological alterations of inflammation foster a wide range of human pathologies. Underscoring this concept, the persistent dysregulation of nucleic acid-associated inflammatory pathways has been associated with the development of chronic liver diseases. The two main etiology agents that are linked with these liver pathologies are hepatitis B virus (HBV) and hepatitis virus C (HPC). These viruses have distinct genomes and viral life cycles but can both repress innate anti-viral defenses through common mechanisms. These strategies are being discussed in our Research Topic \u201cvia comparative analyses of innate immune responses, from biological models (zebrafish and mouse) to human. This underscores the existence of tissue- and species- specificities, and is discussed in six reviews of the Research Topic which cover various aspects, ranging from the role of transposable elements to the limitations of in vivo models and provides cues towards the development of high content therapeutic strategies in relevant physiological models .Innate immunity largely relies on the recognition of evolutionarily conserved structures that can be identified Santa et al. and by Kumar give a comprehensive overview of the regulatory circuitries of nucleic acid-sensing pathways.However, despite major advances in the field of innate immunity to identify the pathways involved in the onset of cytokine production in response to immune-stimulatory nucleic acids, there are still many open questions. Specifically, how these signalling pathways are regulated in respect to various nucleic acid substrates and tissue insults. In this special Research Topic, key opinion leaders in the field offer an overview of (1) the major molecular and cellular aspects of nucleic acid sensing across species; (2) the complexity of innate and adaptive immune responses and their key role in the maintenance of tissue homeostasis; and (3) the intricate connections between deregulated nucleic acid sensing machinery and human disease. For instance, reviews by Constanzo et al. and by Taffoni et al.Even though nucleic acid-associated inflammation is the first line of defense of the host, activation of innate immunity is not always guaranteed. Indeed, microbes and malignant cells have developed a variety of strategies to prevent inflammation, in order to counteract the host response or escape the induction of anti-tumor immunity . SupportHemphill et al. from this Research Topic is discussing the therapeutic potential of the three-prime repair exonuclease 1 (TREX1) targeting as a novel immunotherapy strategy against cancer.Regulating abnormal nucleic acid sensing is emerging as a potent strategy against inflammatory diseases. Thus, PRRs and their downstream effectors have become attractive targets for the identification of biomarkers and the development of therapeutic agents with broad-range efficacy against inflammatory disorders. Review by Nucleic Acid-Associated Inflammation focuses on one specific aspect of nucleic acid sensing, encompassing signaling, regulation, interspecies specificities, and pathology relevance. The Research Topic is equally addressed to expert investigators who may wish to extend their knowledge on inflammation, innate and nucleic acid immunity, and to newcomers to this exciting and quickly progressing field of investigation.In conclusion, each one of the reviews and articles presented in All authors wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.In Vivo Investigation (EMERG\u2019IN\u00a0DOI: 10.15454/90CK-Y371). DO is supported by the Lundbeck Foundation (R335-2019-2138), a young talented cancer researcher grant from Kr\u00e6ftens Bek\u00e6mpelse (R279-A16218), the Br\u00f8drene Hartman Fond, the H\u00f8rslev Fond, the fabrikant Einer Willumsens mindelegat, and the Eva og Henry Fraenkels Mindefond. VT is supported by an LSHTM/Wellcome Institutional Strategic Support Fund (ISSF) Fellowship (204928/Z/16/Z). CV-B is supported by a startup grant from the Dept. of Radiation Oncology at Weill Cornell Medicine  and by WCM Prostate Cancer SPORE Development Research Program Award. EV is supported by ANRS (ECTZ104527), LabEx HepSYS (ANR-10-LAB-28), and the French National Research Agency (ANR-21-CE15-0035-01).NL is supported by the European Research Council , \u201cLA LIGUE pour la recherche contre le cancer\u201d and the \u201cAgence Nationale de Recherche sur le SIDA et les H\u00e9patites virales\u201d (ANRS: ECTZ117448). CL is supported by the EU INFRAIA project VetBioNet (EU H2020 project 731014) and received institutional support from INRAE. The INRAE Infectiology of Fishes and Rodents Facility  belongs to the National Distributed Research Infrastructure for the Control of Animal and Zoonotic Emerging Infectious Diseases through The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Moreover, since 2013, 12 different in vivo inhibition of TASK-1 in rats with A293 at 10 mg/kg/day induced the development of significant early signs of PAH, with abnormal elevation of right ventricular systolic pressure (RVSP), abnormal pulmonary vascular cell proliferation, pulmonary vessel remodeling, and lung inflammation  in a porcine model of persistent AF was associated with an increase in pulmonary arterial pressure (Wiedmann et al., + currents, and the in vitro and in vivo selective TASK1 inhibition reduces the T cell proliferation and cytokine production (Meuth et al., In line with these results, Wiedmann et al., found that chronic in vivo pharmacological inhibition of TASK-1 should be extremely managed in treated-patients with AF.For all these physiological role played by TASK-1 in several tissues, the Based on these results, one can hypothesize that A293 may induce PAH and right ventricular dysfunction in humans. Given the long history of drug-induced PAH [anorexigens (Montani et al., HL, DM, and FA drafted the manuscript. All authors reviewed and revised the final version and approved manuscript submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Biomedicines journal. The mechanisms of HDL modifications and their functional implications was exhaustively reviewed by M\u00e1rquez et al. [Epidemiological studies have shown that low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with increased atherosclerotic cardiovascular disease (CVD). However, accumulating experimental evidence has challenged this epidemiologic notion in the last decade, since HDL-C-raising strategies failed to confer increased cardioprotection in subjects at high risk for cardiovascular disease ,2. Thus,z et al. . Other sz et al.  and subjz et al. , which iz et al. .Beyond the predictive value of compositional and functional properties of HDL, a retrospective study also revealed the role of low HDL-C in predicting the risk of developing coronary artery ectasia in healthy subjects . In lineThe clinical significance of HDL changes in composition or function do not only relate to atherosclerosis. Dysfunctional HDL has also been associated with other diseases, including cognitive impairment ,11 and aRecent findings from epidemiological studies suggest an inverse relationship between HDL-cholesterol (HDL-C) and Alzheimer\u2019s disease (AD). In the context of neurological disabilities, accumulating experimental evidence supports an HDL-mediated protection against memory deficits, neuroinflammation, and endothelial dysfunction . HoweverApart from traditionally assigned cardioprotective favorable functions of HDL , accumulating data suggest that HDL is also involved in host defence as part of immune system (reviewed in ). In linAn impaired insulin signaling is frequently associated with NAFLD and increased risk of cardiovascular disease . Plasma Finally, the work reported by Ced\u00f3 et al.  was a clIn summary, studies published in this Special Issue provided clinical evidence of the usefulness of alterations in HDL composition and function in a wide spectra of diseases and helped define novel targets for the diagnosis/prognosis/therapeutics of cardiovascular/neurological/autoimmune diseases."}
+{"text": "There has been recent debate regarding the efficacy of electroconvulsive therapy in the treatment of depression. This has been based on narrative reviews that contradict existing systematic reviews and meta-analyses. In this special article, we highlight the mistakes that occur when interpreting evidence using narrative reviews, as opposed to conventional systematic reviews and meta-analyses. For example, a group of mental health professionals, patients and relatives recently wrote to the Chair of the Care Quality Commission (CQC) in the UK, stating: \u2018Given the high risk of permanent memory loss and the small mortality risk, the longstanding failure to determine whether or not ECT works means that its use should be immediately suspended until a series of well designed, randomised, placebo controlled studies have investigated whether there really are any significant benefits against which the proven significant risks can be weighed\u2019 Read, . Calls hv. simulated ECT (sECT) for treatment of depression , and RCTs comparing different forms of ECT and pairwise and network meta-analyses of these trials.Briefly, clinical trial evidence for ECT in depression can be divided into original placebo-controlled (sECT) RCTs, further RCTs assessing ECT Ten ECT-sECT RCTs for depression have been published (summarised in n\u00a0=\u00a0294), remission rates were significantly higher for ECT v. rTMS  with a significantly more pronounced reduction of depressive symptoms in the ECT group    and remission . Neither review found a significant difference in discontinuation between groups. Whilst this illustrates improved trial design (contemporary ECT modes and active comparators), these trials usually lack blinding of participants.The original ECT-sECT RCTs, conducted between the 1950s and mid-1980s, would not meet contemporary standards of evidence-based medicine (EBM) . Numerous additional modern RCTs have assessed the efficacy of ECT against non-pharmacological interventions such as rTMS. In a systematic review and meta-analysis comparing ECT with rTMS   of persistent and, for some, permanent brain dysfunction, primarily evidenced in the form of retrograde and anterograde amnesia, and the evidence of a slight but significant increased risk of death, the cost-benefit analysis for ECT is so poor that its use cannot be scientifically justified.\u2019et al., et al., These bold claims directly contradict evidence available at the time, as well as recently published reviews  states only five of ten studies were statistically significant. Such vote-counting is a flawed method of research synthesis, and acknowledged as misleading  (see I2\u00a0=\u00a00) and non-significant . This effect size is comparable to that reported by the UK ECT group, \u22120.91 (95% CI \u22121.27 to \u22120.54) derived from six trials.Given the lack of reporting of an effect size across all included trials, we conducted our own meta-analysis of trials included in the narrative review. Read and Bentall suggested Ulett et al.  be exclu63]) see . Heteroget al. , and cognitive impairment in depression is recognised in MDD  ; the study was powered based on this measure, which showed a statistically significant improved outcome with real ECT  is discouraged\u2019. The failure to employ any standardised assessment of quality critically undermines both any objectivity and ability to draw conclusions about quality \u2013 especially as many such scales exist that are standardised, reliable and widely employed. As noted decades ago, Greenland  and Begg and Mazumdar Kendall's \u03c4  were non-significant. The funnel plot however showed some visual asymmetry and a trim and fill analysis suggested three potentially missing studies \u2013 adjusting the effect size downward from \u22120.85 to \u22120.68.Meta-analyses of small underpowered trials can exaggerate effect sizes  . This has implications for their general criticism of past meta-analyses, where they argue, \u2018All five of the meta-analyses claim that ECT is effective for depression but, as we have seen, they are all of a poor standard, not least because none of them pay sufficient attention to the quality of the papers on which they base this claim.\u2019 The current analysis suggests at least two possibilities: either study quality is not a key driver of effect size in sECT trials or the Read et al. assessment of study quality fails to capture relevant quality differences.Importantly, meta-regression showed the Read et al.  quality et al.  in trials where previous ECT was unknown or unreported (\u22121.13 [95% CI \u22121.50 to \u22120.76]) rather than those reporting previous treatment with ECT (\u22120.67 [95% CI \u22120.97 to \u22120.37]) . Hence, trials where patients previously received ECT did not bias in favour of the ECT arm through patients being \u2018unblinded\u2019. It is also worth noting that significant differences demonstrated when comparing different modes of ECT in contemporary trials  would likely not be consistent with contemporary standards yet are still of high enough standard to contribute to the evidence base. Second, it represents a misunderstanding of principles of EBM that both Read and Bentall  and Readet al.  focus exet al., (et al., et al., et al., et al., Read et al.,  fail to  et al.,  and non-v. sECT and has significant effects on patient safety that merit a public enquiry. Examining their evidence, we have identified numerous substantial problems that stem from these narrative reviews having inherent biases and major methodological shortcomings. We would suggest those concerned with interpreting evidence continue to use conventional standardised methods of systematic review and meta-analysis where possible and that policy decisions must continue to be based on this level of evidence.Recent calls for banning ECT are based on selective narrative reviews written by authors who suggest ECT does not have efficacy et al.'s empirical arguments, moving beyond disagreement is crucial. We therefore advocate for modern trials to optimise ECT side-effect monitoring, and studies to elucidate the mechanism of action of one of the most effective treatments we have in Psychiatry.Whilst we cannot agree with most of Read"}
+{"text": "Editorial on the Research TopicAdvances in Molecular Docking and Structure-Based ModellingThe three-dimensional (3D) structures of proteins form the structural framework of their functions. Having access to the structure allows scientists to better apprehend molecular details of protein functions; it is also crucial for protein engineering, e.g., to modify and optimize an enzyme for a certain biochemical reaction; or for designing new and improved drug molecules based on the structure of the target protein. Structures are also needed to investigate how proteins interact; a vast majority of the protein-protein interface residues are involved in extensive intra-protein interactions apart from inter-protein interactions .https://www.rcsb.org)  , and thephaFold2 , it is ein silico methodologies are often complex, have limitations, and the results must be associated with appropriate statistical and quality measures. The objective of this Research Topic was to bring together various contributions based on cutting-edge computational methodologies; these include computational analysis of structures and complexes with developments and applications that integrate docking and molecular dynamics approaches, and complex experimental data such as cryogenic electron microscopy (cryo-EM).These ab-initio. The first work by Olek and Joseph dealt with the quality of models obtained by cryo-EM. In fact, the final atomic model is often incomplete or contains regions where atomic positions are less reliable or incorrectly built. They presented a software tool for the validation of the backbone trace of atomic models built in the cryo-EM maps. They use the false discovery rate analysis to segregate molecular signals from the background and show how this approach can properly complement current measures Olek and Joseph. Launay et al. tackled the challenging question of scoring in protein\u2013protein docking. They explored several ways to perform consensus-based rescoring. They showed that rescoring performs worse than the traditional physics-based evaluation but the two complement each other and can be used in combination .Two articles underline the importance of new computational approaches for evaluating atomic models derived from experimental data or built Pitard et al. studied the interaction of calmodumin (CaM) with the bacterial virulence factor, Edema Factor (EF). The system is of great interest as orthosteric and allosteric ligands have been proposed to inhibit EF activity. Using state-of-the art MD simulations, they underlined the presence of cavities at the interface between EF and CaM that could be linked to allosteric events Pitard et al.; Tang et al. combined molecular modelling and MDs to apprehend new mechanistic insights into the exciting CRISPR-Cas9 system in the DNA cleavage state. Their results provide useful guidance for engineering new CRISPR-Cas9 editing systems with improved specificity Tang et al.; Kumari et al. look at the Farnesoid X receptor (FXR) that is essential in regulating the network of genes involved in maintaining bile acid and lipid homeostasis. MDs of FXR with or without cofactors allowed a precise description of critical residue positioning during conformational changes that explain FXR activation state underlying main differences between bound and unbound forms Kumari et al.; Ghoula et al. analysed the multi domain ceramide transfer protein (CERT) implicated in the transport of ceramide from the endoplasmic reticulum to the Golgi and plays a major role in sphingolipid metabolism. Combining docking and MD simulations, the binding affinity of 14 ligands was tested. This study suggests a novel inhibitory mechanism of CERT for limonoid compounds involving the stabilization of the sub-domain interface and could help in developing new and potentially more selective inhibitors of this transporter Ghoula et al.Classical approaches such as molecular dynamics (MD) are useful to apprehend new biological systems. In this field, Gheyouche et al. applied different approaches to model the structure of RHOA-ARHGEF1 complex and they further analysed the protein-protein interface. They refined the models using MD simulations and highlighted the importance of data-driven human inspection. The modelled RHOA-ARHGEF1 interface will be extremely useful for the design of inhibitors targeting this protein-protein interaction (PPI). Gheyouche et al. Similarly, Pal et al. look at systems of economic interest. They have characterized, using molecular docking, immune response molecules of duck protein TLR3, TLR7, and RIGI and predicted to have potent antiviral activities against different identified strains of Avian influenza Pal et al.; Gobinath et al. combined experiments and docking approaches in COVID research. They have screened and proposed new indole derivatives on the famous spike glycoprotein of SARS-CoV-2 Gobinath et al.As previously mentioned, experimental 3D structures or structural models are crucial for the design of new drug molecules. Chakraborti et al. looked at the infectious pathogen with a serious global impact: Mycobacterium tuberculosis. There is a constant need to search for novel therapeutic strategies because of the emergence of multidrug-resistant tuberculosis (MDR-TB). Universal stress protein  is a perfect target in this field. A library of 1.9 million compounds was subjected to virtual screening, which led to the selection of 2,000 hits through an enrichment process, then 22 potential binders of Rv1636 were prioritized for experimental validations where two compounds of natural origin showed promising binding affinities Chakraborti et al.; Vedithi et al. looked at the proteome of Mycobacterium leprae. They presented a large set of computational approaches to unravel new potential druggable targets Vedithi et al.At a larger-scale, Souza et al. presented innovative approaches to perform high-throughput ligand-protein docking calculations by using coarse-grained molecular dynamics simulations, based on the most recent version of the Martini force field. Their approach, characterized by excellent computational efficiency, offers a level of accuracy comparable to all-atom simulations Souza et al.; Jiang et al. looked at the Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ib\u03b1 (GPIb\u03b1) implicated in haemostasis and inflammatory responses. They performed a series of \u201cramp-clamp\u201d steered molecular dynamics (SMD) simulations and compared the results with single molecular AFM measures. The concordance in the results underlined the importance of such approach to understand the platelet\u2013leukocyte interaction in haemostasis and inflammatory responses under mechano- and microenvironments Jiang et al.Finally, This special issue is dedicated to the loving memory of Prof. Narayanaswamy Srinivasan who left us too soon on the third of September 2021 . As a pa"}
+{"text": "The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches. Innate immunity, the first line of host defense, is classically triggered in response to pathogen infection or local lesions to promote infection clearance or wound-healing processes. The activation of innate immune responses vastly relies on pattern-recognition receptors (PRRs) that detect danger associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Upon recognition of PAMPs or DAMPs, PRRs trigger signaling cascades leading to the production of soluble mediators, such as type I Interferons, cytokines and chemokines. Pathogen-derived nucleic acids constitute major PAMPs that are detected by a vast array of PRRs that operate in specific subcellular localizations. In recent years, self-nucleic acids, originating from replication stress , DNA or A plethora of cytosolic nucleic acid sensors have been described to participate in triggering Interferon responses. Such receptors notably include the ubiquitous DNA-dependent activator of Interferon regulatory factors (DAI) , AIM2 77, 8, IntHowever, there is emerging evidence for an intricate signaling network beyond the cGAS-STING cascade, which cannot be overlooked in therapeutic strategies aiming to boost STING activation. Of particular importance is the fact that cGAS and STING have been both described as involved in genotoxic stress response and to participate to the maintenance of genomic integrity. Furthermore, the DNA-PK complex, which is best known for its function in non-homologous end-joining (NHEJ)-mediated repair of dsDNA breaks (DSB), has been shown to serve as an alternative route to stimulate type I Interferon production \u201321. In pmini review, we discuss this interconnection between DNA repair mechanisms and nucleic acid immunity, by focusing on the cGAS and IFI16 receptors and the way in which they control STING activation. While several DNA repair proteins have been involved in the fine tuning of inflammatory responses , \u201cLA LIGUE pour la recherche contre le cancer\u201d and the \u201cAgence Nationale de Recherche sur le SIDA et les H\u00e9patites virales\u201d (ANRS). CT was supported by Merck Sharp and Dohme Avenir (MSD-Avenir \u2013 GnoSTic) program, followed by an ANRS fellowship (ECTZ119088). JM was supported by a \u201cConventions Industrielles de Formation par la Recherche\u201d (CIFRE) fellowship from the \u201cAgence Nationale de Recherche Technologie\u201d (ANRT). AS is supported by the ERC-PoC DIM-CrIC (893772). IV was supported by the European Research Council (637763) followed by the Prix Roger PROPICE pour la recherche sur le cancer du pancr\u00e9as of the Fondation pour la Recherche M\u00e9dicale . HC is supported by a PhD Fellowship from \u201cLa Ligue contre le cancer\u201d (TAGQ21108). We acknowledge the SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553 for support.JM was employed by Azelead.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Vaccines entitled \u201cInfluenza Virus and Vaccine Development\u201d. This Special Issue collects one review and seven research papers that cover multiple aspects of influenza vaccine development, including the development of candidate vaccine virus (CVV) and master donor viruses for generating high growth reassortants, new vaccines and adjuvants, assay evaluation and vaccine safety. These investigations provide a wealth of experience and lessons from recent influenza pandemics, which can also be applied to current COVID-19 vaccine development.While the scientific community has been focusing on combating novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the current COVID-19 pandemic, we also want to draw your attention to this Special Issue of The review article by Rockman, Laurie and Barr , highligFour other manuscripts in this Special Issue report how novel vaccines can increase the strength and breadth of immune responses beyond the traditional HA response in animal or clinical studies. Bazhan et al.  describeIn this Special Issue, Carnell et al.  focused The paper by Ambati et al.  investigWe sincerely hope these lessons learned from past and current influenza research will benefit the ongoing battle against the COVID-19 pandemic."}
+{"text": "Matrix nanocomposites are high performance materials possessing unusual features along with unique design possibilities. Due to extraordinary thermophysical characteristic contained by these matrix nanocomposites materials they are useful in several areas ranging from packaging to biomedical applications. Being an environment friendly, utilization of nanocomposites offer new technological opportunities for several sectors of aerospace, automotive, electronics and biotechnology. In this regards, current pagination is devoted to analyze thermal features of viscous fluid flow between orthogonally rotating disks with inclusion of metallic matrix nanocomposite (MMNC) and ceramic matrix nanocomposites (CMNC) materials. Morphological aspects of these nanomaterials on flow and heat transfer characteristics has been investigated on hybrid viscous fluid flow. Mathematical structuring of problem along with empirical relations for nanocomposites materials are formulated in the form of partial differential equations and later on converted into ordinary differential expressions by using suitable variables. Solution of constructed coupled differential system is found by collaboration of Runge\u2013Kutta and shooting methods. Variation in skin friction coefficient at lower and upper walls of disks along with measurement about heat transfer rate are calculated against governing physical parameters. Impact of flow concerning variables on axial, radial components of velocity and temperature distribution are also evaluated. Contour plots are also drawn to explore heat and thermal profiles. Comparison and critical analysis of MMNc and CMNc have been presented at lower and upper porous disks. Our computed analysis indicates that hybrid nanofluids show significant influence as compared to simple nanofluids with the permutation of the different shape factors. Initially, nanofluids are considered as single phase flows but it is experimentally proved that consideration of nanoliquid as two phase compositions is much more beneficial. Yamada et al.2 discussed the combined two or more than two organic and inorganic constituents at nanoscale which are obliged in polymers. This idea executed hybridization of nanoparticles with different organic/inorganic compositions. The hybridization of base fluid with multiply structured nanoparticles change dynamics of industrial world3.With advancement in technology modern thermal management systems like central processing units in computers, light emitting diodes, transistor, solar collectors, audio amplifiers and so forth requires liquids with improved thermal conductivity. Since, ordinary fluids are unable to meet desired requirements for advanced industrial and technological procedures so insertion of nanoparticles in poorly conducting ordinary liquids are managed. The appropriate mixture of nanoparticles in specified ratios has generated exceptional thermal performance of weak thermalized systems. The concept of addition of nanoparticles was inaugurated by Choi and Eastman2, Aluminum Oxide (Al2O3) because of fact that they provide strong wear resistance and compressive power. In addition, majority volume of matrix metal composites are filled by a ceramic such as nitrides, oxides, silicides and borides. To gain optimized usage and evoking of precise nanoscopic features the ceramics as well as metallic elements are uniformly distributed. Zeeshan et al.4 investigated influence of morphological aspects of nanoparticles by varying shape on features of fluid floating across a spinning disk. Ahmad et al.5 depicted magnetized nano squeezed flow between two parallel disks along with consideration of viscous dissipation and multi natured hybrid particles. Haq et al.6 inserted Manganese-Zinc ferrite and Cobalt ferrite in viscous fluid flow between parallel disks and adumbrated enhancement in thermal conductance. Heat transfer features by inducting platelet, cylinder, and brick-shaped copper nanoparticles in water was studied by Khan et al.7. Hajabdollahi et al.8 examined morphometric aspects of (Al2O3) nanoparticles by considering platelets, spherical, cylindrical shapes, and bricks shapes on performance of tube heat exchangers. Kucharik et al.9 discussed absorption of metallic particles in water for formation of colloidal substances used in heat transfer diffusion processes in lasers. Ghozatloo et al.10 analyzed experimentally about dynamics of insertion of gold nanoparticles in water and ethylene glycol and build comparative framework regarding affectivity of particles against viscosity variant base liquids.From advent of twenty-first century a new findings in nanotechnology is discovered which is the concept of matrix nanocomposites materials. It is a two phase material with one phase consisting of solid material and other phase is nanometer sized particles. Nanomaterials are lightweight, highly strength full, sustainable, elevated temperature strengthened, corrosion resisted can be used in a wide variety of applications, e.g. aerospace, automotive, biomedical engineering etc. On basis of such mechanical, electrical, thermal, optical, electrochemical and catalytic features nanocomposites are characterized in to ceramic/metal matrix nanocomposites. MMNC is the material which composes of metal matrix distributed in concrete, ceramic, or organic substances. The reinforcement and distribution of matrix material into nano-scale particles which generates remarkable improvement in mechanical properties of formed composition. In metal matrix composites metals like copper, magnesium, and aluminum are capitalized as base metal. Since, base materials are metal which have stiffness and strength so MMNC is obliged in aviation, aerospace, defensive weapons and other areas. The most widely used reinforcements in matrix nanocomposites are Silicon Carbide (SiC), TiO11 investigated unsteady squeezing flow and upsurge in convective motion of fluid molecules bounded between two parallel disks. Mochizuki et al.12 conducted experimental analysis the mount in thermal conductivity of viscous fluid flowing between two parallel heated disks rotated radially. Characteristics of hall current on hybridized nanoliquid flow across spinning disk was demonstrated by Acharya et al.13. Bhattacharyya et al.14 examined enhancement in heat transfer properties of viscous liquid between two coaxial disks by adding carbon nanotubes. Bhat et al.15 analyzed heat transfer in flow through addition of nanostructures in a porous disk by employing tangential slip level constraint at boundary. Maskeen et al.16 established hybridized nano fluid flow with combination of alumina and copper particles under impact of Lorentz magnetic field. Ghaffar et al.17 numerically studied heat transfer in incompressible flow of fluid between two orthogonally passing coaxial porous disks with interaction of ferromagnetic nanoparticles.Heat is form of energy that arises due to temperature difference. Heat transfer with in flow procedures has received several applications like in electric power production, vehicle propulsion and climate control devices, home heating, and cooling appliances and so many. Heat transmits during the flow by the way of conduction, convection, and radiation. Generally, heat transfer in fluid arises due to convective motion of liquid molecules and enhanced is done by uplifting thermal conductivity of liquid. Researchers have experimentally discovered that this is executed by adding nanoparticles. This experimentation is proved to be successful when cooling and heating of domestic appliance like refrigerator, coils and electrical device is raised by nanoparticles inclusion. Chamkha et al.18 used hybridization of Titanium dioxide with Silicon Carbide in heavy water limited between moveable disks under effect of vertical magnetic field. Use of hybrid nanofluid during treatment of cancer patients was disclosed by Hayat et al.19. Enhancement in thermal transfer by using hybrid nanoliquid during industrial procedures was explained by Hussein et al.20. Devi et al.21 examined hydromagnetic hybrid nano-liquid (Cu-Al2O3/water) for raise in temperature and heat transfer up gradation in liquid flowing in permeable flow domain. Sarkar et al.22 evaluated optimistic impact of hybridization of nanoparticles for enhancing temperature profile. Sundar et al.23 provided comparative analysis regarding heat transfer features attained with addition of ordinary and hybridized nanoparticles.In recent years some inconsistencies in reported results regarding heat transfer rate with addition of nanoparticles is found. So, researchers have tried to use hybridized nanofluid which is engineered suspension of dissimilar nanoparticles in mixture or in composite form. This idea has further improved heat transfer and pressure drop characteristics and removed disadvantages of individual suspension. With the formation of hybridized nanofluids a better thermal network containing synergistic effect of nanomaterials is attained. In this regard several studies is available in literature like Behnam et al.24 analyzed MHD flow and its practical appliance in multiple sectors. The field of magneto hydrodynamics was introduced by Alfven et al.25. Emad et al.26 demonstrated analytical and numerical treatment about hybrid magnetic nano material in porous stretching/shrinking medium. Ghadikolaei et al.27 analyzed heat transfer features of electrical conducting hybridized nano liquid (TiO2-Cu) in water by varying shape of nanoparticles. Hayat et al.28 explored magnetically effected fluid flowing between two parallel spinning disks by using analytical approach. Ahmad et al.29 explored impact of magnetic field on asymmetric flow of fluid and found decrease in momentum profile. Rashidi et al.30 magnetic flow of viscous fluid by interpreting impact of it on thermal conductivity. Raddya et al.31 explored impact of magnetic field on nano-liquid flow in rotating frame and found reduction in velocity against Hartmann number. Mliki et al.32 demonstrated convective flow of nano fluid under appliance of MHD in an enclosure by examining thermo physical features. Turkyilmazoglu et al.33 explicated heat transfer features of magnetized viscous fluid flow generated by spinning disks. Some recent literature about flow characteristics of fluid under appliance of magnetic field in different physical configurations is enclosed in38. Sheikholeslami et al.39 aimed to investigate hot gas flow inside inner pipe and operating fluid in the annulus region filled with nanoparticles composed of CuO. Wang et al.40 analyzed utilization of hybrid nanofluid in solar photovoltaic system using the spectral beam splitting technology. Chuanpan et al.41 described a high-efficiency sensing system working with carbon nanofibers and discussed it efficiency by varying shape and amount of fibers. Guo et al.42 founded application hybridized nano based materials in environmental protection. Yun et al.43 determined degradation performance of nano-TiO2\u00a0as a coating material used in roads and bridge construction. Sheikholeslami & Farshad44 discussed the solar collector system with turbulater effect for hybrid nanoparticles. Hybrid nanofluid is useful to increase the exergy efficiency of solar system and produces higher overall efficiency45.Magneto hydrodynamics describe flow behavior of moving conducting liquid which in turns polarized it. Impact of magnetic field is evaluated in industrial processes like fuel industry, electric generators, nuclear plants, aerodynamics, crystal production and so forth. Tamim et al.To the best of the author\u2019s knowledge there has been a scarcity in research regarding analysis of morphology effect of hybrid nanofluids coupled with matrix metal and ceramic matrix nanocomposites on thermo physical features of fluid flow between two orthogonally placed porous disks. Mathematical modeling in the form of partial differential equations is developed by considering shape and size of different (MMNC) and (CMNC). Later on, attained PDE\u2019s are converted into ODE\u2019s by using appropriate variables. Solution of intricate coupled differential system is attained by implementing Runge\u2013Kutta and shooting method jointly. Impact of involved dimensionless parameters on associated profiles is adorned.2-Cu/water nanoparticles between two orthogonally moving porous coaxial disk in the presence of the external magnetic field applied in z-direction. The diameter of boundary disks is 2r. The physical model takes in a cylindrical coordinate system Let us consider an incompressible, viscous, laminar, unsteady, 2D flow of hybrid nanofluid containing TiOmentclass2pt{minim46HNfd).Law of conservation of mass, momentum, and energy are as follows referred to Kashif et al.Thermophysical properties of  is defined in Hybrid nanofluid effective heat capacitance is denoted byHNfd), and3O4), second (Al2O3), third (TiO2) and fourth (Cu) NP\u2019s (n1 and n2) based on thermal conductivity of (HNfd). The thermal conductivity of copper nanoparticles is high than titanium oxide.HNfd) The thermal conductivity of hybrid nano fluid of specific size and shape factor of NP\u2019s is described as underFor boundary situations the flow state is:Here, Following similarity variables are usedAssociated boundary conditionsR\u2009=\u2009Here, \u03b1\u2009=\u2009R, and consider the case following Majdalani et al.50 when \u03b1 is a constant, Finally, we set F\u2009=\u2009Boundary conditions at lower and upper wall of channelSkin friction and Nusselt number at both porous walls are computed coefficients which are of engineering interest are computed in this section.The The calculation at the lower and upper disk for heat transfer rate (Nusselt numbers) Since attained couple system of ODEs manipulated in Eqs.  and 29)29) are iIn a shooting method, the missing initial condition at the initial point of the Interval is assumed, and the DE is then integrated numerically as an initial value problem. The accuracy of the assumed missing initial condition is then checked by comparing the calculated value of the dependent variable at the terminal point with its given value here. If a difference exist, another value of the missing initial condition must be assumed and the process is repeated. This process is continued until the agreement between the calculated and the given condition. For this purpose, given below Table An extensive representation of non-linear coupled system of ordinary differential equations along with coefficients possessing features of matrix composite materials and hybrid nano fluidPutting values of Eq. , Eq. 2323, Eq. , Eq. 2525, Eq.  and Eq. in Eqs. We followed the RK methodology with the inclusion of shooting methods for the solution purpose of the existing flow model. The following replacement remain ingredient to start the process:First, transform the model system of ODEs Eq.  and Eq. in the fBy interchanging, embedded in Eq.\u00a0, the folConsequently, the initial condition are:46. Table This section is presented to elaborate the impact of flow concerning equations like expansion/contraction ratio parameter entclass1pt{minimamentclasspt{minimaentclass1pt{minimaR was seen in Fig.\u00a0R.Figure\u00a0entclass1pt{minimamentclasspt{minimamentclasspt{minimaIn this study numerical analysis of MHD hybrid nanofluids flows through porous surfaces is adumbrated. Thermophysical features of metallic and ceramic-metallic nanocomposites are combined with hybrid nanofluid. Evaluation about shape, size factors and particle volume fraction on velocity, temperature profile is executed. Numerical and graphical consequences are gained regarding skin friction coefficient and Nusselt number. n\u2009=\u20095.7 shows good results in MMNC than shape factors at both porous walls.Nusselt number atMagnetic parameters have a significant effect on skin friction and Nusselt number for hybrid flow.In absence of injection/suction all governing parameters at lower porous surface show good performance as compared to upper surface.R indicate better results as compared to nanofluids.Hybrid nanofluids under the effect of M and For the contracting case Nusselt and skin friction coefficients for hybrid nanofluid show significant results.Increase in volume fraction thermal boundary layer thickness increases but permeable Reynold number reduces thermal boundary layer thickness.Some key findings are itemized as below"}
+{"text": "Chemical signals are routinely propagated through biomacromolecules to modulate the structure of active sites and protein-protein interfaces. However, our understanding of the fundamental mechanisms coupling disparate regions of proteins is limited by the lack of accurate, atomic resolution information on their intrinsic dynamics. Indeed, the pathways most critical to chemical information flow are often intimately linked with the conformational ensembles populated by biomolecules, and spatially distant from traditional catalytic or ligand binding sites. A \u201choly grail\u201d of biophysical chemistry has been to understand, at the molecular level, how ligand binding information is transmitted through a protein matrix to induce a functional response. Though a majority of information about dynamically-driven biological function comes from lower molecular weight proteins, an exploding number of studies have taken advantage of advances in spectroscopy, electron microscopy, and molecular simulations to synergistically map dynamic pathways that underlie long-range communication in multidomain systems.de novo spatial and temporal regulation of protein function. The articles in this Research Topic tackle this knowledge gap by reporting on the structural and dynamic components that govern intra- and inter-domain crosstalk.The advantage of visualizing the solution ensembles of large biomolecules lies in the potential to leverage flexible hotspots for drug discovery or Redzic et al. demonstrated an intricate link between micro-millisecond protein dynamics and allostery in biliverdin reductase \u03b2 (BLVRB). Strikingly, evolutionary differences in amino acid sequence distal to the catalytic site induce a substantial variability in molecular motions that work in concert to regulate BLVRB function. A thermodynamic and kinetic investigation by Dubrow et al. offers insight into the role of protein motions in organizing biomolecular interfaces. Through site-directed mutagenesis, this work captures the per-residue impact on conformational selection during the binding transition state of influenza A nonstructural protein 1 and human p85\u03b2. The allosteric interactions of cholesterol with the chemokine receptor CCR3, critical to immune cell trafficking, is characterized by van Aalst and Wylie with circular dichroism and fluorescence polarization. The authors identified cholesterol as a critical mediator of substrate binding and receptor activation that drives signal transduction in GTPase assays. Cole and Igumenova used NMR spectroscopy to explore the interplay between Cd2+, Zn2+ and the conserved homology 1 (C1) zinc finger domain of protein kinase C, revealing the atomistic structural and thermodynamic properties of the C1 coordination sphere that facilitate competition between divalent metals.Purslow et al. highlighted the influence of protein dynamics on the activity of bacterial phosphotransferase Enzyme I by dissecting the contributions of active site flexibility to enzymatic turnover, most notably through the rotameric equilibrium of the catalytic His. Another elegant NMR relaxation study, performed by Zeng et al., revealed an RNA-driven disorder-to-order transition in the N-terminus of a bacterial RNase P, which serves as a dynamic checkpoint to ensure substrate alignment and enzyme activation. Baudin et al. reported an NMR structural study of the SERPINE1 mRNA binding protein (SERBP1), revealing SERBP1 to be intrinsically disordered but capable of sampling several compact conformations. The authors further define its RNA binding preferences and propensity for liquid-liquid phase separation, providing seminal molecular details of its mechanism.In another study, Le et al. carried out a novel structural study of the SpeG N-acetyltransferase, defining the structural basis for an allosteric mechanism that is unique within this enzyme family. This work implicates a dynamic loop, along with several \u03b2-strands, as mediators of enzyme activity and lays the foundation for expanded structure-function studies of SpeG. Long-range allostery in \u03b1-tryptophan synthase (\u03b1TS) is shown by D\u2019Amico et al. to involve networks of flexible residues that propagate \u223c25\u00a0\u00c5 chemical signals. Here, a novel role for surface-exposed residues in modulating dynamic crosstalk in \u03b1TS is revealed by NMR and molecular simulations. Skeens et al. and Cui and Lisi explored the intrinsic dynamics of cytokines as a driver for promiscuous and non-overlapping functions. Site-directed mutagenesis, novel structural engineering, and receptor binding demonstrated an intimate link between multi-timescale conformational dynamics and several biological activities.in silico predictions. For instance, Raniolo and Limongelli combined quantum-mechanics and free-energy calculations to improve standard ligand parametrization, allowing enhanced sampling (Funnel-Metadynamics) simulations of the paradigmatic benzamidine/trypsin molecular binding system that elegantly reproduced the high-resolution crystallographic ligand binding mode, providing a very accurate description of the binding mechanism. Hajrediniand and Ghose, instead, showed how enhanced sampling MD simulations could provide insight into the structural mediating role of a conserved \u201ccatalytic\u201d residue that inactivates two distantly related kinase families, i.e., bacterial tyrosine and shikimate kinases.The computational works contributing to this Research Topic covered various flavors and challenges of modern atomistic simulations, demonstrating the benefits of obtaining information with atomistic resolution that can be directly compared with experimental evidence and highlighting the potential of Estarellas et al. computationally assessed changes in the structural and dynamical properties of distinct isoforms of the adenosine monophosphate-activated protein kinase complexes. The comprehensive analysis of molecular dynamics simulations, also involving network theory tools, enabled characterization of key molecular factors that mediated activation of pan-activator PF-739, identifying distinctive features that correlate with the affinities of different isoforms. Massi and Morgan also combined molecular dynamics simulations with network analysis to show that substrate specificity in the enzymatic activity of the oligosaccharyltransferase of Campylobacter lari is regulated by modulation of dynamic allosteric pathways. Finally, Pacini et al. provided a perspective on the future challenges of network theory calculations aimed at elucidating the link between the information encoded in protein primary sequences, their dynamics and functions. Jernigan and Kumar proposed, instead, the use of elastic network models to infer the dynamics of a variety of proteins (with known bound and unbound structures) by observing the transfer of fluctuations among distant regions upon binding of an allosteric ligand.Frontiers in Molecular Biosciences highlights once more the power of combining computational and experimental approaches to characterize protein allostery with atomic resolution. We expect that further strengthening and exploiting such synergy will be instrumental toward a complete dissection of the structure/dynamics/function relationship in proteins and the development of predictive tools to identify allosteric networks and hot spots for drug design.Overall, the collection of manuscripts selected for this special issue of"}
+{"text": "However, few studies integrate genetic, epigenetic, social, and environmental determinants of early life phenotypes to understand their links with diseases in later life. In this Mancilla et al. reviewed the literature to examine health inequality within the context of social epigenomics. Sasaki et al. investigated the effect of sample handling on DNA methylation profiles. Candelo et al. investigated a possible association between Zika virus infection and cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) mutation. Le et al. investigated the mechanisms linking assisted reproductive technology (ART) to cholesterol metabolic and respiratory disorders later in life. Xu et al. investigated the use of maternal serum human leukocyte antigen-G (sHLA-G) to detect prenatal chromosomal abnormalities. Ferreira and Dantas Junior reported a case study of a neonate with Beare-Stevenson Syndrome whose father had Congenital Bilateral Absence of the Vas Deferens (CBAVD). Luo et al. presented a whole exome sequencing study of Joubert Syndrome (JBTS), a type of ciliopathies.This topical collection presents original research, review articles, and case studies on a scope of exposures and health outcomes spanning the pre-natal period through adulthood. Future studies integrating a spectrum of genetic and epigenetic studies along with relevant exposures  have a potential to inform mechanisms that underlie the associations between maternal phenotypes, birth outcomes, and offspring adult diseases."}
+{"text": "Thyroid cancers (TCs) are the most prevalent malignancy of the endocrine system and the seventh most common cancer in women. According to estimates from the Global Cancer Observatory (GCO) in 2020, the incidence of thyroid cancer globally was 586,000 cases. As thyroid cancer incidences have dramatically increased, identifying the most important metabolic pathways and biochemical markers involved in thyroid tumorigenesis can be critical strategies for controlling the prevalence and ultimately treatment of this disease. Cancer cells undergo cellular metabolism and energy alteration in order to promote cell proliferation and invasion. Glutamine is one of the most abundant free amino acids in the human body that contributes to cancer metabolic remodeling as a carbon and nitrogen source to sustain cell growth and proliferation. In the present review, glutamine metabolism and its regulation in cancer cells are highlighted. Thereafter, emphasis is given to the perturbation of glutamine metabolism in thyroid cancer, focusing on metabolomics studies.  KG \u03b1-ketoglutarateTCA tricarboxylic acidOAA oxaloacetateGSH GlutathioneGLUD glutamate dehydrogenaseGOT glutamate oxaloacetate transaminaseGPT glutamate pyruvate transaminaseATC anaplastic thyroid cancerFNAB fine-needle aspiration biopsyCITED1 Cbp/p300-interacting transactivator1TTF-1 thyroid transcription factor 1CEA carcinoembryonic antigenHBME-1 hector battifora mesothelial-1ATP adenosine triphosphateGln glutamineNEAA non-essential amino acidASCT2 amino acid transporter-2GLS glutaminasemTORC1 mammalian targets rapamycin complex 13 TriiodothyronineTGSSG oxidized glutathione Globally, thyroid cancers (TCs) are the most common head and neck malignancy and the seventh most prevalent cancer in women . HistolThe complexity of cancer in terms of diverse processes that drive the formation, growth, development, and progression of tumor cells continues to present a great challenge to the medical field. Over the past decade, many theories of the molecular mechanisms involved in cancer with a focus on individual factors and processes have emerged. Presently, several defined hallmarks for the cancer process are co-opted together to provide a conceptual framework for the complexity inherent in cancer . MetaboGlutaminolysis is another considerable metabolic reprogramming of cancer cells that mediates anaplerotic reactions to supply tricarboxylic acid (TCA) cycle intermediates . GlutamThis paper will review the experiments conducted on the role of Gln metabolism in TCs with additional consideration on possible mechanisms linking perturbation of Gln metabolism to pathological conditions.4+ and can occur in several tissues such as the brain, liver, lungs, adipose and skeletal muscles . Furtheal., 2007; Roth, 2al., 2007). This ral., 2007). 4+ into Gln and ATP products  and glutaminase. GS in the cytosol is subject to transform glutamate plus NHal., 2017; Krebs, al., 2017). In facal., 2017; Neu et al., 2017). It is al., 2017). GLS inal., 2016; Curthoyal., 2016).via SLC7A5/ SLC3A2, and leucine enters the cell; thereby, adapting a rate-limiting step for mTORC1 ac-tivation . Among  Figure 1 . Moreoval., 2017). Furtheal., 2017; Yang etal., 2017). It shoal., 2017). In thial., 2009). Besideal., 2009). Additial., 2009), c-Jun al., 2009), p53 , K-Ras al., 2009), Rb , and Rhal., 2009) have be3) hormone produced by the thyroid gland is essential for numerous functions in the body. T3 can modulate Gln release rate from several tissues, including the liver, kidney, intestine, and immune system cells . Althoual., 1990). Nevertin vivo/in vitro metabolites . Over t1H HRMAS NMR spectroscopy to find metabolic changes in benign (nodular goiter (NG)), malignant , and normal thyroid tissue lesions , no neoplastic nodules (NN), follicular adenomas (FA), and malignant thyroid cancer [65]. In that study, glutamate was one of the remarkable elevated metabolites in all samples . The real., 2013). Metaboal., 2013). D\u2010glutal., 2013, Seo et al., 2013, Tian etal., 2013). Table al., 2013; Gu et aal., 2013; Lu et aal., 2013; Ryoo etd cancer . In thatal., 2013; Skorupaal., 2013; Tian etal., 2013; Wang etal., 2013; Wojtowial., 2013; Xu et aal., 2013; Zhou etal., 2013) shows a1H-NMR spectroscopy combined with GC/flame ionization detector (FID)/MS techniques  in comparison with healthy thyroid tissues (n = 10). Their work led to the observation that the total GSH was increased in cancer lesions compared to the healthy control group , MNG (n = 16), and healthy volunteers (n = 20), in a GC-MS-based metabolomics approach. It was observed that glutamic acid level was substantially increased in the PTC group compared to healthy subjects. Moreover, pathway analysis showed perturbations in D-Gln and D-glutamate and GSH metabolism with common impacts in both PTC and MNG tumorigenesis . While,al., 2020). Our teBRAF V600E mutation, and the expression of ASCT2 expression was raised in MTC , FTC: 112), MTC: (70), poorly differentiated carcinoma PDC: (23), and ATC: (8), and follicular adenomas, FA (152), a distinct expression pattern in Gln metabolism-related protein among the histopathological subtypes of thyroid cancer was identified . In thaal., 2016). Microa2, MTC:  and tissue samples using several molecular and biochemical approaches revealing that the GLS, a key enzyme in glutaminolysis, was overexpressed in cancer specimens and played a prominent role in the development and progression of PTC . In 201At a glance, increasing evidence suggests that Gln, as a NEAA, plays an important role directly or indirectly in tumorigenesis and cancer cell survival. However, despite the emerging understanding of the biological relevance of Gln in cancer, the research underlying perturbation of Gln metabolism on TCs is restricted. From the studies mentioned above, it is evident that most of the metabolomics studies that reported changes of Gln/glutamate and related metabolic pathways were those that performed NMR approaches with untargeted strategies. Hence, it will be essential to perform quantitative and targeted assays in cohort projects to unravel the biological mechanism underlying Gln metabolism and then find the effect of other factors on it in TCs. Thyroid gland plays pivotal roles in the growth and development of the human body and keeps metabolism under control, and by releasing certain hormones, regulates Gln metabolism. Therefore, significant efforts must be made to untangle the role of Gln metabolism in thyroid tumorigenesis, which can result in a comprehensive understanding of disease progression and ultimately lead to the discovery of novel therapeutic strategies. Crispin R. Dass and Mehdi Hedayati  22432500, Fax: +98(21) 22416264, E-mail: hedayati47@gmail.com, hedayati@endocrine.ac.ir) contributed equally as corresponding author.The authors declare that they have no conflict of interest.All authors contributed to the study conception and design. The first draft of the manuscript was written by Raziyeh Abooshahab. Kourosh Hooshmand and Fatemeh Razavi edited the manuscript. Mehdi Hedayati and Crispin R. Dass approved the final version. All authors participated in the critical revision of the manuscript for important intellectual content."}
+{"text": "Culinary skills are important objects of study in the field of Public Health. Studies that propose to develop instruments for assessing such construct show lack of methodological uniformity to report validity and reliability of their instruments.To identify studies that have developed instruments to measure culinary skills in adult population, and critically assess their psychometric properties.We conducted a systematic review according to the PRISMA statement. We searched literature PubMed/Medline, Scopus, LILACS, and Web of Science databases until January 2021, and consulted Google Scholar for relevant grey literature. Two reviewers independently selected the studies, conducted data extraction, and assessed the psychometric quality of the instruments. A third reviewer resolved any doubts or disagreements in all steps of the systematic review.The search identified 1148 potentially relevant studies, out of which 9 met the inclusion criteria. In addition, we included 3 studies by searching the related articles and the reference lists of these studies, totaling 12 included studies in this review. Ten studies reported the development of tools measuring culinary skills in adults and 2 studies performed cross-cultural adaptations of original instruments. We considered adequate quality of internal consistency reliability in four studies. One study received adequate rating for test-retest reliability. No studies presented adequate rating for content validity and four studies showed satisfactory results for at least one type of construct validity. One study reported criterion validity and the quality of this psychometric property was inadequate.We identified many studies that surveyed culinary skills. Although the isolated measures appraised in this review show good promise in terms of quality of psychometric properties, no studies presented adequate measures for each aspect of reliability and validity. A more consistent and consensual definition of culinary skills is recommended. The flaws observed in these studies show that there is a need for ongoing research in the area of the psychometric properties of instruments assessing culinary skills. The discussion about the improvement of culinary skills and food practices has proven to be an important object of study in the field of Public Health; these skills are key factors associated with eating behaviors and with several complexities that represent social determinants of health .Several authors define the term culinary skills in their publications \u20136, howevCulinary skills are associated with other concepts that involve the practice of proper and healthy eating, such as food literacy, which takes into account the broader social and environmental dimensions of eating together, associated with an individual\u2019s abilities . Those cTime devoted to cooking has decreased and has been viewed as a global trend: food industry investments in advertising and marketing to \u201csolve the everyday food problem\u201d devalue cooking as an emancipatory competence associated with a healthy food routine . Such deet al. (2001) [The main source of cooking knowledge and skills is through parents \u201317. This. (2001)  found frIn this scenario, culinary skills among adults, especially those responsible for preparing household meals, have been an important focus of research , 17, 19.Before being considered suitable, the instruments must offer accurate, valid, and interpretable data for the population\u2019s assessment. Moreover, the measures are supposed to provide scientifically robust results. These results are established based on measures of reliability and validity of the instruments \u201322. ReliThere are public health policies focused on cooking in several parts of the world . Despiteet al. (2014) [McGowan . (2014)  conducteAdditionally, previous reviews have not proposed to appraise the quality of psychometric properties of instruments measuring culinary skills, which justifies the importance of this study, given the fact that the diagnosis of one\u2019s skills entrusted to the application of these instruments may be flawed. This could result in planning inappropriate food and nutrition educational actions for providing emancipatory and self-care practices.Therefore, this systematic review aimed to identify studies that have developed instruments to measure culinary skills in adult population, and critically appraise the quality of their psychometric properties.We hope that this study can provide evidence-based guidance on the psychometric properties of instruments measuring culinary skills, to subsidize the selection of valid and reliable instruments by healthcare professionals to assess these subjects in clinical and public health settings and avoid unrealistic expectations about the information that such measures may provide.http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42019130836). The protocol is available in the We registered the protocol of this systematic review on the International Prospective Register of Systematic Reviews . A third reviewer (T.M.L.) resolved any doubts or disagreements between the reviewers regarding the inclusion or exclusion of articles. The third reviewer compared the results of the independent selection of articles carried out by the two reviewers. If the third reviewer identified any differences, he would ask the two authors to discuss their opinions. If the two reviewers did not reach an agreement, the third reviewer would present his opinion.This review, included articles meeting the following criteria: 1) address culinary skills in adults; 2) describe the instrument\u2019s validation and reliability process, which can be original or adapted instruments. No filters for year of publication, country or language were employed. Articles that developed original instruments or reporting cross cultural adaptation of instruments addressed to measure culinary skills in children and adolescents or those whose instruments were not available (in the article or upon request to the authors) were excluded. For initial screening of abstracts and titles, we used the  Reviews . Two autTwo authors (A.R.T. and D.B.) independently performed data extraction using a preformatted spreadsheet in Microsoft Excel. A third reviewer (T.M.L.) resolved any disagreements or doubts resolved any disagreements or doubts occurred in this step, by comparing the data extraction carried out by the two reviewers. If the third reviewer identified any differences, he would ask the two authors to discuss their interpretations. If the two reviewers did not reach an agreement, the third reviewer would present his opinion. We also consulted the third reviewer in case of any doubts regarding the inclusion of potentially relevant articles identified during this step of the systematic review.The information extracted consisted of descriptive data of the study .et al. [et al. (2007) [We determined the psychometric quality according to the rating system adapted from Hair Jr, Black, Babin et al. ; Pedrosaet al. ; and Ter. (2007) . The criet al., 2011 [et al, 2017 [et al, 2011 [et al, 2018 [et al, 2017 [et al, 2019 [et al, 2019 [et al, 2013 [et al, 2013 [The electronic search (including gray literature databases) identified 1148 potentially relevant studies. After reviewing the titles and abstracts, we selected 16 articles for full-text examination. Of these, nine studies  met theal, 2013 ). We ideal, 2013 ; Condraset al, 2011 [et al, 2013 [et al, 2017 [et al, 2019 [et al, 2019 [et al, 2013 [et al, 2018 [et al, 2011 [et al, 2017 [et al, 2011 [Studies were carried out in the United States of America , Brazilal, 2017 ; Martinsal, 2019 ), Canadaal, 2019 ; Kennedyal, 2019 ), Switzeal, 2013 ), Portugal, 2018 ), Scotlaal, 2011 ) and Noral, 2017 ). All ofal, 2011 ).et al, 2013 [et al, 2017 [et al l, 2019 [et al, 2019 [et al, 2017 [et al, 2018 [et al, 2011 [et al, 2013 [et al, 2011 [et al, 2011 [et al, 2011 [et al, 2019 [et al, 2019 [et al, 2018 [Included papers had distinct purposes: those reporting the development of an original instrument, or cross-cultural adaptation of a tool to explicitly measure cooking/food skills or a part thereof (n = 7) and original tools developed to evaluate a cooking and food skills intervention (n = 5). Most tools assessed cooking skills in adults from a particular country , parental, 2019 ), univeral, 2019 ; Jomori al, 2017 ; Kowalkoal, 2018 ) and adual, 2018 ; Condrasal, 2011 ; Condrasal, 2013 ; Barton al, 2011 ). Study al, 2011 , Condrasal, 2011 ; Martinsal, 2019 ; Kennedyal, 2019 ; Kowalkoal, 2018 ; Michaudal, 2018 ; Warmin,al, 2018 ; Vrhovnial, 2018 ). The paAll studies provided description of the construct, with conceptual framework or clear rationale to define their instruments\u2019 construct.et al, 2011 [et al, 2013 [et al, 2011 [et al., 2017 [Six studies reported the development  or crosl., 2017 ) aiming et al. (2011) [et al. (2013) [et al. (2017) [Michaud (2007) , develop. (2011)  reported. (2013)  then ada. (2017)  describeet al. (2011) [et al., 2011 [et al., 2013 [et al., 2017 [Barton . (2011)  also des. (2011) ; Warmin,. (2011) ; Condrasl., 2011 ; Condrasl., 2013 ; Jomori l., 2017 ).et al., 2013 [et al., 2018 [et al., 2017 [et al., 2019 [et al., 2019 [The remaining studies  describet al., 2013 [et al., 2018 [The Cooking Skills Scale  focusedet al. (2017) [rate how good they are at: Microwave food, including heating ready-meals).Lavelle . (2017)  developeet al.\u2019s cooking scale (2013) [et al.\u2019s cooking confidence measure (2017) [et al., (2019) [Unlike the items shown in Hartmann e (2013)  and Lavee (2017) , the Coo, (2019)  focused et al.\u2019s food skills confidence measure (2017) [et al.\u2019s food skills questionnaire (2019) [et al.\u2019s [rate your confidence in boiling, steaming or stewing) and using basic ingredients and seasoning . Vrhovnik\u2019s Food skills survey tool (2012) [Lavelle e (2017)  consistee (2019)  focused et al.\u2019s  instrumel (2012)  also conet al., 2019 [et al., 2013 [et al., 2013 [et al., 2011 [et al., 2019 [et al., 2019 [et al., 2018 [et al., 2017 [et al., 2011 [et al., 2017 [et al., 2018 [et al., 2011 [et al., 2017 [et al., 2019 [et al., 2019 [et al., 2011 [et al., 2011 [et al., 2018 [et al., 2017 [et al., 2019 [et al., 2019 [et al., 2013 [The studies reported analysis of the psychometric properties of their instruments: Only two studies presented statistical methods derived from the experts\u2019 judgment for content validity . Six oul., 2019 ; Condrasl., 2013 , Hartmanl., 2013 ; Barton l., 2011 ; Kennedyl., 2019 ; Martinsl., 2019 ). Two stl., 2018 , Jomori l., 2017 ). Only ol., 2017 ) reportel., 2017 ; Condrasl., 2011 ; Jomori l., 2017 ; Kowalkol., 2018 ; Barton l., 2011 ; Vrhovnil., 2011 ; Lavellel., 2017 , Kennedyl., 2019 ; Martinsl., 2019 ) and/or l., 2019 ; Warmin,l., 2019 ; Condrasl., 2011 ; Barton l., 2011 ; Kowalkol., 2018 ; Lavellel., 2017 , Kennedyl., 2019 ; Martinsl., 2019 ; Hartmanl., 2013 ). Table We describe the quality of the psychometric properties of the instruments in et al., 2011 [et al., 2018 [et al., 2017 [et al., 2019 [et al., 2017 [et al., 2019 [et al., 2011 [et al., 2013 [et al., 2013 [We considered adequate quality of internal consistency reliability in four studies  Three sl., 2019 ; Jomori l., 2017 ; Kennedyl., 2019 ) showed l., 2011  did not l., 2011  did not l., 2011 ; Condrasl., 2013 ; and Harl., 2013 ) did notet al., 2011 [et al., 2013 [et al., 2018 [et al., 2011 [et al., 2017 [et al., 2019 [et al., 2019 [et al., 2018 [et al., 2019 [Kappa, despite adequate design and method. Five studies showed inadequate time interval . Howevel., 2018 ; Martinsl., 2019 ), since l., 2011 ; Hartmanl., 2013 ) or inadl., 2013 ; Warmin,l., 2013 ; Condrasl., 2011 ; Lavellel., 2017 ); therefet al., 2019 [et al., 2017 [et al., 2011 [et al., 2011 [et al., 2013 [et al., 2019 [et al., 2013 [No studies reporting the development or small changes of an original instrument provided adequate measures to show content validity. The authors did not calculate any index of agreement for content validity , or stal., 2013 ; Kennedyl., 2019 ). Moreovl., 2013 ).Regarding construct validity, six studies reported at least one kind of analysis .et al., 2011 [et al., 2018 [et al., 2017 [et al., 2017 [et al., 2017 [et al., 2017 [Self-Efficacy for Using Basic Cooking Techniques (SECT)). Two studies performed cross-cultural adaptations of original instruments . We clal., 2017 ) and retl., 2017 ). In addl., 2017 ), hence,l., 2017 ). Jomoril., 2017  performel., 2017  and Kowal., 2018 ). One ofl., 2018 ). Six stl., 2018 ; Condrasl., 2013 ; Hartmanl., 2013 ; Barton l., 2011 ; Kennedyl., 2019 ; Martinsl., 2019 ).Most studies did not provide information on criterion validity. Only one study  performTo our knowledge, this is the first systematic review to identify and appraise quality of psychometric properties of instruments for assessing culinary skills in adults. This article has provided a comprehensive critical analysis of the studies\u2019 characteristics and their psychometric properties. We found twelve studies developing original instruments to measure culinary skills in adults, or performing cross-cultural adaptations.This systematic review has highlighted gaps in these instruments, suggesting the need to develop new studies with robust and standardized psychometric methodology that shows validity and reliability of culinary skills measurements. Although we considered adequate quality of internal consistency reliability in four studies, only one study received adequate rating for stability (test-retest reliability). No studies developing original instruments presented satisfactory measurement for content validity since the authors did not calculate any index of agreement. Only four studies showed satisfactory results for at least one type of construct validity  and only one study reported criterion validity, however, we considered inadequate quality of this measurement property. These results indicate that although there are isolated measures appraised in this review that show good promise in terms of quality of psychometric properties, no studies presented satisfactory results for each aspects of reliability and validity.et al., 2019 [Most studies are originally from countries whose native language is English. One Brazilian study  original., 2019 .et al., 2011 [Regarding submission of psychometric studies for ethical approval, one study  justifil., 2011 , 50.et al., 2019 [Most studies reported the development of scales, indexes, and questionnaires. One study classified their instrument as an index ; howevel., 2019 .A scale, on the other hand, measures levels of intensity at the variable level, like to what extent a person agrees or disagrees with a particular statement. A scale is a type of measure composed of several items that have a logical or empirical structure among them. The most commonly used scale is the Likert scale. The sum of scores for each of the statements creates an overall score of the intensity related to the assessed latent phenomenon .et al., 2013 [et al., 2018 [et al., 2019 [The majority of the included studies presented instruments with items assessing cooking self-efficacy (regarding food preparation techniques), meal planning and food selection and purchase. The main difference between the instruments referred to the conceptualization of culinary skills: some authors comprehend that such skills comprise the ability to prepare certain dishes, including those based on pre-prepared products and convenience foods . Howevel., 2019 . Thus, ul., 2019 . Hence, et al. (2017) [et al. (2019) [Some authors identify cooking skills as a distinct construct from food skills. Lavelle . 2017)  define c. (2017)  however,. (2019)  seem to . (2019)  conceptu  define . (2019) .Although all instruments reported some psychometric information, the evaluation of the psychometric quality using the criteria adopted in this systematic review exhibited some missing data.et al., 2011 [et al., 2017 [et al., 2018 [et al., 2011 [et al., 2017 [et al., 2019 [et al., 2019 [Regarding the reliability of the instruments, most studies reported internal consistency reliability . Internl., 2019 .et al., 2019 [et al., 2017 [Cooking Behavior scale . Similar results were observed in Jomori et al.\u2019s (2017) [Cooking Behavior (CB) and Cooking Attitude (CA) scales showed low internal consistency reliability. The later authors argued that problems in the process of cross-cultural adaptations concerning translation of the original instrument into Brazilian Portuguese might have occurred. The items corresponding to these scales might not represent the constructs the authors intended to measure [Three studies showed insufficient results for Cronbach\u2019s alpha . Two ofl., 2017  showed is (2017)  study: T measure . Thus, i measure .et al. (2011) [Barton . (2011)  did not . (2011)  tested oet al., 2011 [et al., 2011 [et al., 2013 [et al., 2017 [et al. (2013) [Kappa values (<0.7) in two studies that reported test-retest reliability. Therefore, we rated inadequate quality of this attribute.We considered indeterminate quality of stability reported in six studies, due to insufficient sample size or inadequate time interval to perform test- retest reliability . Hartma. (2013)  performe. (2013) . Particiet al., 2013 [et al., 2013 [et al., 2011 [et al., 2019 [et al., 2019 [Studies that relied exclusively on internal consistency reliability and stability analysis, without performing other psychometric measurements to validate their instruments, may not provide trustworthy results because these instruments reproduce only a consistent result in time and space from different observer (reliability), without measuring exactly what they propose  , 53. Sixl., 2013 ; Hartmanl., 2013 ; Barton l., 2011 ; Kennedyl., 2019 ; Martinsl., 2019 ). The auAll studies aiming to develop and validate an original instrument failed to show proper content validity: most studies relied on face validity, literature research, and experts\u2019 judgment; however, the authors did not calculate any index to confirm experts\u2019 agreement. Content validity based on the use of statistical methods derived from the experts\u2019 judgment, proves itself to be essential. Otherwise, the mere fact that the experts report on the lack or excess of items representative of the construct, or that they simply determine to what extent each element corresponds to the latent phenomena, does not itself provide relevant information for the validation process , 39, 54.et al., 2011 [et al., 2017 [et al., 2018 [et al., 2017 [et al., 2017 [et al., 2017 [et al., 2018 [We evaluated the quality of construct validity measures of studies reporting structural validity , hypothl., 2017 ; Jomori l., 2017 ) or crosl., 2017 ; Kowalkol., 2018 ). We obsa priori ideas about the latent variables researchers intend to measure [Regarding structural validity, two studies performed principal component analysis and three studies performed exploratory factor analysis. No studies performed Confirmatory Factor Analysis (CFA). According to Gruijters, 2019 , explora measure , 31.et al., 2017 [et al., 2018 [Only two out of five studies reporting structural validity  describl., 2018 .EFA is a \u201clarge-sample\u201d procedure and that generalizable or replicable results are unlikely if the sample is too small.Michaud (2007)  performeet al. (2017) [Self-Efficacy for Using Basic Cooking Techniques (SECT)). This type of validity evaluates the presence of differences in the measurements obtained between the groups, not whether the measure actually measures the intended construct [The cross-cultural adaptation of Michaud\u2019s (2007)  instrume. (2017)  was adeqonstruct , hence, Vrhovnik (2012) did not provide statistical results for items factor loadings, which may imply inadequate decisions regarding retention or exclusion of an item .et al.\u2019s study (2017) [Buying in Season; Using leftovers to create another meal; Keeping Basics in the cupboard and Reading the best before date), however they were retained in the \u2018Food Skills\u2019 factor. When a variable is found to have more than one significant loading, it is hard to make those factors be distinct and represent separate concepts [a priori factor structure could be flawed [Microwave food (not drinks/liquid) including heating ready-meals\u2019. The Brazilian Food Guide (2014) states that although microwaving may be used in meal preparation  it is not seen as a cooking skill.Despite satisfactory results for convergent validity in Lavelle y (2017) , the expconcepts . If an ie flawed . Moreoveet al., 2018 [et al.\u2019s cooking skills instrument (2013) [Kowalkowska l., 2018  performet (2013) . Howevert (2013)  recommenRegarding criterion validity, little information was available in the included studies. Only one study  presented criterion validity . However, we considered inadequate quality of this attribute. These findings were expected since most of the time, the criterion validity is a challenge for the researcher, because it demands a \u201cgold standard\u201d measure to be compared with the chosen instrument, which cannot be easily found in all knowledge areas , 59.This review has some limitations. It is possible that some studies were missed out because they were not indexed in the databases searched, or were published for institutions, foundations, or societies. In addition, although the criteria were adapted from previous studies, the difficulty of interpreting the studies may have under- or overestimated the quality of the instruments\u2019 psychometric properties.This review identified many studies surveying culinary skills; we considered most instruments insufficient, according to the quality of their psychometric properties. Thus, the flaws observed in these studies show that there is a need for ongoing research in the area of the psychometric properties of instruments assessing culinary skills. Moreover, our findings contribute to supporting the selection of valid and reliable instruments by healthcare professionals in clinical and Public Health settings.Measuring culinary skills involves several separate but related domains, which integrate other constructs related to the culinary practices. Therefore, it is recommended that a more consistent and consensual definition of culinary skills as a construct be generated. Instruments should cover items and domains without overestimating one\u2019s skills, based on his/hers ability of heating convenience food. Considering items measuring culinary skills related to the use of using basic ingredients and seasoning proves itself essential for greater understanding of barriers and facilitators related to healthy culinary practices.S1 Appendixhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019130836.From: Aline Rissatto Teixeira, Daniela Bicalho, Tacio de Mendon\u00e7a Lima. Evidence for the validation quality of culinary skills instruments: a systematic review. PROSPERO 2019 CRD42019130836. Available from: (PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S1 Table10.1371/journal.pmed1000097.From: Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file."}
+{"text": "The importance of prenatal maternal somatic diseases for offspring mood and anxiety disorders may be overlooked or undervalued. We conducted the first systematic review and meta-analysis assessing the risk of offspring mood and anxiety disorders in the context of prenatal maternal somatic diseases.We screened articles indexed in Embase , PsycARTICLES and PsycINFO databases up to August 2021. 21 studies were included. We examined the overall associations between prenatal maternal somatic diseases and offspring mood/anxiety disorders. Analyses were stratified according to maternal somatic diseases and follow-up duration.We observed an increased risk of mood and anxiety disorders in the context of prenatal maternal somatic diseases ; maternal obesity, hypertensive disorders  and infertility  were risk factors for mood disorders; maternal polycystic ovary syndrome , severe obesity  and moderate obesity  were risk factors for anxiety disorders. Prenatal maternal somatic diseases increased the risk of mood disorders in childhood and adulthood , as well as the risk of anxiety disorders in adulthood .The results indicate that prenatal maternal somatic diseases are associated with offspring mood and anxiety disorders, and that the associations may be long-lasting. Mood disorders (bipolar and depressive disorders) and anxiety disorders  are complex mental disorders resulting from multiple factors such as genetic predisposition, parenting style, family environment, socioeconomic status. Fetal origins of mental disorders have been attracting increasing attention. Awareness of prenatal risk factors is crucial for prevention strategies.et al., et al., et al., et al., et al., et al., Prenatal maternal health plays an important role in the subsequent mental health of offspring  , PsycARTICLES (via EBSCO) and PsycINFO (via EBSCO). The search strategy consisted of relevant Medical Subject Heading (MeSH) terms, Emtree term-exploded, keywords and word variants. The detailed search strategies for each database were fully described in online Supplementary Table S1. In addition, we searched the reference lists of all included studies, related reviews for further potential studies.in utero , (2) control group(s): had a comparison group(s) without the exposure(s), (3) outcomes: included mood or anxiety disorders diagnosed according to any recognised diagnostic criteria or self-report , (4) statistical indicators were provided to examine the effect of prenatal maternal somatic diseases on mood or anxiety disorders in offspring, (5) study design: cohort studies, including population-based cohort studies and registry-based studies.Articles were eligible if they met the following criteria: (1) exposures: offspring were exposed to maternal somatic diseases Articles were excluded if they met the following criteria: (1) exposed group was mixed with maternal somatic diseases diagnosed postpartum; (2) reviews, meta-analyses, abstracts or conference proceedings.When there were multiple groups of useful data in one article, only the data derived from the group with the largest sample size or the most severe exposure  were selected for the meta-analysis. In addition, we did not delete articles that presented overlapping samples as they included different maternal somatic diseases or outcomes, but only the data from the largest sample size was used in the meta-analysis.After removing duplications, titles and abstracts were reviewed independently by two researchers for initial screening, and then full text. Any disagreement was resolved through group discussions. Endnote was used as the bibliographic software.Two researchers independently extracted data. Any disagreement was resolved through group discussions. The following data were extracted: author, year of publication, the country where the study was conducted, sample and source, exposure and measure, outcome and measure, adjusted confounders, and measure of association. All included articles were assessed in terms of methodological quality according to the Newcastle\u2013Ottawa Quality Assessment Scale (NOS) for cohort studies. NOS consists of eight items across three domains: selection , comparability  and outcome . Studies were graded as good quality (7\u20139 stars), fair (4\u20136 stars) and poor (0\u20134 stars).Q test and I2 statistics were used to evaluate the heterogeneity. A fixed-effects model was adopted when I2\u00a0<\u00a050%, otherwise, a random-effects model was used. Funnel plot, trim and fill method and Egger test were used to detect potential publication bias. To assess the stability of the meta-analysis, sensitivity analysis was performed. Sensitivity analysis was performed by excluding studies one by one to explore the impact of each study on the overall results. Furthermore, analyses were stratified according to maternal somatic diseases and follow-up duration (or offspring's age at diagnosis). Quantitative meta-analysis was conducted for an outcome when more than one study presented relevant data. The reason why we adopted stratified analysis rather than traditional subgroup analysis was that the former can make better use of the data in our study. Analyses were performed with Stata 16.0.The method was based on the relative risk (RR) with 95% confidence intervals (CIs) obtained in each study. If the RR was not reported, the hazard ratio (HR)/odds ratio (OR) is considered to be approximately equal to RR. RRs fully adjusted were preferentially pooled in our analyses. Cochrane et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In total, 21 articles were eligible for inclusion   .Fig. 2.Analyses were stratified according to maternal somatic diseases. Pooled effect of two studies showed that maternal obesity was significantly associated with offspring mood disorders  . In the et al., et al., et al., et al., et al., et al., et al., In the stratified analyses, we did not perform meta-analyses for maternal PCOS, cancer, asthma, diabetes, thyroid diseases and rheumatoid arthritis due to the limited number of eligible studies. These studies reported that prenatal exposure to maternal PCOS , including childhood (aged\u00a0<\u00a018 years) and adulthood (aged\u00a0\u2a7e\u00a018 years). In the meta-analysis of five studies, prenatal maternal somatic diseases were associated with the increased risk for mood disorders in childhood  . The metet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., I2\u00a0=\u00a033%, p\u00a0>\u00a00.05)  .Analyses were stratified according to maternal somatic diseases. Pooled effect of two studies showed that the risk of offspring anxiety disorders significantly increased in the context of maternal PCOS  . In the et al., et al., In the stratified analyses, we did not perform a meta-analysis for maternal infertility and hyperemesis gravidarum due to the limited number of eligible studies. One study reported a significant association between maternal infertility and anxiety disorders of offspring . In the meta-analysis of five studies, prenatal maternal somatic diseases were not associated with offspring anxiety disorders in childhood  . The metp\u00a0>\u00a00.05), the asymmetric funnel plot suggested the possibility of publication bias . The \u2018trim and fill\u2019 method was then used to recalculate the pooled results. The adjusted pooled effect of mood disorders exhibited a similar trend with two potential studies filled  . The result for anxiety disorders was not altered with two potential studies filled   .Fig. 4.Sensitivity analysis did not significantly alter these findings, indicating that our results were relatively stable .To our knowledge, this is the first systematic review and meta-analysis assessing the risk of offspring mood and anxiety disorders in the context of prenatal maternal somatic diseases. The overall meta-analyses confirmed that prenatal maternal somatic diseases were associated with an increased risk of mood and anxiety disorders in offspring. For mood disorders, we identified that maternal obesity, hypertensive disorders, and infertility were risk factors. For anxiety disorders, risk factors were maternal PCOS and obesity. Furthermore, our study emphasised the impact of prenatal maternal somatic diseases on mood and anxiety disorders may be long-lasting.et al., et al., The overarching finding of the meta-analysis showed that prenatal maternal somatic diseases were related to offspring mood/anxiety disorders. Mood and anxiety disorders are complex mental disorders, the RRs generally <2 indicated that they each modulated risk by a relatively small. Prenatal exposure to both maternal somatic diseases and psychiatric factors implicates an adverse intrauterine environment, but they might point toward differing underlying mechanisms of an increased risk of mood/anxiety disorders. Although most of the included studies (16 of 21) adjusted maternal psychiatric disorders or distress, the effect of maternal psychosocial factors cannot be excluded, as a relationship has been reported early between somatic diseases and mental health  were associated with an increased risk of mood disorders in offspring, but the association with anxiety disorders was not statistically significant. Although a previous meta-analysis found that preeclampsia was associated with an elevated risk of offspring schizophrenia, the association with other psychiatric disorders was inconclusive  was significantly stronger than those postnatally diagnosed  in one of our included studies (Momen In the context of maternal somatic diseases, the risk of mood disorders was increased in both childhood and adulthood, as was the risk of anxiety disorders in adulthood. The findings suggested that the effects of prenatal maternal somatic diseases were long-lasting and even persist into old age. However, the results should be interpreted with caution because the two ages were not evaluated in the same study.There are some limitations as well. First, although a total of 21 studies were included, the majority of the studies were from northern European populations, and there was a lack of data from Asian populations. Second, when it came to specific exposures, the number of studies was small, and for some exposures, there were not enough studies to allow quantitative analysis. Third, a pooled risk consistently adjusted for the same variables could not be reached because different variables are adjusted in each study. Forth, different diagnostic criteria and follow-up periods were adopted for the same outcome, which may be the reason for the significant heterogeneity of some results. Fifth, in the context of maternal somatic disease, the effects of the disease itself and treatment measures are included, yet we cannot distinguish their effects in the associations. Sixth, it may be difficult to diagnose children, though mood and anxiety disorders occur at any time throughout the lifespan. And both mood and anxiety disorders may not be diagnosed for a long time after the onset. Therefore, the real risk may be underestimated.In conclusion, the results of our study indicate that prenatal maternal somatic diseases can be associated with offspring mood and anxiety disorders, and that the associations may be long-lasting. These findings advance the understanding of the prenatal origins of risk for mood and anxiety disorders. More high-quality prospective studies are needed to resolve the limitations mentioned above."}
+{"text": "The ancient membrane protein TSPO is phylogenetically widespread from archaea and bacteria to insects, vertebrates, plants, and fungi. TSPO\u2019s primary amino acid sequence is only modestly conserved between diverse species, although its five transmembrane helical structure appears mainly conserved. Its cellular location and orientation in membranes have been reported to vary between species and tissues, with implications for potential diverse binding partners and function. Most TSPO functions relate to stress-induced changes in metabolism, but in many cases it is unclear how TSPO itself functions\u2014whether as a receptor, a sensor, a transporter, or a translocator. Much evidence suggests that TSPO acts indirectly by association with various protein binding partners or with endogenous or exogenous ligands. In this review, we focus on proteins that have most commonly been invoked as TSPO binding partners. We suggest that TSPO was originally a bacterial receptor/stress sensor associated with porphyrin binding as its most ancestral function and that it later developed additional stress-related roles in eukaryotes as its ability to bind new partners evolved. E. coli and Saccharomyces cerevisiae  was found to be a monomer   was conclusively shown to be located in the ER/Golgi by fluorescent tagging of N-terminal 6-histidine-tagged AtTSPO  in organisms of all kingdoms, questions that may only be answered by identifying specifically associated proteins.On the surface this ancient protein appears to have very different functions in different organisms, yet most of these functions relate to stress-induced changes in metabolism.2+ signaling  may alter TSPO\u2019s binding to its partners, thereby affecting its role in various metabolic processes.It has been suggested that TSPO was originally a bacterial receptor/stress sensor that developed additional roles in eukaryotes  (Gatliff and Campanella Perhaps the most widely researched interaction of TSPO is that with the voltage-dependent anion channel (VDAC), a channel in the mammalian OMM that controls a wide range of processes involving transport of molecules into and out of mitochondria . This finding led the authors to suggest that TSPO could be directly or indirectly involved in regulation of the UPR (Rolland et al. Another potential TSPO interacting partner was proposed by Jurkiewicz et al. : the NACPseudomonas strains suggested several proteins for further study (Leneveu-Jenvrin et al. Pseudomonas homolog of VDAC, was predicted to functionally interact with TSPO (Leneveu-Jenvrin et al. RsTSPO and Sinorhizobium meliloti TSPO (Leneveu-Jenvrin et al. RsTSPO; the Kat B catalase, also predicted to interact with S. meliloti TSPO; hemolysin II/III, virulence factors that remove iron from heme; the adenine phosphoribosyltransferase Apt; a putative nucleoside-diphosphate-sugar epimerase Pfl01_0720 and the UDP-N-acetylmuramate-alanine ligase MurC, both involved in cell wall synthesis; orthologs of the thiol oxidoreductase PSPTO4367, involved in oxidative stress protection; and finally a putative hybrid histidine kinase Pfl01_2810, the interaction with which was suggested to be specific to P. fluorescens Pf0-1 (Leneveu-Jenvrin et al. RsTSPO (Li et al. A STRING database search for functionally-interacting partners for TSPO from RsTSPO (Yeliseev et al. AtTSPO (Jurkiewicz et al. Amid its many proposed binding partners and functions, can an ancestral function and partner for TSPO be discerned? It seems reasonable to conclude that some part of TSPO function, along with aspects of its structure, must be conserved throughout evolution, as mammalian TSPO has been shown to functionally substitute for the bacterial F. diplosiphon (Busch et al. Drosophila had reduced mitochondrial respiration and increased mitochondrial oxidative stress (Lin et al. The most widely observed function in all organisms is the binding of porphyrins, with affinities ranging from low micromolar in bacteria (e.g., 5\u00a0\u00b5M in the cyanobacterium In higher plants, the role of porphyrins and oxidative stress are strongly connected (Frank et al. R. sphaeroides (Yeliseev and Kaplan The handing of porphyrins to porin for export in bacteria, similar to what has been suggested for TSPO is an ancient protein whose varied and complex functions appear to be dictated by its location and its orientation in the membrane, as well as its binding partners. In many aspects of its behavior TSPO resembles a receptor or sensor; indeed, it shows some structural similarity to GPCRs (Li et al."}
+{"text": "Mining genetic variation including structural variation from mammalian genomes is a crucial step towards investigating the relationship between genotype and phenotype. However, compared to the detection of single nucleotide variants and small indels, characterizing large and particularly complex structural variation is much more difficult and less intuitive . In the et\u00a0al. presented high-quality draft genomes of the grey wolf (Canis lupus) and dhole , and then identified a large number of dog-specific structural variants [In the paper, Wang variants . Functio"}
+{"text": "Among the multiple reasons why plasticity rules in vivo might differ significantly from in vitro studies is that extracellular calcium concentration use in most studies is higher than concentrations estimated in vivo. STDP, like many forms of long-term synaptic plasticity, strongly depends on intracellular calcium influx for its induction. Here, we discuss the importance of considering physiological levels of extracellular calcium concentration to study functional plasticity.Since its discovery, spike timing-dependent synaptic plasticity (STDP) has been thought to be a primary mechanism underlying the brain\u2019s ability to learn and to form new memories. However, despite the enormous interest in both the experimental and theoretical neuroscience communities in activity-dependent plasticity, it is still unclear whether plasticity rules inferred from  Spike timing-dependent plasticity (STDP) is a form of long-term synaptic modification thought to constitute a mechanism underlying formation of new memories. The polarity of synaptic modifications is controlled by the relative timing between pre- and post-synaptic action potentials , commonly between 2 and 3 mM  and [Ca2+]e (S\u00fcdhof, 2+]e is associated with decreased synaptic transmission (Borst and Sakmann, 2+]e and is not triggered by Ca2+ entry via VDCC (Scanziani et al., Neocortical STDP relies heavily on presynaptic glutamate release and presynaptic firing rate (Markram et al.,  S\u00fcdhof, . Reducedin vitro under physiological conditions will allow a more robust application in vivo.All studies use different protocols . The numin vitro studies, and by definition, in vivo studies are inherently in a physiological calcium concentration. First demonstration of STDP in vivo was performed in the retinotectal pathway of Xenopus (Zhang et al., in vitro studies are performed in juvenile rodent while in vivo studies are performed in older animals. This may constitute an additional limitation to the transposition of the results observed in vitro. Several studies suggest that the capacity to induce t-LTD decreases with age (Banerjee et al., in vivo are obtained in the anesthetized animal. Although there are variations in extracellular calcium concentration of about 0.2 mM between awake and anesthetized animals (Ding et al., In opposition to As demonstrated by Inglebert et al. fine tuning of pre- and postsynaptic activity can restore t-LTD and t-LTP in physiological extracellular calcium condition. But would it be possible to restore classic plasticity rules under regular patterns of activity? The key component could be neuromodulation. Interestingly, replay of activity from place-cells with overlapping firing field in hippocampal slices induced t-LTP only in the presence of Carbachol, a cholinergic agonist (Isaac et al., The use of physiological external calcium concentration not only modulates the learning rules for long-term synaptic plasticity but it also enhances context-dependent synaptic plasticity. Analog-digital modulation of action potential-evoked synaptic transmission lies on modification of spike shape, by either broadening the axonal spike (Shu et al., H or IA (Daoudal and Debanne, Hebbian plasticity and Intrinsic plasticity are closely linked and are synergistically modified (Debanne et al., YI and DD wrote the article and YI built the figures. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Dear Editor,Rosmarinus officinalis) extracts have been extensively studied for their ability to ameliorate traits of metabolic dyshomeostasis . Carnosal., 2015). Carnosal., 2015; Lee et al., 2015; Lipina al., 2015; Naimi eal., 2015; Ou et aal., 2015, 2018[13al., 2015; Park anal., 2015; Song etal., 2015; Tsai etal., 2015; Wang etal., 2015, 2019[24al., 2015; Xie et al., 2015, 2018[29al., 2015), antiobal., 2015), and neal., 2015) propertal., 2015).Rosemary or rosemary-derived preparations have been demonstrated to modulate glycemic parameters in human subjects. Consumption of rosemary tea for 90 days has been reported to reduce glycated hemoglobin levels in addition to alleviating insulin resistance in type 2 diabetes subjects . ReductAuthors are thankful to Jain (Deemed to be University), Bangalore for the support.None."}
+{"text": "Micronutrient deficiencies are known to affect more than two billion people globally . The magn = 32) of the studies in this systemic review measured child health outcomes in early infancy while the remainder measured outcomes in children whose ages ranged from 24 h after birth until school age. Quezada-Pinedo et al. concluded that there was a need for more high-quality studies examining the long-term effects of maternal iron status during pregnancy on child health outcomes.Several articles in this issue focus on anaemia and iron deficiency. In a systematic review including 44 studies published from 1975 to January 2021, Quezada-Pinedo et al. [In a narrative review including 14 articles published in the 10 years up until 2021, Wawer et al.  reportedThe World Health Organization recommends iron and folic acid (IFA) supplementation for all pregnant women to prevent anaemia and adverse foetal outcomes . In a stThe original research by Ahmed et al.  found a n = 71,728), Sol\u00e9-Navais et al. [n = 2628), the authors failed to observe any association between whole blood selenium concentration and birth weight or SGA. Sol\u00e9-Navais et al. pointed out that this lack of association could be due to the homogenous group of subsamples with fairly good selenium status. The authors concluded that, while a maternal diet rich in selenium during pregnancy may be beneficial for foetal growth, further interventional studies were needed to confirm the causal relationship.Using data from a large Norwegian pregnancy cohort  published prior to October 2020, Zgliczynska and Kosinska-Kaczynska [In another review including 85 studies published between 1981 and 2020, Jouanne et al.  reportedThe collection of articles in this issue brings together the latest research on a broad range of topics on micronutrients and pregnancy, including the prevalence of various micronutrient deficiencies and their risk factors, as well as highlights the potential benefits of adequate micronutrient and/or risk of deficiencies on children\u2019s birth outcomes. I am sure that the findings of these studies will contribute to enhancing our current knowledge of the importance of micronutrients during pregnancy and will encourage readers to conduct further studies in this important area of research."}
+{"text": "Clostridium clariflavum for utilization in biofuel industry\u2019 by Asma Zafar et al., RSC Adv., 2021, 11, 9246\u20139261, DOI: 10.1039/D1RA00545F.Correction for \u2018Efficient biomass saccharification using a novel cellobiohydrolase from  The authors regret that in the original article, the name and affiliation for one of the co-authors (Hasan Ufak Celebioglu) were incorrectly given. The correct name and affiliation are shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Retirement is a major life transition that may improve or worsen mental health, including depression. Existing studies provide contradictory results. We conducted a systematic review with meta-analysis to quantitatively pool available evidence on the association of retirement and depressive symptoms.v. cross-sectional studies), study quality score (QS) and considering studies using validated scales to diagnose depression. Heterogeneity between studies was evaluated with I2 statistics.We applied PRISMA guidelines to conduct a systematic review and meta-analysis to retrieve, quantitatively pool and critically evaluate the association between retirement and both incident and prevalent depression and to understand better the potential role of individual and contextual-level determinants. Relevant original studies were identified by searching PubMed, Embase, PsycINFO and the Cochrane Library, through 4 March 2021. Subgroup and sensitivity meta-analyses were conducted by gender, study design  from 60 datasets suggested a protective effect of retirement on the risk of depression , although with high statistical heterogeneity between risk estimates . Funnel plot asymmetry and trim and fill method suggested a minor potential publication bias. Results were consistent, confirm their robustness and suggest stronger protective effects when progressively restricting the included studies based on quality criteria: (i) studies with the highest QS , (ii) studies with a high QS and using validated assessment tools to diagnose depression  and (iii) studies of high quality, using a validated tool and with a longitudinal design . We observed a progressive reduction in funnel plot asymmetry. About gender, no statistically significant difference was found .Forty-one original studies met our a priori defined inclusion criteria. Meta-analysis on more than half a million subjects (Pooled data suggested that retirement reduces by nearly 20% the risk of depression; such estimates got stronger when limiting the analysis to longitudinal and high-quality studies, even if results are affected by high heterogeneity.As retirement seems to have an independent and protective effect on mental health and depressive symptoms, greater flexibility in retirement timing should be granted to older workers to reduce their mental burden and avoid the development of severe depression. Retirement may also be identified as a target moment for preventive interventions, particularly primary and secondary prevention, to promote health and wellbeing in older ages, boosting the observed impact. Briefly, we used a combination of free text and exploded MeSH headings, identifying: (i) the concept of \u2018retirement/transition to retirement\u2019 and (ii) \u2018depression/depressive symptoms\u2019. Further studies were retrieved from manual reference listing of relevant articles and consultation with experts in the field. Details on inclusion and exclusion criteria are reported in ad-hoc developed data extraction spreadsheet. The data extraction spreadsheet was piloted on ten randomly selected papers and modified accordingly. Data extraction included: full reference details, country of study conduction, study design, study setting, study population details, sample size, exposure details, outcomes of interest, including validated assessment tools for depression, and quantitative results, including ESs and corresponding confidence intervals (CIs). Corresponding authors were contacted by e-mail in case of incomplete data. Quality appraisal of included studies was carried out applying the 14-item scoring system developed by Shim et al. for population-based studies on retirement as a risk factor  in a two-step process; a first screening was performed based on title and abstract. Then, full texts were retrieved for a second screening. At both stages, disagreements among reviewers were resolved by consensus and by consulting a third senior author (A.O.) when disagreement persisted. Data were independently extracted by two authors (V.G. and G.P.V.), supervised by a third author (A.O.), using an et al., s.e.s), we mathematically converted them into ORs with corresponding CIs  and visual inspection of funnel plots. We performed sensitivity analyses progressively limiting meta-analysis to: (i) high-quality studies; (ii) high-quality studies using validated scales to diagnose depression; (iii) high-quality longitudinal studies using validated scales to diagnose depression. Moreover, we conducted a subgroup meta-analysis by gender strata and study design.We performed descriptive analysis to report and pool the characteristics of included studies using ranges and average values. With regard to the pre-specified outcomes of interest, we would expect variability between studies, e.g. by study design and population. We, therefore, applied random-effects meta-analyses to acquire estimates of the association between retiring and risk of depression/depressive symptoms, rather than to assume a single true value in a fixed-effects approach  software.We assessed publication bias with funnel plot visual inspection  published in the last 5 years. The majority of the studies  were conducted in Europe  and in the USA . Four studies were conducted in Asia, one in Brazil, one in Australia; four were multi-centre studies conducted at the global and European level.We identified 2470 studies by searching the selected databases and listing references of relevant articles. After removing duplicates, 1619 records were retrieved. Papers were screened and selected, as illustrated in n\u00a0=\u00a012, 60.0%) having less than 10 years of follow-up. Most of the longitudinal analyses were derived from the Survey on Health and Ageing and Retirement in Europe , followed by the Health and Retirement Study  and the Gaz et Electricit\u00e9 cohort study . Twenty-one studies (51.2%) had a cross-sectional study design, while only one study reported both cross-sectional and longitudinal data . One study included only males  studies were longitudinal studies; their follow-up time ranged from 2 to 25 years, with most of them  and Question 13 [Was the loss to follow-up appropriately addressed and/or adequately described in the study?] (n\u00a0=\u00a011) reported the lowest scores .More than ninety per cent of included studies used validated tools to diagnose depression-related outcomes, including the Center for Epidemiologic Studies Depression scale (CES-D) in 17 studies (41.5%), the Euro Depression-scale (EURO-D) in eight studies (19.5%), the Geriatric Depression Scale (GDS) in three studies (7.1%) and the Zung Self-rating Depression Scale (ZSDS) in two studies (4.9%). The International Classification of Diseases-10 (ICD-10) was used to identify depression-related conditions in three studies (7.1%). The Patient Health Questionnaire-8 (PHQ-8), the Hospital Anxiety and Depression Scale (HADS), the Composite International Diagnostic Interview (CIDI), the Depression Adjective Check List (DACL) and the Clinical Interview Schedule-Revised (CIS-R) were used in only one study each . Three sn\u00a0=\u00a015, 36.6%) of included studies reported a statistically significant negative association between retirement and depression (i.e. retirement decreased the risk of depression)  reported a positive association  did not report statistically significant associations between retirement and depression  (n\u00a0=\u00a019), ORs (n\u00a0=\u00a011), \u03c72 (n\u00a0=\u00a03), relative risks (RRs) (n\u00a0=\u00a01), hazard ratios (HRs) (n\u00a0=\u00a01) and mean differences (n\u00a0=\u00a02). Almost all included studies reported adjusted effect estimates . The funnel plot resulted slightly asymmetrical at visual inspection, showing a low potential for publication bias, not confirmed by Egger's linear regression test . Moreover, the ES change after the trim and fill method was minor [0.84 (95% CI\u00a0=\u00a00.75\u20130.94)], and two studies were trimmed in the lower right quarter of the funnel plot . Then, we limited the analysis to studies with high QS and using validated assessment tools to diagnose depression. In this analysis, 44 datasets were included, for a total of 239\u00a0453 subjects, strengthening the significant association between retirement and decreased risk of depression . Finally, only studies (i) with a QS equal or higher than 15, (ii) using validated assessment tools to diagnose depression and (iii) with a longitudinal study design were included. We report a statistically significant association between retirement and depression , with high statistical heterogeneity , but no publication bias, as confirmed by funnel visual inspection and Egger's test , a statistically significant association between retirement and depression was equally found  and high heterogeneity  and high heterogeneity between studies (Gender-strata meta-analyses are reported in online Supplementary Fig. 2b and 2c. When only considering women, the analysis included 21 datasets and a total of 219\u00a0655 subjects, reporting no statistically significant association between retirement and depression (pooled ES\u00a0=\u00a00.79, 95% CI\u00a0=\u00a00.61\u20131.02, ogeneity . About m studies . In bothPooled data from 41 original studies and more than half a million subjects suggested that retirement or transition to retirement reduce by nearly 20% the risk of depression or depressive symptoms; such estimates remain consistent when limiting the analysis to longitudinal and high-quality studies.et al., Before interpreting our findings further, we must account for the considerable heterogeneity among the included studies, which might limit the generalisability of pooled effect estimates. To overcome this and test the results level of strength, we first applied a random-effect model. Secondly, we conducted sensitivity and stratified meta-analyses by study design and QS. The reasons behind the high level of heterogeneity among the included studies are to be explored in light of, on one side, the wide variety of studies\u2019 designs, settings and populations, definitions and methodological quality and, on the other side, of the complex, multi-determinant and multi-mediator relationship between the process of retirement and mental health and wellbeing (Pesaran et al., Despite half of the retrieved studies being cross-sectional, which did not allow us to explore causality, they accounted for less than one-third of included subjects. Another limitation to consider is that duration of retirement was not reported in most studies, so we could not differentiate among the potential risk of depression for short- or long-term exposure to retirement. A subgroup analysis considering the work before retiring was not possible since only two included studies stratified results for this variable (Belloni To the best of our knowledge, this is the first systematic review and meta-analysis pooling all original studies investigating the association of retirement with prevalent and incident depression. We used a comprehensive range of databases and search terms to maximise the number of studies retrieved and minimise the chance of publication bias. Besides, further studies were retrieved from the reference listing of relevant articles. Such a comprehensive and rigorous summary of the available evidence offers several meaningful insights, valuable to plan, implement and evaluate public health and preventive strategies, public policies, as well as future avenues of research.Despite the well-known assumption that considers retirement as a potentially stressful life event Kremer, , one of Characteristics of the transition refer to the type and conditions of retirement, which were available in 76% of included studies. For instance, we report different impacts on depression between voluntary and involuntary retirement, with the more considerable impact of the latter (Mosca and Barrett, et al., et al., et al., et al., et al., There is extensive literature on how employment characteristics influence health after retirement (Hernberg, et al., et al., et al., With reference to resources, access to social and financial resources around retirement might compensate and mitigate the impact of lifestyle changes and the psychological consequences of retiring. We reviewed data where the risk of depression at retirement is differentially distributed by household socioeconomic status (Arias-De La Torre Concerning individual appraisal, personality characteristics influence the meaning assigned to retirement and the ability to cope with this change. Negative expectations and fears about retirement are more likely related to adverse repercussions on individuals\u2019 wellbeing (Barnes-Farrell, Regarding gender, differences in primary role between women and men, at home and work, respectively, could explain differences in adapting to the event and in health outcomes by gender Moen, , but neeet al. (et al. (et al. (Overall and sensitivity analyses results are consistent with other reviews on the topic. Van Der Heide et al.  focused  (et al.  analysed (et al. ; they suet al., et al., et al., et al., et al., et al., et al., Regarding public health and preventive strategies, we demonstrated that, besides other factors influencing the risk of late-life depression, transition to retirement, as a life event that almost the entire population experience at some point (Clark and Oswald, et al., et al., et al., et al., About public policies, our data complement the accumulating evidence on the impact of pension reforms on health and mental health (Eibich, et al., et al., Concerning research, it clearly emerges from our analysis that, in order to reduce heterogeneity and accumulate solid evidence, shared methodological standards and definitions should be followed in the future. More extended longitudinal studies should be preferred so as to reduce inverse causality issues and might help disentangle and quantify the different components that mediate the effects of retirement on the risk of depression and its determinants and monitor such association's temporal evolution. It would also be necessary to further differentiate between contextual and individual characteristics to adapt coping strategies at the public health and clinical levels. Special attention should be paid to health inequalities to investigate better socioeconomic status indicators role in the relationship between retirement and health (Adler As a matter of fact, despite current trends in extending working lives, life expectancy after regular retirement is projected to grow faster than increases in the pension age, reaching 20.3 years for men and 24.6 years for women in 2050 OECD, . Therefo"}
+{"text": "This review outlines how CRISPR/Cas9 has transformed T cell research allowing immunologists to rapidly probe the roles of genes in T cells thus paving the way for novel therapeutics. Furthermore, this review describes how these tools reduce the requirement for genetic mouse models, while increasing the translational potential of T cell research.Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 allows for precise gene targeting in mammalian cells, including T cells, allowing scientists to disrupt or edit specific genes of interest. This has enabled immunologists to investigate T cell functions as well as opened the path for novel therapeutics involving gene editing of T cells  By enabling easy, swift, and precise manipulation of the genetic code, scientists can probe the roles of novel genes with an unprecedented speed and precision. The Nobel prize awarded to Jennifer Doudna and Emmanuelle Charpentier in 2020 for their discoveries of CRISPR/Cas9 celebrates the beginning of a biological revolution. CRISPR was discovered in bacteria as a defense mechanism used to disrupt invading foreign DNA from invading bacterial viruses (i.e. bacteriophages) by guiding a DNA cleaving nuclease to the foreign genomic DNA  composed of a trans-activating CRISPR RNA (tracrRNA), which facilitates binding of the Cas9 enzyme, and a CRISPR RNA (crRNA), which engages the target DNA and the tracrRNA bound in the Cas9 enzyme, thus guiding the enzyme specifically to its target site. The gRNA-bound Cas9 enzyme binds gRNA-complementary genomic DNA sequences upstream of protospacer adjacent motifs (PAM)  with high specificity and efficacy  . These et al., et al., in vivo after Cas9-mediated editing. To overcome this challenge, scientists could combine Cas9-modified human T cells with organoid systems, where organized three-dimensional tissue cultures are grown in culture , and are limited to studying certain tissue types. Cas9-edited human T cells can also be studied in vivo in so-called humanized mice, which are immunodeficient mice that are reconstituted with human immune cells. These have shown some potential in increasing translational potential of therapies from preclinical models (Tao and Reese, et al., in vivo setting. Unfortunately, these models are not trivial to set up and are generally not broadly available to the research community (et al., CRISPR/Cas9 has already aided in discovery of multiple gene programs critical for human T cell activation, proliferation, and signaling (Shifrut ommunity  (Allen e et al., . NonetheIn summary, these described model systems have the advantage of being high throughput compared with conventional genetically modified mouse models. Furthermore, as Cas9-edited human T cells are somewhat easier to generate, it is now possible to conduct studies in a model with greater translational potential, while accommodating the principles of the 3Rs. These benefits of using CRISPR/Cas9 in T cell research are also applicable to many other cell types. Although it is still a challenge to effectively implement these tools with many other primary human cell types, future innovation will likely enable this.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., CRISPR/Cas9 has further allowed for generation of genetically modified T cells that can be used in patients for therapies. CRISPR/Cas9 has been adapted for generating efficacious CAR-T cells for therapy, which have an artificially introduced antigen receptor (Eyquem CRISPR/Cas9 has changed the way scientists conduct research in multiple fields, including the field of immunology. In T cell research CRISPR/Cas9 mutagenesis has already been used for multiple important discoveries, and has paved the way for novel, faster, and more translational techniques that in coming years have the potential to disrupt the way T cell studies are performed. Future developments will likely further enable CRISPR/Cas9-mediated development of highly efficacious T cells for cancer therapies, including CAR-T cells and adoptive T cell transfer."}
+{"text": "Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020\u2019 by Percivalle et al., published on 18 June 2020, incorrect protocol numbers were mistakenly quoted in the Ethical statement. The text was corrected on 20 January 2022 at the request of the authors. In the article \u2018"}
+{"text": "More than 85% of pre-clinically tested drugs fail during clinical trials, which results in a long, inefficient and costly process, suggesting that animal models are often poor predictors of human biology . The abiThe research topic of this issue is aimed at providing further context to the use of iPSC-derived cells  as disease models (\u201cdisease in a dish\u201d models) for screening leads for drugs.In this context, Trudler et al. , Lu QianWang et al.  describeAccording to Vokner et al.\u2019s  review, Interestingly, iPSC-based models can also serve for screening potential drugs against complex diseases such as Parkinson\u2019s disease , AlzheimThe model of iPSC-derived cardiomyocytes with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), studied by Knottnerus et al. , impliesiPSC-derived cardiomyocytes also serve as attractive models for dilated cardiomyopathy, such as propionic acidemia (PA), caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme  and in CUrea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. Zabulica et al.  demonstrTo study the rare disease riboflavin transporter deficiency (RTD), Marioli et al.  used iPSAmong the applicative future goals in studying iPSCs is the potential to generate patient specific organs such as liver, hearth patch, etc. Olgasi et al.  describePregnancy miscarriages have many unknown causes and are complex processes that require solution. Bohnke et al.  were abl"}
+{"text": "Homocysteine levels can be increased by different conditions including genetic factors, diet, life style, several medications, etc. Elevated levels of homocysteine, called hyperhomocysteinemia (hHcy), are associated with a higher risk of neurovascular diseases, dementia, migraine, developmental impairments or epilepsy. The mechanisms underlying the neurotoxicity of homocysteine include oxidative stress, DNA damage, protein thiolation or protein homocysteinylation, triggering apoptosis and excitotoxicity. Recent data indicate that inflammation during hHcy comes along with increased levels of several cytokines and changes in DNA methylation.Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine. The concentration of homocysteine is regulated by two key pathways: remethylation back to methionine or transsulfuration to cysteine with the simultaneous production of hydrogen sulfide , which is a major regulator of cellular methylation reactions that occur in eukaryotic and prokaryotic organisms. SAHase activity is a significant source of homocysteine and adenosine. The author presents structural characteristics of the two principal domains of the SAHase subunit, which are based on the Rossmann fold. The study highlights similarities and differences in the spatial arrangements of both major domains. In his review, Brzezinski  summarizIn their review Rizzo and Lagane  summarizhHcy which has been linked to different systemic and neurological diseases, is well known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD), and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Oxidative stress, endoplasmatic reticulum (ER) stress, inflammation, and epigenetic modifications have been suggested as possible mechanisms of hHcy-induced blood retinal barrier (BRB) dysfunction. More recently hHcy-induced brain inflammation was reported as a mechanism of blood-brain barrier (BBB) dysfunction and pathogenesis of Alzheimer\u2019s disease (AD). The contribution by Tawfik et al.  focuses The original study by Elsherbiny et al.  demonstrIn the paper by Kovalska et al. , a methiN-methyl-d-aspartate receptors (NMDARs) and a reducing agent. In the paper by Sibarov et al. [Homocysteine (HCY) combines distinct pharmacological properties as an agonist of v et al. , the rolIvanova et al.  provide 2S in kidney ischemia-reperfusion injury and oxidative stress in the heart.Hydrogen sulfide has been implicated in cardiovascular protection through redox balance and vessel relaxation. The paper by Wijerathne et al.  emphasiz2S. Prenatal hyperhomocysteinemia (hHCy) was found to induce behavioral impairments and oxidative stress in brain tissue of rats, with a decreased expression of the H2S generating enzyme-cystathionine-beta synthase and concentrations of H2S in the brain. The administration of the H2S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral studies together with biochemical studies will improve our knowledge about homocysteine neurotoxicity and proposes H2S as a potential agent for the therapy of hHcy-associated disorders.Finally, Yakovleva et al.  accentuaThis Special Issue describes several pathological conditions associated with elevated levels of homocysteine, some further mechanisms of homocysteine action, and opens new possibilities for treatments."}
+{"text": "Cell membranes develop extraordinarily complex lipids and proteins geared to perform functions required by cells. The collective processes occurring within membranes strongly impact their cellular behavior and biochemistry; thus, understanding these processes poses unique challenges due to the often complex and multiple interactions among membrane components. The plasma membrane surface accommodates different types of lipid and protein clusters; however, the functional role of membrane surface clustering has not been fully understood yet. Super-resolution microscopy (SRM) has been extremely helpful in expanding our knowledge and changing the paradigm on both the structure and function of these clusters. These SRM techniques have been used to examine the organization and dynamics of plasma membrane components, thus giving insight into the fundamental interactions determining membrane functions.Membranes Special Issue, entitled \u201cDynamics and Nano-Organization in Plasma Membranes\u201d, presents both an update and a comprehensive overview of recent developments in plasma membrane nano-organization. It features eight contributions, namely six research papers and two reviews. A brief descriptive summary of the scientific contributions is reported here. This Kure et al.\u2019s  review p2/s, which is comparable to similar studies of other aquaporins. From the kICS analysis, it can be concluded that the addition of actin polymerization-inhibiting compounds, cytochalasin D and latrunculin, did not significantly affect the diffusion coefficient of AQP9 in these cells, indicating that there was no correlation between the actin cytoskeleton network and AQP9; in addition, decreases in the diffusion coefficients were observed when adding Methyl-\u03b2-Cyclodextrin (M\u03b2CD). These observations, when combined, suggest that, unlike other AQPs , AQP9 is not a nano-domain membrane protein.Kure et al.  also repIn the paper by Jaszul et al. , the molSezgin et al.  reportedYang et al.  reviewedIn their paper, Allender et al.  discusseLast, Tintino et al.  studied In conclusion, the papers in this Special Issue provide a significant contribution to increasing our understanding of the complexity in cell membrane organization. Super-resolution microscopy techniques are highlighted as powerful tools for obtaining new information about plasma membrane nano-organization, nanodomains, lipid as well as protein diffusion, along with membrane proteins and their interaction with plasma membranes. Moreover, important contributions related to the development of new methodologies to generate model lipid membranes as well as an alternative theory were described in order to explain the physical origin of membrane domains."}
+{"text": "Dvorak describes that VEGF is widely believed to induce angiogenesis by its direct mitogenic and motogenic actions on vascular ECs. However, he emphasizes the role of VEGF in vascular permeability, the role of delayed hypersensitivity in pathological stroma generation, particularly extravascular fibrin deposition and clotting within the tumor microenvironment (TME). Based upon his prior work where he concludes that tumors are \u201cwounds that do not heal,\u201d he now proposes that tumors are wounds that continually exhibit elements of local healing but do damage the host (patients) whereas the healing process actually facilitates tumor survival and growth. Moreover, solid tumors, and healing wounds feature enlarged feeder arteries, draining veins, and several other abnormal vessel types in addition to new angiogenic blood vessels. He also proposes that that VPF/VEGF induces stroma formation primarily by way of its potent \u201cVPF\u201d function. Much remains to be explored about the signaling and functions of VEGF in wound healing, tumor progression and chronic inflammatory diseases.We begin with vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most important growth factor in EC and vascular biology. This important proangiogenic molecule was discovered over 3\u00a0decades ago by the Dvorak Laboratory at Harvard Medical School  and was Wang et al. describe the basics of VEGF/VEGFR-2 signaling and provide an update on VEGFR-2 signaling-mediated physiological and pathological functions as well as potential treatment strategies. Potent VEGF signaling also promotes angiogenesis and dictates arterial fate but inhibits venous specification, and this may depend on Notch signaling status  and thus conferring therapeutic resistance. They also discuss the Notch signaling crosstalk between CSCs and vascular ECs within the TME. They believe that therapeutic approaches could be developed by targeting the essential role of Notch pathway in CSCs and development of the arteriolar niche that promotes the self-renewal of CSCs  , a predog status . Akil et of CSCs .Alfaidi et al. emphasize the role of Nck1/2 adaptor proteins in vascular biology, vascular permeability and angiogenesis, and discuss their therapeutic potential. A study on an adaptor protein widely expressed in vascular ECs by Liu et al. demonstrates that the mitogen-inducible gene 6 acts as a potent anti-angiogenic factor in the regulation of physiological and pathological angiogenesis. In terms of anti-angiogenesis, thrombospondin-1 (TSP-1) is one of the first discovered endogenous angiogenesis inhibitor, and negatively regulates EC functions . Although VEGF-activation of Notch signaling is known as the key to arterial specification, they have performed carefully analysis in the settings of de novo vasculogenesis of the dorsal aorta during early embryogenesis and vasculature development in the neonatal mouse retina and described novel signaling mechanisms and a new understanding of this subject. They also emphasize the role of shear stress in the maintenance of arterial identity after blood circulation is established, as shear-induced Notch signaling activation and cell cycle arrest may contribute to A/V specification process  mainly originates from the mitochondria in diabetes, a study from Zhao et al. describe the paradox of adenosine monophosphate-activated protein kinase (AMPK), a heterotrimeric serine-threonine kinase, in the involvement of vascular remodeling and the development of pulmonary hypertension. They emphasize the differential effects of AMPK on pulmonary vasoconstriction and pulmonary vascular remodeling, which may also be involved in the regulation of pathological microvascular remodeling and angiogenesis under obese conditions . They functionally classify ECs as quiescent ECs involved in maintaining homeostasis, proliferative ECs, inflammatory ECs, remodeling ECs, ECs involved in EndMT, and ECs involved in angiogenesis. This classification may well explain two new connected processes such as inflammatory angiogenesis and non-inflammatory regenerative angiogenesis dissected in hind-limb ischemia-triggered angiogenesis  shows that lipopolysaccharide induces transcriptional activation of forkhead box protein C2 and promotes itself expression in a histone acetylation manner using lung ECs and a sterile sepsis model in neonatal mice.EC heterogeneity is emerging as an important area in vascular biology. It is well known that ECs show tissue- and organ-specificity, and significantly contribute to the formation of different types of blood and lymphatic vessels. They serve as an important cell type in the development of vasculogenesis, angiogenesis, venogenesis and arteriogenesis under physiological and pathological conditions. As newly classified innate immune cells , ECs areogenesis . Dawson Fang et al. propose that an EndoMT program is partially and reversibly activated event in angiogenic ECs to support acquisition of the subset of mesenchymal characteristics, which is necessary to develop sprouting angiogenesis. They also discuss the potential signaling and regulatory mechanisms that may control the EndoMT program as well as potential therapeutic approaches in cancers. EndoMT is known to be regulated by transforming growth factor-\u03b2 (TGF-\u03b2) family. Ma et al. report that TGF-\u03b22 may be essential for this process by regulation of the balance between transcription factor SNAIL and ID factors  and this may also regulate angiogenesis . Additionally, a study by Hunyenyiwa et al. shows that obesity inhibits angiogenesis via TWIST1-SLIT2 signaling, similar to an angiogenic phenotype occurred in tumor angiogenesis under diet-induced obesity conditions  and partial epithelial-to-mesenchymal transition (EMT)/EndoMT have been extensively reported. EndoMT is a process whereby an EC undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell. In a hypothesis and theory article, nditions . It shouPaulson et al. show that primary cilia exists in lymphatic vasculature, and surprisingly is expressed on the abluminal surface of the lymphatic vessel. They also present evidence that lymphatic vessel patterning is regulated by a primary cilium protein IFT20 in lymphatic ECs during development and inflammation, which could lead to a new paradigm in the field of lymphangiogenesis. Last but not the least, Norden and Kume provide an elegant review about current status and the mechanisms by which lymphatic permeability and function are regulated in a tissue- and organ-specific manner, including lacteals of the small intestine. Disrupted lymphatic EC junctions are associated with various diseases, including lymphatic leakage present in chylothorax and lymphedema, metabolic syndrome, and impaired immune surveillance. They also describe key signaling pathways and factors that control lymphatic EC junctional integrity including VEGF, S1P, LPA signaling molecules and FOXC1 and FOXC2 transcription factors as well as RhoA/ROCK and Ephrinb2-Ephb4 pathways.In addition to new sprouting from blood vessels, the sprouting of lymphatic vessels, lymphangiogenesis, is actively involved in many pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema. Cilia, a microtubule-based organelle expressed on the apical surface of blood ECs is thought to function as a blood flow sensor. via toll-like receptor 2 signaling (de novo arteriogenesis, particularly under pathological conditions (Ren et al.; Heterogeneous endothelium and vasculature play a pivotal role in the regulation of tissue and organ homeostasis in human health and disease progression. This topic only covers the tip of iceberg in the field of EC and vascular biology, and significant studies are urgently needed to move the field forward. One emerging area is the immunological properties of ECs and their role in angiogenesis and lymphangiogenesis. ECs show distinguished immunological functions and have innate and trained immunity . McCoy eignaling . Secondlignaling . The resignaling . Thirdly"}
+{"text": "Mast et al. analyzed transcriptome data derived from RNA-sequencing (RNA-seq) of COVID-19 patient bronchoalveolar lavage fluid (BALF) samples, as compared to BALF RNA-seq samples from a study investigating microbiome and inflammatory interactions in obese and asthmatic adults . Based on their analysis of these data, Mast et al. concluded that mRNA expression of key regulators of the extrinsic coagulation cascade and fibrinolysis were significantly reduced in COVID-19 patients. Notably, they reported that the expression of the extrinsic coagulation cascade master regulator Tissue Factor (F3) remained unchanged, while there was an 8-fold upregulation of its cognate inhibitor Tissue Factor Pathway Inhibitor (TFPI). From this they conclude that \u201cpulmonary fibrin deposition does not stem from enhanced local [tissue factor] production and that counterintuitively, COVID-19 may dampen [tissue factor]-dependent mechanisms in the lungs\u201d. They also reported decreased Activated Protein C (aPC) mediated anticoagulant activity and major increases in fibrinogen expression and other key regulators of clot formation. Many of these results are contradictory to findings in most of the field, particularly the findings regarding extrinsic coagulation cascade mediated coagulopathies. Here, we present a complete re-analysis of the data sets analyzed by Mast et al. This re-analysis demonstrates that the two data sets utilized were not comparable between one another, and that the COVID-19 sample set was not suitable for the transcriptomic analysis Mast et al. performed. We also identified other significant flaws in the design of their retrospective analysis, such as poor-quality control and filtering standards. Given the issues with the datasets and analysis, their conclusions are not supported. Since the emergence of SARS-CoV-2 in December of 2019, there have been over 230 million reported cases and more than 4.7 million deaths . The sciIn Mast et al. the authors concluded that the extrinsic coagulation cascade regulation in the lung was not majorly impacted by SARS-CoV-2. They proposed that the bradykinin storm mediated pathogenesis originally proposed in The first issue we identified was related to the designation of the BALF bulk RNA-sequencing samples from Michalovich et al (GEO data set - PRJNA434133) as \u201cHealthy Controls\u201d by Mast et al. Analysis of the meta-data associated with the described \u201cHealthy Control\u201d subjects published in Michalovich et al. demonstrates that their samples were overall not healthy and also not representative of the average American population in terms of obesity  (42.4%),The issues with using the samples from Michalovich et al. as the healthy control samples is made clear in the findings of the original manuscript. The study found significant changes in systemic and pulmonary inflammation when comparing individuals with obesity, asthma, or smoking history to their healthy subjects. Specifically, they found elevated levels of circulating inflammatory mediators  and proteins regulating coagulation . Additionally, they reported significant changes in BALF concentrations of C reactive protein, Serum Amyloid Alpha, IL-5, and other proteins that would impact coagulation and inflammation. Gene ontology analysis of transcriptional differences in the BALF that were published in Michalovich et al. identified significant enrichments in tissue remodeling and inflammation ontologies amongst obese and asthmatic groups relative to the three healthy controls. These significant inflammatory, pro-coagulant, and transcriptional changes within the samples that Mast et al. designated as \u201chealthy controls\u201d have many overlapping similarities with the phenotypic changes that are associated with SARS-CoV-2. Such changes would significantly disrupt the ability to accurately characterize SARS-CoV-2 differential expression as these comorbidities are not controlled for in Mast et al. The presence of such disparate sample types within the \u201chealthy control\u201d group does not yield an averaged and more representative control group as was implied in Mast et al., instead the pro-coagulant transcriptional changes associated with the co-morbidities observed in much of the control group would likely mask relevant COVID-19 induced transcriptional changes. Additionally, averaging of highly disparate samples within the control group during differential expression analysis would not yield a more representative data set, but rather would generate a noisy control group with averages significantly weighted towards more abundant sample types.Based on the description of the RNA sequencing library preparation methods described in Zhou et al. and Michalovich et al., very different approaches were used to prepare sequencing libraries. The type of library preparation can significantly modify the RNA content of sequencing libraries via polyA enrichment, rRNA depletion, and other major differences in molecular processes underlying library preparation. Dissimilar libraries, particularly those with non-similar polyA enrichment and ribosomal RNA (rRNA) depletion, cannot reliably be used for differential expression analysis with transcripts per million (TPM) based normalization, which Mast et al. utilized in their analysis .Michalovich et al. uses libraries that are enriched for mRNA via polyA enrichment, while Zhou et al. does not. Michalovich et al. also uses a TruSeq Stranded RNA library Prep kit with RiboZeroTMGold ribodepletion probes. This library preparation approach yields libraries that are selectively depleted of ribosomal reads (which are the predominant RNA species in cells), while enriching for mature mRNA transcripts . By contTo confirm the functional differences in library preparation methods, we analyzed the proportion of reads aligning to rRNA transcripts using the same CLC genomics alignment settings and reference transcriptomes described in Mast et al. This confirmed that the total rRNA content was at a significantly greater proportion in SARS-CoV-2+ patient samples relative to control samples.  The amouRNA-seq approaches for differential expression analysis require that enough sequencing reads be collected to accurately quantify the total expression of transcripts across the genome. In order to have statistical meaningful numbers of reads mapping to each gene for differential expression analysis minimum read depth requirements must be met. If a particular transcript is lowly expressed relative to other transcripts, then a low number of reads may be stochastically detected during sequencing. Such a dynamic could artificially inflate or deflate the relative expression of a particular transcript, especially when normalization approaches are applied to compare libraries sequenced at different depths or with radically different RNA compositions. It is generally accepted in the field that experiments investigating eukaryotic global gene expression typically require at least 30 million poly-A and ribo-depleted reads per sample . In humaIn Mast et al., there are major discrepancies in the relative depths of the sequencing libraries used for the \u201chealthy control\u201d samples and the SARS-CoV-2+ patient samples . Of the To illustrate a specific instance, Mast et al. report that thrombomodulin (THBD) expression in the BALF was decreased by 2200% during SARS-CoV-2 infection. They reported the expression level to be approximately 9.6 counts per million reads in COVID-19 infection and 224 counts per million reads in the control sample set. However, at the level of raw counts, control samples averaged 8,377.68 counts while COVID-19 positive samples averaged 59.88 counts. The normalization process for the counts per million based normalization was further biased by the inclusion of between 16%\u201380% of the total rRNA in only COVID-19 samples. These rRNA reads would be included in the total number of mapped reads used to calculate the CPM normalization factor in a manner that was not consistent with the normalization of control samples.  Additionally, such a bias would significantly decrease the likelihood of detecting mRNA transcripts in the COVID + genes, including thrombomodulin transcripts. These confounding factors could bring into question the accuracy of the reported magnitude of the differential expression, the reported directionality of the differential expression, and the subsequent pathway analysis performed.The significant issues we have identified regarding the heterogeneity of control samples, dissimilar library preparation methods, and insufficient sequencing depth collectively bring into doubt the validity of many of the conclusions drawn in Mast et al. The normalized manner in which the gene expression data were reported in the supplement and manuscript of Mast et al. made it difficult for reviewers and readers to identify these issues when analyzing the manuscript. Mast et al. additionally did not provide supplemental data regarding the raw reads that were processed during alignment, the raw counts that were normalized and processed during differential expression analysis, or any NGS quality control standards that should have been conducted by the authors before analyzing the data set. From our analysis of their raw data, we conclude that the sample set and experimental design implemented in Mast et al. are fundamentally flawed. The concerns are significantly magnified knowing that others researching COVID-19 are citing these poorly substantiated results in publications  or integUpon processing the raw data as described in our results section, serious issues with relative sequencing depth quickly became apparent. Review of the count data which we have summarized in Table 2 and the differential expression results for genes of interest reported in Table 1 of Mast et al. demonstrate the flawed nature of this analysis. Overall, 23 out of 35 genes of interest reported in Mast et al. average less than 10 mapped reads per gene but were still included in the analysis.  8 of thoBy far the most notable result reported in Mast et al. is the reported observation that tissue factor, the key initiator of the extrinsic coagulation cascade, is not significantly impacted by SARS-CoV-2 infection. They reported no significant difference in expression levels and concluded that tissue factor biology was not a significant factor in the thrombotic complications of SARS-CoV-2 in the lung. They postulated that COVID-19 may dampen tissue factor dependent mechanisms in the lung. This analysis was confounded by the above-described issues including relative depth, rRNA differences between control and COVID sample sets, and normalization This statement is important as the field has also begun converging on tissue factor as a key player in the pathogenesis and coagulopathy complications of SARS-CoV-2 infection. For instance, patients with COVID-19 have been shown to have elevated levels of tissue factor laden microvesicles circulating in their blood, along with other markers of the extrinsic coagulation cascade . FurtherAt the time the manuscript was submitted, several higher quality data sets were available and the authors of Mast et al. should have redone their analysis on sample sets that were collected with the intent of resolving transcriptomic signatures to accurately characterize the host response to SARS-CoV-2 . Additio"}
+{"text": "In the search for effective therapeutic strategies for depression, repetitive transcranial magnetic stimulation (rTMS) emerged as a non-invasive, promising treatment. This is because the antidepressant effect of rTMS might be related to neuronal plasticity mechanisms possibly reverting connectivity alterations often observed in depression. Therefore, in this review, we aimed at providing an overview of the findings reported by studies investigating functional and structural connectivity changes after rTMS in depression.A bibliographic search was conducted on PubMed, including studies that used unilateral, excitatory (\u2a7e10 Hz) rTMS treatment targeted on the left dorsolateral prefrontal cortex (DLPFC) in unipolar depressed patients.The majority of the results showed significant TMS-induced changes in functional connectivity (FC) between areas important for emotion regulation, including the DLPFC and the subgenual anterior cingulate cortex, and among regions that are part of the major resting-state networks, such as the Default Mode Network, the Salience Networks and the Central Executive Network. Finally, in diffusion tensor imaging studies, it has been reported that rTMS appeared to increase fractional anisotropy in the frontal lobe.The small sample size, the heterogeneity of the rTMS stimulation parameters, the concomitant use of psychotropic drugs might have limited the generalisability of the results.Overall, rTMS treatment induces structural and FC changes in brain regions and networks implicated in the pathogenesis of unipolar depression. However, whether these changes underlie the antidepressant effect of rTMS still needs to be clarified. No limitation was posed regarding publication date. We included studies using unilateral, excitatory, high-frequency (\u2a7e10\u00a0Hz) TMS treatment targeting the left DLPFC. Only studies that investigated brain structural and FC using whole-brain neuroimaging techniques before and after rTMS protocols in depressed patients were included. Studies (a) employing other techniques , (b) based on bilateral or inhibitory rTMS protocols, or (c) targeting areas other than left DLPFC were excluded. The reference list of the selected articles was checked in order to find relevant references not emerged from the main query. Only 13 studies were selected as eligible. Of these, two studies included, in addition to unipolar depressed patients, a small cohort of depressed bipolar disorder type II patients. Finally, nine studies used resting-state functional magnetic resonance imaging (rs-fMRI), three studies employed diffusion tensor imaging (DTI) techniques, and one study employed single-photon emission computed tomography (SPECT).Connectivity changes induced by rTMS treatment are briefly discussed below, divided according to the investigated connectivity domain. FC results focused on two brain areas, the DLPFC and the subgenual anterior cingulate cortex (sgACC), whose connectivity emerged to be affected by the selected rTMS protocol. Although our focus was on connectivity changes from before to after rTMS, we also listed, when reported, the baseline features predictive of treatment response.et al. , a decrease in FC between sgACC and DMN, consistently with the result reported by Liston et al. (v. sham) on the Montgomery-\u00c5sberg Depression Rating Scale (MADRS) and FC was demonstrated, suggesting that reduction in FC between sgACC and DMN may parallel the reduction in depressive symptoms, with no specific effect of active v. sham rTMS. Moreover, with regards to the CEN, the authors found a decrease in FC between sgACC and CEN. This last result is in contrast with the one reported by Liston et al. , a marker of white matter microstructure, measured through DTI  and major resting-state networks ) were found to be associated with rTMS treatment, possibly mediating rTMS therapeutic efficacy.et al., et al., et al., et al., et al., et al., et al., In particular, in the reviewed studies, a decrease in FC between DLPFC  is part of the SN, a key circuit directing attention and cognitive control Menon, , and comet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The three DTI studies here reviewed (Kozel et al., et al., The reviewed studies suffer from some limitations. First, the sample size was often modest and some studies (Liston In conclusion, the abovementioned results support the hypothesis that rTMS induces neuronal plasticity and reorganisation of key networks in the pathogenesis of unipolar depression. However, whether these changes underlie the antidepressant effect of rTMS is not defined yet. Further studies including larger and more homogeneous samples are needed to better clarify the effect of rTMS on brain connectivity and the relationship with its therapeutic effect in unipolar depression.All data described in this review have been included in"}
+{"text": "Dear Editor,The diverse microbial community present in the human intestine plays a vital role in translating the food to nutrients and metabolites essential for maintaining host physiology, including digestion, lipid and glucose metabolism, immune homeostasis, and proper development of the brain and cognitive functions . Consumal., 2018). Modulaal., 2018). The poal., 2018; \u00c1ngel Gal., 2018). A deepal., 2018; Conternal., 2018; de Olival., 2018; Guevaraal., 2018; Istas eal., 2018; Lima etal., 2018; Medina-al., 2018; Ntemirial., 2018; Park etal., 2018; Vilela al., 2018) summariThe authors thank the American University of Ras Al Khaimah for the support and facilities provided.The authors declare no conflict of interest."}
+{"text": "Khatouri et al., RSC Adv., 2021, 11, 7059\u20137069, DOI: 10.1039/D0RA09804C.Correction for \u2018Effect of hydrophobically modified PEO polymers (PEO-dodecyl) on oil/water microemulsion properties:  The authors regret that the name of one of the authors  was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Dear editor,We are grateful for the comments of \u201cEarliest details of Dermatology by Ayurveda\u201dSimilarly, we are grateful for the comments by Mirzaei MR et al.None declared.Iago Gon\u00e7alves Ferreira: Conception and/or design of the study; literature review and article selection; content analysis; results analysis; preliminary review and final drafting.Magda Blessmann Weber: Conception and/or design of the study; literature review and article selection; content analysis; preliminary review and final drafting.Renan Rangel Bonamigo: Conception and/or design of the study; literature review and article selection; content analysis; preliminary review and final drafting.None declared."}
+{"text": "Childhood trauma is associated with an elevated risk for psychosis, but the psychological mechanisms involved remain largely unclear. This study aimed to investigate emotional and psychotic stress reactivity in daily life as a putative mechanism linking childhood trauma and clinical outcomes in individuals at ultra-high-risk (UHR) for psychosis.N = 79 UHR individuals in the EU-GEI High Risk Study. The Childhood Trauma Questionnaire was used to assess self-reported childhood trauma. Clinical outcomes were assessed at baseline, 1- and 2-year follow-up.Experience sampling methodology was used to measure momentary stress, affect and psychotic experiences in the daily life of \u03b2 = \u22120.14, p = 0.010) and negative affect  was modified by transition status such that stress reactivity was greater in individuals who transitioned to psychosis. Moreover, the association of stress with negative affect  and psychotic experiences  was greater in individuals exposed to high v. low levels of childhood trauma. We also found evidence that decreased positive affect in response to stress was associated with reduced functioning at 1-year follow-up . In addition, there was evidence that the association of childhood trauma with poor functional outcomes was mediated by stress reactivity , but no evidence that stress reactivity mediated the association between childhood trauma and transition .The association of stress with positive (Emotional and psychotic stress reactivity may be potential mechanisms linking childhood trauma with clinical outcomes in UHR individuals. The effects of childhood trauma will be mediated via pathways through stress reactivity (i.e. a mediation model).Furthermore, other possibilities of how childhood trauma and stress reactivity may combine with each other may be relevant  the magnitude of associations between momentary stress and negative affect, positive affect and psychotic experiences is modified by transition status, and (ii) the effect of childhood trauma on transition status will be mediated via pathways through stress reactivity (i.e. a mediation model).et al., et al., The sample comprises UHR individuals from London (UK), Melbourne  and Amsterdam/The Hague (the Netherlands) recruited as part of the EU-GEI High Risk Study . The target constructs  show high and continuous variation over time. To obtain a representative sample of participants\u2019 experiences in daily life and to capture relevant variation in these target constructs with high resolution, a time-contingent sampling design with a blocked random schedule and a high-sampling frequency was used for ESM data collection, i.e. ten times a day for six consecutive days at random moments within set blocks of time , an established 25-item self-report measure enquiring about traumatic experiences during childhood . Second, we added two-way interaction terms for stress\u00a0\u00d7\u00a0childhood trauma to examine whether the associations between momentary stress, negative affect, positive affect and psychotic experiences were modified by childhood trauma (H2). The hypothesis that the associations of momentary stress with affect and psychotic experiences were greater in individuals exposed to high v. low levels of childhood trauma  was tested by using the \u2018testparm\u2019 command for computing Wald tests to assess statistical significance of two-way interaction terms and the \u2018lincom\u2019 command to compute linear combinations of coefficients  nested within participants (level-2), the \u2018mixed\u2019 command in Stata 15 was used to fit two-level, linear mixed models . To control for confounding of findings by comorbid disorders, all analyses were controlled for comorbid major depressive and anxiety disorders. In addition, analyses for testing H3 and H4 were controlled for time to follow-up to account for variation in time to follow-up. Unadjusted analyses and sensitivity analyses in a restricted sample assessed in a \u00b16 month time interval around the expected follow-up time points are displayed in online Supplementary materials 4\u20136.Restricted maximum-likelihood (H1 and H2) or maximum-likelihood estimation (H3 and H4) were applied, allowing for the use of all available data under the relatively unrestrictive assumption that data are missing at random and if all variables associated with missing values are included in the model . Assessment of clinical outcomes was completed for 48 participants at 1-year follow-up  and 36 participants at 2-year follow-up . Nine individuals (11%) transitioned to psychosis by the final follow-up time point. Participants were on average 23 years old (s.d.\u00a0=\u00a04.93) and 56% were women. The majority (67%) of the sample was white, followed by 15% with black ethnicity. Seventy-six percent of the participants were diagnosed with a comorbid axis I disorder. Comparing the current study's participants to individuals included in the EU GEI High-Risk study, for whom ESM data were not collected (N\u00a0=\u00a0266), there were no differences in demographics  or overall prevalence of comorbid disorders . However, the current sample showed higher levels of childhood trauma , a higher prevalence of specific phobias  and a lower prevalence of major depressive disorder  compared to participants, for whom ESM data were not collected  0.27 to 0.36, p\u00a0<\u00a00.001) and psychotic experiences  as well as with a moderate decrease in positive affect .Momentary stress was associated with small to moderate increases in negative affect  and psychotic experiences . Furthermore, we found a non-significant indication that childhood trauma modified the association between momentary stress and positive affect .Childhood trauma modified the associations of momentary stress with negative affect  and lower level of functioning  at 1-year follow-up .B\u00a0=\u00a01.74, 95% CI 0.36 to 3.11, p\u00a0=\u00a00.016). Moreover, perceptual abnormalities at 1-year follow-up were predicted by emotional  and psychotic stress reactivity . There was no evidence that emotional or psychotic stress reactivity predicted anxiety or tolerance to normal stress.Decreased positive affect in response to stress was associated with higher illness severity . We found no evidence that emotional and psychotic stress reactivity mediated the association of childhood trauma and level of functioning. The association of childhood trauma and unusual thought content at 2-year follow-up was mediated by increased negative affect in response to stress . In addition, the association of childhood trauma and perceptual abnormalities at 1-year follow-up was mediated by increased negative affect  and psychotic experiences in response to stress . High levels of childhood trauma were associated with more intense reactivity in the form of a stronger increase of negative affect and psychotic experiences in response to stress, which, in turn, was associated with higher illness severity, unusual thought content and perceptual abnormalities at follow-up. We found no evidence for direct effects of childhood trauma on anxiety and tolerance to normal stress and no mediation via stress reactivity.In exploratory analyses, there was no evidence for a direct effect of childhood trauma on transition status and no mediation via stress reactivity .Using an experience sampling design, we found strong evidence that minor daily stressors were associated with emotional and psychotic stress reactivity in UHR individuals (H1). Childhood trauma modified the effect of daily stressors on negative affect and psychotic experiences, with more intense psychotic experiences and stronger increases in negative affect for individuals exposed to high levels of childhood trauma (H2). In addition, we found some evidence to suggest stress reactivity predicts clinical outcomes at follow-up (H3). Finally, there was partial evidence that stress reactivity mediates the association of childhood trauma and clinical outcomes (H4).et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The reported findings should be interpreted in light of several methodological considerations. First, childhood trauma was measured with a retrospective self-report questionnaire. A common concern about retrospective self-report is that recall bias and cognitive distortions might lead to invalid ratings (Dill et al., et al., In accordance with previous ESM studies, we found that momentary stress was associated with small to moderate increases in negative affect and psychotic experiences and moderate decreases in positive affect in UHR individuals (Reininghaus et al., et al. (et al., et al., et al., et al., et al., et al., et al., et al., When considering the role of childhood trauma and stress reactivity in clinical trajectories, several possibilities of how these may combine with each other may be relevant (Schwartz and Susser, , et al. , we inveet al., et al., et al., et al., Taken together, our findings underscore the relevance of reactivity to daily stressors as a putative mechanism linking childhood trauma with clinical outcomes in UHR individuals. Adding evidence to the mediated synergy model, the study suggests early adversity in childhood links to more severe clinical trajectories via, and in interaction with, subsequently elevated stress reactivity in adulthood. Therefore, the findings underline the relevance of ecological momentary interventions targeting stress reactivity in daily life (e.g. EMIcompass, a transdiagnostic ecological momentary intervention for improving resilience in youth; Schick"}
+{"text": "Prostate cancer (PCa) is one of the most frequently diagnosed malignancies of men in the world. Due to a variety of treatment options in different risk groups, proper diagnostic and risk stratification is pivotal in treatment of PCa. The development of precise medical imaging procedures simultaneously to improvements in big data analysis has led to the establishment of radiomics - a computer-based method of extracting and analyzing image features quantitatively. This approach bears the potential to assess and improve PCa detection, tissue characterization and clinical outcome prediction. This article gives an overview on the current aspects of methodology and systematically reviews available literature on radiomics in PCa patients, showing its potential for personalized therapy approaches. The qualitative synthesis includes all imaging modalities and focuses on validated studies, putting forward future directions. In global cancer statistics of men prostate cancer (PCa) is the most frequently diagnosed malignancies in the world and the fifth leading cause of death worldwide The Radiomics Pipeline Figure  is the e(1) Image acquisition and preprocessing(2) High-throughput feature extraction(3) Data integration and data analysisThe Image Biomarker Standardization Initiative (IBSI) published a reference manual to harmonize the feature extraction by providing (i) definitions, (ii) a standardization of the radiomics pipeline, (iii) reference datasets and (iv) a reporting scheme e.g., by intensity inhomogeneity correction or noise filtering for MR-images All imaging modalities mentioned in the introduction can be utilized for PCa radiomics: TRUS, MRI, PSMA-PET, CT and bone scan. It is important to mention that heterogeneities in image acquisition und image reconstruction algorithms due to different local standards are culpable for missing repeatability and reproducibility of RF The spatial and gray level information of the segmented voxels is used in numerous mathematical calculations to extract pre-defined \u201chand-crafted\u201d RF. They can be computed with various open-source packages like PyRadiomics e.g., the depth of a tree or a deep-learning architecture and (iii) one test set for the final assessment. The latter might be used independently for validation. During cross-validation (CV) usually small datasets are divided accordingly in an iterative process. K-fold CV partitions the dataset in k subsets using one as a validation and the rest for training. This process is repeated for each subset. Leave-one-out CV operates similarly but leaves one patient for validation while using the rest for training CV should be used with caution especially with leave-one-out CV tending to be overly optimistic Often a vast number of RF are computed, and the abundance of RF demands feature selection and/or reduction to avoid overfitting and to exclude not relevant or redundant features. Many features are correlated with each other; these redundant features might be depicted with heatmaps and should be omitted st order features and texture features. Shape features describe the morphology of the VOI for instance the size, volume or diameter. 1st Order features are based on an intensity histogram derived of the segmented voxels et al. the gray level co-occurrence matrix (GLCM) assesses the gray levels of pairs of neighboring voxels \u201cHand-crafted\u201d RF st of January 2014 st of January 2021. 251 articles were located. Additionally, 22 manuscripts were identified through other sources . 35 duplicates were removed. Only articles that met inclusion criteria were included. Finally, 77 studies were included in the qualitative synthesis. Please see Figure Studies eligible for inclusion complied with the following criteria: articles had to be on PCa radiomics with predefined \u201chand-crafted\u201d features derived from MRI, TRUS, CT, Choline- or PSMA-PET and needed to apply internal or external validation. Excluded were papers not written in English and non-original articles. Two of the co-authors (SKBS and ASB) performed independently a PubMed/Medline, EMBASE and Cochrane Library database search for the terms: (cancer of prostate[MeSH Terms]) AND ((texture features) OR (radiomics)). If the two independent readers included or excluded studies differently a third reader (CZ) decided on eligibility. This was performed in 11 cases. The time period considered in this literature review was from 1Furthermore, ongoing clinical trials were screened on \u201cclinicaltrials.gov\u201d. Studies eligible for inclusion fulfilled the following criteria: ongoing trials on PCa RFs with \u201chand-crafted\u201d features derived of MRI, TRUS, CT or PSMA-PET. Trials with unknown status were excluded. CZ performed the search for the terms (\u201cCondition or disease: prostate cancer\u201d AND \u201cradiomicsl\u201d OR \u201ctexture features\u201d). Six trials were located, and one trial (NCT03294122) was excluded due to unknown trial status.Literature research revealed 57 original papers computing RF on multiparametric magnetic resonance tomography (mpMRI) imaging  et al. proposed a RF based framework for PCa detection and localization et al. (ROC-AUC 0.683-0.768 across 3 sites), showed good area under the receiver operating characteristics curve (ROC-AUC) for PCa detection et al. developed a framework of combined T2w, DWI and DTI features for differentiation of PCa and non-PCa voxels et al. demonstrated that the addition of DCE-RFs does not improve performance of T2w and DWI-RF based models to detect clinically significant PCa in the PZ et al. showed lower results for a PZ specific classifier for PCa detection with ROC-AUC of 0.6-0.71 In two preliminary studies, Cameron et al. introduced novel RF based on Joint Intensity Matrix to predict GS (ROC-AUC 0.64-0.82 depending on GS groups) et al. however, could not show that ADC features were predictive for GS upgrading in intermediate-risk prostate cancer et al. demonstrated that RF and quantitative histomorphometry correlate and are predictive for GS et al. investigated the prediction of clinically significant PCa (GS\u22657) in PIRADS 3 lesions, which could be a useful tool for biopsy guidance et al. reported that RFs from T2w and DWI sequences are associated with clinically significant PCa, being even more relevant than PIRADSv2 evaluation in some patients GS prediction and discrimination were assessed in 22 studies et al. and Zhang et al. showed that mpMRI derived RFs show good performance for bone metastasis prediction in untreated PCa with an ROC-AUC up to 0.92 et al. externally validated an ADC based RF (SZEGLSZM), which was identified in a previous study et al. demonstrated a ML classifier derived from T2w and ADC RF with good prediction of BCR after surgery or RT. which was externally validated with a AUC of 0.73 et al. showed good performance for BCR prediction after RT of localized PCa et al. elaborated a quality system to asses automated prostate segmentations with external validation et al. and Giannini et al. addressed RF-based PCa segmentation Five studies investigated RF for the prediction of extracapsular extension and reported high AUC values between 0.80-0.90 for radiomic signatures based on T2w and ADC sequences Literature research revealed five original papers et al. reported two distinct RFs  with good performance to detect significant PCa lesions not visible in PSMA-PET/CT. This result was externally validated by an independent cohort et al. demonstrated a RF based machine learning model to predict lymph node involvement, presence of metastases, GS prediction (\u22658) and presence of extracapsular extension Three studies aimed for GS discrimination Literature research revealed six original papers using CT scans et al. implemented RF for automatic prostate gland delineation in TRUS images et al. suggested that RF derived from CT images might enhance interpretation of treatment response of bone metastases et al. demonstrated that RFs derived from CT images of PSMA-PET/CT scans could accurately distinguish between metastatic lesions and sclerotic area et al. outperformed conventional measures for detection of lymph nodes metastases GS discrimination by RF was the aim of four studies using TRUS In total, 5 studies were identified using mpMR imaging n = 4), PET (n = 1), CT (n = 1) and bone scans (n = 1) to extract RF  may outperform biopsy mapping for GS 7 vs \u22658 discrimination et al. examined the PSMA expression in a combined cohort of more than 18 000 radical prostatectomy specimens and observed a correlation between PSMA expression and the GS The other focus is GS discrimination, reflecting the need for improvements in risk stratification. It is not surprising that most of the studies chose GS discrimination, since GS is the most established histologic biomarker. In clinical routine, the GS before primary PCa therapy is evaluated in tissue cores obtained by biopsy. However, due to intratumoral heterogeneity the GS in biopsy cores and prostatectomy specimen is discordant in 20-60% of the patients e.g. by genomic analyses) might outperform GS for risk prediction et al. showed weak correlations between RF and hypoxia gene expressions, providing an opportunity to assess the hypoxia status in PCa et al. and Switlyk et al. demonstrated an association between RF and the genetic marker phosphatase and tensin homolog et al. identified radiomic signatures which reflected genes that are over- and underexpressed in aggressive prostate cancer et al. suggests that RF signatures could distinguish between lesions of different aggressiveness However, several studies proposed that a thorough analysis of PCa tissue characteristics  address extraprostatic extension (n = 6), BCR (n = 6), segmentation (n = 4), bone metastasis (n = 3), lymph node detection (n = 3) and radiotherapy toxicity (n = 2). Considering that most PCa patients are long-term survivors after treatment a reliable prediction of toxicity is warranted. Due to the lack of predictive models for toxicity prediction, we consider this field of major interest for future studies. Some of the excluded studies featured interesting concepts for the use of radiomics and treatment associated toxicity in PCa patients. Radiotherapy toxicity prediction was investigated for femoral head fractures Overall, most of the included studies presented good to high AUC values. However, these findings need to be considered diligently regarding publication bias and the variability observed in RF. As illustrated above the radiomic pipeline is a sequence of operations and each operation can be modified et al. developed a 3D printable phantom to measure repeatability and reproducibility of MRI-based radiomic features which could facilitate multi-center studies to harmonize image protocols and thereby tackling some of these challenges Texture features are increasingly sensitive to acquisition parameters with growing spatial resolution Multiple segmentations can reduce variability and bias in RF extraction of manually, semiautomatically or automatically segmented VOIs et al. investigated different generally adopted image intensity normalization techniques for T2w-MRI images and demonstrated a relevant impact on reproducibility of RFs Isaakson et al investigated normalization techniques to enhance comparability across different subjects and visits et al. investigated the variability of RF in MRI by using different filters, normalization, and image discretization techniques and observed that RF were sensitive to these pre-processing procedures. Hence, they recommended detailed reporting of the pre-processing steps and the use of open-source software et al. reported that ComBat harmonization is efficient and enables MRI data pooling from different scanners and centers Schwier et al. investigated repeatability of RF derived from CBCTs and reported that only five radiomic features were repeatable in < 97% of the reconstruction and preprocessing methods et al. proposed an approach to assess RF stability without multiple acquisitions and segmentations that could be used for preliminary RF selection. In addition, the authors advocated that RF derived of ADC maps behave differently based on the region extracted e.g. RF derived from head and neck tumors are less stable than those derived of sarcomas et al. recommends to investigate the repeatability of RF for every tumor type as well and for every PET-Tracer Two studies investigated repeatability of MRI-derived RFs and concluded that repeatability of many RFs is moderate and that a set of reproducible image features is desirable These papers demonstrate the fragility of RFs and the need of reproducible RF sets in order to enable a broad clinical application.et al. pitfalls could be uncovered and described Consequentially, more research on prostate MRI and PSMA-PET RF robustness should be performed. Other approaches to tackle RF variability is the standardization of RF definitions and calculations which IBSI tries to promote Nevertheless, validation is pivotal considering the variability of RF. 35 of 238 articles were excluded due to missing validation. In internal validation different types might be utilized like the aforementioned ML algorithms, k-fold CV or leave-one-out CV, as well as independent datasets for model development and validation. A proper methodology and the separation of training and validation dataset is demanded at all times et al. used deep learning in combination with \u201chand-crafted\u201d features and has successfully applied it in differentiating unilateral breast cancer from low-risk patients Many studies used ML for model building and verification. ML and deep learning as a subfield are emerging and harbor great potential This review focusses on the clinical aspects of RF demonstrating its great potential to affect management of PCa. However, some technical aspects have not been further investigated: information on the used algorithms for RF extraction or ML approaches were not provided. Additionally, we did not state whether the published models or the parameters are publicly available.In conclusion, most research in PCa radiomics focuses on PCa detection and GS discrimination. MRI as SoC is the most used imaging modality for RF computation for now, but PSMA-PET is gaining evidence in a wide variety of clinical settings. Most of the results suggest good to high performance of radiomics models but should be considered carefully due to RF variability. Further research is demanded on RF sensitivity and robustness especially on RF extracted of prostate MRI and PSMA-PET."}
+{"text": "Inflammation is divided into acute inflammation and chronic inflammation. Chronic inflammation has been proved to be one of the major culprits of tumor occurrence and development . Once acLiu et al. described the role of IL-17A in Chronic Obstructive Pulmonary Disease (COPD), and discussed that IL-17A and its downstream regulators are potential therapeutic targets for COPD and subsequently COPD-derived lung cancer. Zhang et al. explored the role of FDX1 in the prognosis and metabolism of lung adenocarcinoma. They showed that FDX1 was closely related to glucose metabolism, fatty acid oxidation and amino acid metabolism. Another interesting study performed by Zeng et al. found chemokine ligand 14 (CXCL14) is involved in the proliferation and migration of ROS-induced colorectal cancer (CRC) cells, suggesting that aberrant ROS may promote colorectal cancer cell proliferation and migration through an oncogenic CXCL14 signaling pathway. Also, Wang et al., from another aspect, discussed the carnitine palmitoyltransferase system as a new target for anti-inflammatory and anti-cancer therapy, which may work as a promising anti-inflammatory/anti-tumor therapeutic strategy for numerous disorders. In tumor microenvironment field, Du et al. studied the tumor microenvironmental m6A as a prognostic biomarker associated with the hepatocellular carcinoma (HCC). And Wei et al. found that inhibition of BCL9 modulates the cellular landscape of tumor-associated macrophages in colorectal cancer.Here, we are committed to developing new strategies and treatments to activate the immune system of patients with chronic inflammation and cancer, in order to discover new drugs that can be used to combat chronic inflammation and induce cancer immune activation. In our research topic, Wu et al. explored T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which is highly expressed in a subset of Treg cells, as a novel target for bladder cancer immunotherapy. Li et al. discussed the cGAS-STING pathway to explore the DNA immune recognition regulation in autoimmune disease and cancer. They summarized the current progress on cGAS-STING pathway modulators and laid the foundation for further investigating therapeutic development in autoimmune diseases and tumors. Wang et al. discussed the inhibitory effect of methylseleninic acid on esophageal squamous cell carcinoma through EGFR-IL-6 signaling axis. For metastatic cancer, Guo et al. used a xenograft model in zebra fish, and found lncRNA OR3A4 acts as the inflammatory cytokine to promote the proliferation and metastasis of ovarian cancer through KLF6 pathway.Today, in cancer prevention and treatment, many clinical trials aiming at evaluating the efficacy of inflammatory regulators are underway. Though the single use of anti-inflammatory drugs has shown limited efficacy in cancer treatment, inflammation modulators can synergistically increase the anti-cancer drug\u2019s efficacy in cancer therapies . For example, in some patients with advanced cancer, after conventional treatment, immunotherapy can still alleviate or even prevent the further development of disease . It is wIn summary, the collection of aforementioned articles in this research topic provide either overview of novel targets in immunotherapy, or new fundamental findings and summaries related to chronic inflammation and cancer. Additional researches, for example, drug delivery systems and synthetic antibody engineering, are needed to gain further insights as we move toward to improve the safety and efficacy of novel immunotherapy applications in chronic inflammation and cancer."}
+{"text": "Stroke is a multifactorial disease and an extremely serious and socially important medical condition ,2. A recThis Special Issue (SI) entitled \u201cGenomics of Stroke\u201d provides a platform for a wide range of papers related to genetic studies of the pathogenesis, progression, diagnosis, and treatment of stroke. This SI includes six research articles and four reviews.The research articles in our SI are focused on association and functional studies of stroke-related genes or noncoding RNAs, and model systems, as well as pharmacogenomics and bioinformatics studies of stroke.First, we consider a paper entitled \u201cMicroRNA Analysis of Human Stroke Brain Tissue Resected during Decompressive Craniectomy/Stroke-Ectomy Surgery\u201d by Carlson et al. It should be noted that the authors conducted a comprehensive study. Specifically, human brain samples were obtained during craniectomy and brain tissue resection in patients with severe stroke who had life-threatening brain swelling. The tissue samples were subjected to histopathological and immunofluorescence microscopy evaluation, next-generation miRNA sequencing (NGS), and bioinformatic analysis . As a reThe role of another type of regulatory RNA\u2014namely, circular RNAs (circRNAs), in cerebral ischemia conditions was studied by Filippenkov et al., as reported in their paper entitled \u201cGenome-Wide RNA-Sequencing Reveals Massive Circular RNA Expression Changes of the Neurotransmission Genes in the Rat Brain after Ischemia\u2013Reperfusion\u201d. This type of RNA remains a highly promising target for research. Filippenkov et al. conducted a genome-wide RNA-Seq analysis of the subcortical structures of the rat brain containing an ischemic damage focus and penumbra . They fop = 0.048). SNPs rs62278647 and rs2316710 (PTX3) were associated significantly with IS . These correlations for rs62278647 and rs2316710 were found only in women, which suggests a sex-specific association of the PTX3 polymorphism [Interesting results were also obtained by Khrunin et al. in their paper entitled \u201cExamination of Genetic Variants Revealed from a Rat Model of Brain Ischemia in Patients with Ischemic Stroke: A Pilot Study\u201d. The authors were able to correlate the results of gene expression obtained in a rat model of tMCAO with the genomic characteristics of patients with ischemic stroke (IS). Previously, the authors had developed a bioinformatic approach to exploring single-nucleotide polymorphisms (SNPs) in human orthologues of rat genes expressed differentially under conditions of induced brain ischemia . Using tLee et al. present their paper entitled \u201cAssociation of CYP26C1 Promoter Hypomethylation with Small Vessel Occlusion in Korean Subjects\u201d related to epigenetic studies of stroke. In their study, the authors measured the level of DNA methylation in the CYP26C1 promoter and the 5\u2032 untranslated region of 115 normal subjects and 56 patients in Korea with small-vessel occlusion (SVO) . They foTanaka et al. present their paper entitled \u201cInfluence of Renal Impairment and Genetic Subtypes on Warfarin Control in Japanese Patients\u201d, which refers to pharmacogenomic research. It is known that warfarin is an effective means of anticoagulant therapy. However, warfarin has a narrow therapeutic range and shows a wide variation in doses between patients because of numerous environmental and genetic factors that influence warfarin pharmacokinetics and pharmacodynamics. Moreover, the genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses ,11,12. TFinally, our SI includes an interesting research article by Leira et al. based on the application of bioinformatics methods entitled \u201cNetwork Protein Interaction in the Link between Stroke and Periodontitis Interplay: A Pilot Bioinformatic Analysis\u201d. In this exploratory study, the authors conducted a protein\u2013protein network interaction (PPI) search with documented encoded proteins for both stroke and periodontitis . Genes oAdditionally, results and prospects for stroke genomics were systematized and discussed in substantial reviews.The first review in our SI entitled \u201cMonogenic Causes of Strokes\u201d by Chojdak-\u0141ukasiewicz et al. reports that monogenic disorders are rare but play significant roles in the causes of strokes, especially in young people. The monogenic causes of stroke are recognizable by key clinical features and radiographic pictures. Genetic tests are expensive but should be part of routine diagnostic procedures in younger patients with cerebrovascular events, especially in the absence of typical vascular risk factors . The mosThe SI also includes a review characterizing one of the examples of ethnic features of stroke genomics. In their review entitled \u201cGenetic and Genomic Epidemiology of Stroke in People of African Ancestry\u201d, Prapiadou et al. describe significant racial/ethnic differences in the incidence, subtype, and prognosis of stroke between people of European and African ancestry, of which only about 50% can be explained by traditional stroke risk factors . HoweverAnother review entitled \u201cThe Genetic Landscape of Patent Foramen Ovale: A Systematic Review\u201d by Paolucci et al. will undoubtedly attract attention to our SI. It should be noted that paradoxical embolism through patent foramen ovale (PFO) is an important cause of cryptogenic IS, especially in younger patients. Consistent with this observation, the rate of PFO in siblings of young patients with IS and PFO is three times higher than in siblings of patients without PFO ,17,18. IFinally, the review entitled \u201cInfluence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients\u201d by Edwards et al. is of substantial interest for our SI. This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology . Hp is aIn conclusion, the diversity and quality of the studies presented in this SI indicate the constant advancement of knowledge in the field of genomics of stroke.We hope that our SI will be useful and interesting for readers. Further development of the field of stroke genomics will bring society closer to improving diagnostic, prognostic, and therapeutic measures to combat stroke and related pathologies."}
+{"text": "Mental health (MH) service users have increased prevalence of chronic physical conditions such as cardio-respiratory diseases and diabetes. Potentially Preventable Hospitalisations (PPH) for physical health conditions are an indicator of health service access, integration and effectiveness, and are elevated in long term studies of people with MH conditions. We aimed to examine whether PPH rates were elevated in MH service users over a 12-month follow-up period more suitable for routine health indicator reporting. We also examined whether MH service users had increased PPH rates at a younger age, potentially reflecting the younger onset of chronic physical conditions.A population-wide data linkage in New South Wales (NSW), Australia, population 7.8 million. PPH rates in 178 009 people using community MH services in 2016\u20132017 were compared to population rates. Primary outcomes were crude and age- and disadvantage-standardised annual PPH episode rate (episodes per 100 000 population), PPH day rate  and adjusted incidence rate ratios (AIRR).MH service users had higher rates of PPH admission  and a larger number of hospital days  than other NSW residents due to increased likelihood of admission, more admissions per person and longer length of stay. Increases were greatest for vaccine-preventable conditions , and chronic conditions . The highest number of admissions and relative risks were for respiratory and metabolic conditions, including chronic obstructive airways disease  and diabetic complications . One-quarter of excess potentially preventable bed days in MH service users were due to vaccine-related conditions, including vaccine-preventable respiratory illness. Age-related increases in risk occurred earlier in MH service users, particularly for chronic and vaccine-preventable conditions. PPH rates in MH service users aged 20\u201329 were similar to population rates of people aged 60 and over. These substantial differences were not explained by socio-economic disadvantage.PPHs for physical health conditions are substantially increased in people with MH conditions. Short term (12-month) PPH rates may be a useful lead indicator of increased physical morbidity and less accessible, integrated or effective health care. High hospitalisation rates for vaccine-preventable respiratory infections and hepatitis underline the importance of vaccination in MH service users and suggests potential benefits of prioritising this group for COVID-19 vaccination. Disadvantage, lifestyle, increased prevalence of chronic illness, medication side effects, reduced help-seeking and the accessibility and quality of health care all contribute to this mortality gap  rates of PPH in MH service users, examining whether increased rates observed in longer-term follow-up studies are also observed over shorter time periods more suitable for routine indicator reporting. Second, to examine the relationship between age and the risk of PPH admission. People with MH conditions have a younger age at onset of risk factors such as obesity and conditions such as cardiovascular disease  state government hospital and community services are provided through 15 geographically organised Local Health Districts and three Speciality Health Networks, which are responsible for physical care  as well as MH care. State government-operated community MH services are organised around geographical catchment areas, are free of charge and can be accessed without referral by a General Practitioner (primary care physician). Private office-based primary and specialist care, private hospital care, and pharmaceuticals are funded or subsidised by the Australian Federal Government with a varying degree of consumer co-payment. Referral by a General Practitioner is required to access subsidised private specialist care. Private hospitals mainly provide non-emergency care (including voluntary MH care) for individuals opting in to private health insurance: in the study period, private hospitals provided 23% of total acute overnight hospital episodes in NSW and 27% of acute overnight hospital days  MH service user status, defined as any contact with state specialist MH services in the preceding 2 years, (ii) age and (iii) socio-economic status of person's area of residence. MH service user status was defined by linkage to state-wide community MH datasets.The study group (MH group) were NSW residents aged 0\u2013100 years who had clinical contact with any NSW government  ambulatory MH service between 1 July 2015 and 30 June 2017. These included face-to-face, telephone or videoconference contacts in community MH centres, home visits, hospital outpatient clinics or emergency departments. Services to non-NSW residents, administrative contacts, case conferences and in-reach services to hospital inpatients were excluded. Age, sex and area of residence were defined at the index contact in the observation period. Primary care, private specialist care and non-government organisation contacts are not available in the dataset.The main outcome was admission to any NSW public or private hospital in 1-year observation period between 1 July 2016 and 30 June 2017 with a primary or secondary diagnosis of a PPH, as defined using Australia's national specification  program, a data linkage examining premature mortality in MH service users. Data were linked by the NSW Centre for Health Record Linkage . Data sets and linkage methods are described elsewhere  any PPH, (ii) three PPH groups  and (iii) 21 individual PPH conditions. For ease of interpretation, chronic conditions were further sub-grouped into cardiovascular, metabolic and respiratory conditions, and acute conditions into acute infections, seizures and other acute conditions. Episodes with multiple PPH diagnoses were counted separately for condition-specific rates but treated as a single episode when calculating overall PPH rates. Age-specific rates were calculated using 5-year bands defined by age on 30 June 2016. Differences in the proportion of people with any PPH were tested using a two-sample test of proportions. Differences in the number of PPH episodes per person and the average length of stay of PPH episodes were compared using Wilcoxon's rank-sum test.Adjusted Incidence Rate Ratios (AIRRs) were calculated by direct standardisation to the NSW non-MH population distributions for age group and for the socioeconomic disadvantage index of the person's area of residence (expressed as a quintile). Disadvantage was measured using the Australian Bureau of Statistics Index of Relative Socioeconomic Disadvantage (IRSD)  PPHs occurring prior to first MH contact in the observation period, (ii) admissions to private hospitals and (iii) PPH with associated MH care.The study was approved by the NSW Population and Health Service Research Ethics Committee  and the Aboriginal Health and Medical Research Council of NSW (Ref 1564/19).The study is overseen by (i) a Steering Committee which includes representation from peak organisations representing NSW health consumers, MH service users and MH carers, and (ii) an Aboriginal Advisory Committee which includes Aboriginal people with lived experience, community organisation, policy and research expertise.et al., A total of 178\u00a0009 people had contact with NSW ambulatory MH services in the observation period. Half (50.1%) were male. MH service users were younger than the NSW population: most were aged between 15 and 44 , see Supplementary Table s2. Diagnostic characteristics of our community cohort are described elsewhere: the most common specific diagnoses are affective disorders, psychotic disorders and other MH conditions including anxiety and adjustment disorders , particularly chronic obstructive airways disease . Rates were also significantly increased for metabolic conditions  including diabetic complications  and for cardiovascular conditions . Amongst acute conditions, the highest rate ratios were for seizures and epilepsy , which comprised 12% of total PPH admissions in the MH group but only 5% in the non-MH group.After adjustment for age and disadvantage, MH service users experienced 3.6 (95% CI 3.5\u20133.6) times the rate of PPH compared to other NSW residents . AIRR weother vaccine-preventable conditions , which includes hepatitis B and C, mumps, herpes zoster, diphtheria and pertussis, as well as for vaccine-preventable pneumonia and influenza  which includes influenza and haemophilus or streptococcal pneumonia.PPH risk was increased for both categories of vaccine-preventable conditions. Risk was elevated for The risk of PPH admission varied with age . Preventable hospital days were increased in most conditions, particularly chronic respiratory conditions , diabetes complications , vaccine-preventable conditions , acute pneumonia  and seizures and epilepsy . The average length of stay was increased for almost all PPH conditions.MH service users had more than five times the number of hospital days per 100\u00a0000 population  compared with other NSW residents . Chronicchronic obstructive pulmonary disease, diabetic complications, congestive cardiac failure, cellulitis, seizures and urinary tract infection. Vaccine-preventable conditions contributed nearly one-quarter (24.5%) of excess bed days because of their greater incidence and substantially increased length of stay.MH service users experienced 63\u00a0134 days in the hospital due to PPH conditions in 2016\u20132017; 80% more than the expected number among other NSW residents , excluding PPH admissions to private hospitals significantly increased the gap between MH service users and other NSW residents, because MH service users had fewer PPH admissions in private hospitals. Excluding PPH episodes occurring in specialised MH units, or PPH episodes occurring prior to a person's first community MH contact did not significantly alter the AIRR for PPH episode rates and caused a small but statistically significant reduction in AIRR for PPH days.et al., et al., et al., et al., et al., In the NSW population of nearly 8 million, MH service users had 3\u20134 times more preventable hospital admissions for physical health care, were admitted at a much younger age and spent substantially longer in hospital for equivalent conditions when compared to people without MH service contact. These findings are likely to reflect several interacting factors. First, rates of medical morbidity are increased in people with MH conditions. Our finding of more than five-fold increases in admission rates for chronic respiratory disease and diabetes complications is consistent with the increased prevalence of these conditions in people with MH conditions (Firth et al., et al., et al., et al., et al., Second, increased preventable admission is likely to reflect health system factors. PPHs are an effective measure of access to primary and specialist care (Parchman and Culler, et al., We found that MH service users had five-fold increases in per capita rates of preventable hospital bed days. Of the total, 80% of bed days for MH service users were excess to those which would be expected if PPH incidence and the average length of stay were the same as for other NSW residents. MH service users are around 2% of the NSW population, but account for around 10% of preventable bed days for chronic respiratory and metabolic conditions and up to 20% of bed days for vaccine-preventable conditions. These findings highlight the significant burden of these preventable hospitalisations for individuals and for the health system. The finding of longer average stays for equivalent conditions underlines the importance of proactive consultation-liaison psychiatry, and integrated physical and MH care in general hospital settings (Oldham higher than in earlier cohorts with longer follow-up periods. Kisely et al. (et al. (The current study examined whether increased PPH rates reported in previous longer-term studies were also observed over a 12-month time period more suitable for routine indicator reporting. Relative rates in the current study were y et al.  examined (et al.  followedet al., The second aim of the current study was to examine the interaction between age and PPH in MH service users. One study has reported a U-shaped relationship between age and PPH rates, finding higher rates of PPH among children, youth and older people (Guo This study uses linked data from routine health collections and therefore shares the limitations and biases of such data sets. In particular, the current dataset is biased towards the identification of people with more acute or severe MH conditions. Each year more than 10% of Australians access a MH service (Australian Institute of Health and Welfare, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., relative risk. However, our findings may not generalise directly to other health systems which use different definitions.Medical comorbidity and premature mortality in MH care is a global problem (Liu et al., et al., et al., et al., Socioeconomic disadvantage influences population PPH rates (Pappas et al., Twelve-month PPH rates appear to be a potentially useful indicator for measuring the personal and health system impacts of increased medical morbidity in MH service users. Collaborative efforts such as the \u2018Equally Well\u2019 initiatives in the UK, Australia and New Zealand (National Mental Health Commission,"}
+{"text": "Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. There is currently no effective treatment, which makes preclinical prediction for AD particularly important  applications.Wang X. et al., focus on subjects with low and high plasma A\u03b2 levels among individual with SCD. They investigate the microstructural changes in white matter (WM) based on diffusion tensor imaging from dataset of Sino Longitudinal Study on Cognitive Decline (SILCODE). Result shows a correlation between WM integrity  and plasma \u03b2-amyloid (A\u03b2) 40 levels rather than A\u03b242 in individuals with SCD. This indicates plasma A\u03b240 levels may represent a useful biomarker to predict different trajectories of aging in individuals with SCD.The author Qiao et al., analyses the associations between WM disruptions and cognitive declines at the early stage of subcortical vascular cognitive impairment (SVCI). This study concludes the damage of long WM in right hemisphere in the pre-SVCI patients and correlated with declines in executive functions and spatial processing.Another case-control study by Huang et al., uses multi-kernel support vector machine (SVM) to examine whether WM structural networks can be used for screening SCD and aMCI. Their findings promote the development of potential brain imaging markers for the early detection of AD.The study by Yang et al., explore microstructural and cerebral blood flow (CBF) abnormalities in individuals with SCD plus and aMCI. They point out the mean kurtosis of DKI may be used as an early potential neuroimaging biomarker and may be more sensitive than CBF at the very early stage of AD.Based on diffusional kurtosis imaging (DKI) and three-dimensional (3D) arterial spin labeling (ASL), Wu Z. et al., examines group differences in gray matter surface morphometry, including cortical thickness, the gyrification index (GI), and the sulcus depth. The authors aim to track the progression of the disease in different stages of AD, including health controls, early MCIs, late MCIs, and ADs. Based on region-of-interest (ROI) analysis, their study shows that cortical thickness and sulcus depth indices are predominant during AD progression while GI is insensitive. The findings highlight the relevance between gray matter surface morphometry and the stages of AD, laying the foundation for in vivo tracking of AD progression.The paper by Fu et al., extracts gray matter volumes to predict the regional densities in the whole brain in normal control (NC), SCD, Amnestic mild cognitive impairment (aMCI) and AD. In this study, decreased structural covariance and weakened connectivity strength are observed in SCD compared with NC. In addition, increased structural covariance in aMCI and decreased structural covariance in AD are also found. These results provide evidence to the structural disconnection hypothesis in individuals with SCD.The study by Li et al., points out the impairment in spatial navigation (SN) in patients with MCI. They demonstrate that structural connectivity network abnormalities, especially in the frontal and parietal gyri, are associated with a lower SN accuracy, independently of white matter hyper intensities, which providing a new insight into the brain mechanisms associated with SN impairment in MCI.The study by Cui et al., points out different functional activity of the SCD patients with aMCI patients, which suggest SCD may be a separate stage of cognitive decline before aMCI and is helpful to the study of preclinical cognitive decline.The study by Tao et al., further identify individuals with SCD or aMCI from healthy control (HC) and to describe the relationship of pathological changes in these two stages. They conclude that the neural degeneration from SCD to aMCI follows a gradual process, from abnormalities at the nodal level to those at both nodal and network levels.Based on the topological characteristics of the WM network, Chen Q. et al., identifies distinct functional states and explore the reconfiguration functional connectivity (FC) in individuals with SCD. Results indicate that the alterations of dynamic FC may underlie the early cognitive decline in SCD patients and could be served as sensitive neuroimaging biomarkers.The study by Wei et al., discover four interactions among self-reference network (SRN), dorsal attention network (DAN), and salience network (SN) using resting-state fMRI. These results point out that the influence of the SRN in the ultra-early stages of AD is non-negligible.Taking the important role of self-reference processing into account, Xu et al., explores the specific characteristic based on the multimodal brain networks, including individual morphological, structural and functional brain networks. Results highlight the role of cortical-subcortical circuit in individuals with SCD, providing potential biomarkers for the diagnosis and prediction of the preclinical stage of AD.The study by Wu L. et al., investigates the cognitive impairment in individuals with chronic pontine stroke based on voxel-mirrored homotopic connectivity. Results indicate the important role of lingual gyrus and precuneus as ROIs in the early diagnosis of cognitive impairment individuals with chronic pontine stroke.The study by Wang Y. et al., demonstrates that the carotid calcifications are associated with post-stroke cognitive impairment (PSCI). They conclude that the significant role of large vessel atherosclerosis in PSCI should be concerned in future study.The study by Chen Y. et al., concludes that the methylation of peripheral NCAPH2 could be used as a useful peripheral biomarker in the early stage of AD screening. Low levels of NCAPH2 methylation are observed in SCD, and which is independent of the APOE \u03b54 status. In addition, there is a positive correlation between NCAPH2 methylation levels and the hippocampal volumes in SCD APOE \u03b54 non-carriers.The study by Dakterzada et al., compares the results of Innotest enzyme-linked immunoassay (ELISA) with two automated methods (Lumipulse and Elecsys). Both Lumipulse and Elecsys methods are highly concordant with clinical diagnoses, and the combination of Lumipulse Ab42 and P-tau has the highest discriminating power. They recommend both automated methods for the measurement of CSF biomarkers.The study by Shi et al., explores whether adenosine receptor 1 (A1 R) is involved in electroacupuncture (EA) pretreatment induced cognitive impairment after focal cerebral ischemia in rats. The results showed that EA pretreatment revered cognitive impairment, improved neurological outcome, and inhibited apoptosis at 24 h after reperfusion. Pretreatment with CCPA (a selective A1 receptor agonist) could imitate the beneficial effects.The study by Lin et al., examines the relationship between spinal cord injury (SCI) and olfactory dysfunction. They point out that the SCI initiates pathological processes, including inflammatory response and impaired neurogenesis. These results provide a basis for pathological mechanisms of early neurodegenerative diseases involving the olfactory bulb and enable early clinical drug intervention.The study by Wu P. et al., proposes the sustained clinical efficacy of unilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in Chinese patients with ET.Essential tremor (ET) is occasionally associated with a high risk for MCI and dementia. The retrospective study by JJ, YH, and FJ have written this editorial for the Research Topic they have edited. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The study of child and adolescent learning has generally focused on aspects specifically tied to individual academic performance. However, a new emerging perspective is that any \u201cdeficit\u201d and/or disability and conversely any achievement is not the result of a single event, such as an isolated reaction, but it is formed, through numerous biosocial contributing variables, during a child's attempt to adapt to learning conditions and settings. The fit between such adaptations and normative criteria  is often associated with labels such as \u201cfulfillment,\u201d \u201cstrengths\u201d \u201cresilience\u201d or \u201cweaknesses,\u201d \u201crisk,\u201d \u201cvulnerability\u201d and \u201cdisability.\u201dThis Research Topic explored the overlapping challenges and themes related to developmental adaptations (as defined above) in the context of formal and informal settings for learning primarily within childhood and adolescence.Jefferies et al. investigated the relationships between the multidimensional constructs of physical literacy and resilience in 227 school Canadian children aged 9\u201312 years old. They found that resilience was predicted by movement capacity, confidence, and competence, environmental engagement, and overall perceptions of physical literacy. Their research highlights the importance of introducing physical literacy in schools.To start off in this path, Ato et al. examined the impact of temperament on academic achievement and sociometric status in a sample of 295 6\u20137-year-old Spanish children. Parents completed the Temperament in Middle Childhood Questionnaire, while sociometric status and academic achievement were derived from teachers' reports. Latent profile analysis showed that Children in the \u201cNegative/Undercontrolled\u201d profile were at higher risk for academic failure and peer rejection, while \u201cSociable/High regulated\u201d showed the reverse pattern. The findings have very important (so far underexplored) implications for ways in which schools could integrate \u201cdifficult children.\u201dIn a similar vein, Yao et al. examined the association of dopamine-related genes with mental and motor development and gene-environment interaction in 201 preterm and 111 term Taiwanese children, who were followed from 6 to 36 months and were genotyped for 15 single-nucleotide polymorphisms (SNPs) in dopamine-related genes . MAOA SNPs were robustly associated with the mental (but not motor) development scores throughout early childhood in the premature children but not in the term counterparts. This warrants further investigations on whether the MAOA variants could help develop personalized interventions for preterm children.Two contributions focused on early developmental determinants. Firstly, Li et al. examined whether executive function training (EFT) could improve children's emotional competence (EC). Fifty-five 4-year-old Chinese children were assigned to either EFT or no-EFT group. Pre-test vs. post-test training between-and- within-subjects effects were analyzed to quantify improvement. EFT was associated with significantly higher scores on EC and changes in inhibition control and working memory abilities significantly predicted variation in EC. The findings suggest that intervening on inhibition control and working memory abilities via training may improve preschool children's emotional abilities.Considering another early developmental period, Caramia et al. recruited 29 young Italian adolescents to test whether walking with a smartphone increased fall and injuries risk, and to quantify these possible outcomes, participants were asked to walk along a walkway, with and without a concurrent writing task on a smartphone. Concurrency of walking and smartphone use resulted in reduced step length, gait speed and general aspects of gait stability, regardless of experience or frequency of use, suggesting that using the smartphone while walking may determine an increased risk of injury or falls also for young digital natives.At the other end of the spectrum, adult studies have shown that the concurrency of a smartphone-related task and walking can increase instability and risk of injuries. Zhao et al. developed the Brief Haze Weather Health Protection Behavior Assessment Scale-Adolescent Version (BHWHPBAS-AV), and tested its validity and reliability in two randomly selected districts of Baoding, China, and involving 22 middle-school classrooms and 1,025 valid questionnaires. The BHWHPBAS-AV scale showed promising reliability and validity suggesting it may be applied to assess adolescent haze weather health protection behavior, and help school and medical staff administer targeted behavioral and preventative interventions or health education programs.Adopting an approach to prevent air pollution, Grant et al. assessed the cognitive profiles of 360 Canadian adults and children ranging from 7 to 80 years of age with disability in reading alone, mathematics alone and both (comorbidity), with tests widely used in both psychoeducational and neuropsychological batteries. Through a systematic exhaustive review of clinical neuroimaging literature, they mapped the complex set of domain-specific and domain-general impairments shown in the comorbidity of reading and mathematical disabilities to correspondingly plausible neuroanatomical substrates of dyslexia and dyscalculia. According to their hypothetical model, reading-math comorbidity seems due to atypical development of the left angular gyrus. This neuroeducational framework may assist to improve both early prediction and intervention across developmental periods.In a second prevention study, Malboeuf-Hurtubise et al. reported a pilot study based on a new intervention, which combines mindfulness meditation and Philosophy for Children (P4C) activities, with the goal of improving mental health in pre-kindergarten children. Thirty-eight pre-kindergarten Canadian children took part in this study and were randomly allocated to the experimental or wait-list control conditions. Teachers completed pre- and post-intervention questionnaires. Although there were no significant effects, some improvement trends were found for internalized symptoms and hyperactivity. The results partly contradict previous research and suggest that mindfulness and P4C may not be effective intervention for mental health in children. However, the study also suggests a host of other confounding variables that might be responsible for the null findings and should be addressed in future research.Finally, In summary, this Research Topic collection explored how children's preferences, profiles and predispositions are shaped by the social and biological activities that form the background of their everyday living. These papers addressed integrated multidisciplinary issues of education, development and public health, contributing practical examples of viable and sustainable local targeted programs, which, hopefully, may stimulate future research.AD'A wrote the first draft. All authors contributed equally to edit to final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "GBA1, the gene encoding the enzyme glucocerebrosidase. Deficiency of glucocerebrosidase leads to the accumulation of the substrates glucocerebroside and glucosylsphingosine in macrophages and neuronal cells. Variants in GBA1 are a significant genetic risk factor for Define- Parkinson disease (PD)  methods  is a rare autosomal recessive lysosomal storage disorder caused by pathologic variants in GBA1 is located in a gene-rich region on chromosome 1q21 that encompasses seven genes and two pseudogenes within an 85-kb region , non-processed pseudogene, GBAP1 , encoding for part of the mitochondrial outer membrane import complex protein 1, which is transcribed convergently to GBA1 , which now includes over 600 different GBA1 variants with differing predicted clinical significance (https://www.centogene.com/centolsd.html). Many NGS protocols have utilized short-read sequencing, which can provide data at a relatively low cost and high accuracy but may be less reliable in cases where there are structural variants and repetitive or highly homologous regions (Mandelker et al., GBA1, Zampieri et al. initially aligned reads to the whole genome, but missed almost all recombinant alleles, which had aligned preferentially to GBAP1 (Zampieri et al., GBA1 rather than the whole genome, they were able to identify recombinant variants that had initially been false negatives, except for the 55-bp deletion mutation. Alignment against the whole genome did not significantly affect the mapping quality and coverage of missense mutations unrelated to recombination. Care should therefore be taken not only in the library preparation, but also in data analysis steps of NGS pipelines to sequence GBA1.Next-generation sequencing is able to generate vast amounts of sequence data and has been applied to identify variants in GBA1 variants using the Oxford Nanopore MinION (Leija-Salazar et al., NciI. Another study aimed to expand upon this protocol by refining and applying it to the discovery of GBA1 variants in a PD longitudinal cohort from New Zealand (Graham et al., GBA1 and updated the software pipeline, improving accuracy and reducing the computational workload, but were unable to detect any recombinant gene conversion alleles or deletions of >50 bp.The introduction of long-read sequencing technology in recent years addressed some limitations of short-read sequencing (Goodwin et al., GBA1 is complicated by complex gene-pseudogene rearrangements and recombination. Recombinant alleles make up a significant proportion of GBA1 mutations and sites of recombination events have been identified between intron 2 to exon 11 (Hruska et al., GBA1 and its pseudogene, there is an increased likelihood of both reciprocal and non-reciprocal recombination (Tayebi et al., NciI. In this allele, the site of crossover of chromosomal mispairing between gene and pseudogene occurs within intron 9 and continues to the 3'-UTR of the gene, introducing three exon 10 nucleotide mismatches (Latham et al., RecTL, covers the pseudogene sequence from intron 8 or the beginning of exon 9 [GBAP1 (Martinez-Arias et al., MTX and its pseudogene as well (Tayebi et al., GBA1 alleles (Velayati et al., Accurate and comprehensive NGS analysis of GBA1 gene rearrangements cannot be sufficiently captured using most current NGS methods. Several recent studies using NGS technology without Sanger sequencing validation have not reported the presence of recombinant alleles, including a recent study performed on more than 3,000 PD cases (den Heijer et al., The complexity of de novo or germline mutations on the maternal allele (Saranjam et al., GBA1 and S78L in MPZ (Benko et al., GBA1 mutation on the same allele (Hassan et al., GBA1 screening, and for now, Sanger sequencing should be used for the most accurate genotyping.Gaucher disease is an autosomal recessive disorder that usually results from the inheritance of a mutant allele from each parent. Increasing evidence suggests this may not always be the case, and that there are important exceptions to the traditional Mendelian pattern of inheritance, such as new mutations or uniparental disomy (Nakka et al., GBA1 in many Parkinson disease NGS analyses, it is important to consider the effects of the nearby homologous pseudogene. Recombinant alleles in GBA1 have been identified in patients with GD and with PD that might be missed when relying on NGS analysis alone without Sanger sequencing validation.Next-generation sequencing allows for unbiased simultaneous analysis of many genes. In addition, it makes it more feasible to analyze specific genes in larger cohorts for the study of common diseases like Parkinson disease. With the inclusion of GBA1 confirmed by Sanger sequencing. In addition, there is evidence to suggest that the choice of polymerase used could be a factor in the accuracy of NGS variant identification. A recent study performed a large-scale screening of GBA1 based on an NGS protocol and found a significant number of false negatives due to a polymerase-dependent allelic imbalance (den Heijer et al., Challenges exist in short-read NGS methods for sequencing highly homologous regions. The shorter reads cannot be mapped uniquely to the reference genome, especially in cases where there are recombinant alleles aligning to the homologous region. A computational custom scaffold-based approach was recently introduced to improve the detection and phasing of targeted complex variants using short reads (Zeng et al., GBA1 from their pseudogenes. An additional advantage is the ability to phase mutations and assign haplotypes. It can also detect intronic SNPs. There are still some limitations, including high costs, low throughput, and high per-base error rates. Long-read NGS also has a limited ability to accurately resolve homopolymers and to detect small insertions and deletions. Importantly, it is still unable to consistently detect recombinant alleles.Long-read NGS has many advantages, one of which is an improved ability to discriminate functional genes such as GBA1 variants and recombination remains Sanger sequencing. Without validation by Sanger sequencing, the frequencies of GBA1 variants based on NGS analysis may be underestimated, particularly for complex recombinant alleles. Real-time PCR can also be used to identify recombinant alleles (Velayati et al., GBA1 NGS analysis, it is still currently limited in its capacity to recognize recombinant alleles. The shortcomings identified will likely also be pertinent for the analysis of other genes with highly homologous pseudogenes. As sequencing technology continues to rapidly progress, we will likely continue to see improved detection of GBA1 variants. This has exciting potential for clinical diagnostics and studies of large patient cohorts.The most accurate method for detecting all EW: drafted the manuscript and figure. NT: organized the topic, reviewed the literature, and edited the manuscript. ES: conceived of the topic and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Motoric Cognitive Risk (MCR) syndrome is a clinical syndrome combining slow walking speed and subjective cognitive complaints (SCC) that was first reported by Verghese et al. in 2013 [Recently, we reported that MCR is associated with anxio-depressive disorders and depression (ADDD) in a cross-section of a large population-based cohort known as \u201cThe Canadian Longitudinal Study on Aging\u201d . We demoThe risk of major neurocognitive disorders in individuals with MCR is more than twice that of those without MCR . FurtherIn addition to MCR, depression has been independently associated with an increased risk of major neurocognitive disorders . In indi"}
+{"text": "Cancer research in the field of Computational Systems Biology attempts to address questions that will advance current knowledge in the mechanisms of cancer progression or treatment resistance. By analyzing multi-omics data and developing a predictive mathematical and/or computational model of an unknown biological system, we can systematically understand 1) the mechanisms that tie altered gene expression and downstream molecular mechanisms to functional cancer phenotypes ; 2) and/Artificial Intelligence (AI) Optimized Systems Modeling for the Deeper Understanding of Human Cancers\u201d in Frontiers in Bioengineering and Biotechnology, and Frontiers in Genetics aims to provide an international forum for:1) bringing together the greatest research efforts in cancer-specific molecular/network signature identification by integrating multi-omics/multi-level data;etc., to provide novel ideas and solutions in mathematical modeling for tumor growth, drug resistance, and targeting effect prediction;2) exploring future-generation interesting and practical biomedical applications in AI, machine learning, big data sciences, knowledge-based system, 3) addressing the real-world challenges in the fields of AI-based patient diagnosis or disease progression prediction by utilizing modern machine learning or statistical strategies, and produce a more reliable and promising application environment to develop those technologies.This special issue entitled \u201cetc. The final acceptance rate is 50% with 18 accepted papers in this special issue. The summaries of these papers are outlined below.1) New bioinformatic approaches to Identify key molecular/network signatures for precision diagnosis or treatment of cancersSubmission for this special issue started from May 2020 and closed in Oct 2020. In nearly one and half years, we received in total 36 paper submissions. All submitted manuscripts had gone through at least two rounds of revision with reviewers in the related fields, including bioinformatics, computational biology, machine learning, and clinical study, Identification of signatures of prognosis prediction for melanoma using a hypoxia score\u201d by Shou et al. The authors developed a computational method to identify the gene signatures of melanoma in hypoxic condition for prognosis prediction.In the article entitled \u201cIdentifying hypoxia characteristics to stratify prognosis and assess the tumor immune microenvironment in renal cell carcinoma\u201d by Zhang et al. The authors established a hypoxia-related risk model to predict the prognosis of patients.In the article entitled \u201cPrediction of Radiosensitivity in Head and Neck Squamous Cell Carcinoma Based on Multiple Omics Data\u201d by Liu et al. The authors identified 12-gene signature based on multiple omics data achieved the best ability for predicting radiosensitivity in Head and Neck Squamous Cell.In the article entitled \u201cAn Effective Graph Clustering Method to Identify Cancer Driver Modules\u201d by Zhang et al. The authors proposed a graph clustering method, called \u201cMCLCluster\u201d, to identity cancer driver modules that drive cancer progression.In the article entitled \u201cExploring the differential expression and prognostic significance of the COL11A1 gene in human colorectal carcinoma: an integrated bioinformatics approach\u201d by Patra et al. The authors developed an integrated bioinformatics approach to reveal the COL11A1 gene as a prognostic biomarker in colorectal carcinoma.In the article entitled \u201cMicroRNA-126 Modulates Palmitate-induced Migration in HUVECs by Downregulating Myosin Light Chain Kinase via the ERK/MAPK Pathway\u201d by Zhu et al. The authors evaluated the effects of miR-126 on the cell migration and uncovered the underlying mechanism in HUVECs treated with palmitate.In the article entitled \u201cIntegrated analysis of DEAD\u2010box helicase 56: a potential oncogene in osteosarcoma\u201d by Zhu et al. The authors set up a novel integrated analysis protocol and found that DDX56 is a potential therapeutic target for the treatment of osteosarcoma.In the article entitled \u201cA machine learning approach for tracing tumor original sites with gene expression profiles\u201d by Liang et al. The authors developed a machine learning approach by integrating random forest and Naive Bayesian, to predict the primary origin sites of tumors.In the article entitled \u201cA deep learning framework to predict tumor tissue-of-origin based on copy number variation\u201d by Liang et al. The authors proposed a deep learning framework composed of an autoencoder (AE) and a convolution neural network (CNN) to predict the primary origin sites of tumors.In the article entitled \u201cTOOme: a novel computational framework to infer cancer tissue-of-origin by integrating both gene mutation and expression\u201d by He et al. The authors integrated somatic mutation and gene expressions t infer the primary original sites of tumor and obtained a great accuracy.2) New studies of clinical informatics for speeding up the development of cancer diagnosisIn the article entitled \u201cDiagnosis of cervical cancer with parametrial invasion on whole-tumor dynamic contrast-enhanced magnetic resonance imaging combined with whole-lesion texture analysis based on T2-weighted images\u201d by Li et al. The authors integrated DCE-MRI images and texture analysis for diagnosis cervical cancer.In the article entitled \u201cPredictive value of the texture analysis of enhanced computed tomographic images for preoperative pancreatic carcinoma differentiation\u201d by Zhang et al. The authors extracted 396 features from patient CT images and selected the optimal feature subset to predict the pathological degree of differentiation of pancreatic carcinoma.In the article entitled \u201cRA-UNet: A hybrid deep attention-aware network to extract liver and tumor in CT scans\u201d by Jin et al. The authors developed a 3D network model, RA-UNet, to precisely extract the liver region and segment tumors from the liver. Testing on public datasets show that the proposed architecture obtains competitive results.In the article entitled \u201cClassification of Infected Necrotizing Pancreatitis for Surgery within or beyond Four Weeks Using Machine Learning\u201d by Lan et al. The authors applied machine learning models to predict the optimal timing of surgical intervention and identified the key factors associated with surgical timing for infected necrotizing pancreatitis.In the article entitled \u201cPrediction of Proximal Junctional Kyphosis after Posterior Scoliosis Surgery with Machine Learning in the Lenke 5 Adolescent Idiopathic Scoliosis Patient\u201d by Peng et al. The authors developed a machine learning model for proximal junctional kyphosis (PJK) prognostication in Lenke 5 adolescent idiopathic scoliosis (AIS) patients undergoing long posterior instrumentation and fusion surgery.In the article entitled \u201cA New Method Based on CEEMD Combined with Iterative Feature Reduction for Aided Diagnosis of Epileptic EEG\u201d by Peng et al. The authors proposed a computational method based on complementary ensemble empirical mode decomposition (CEEMD) combined with iterative feature reduction for aided diagnosis of epileptic EEG.3) New strategies for optimizing the data preprocessing and quality controlIn the article entitled \u201cAssessing the impact of data preprocessing on analyzing next generation sequencing data\u201d by He et al. The authors compared commonly used data preprocessing software and found differences in the detection of hotspot mutations and HLA typing. They also explained the impact of data preprocessing steps on downstream data analysis results.In the article entitled \u201cRF-PCA: A New Solution for Rapid Identification of Breast Cancer Categorical Data Based on Attribute Selection and Feature Extraction\u201d by Bian et al. The authors developed a hybrid model RF-PCA, which significantly reduce the time required for the classification, but also improved the accuracy.In the article entitled \u201cThe guest editors would like to thank all authors submitting their valuable works to this special section of Frontiers in Bioengineering and Biotechnology, Frontiers in Genetics, as well as all peer-reviewers for their great effort reviewing the submitted articles, providing constructive comments and suggestions and assisting the editors reaching the final decision. Special thanks will be sent to the editor-in-chief (EIC), Ranieri Cancedda and Jos\u00e9 AG Ag\u00fandez, for their precious time and valuable instructions that help us prepare and finalize this special issue."}
+{"text": "They constitute important components in the human diet, acting as nutraceutical compounds with antioxidant, chemopreventive, antimitotic, neuroprotective, cardioprotective, and anti-inflammatory activities. Several phenylpropanoids are considered high-value biochemicals employed in the production of fragrances, pharmaceuticals and biopolymers  functional characterization of genes involved in the phenylpropanoid metabolism and its coordination with physiological processes; and (4) biotechnological approaches to exploit the economic, medicinal, and nutraceutical potential of phenylpropanoids.This Research Topic aimed to gather recent findings in all aspects of phenylpropanoid metabolism gained by means of systems biology approaches and the utilization of biotechnology to exploit the economic, medicinal and nutraceutical potential of phenylpropanoids. The topic is organized into four sections: (1) structural, molecular and computational approaches toward unraveling the biosynthetic pathways involved in synthesis of diverse phenylpropanoid-derived metabolites; (2) discovery of genes and/or gene networks involved in distinct aspects of phenylpropanoid metabolism Delli-Ponti et al. (in this volume) have reviewed how gene expression and co-expression networks can be used as tools to uncover specialized metabolism biosynthetic pathways. Also using a computational approach, Elder et al. (in this volume) have applied density functional theory (DFT) calculations to evaluate the thermodynamics of coupling modes and subsequent rearomatization reactions between coniferyl alcohol and hydroxystilbene glucosides, which has been detected as a natural monomer in the bark lignin of Norway spruce.The chemical diversity of phenylpropanoids results from the modification and amplification of a set of core structures derived from the shikimate pathway. A vast array of regulatory proteins, biosynthetic enzymes, oxidases and other genes are recruited to produce the various classes of phenolic metabolites. Additionally, many phenylpropanoids are specific to just one or a few plant species, underscoring the complexity of phenylpropanoid biosynthesis and the need for comprehensive characterization studies in diverse species that expand our knowledge base beyond traditional model plant and crop species. Structural, molecular and computational approaches have been applied to identify genes, enzymes and metabolites involved in the biosynthesis of phenylpropanoids in different plants. Du et al. (in this volume). Lignin is a phenolic polymer important for plant growth and development but it is also considered a major bottleneck to the efficient conversion of plant biomass into downstream products. Rosado et al. (in this volume) have reported an in-depth characterization of the structural characteristics of lignins present in rice husks and straw, which are agricultural by-products that can be used to produce chemicals and materials in biorefineries. To identify the timing and key parameters of cell wall recalcitrance across different switchgrass genotypes, Saha et al. (in this volume) measured cell wall composition and phenylpropanoid/lignin biosynthesis gene expression in three switchgrass genotypes representing lowland and upland ecotypes. Yao et al. (in this volume) reviewed recent progress in defining the lignin biosynthetic pathway in lycophytes, monilophytes, gymnosperms, and angiosperms, and integrated new insights on major transcriptional regulators. In another study with evolutionary implications, Rencoret et al. (in this volume) structurally characterized the lignin-like fractions isolated from several ancestral plants, including those from moss, lycophyte, horsetail, fern, cycad, and gnetophyte species. Blaschek and Pesquet (in this volume) provided an overview of the differences and similarities in the structures, reaction mechanisms, substrate specificities, and functional roles between phenoloxidases. Because grasses are able to synthesize phenylpropanoids from either phenylalanine (Phe) or tyrosine (Tyr), Simpson et al. (in this volume) employed 13C isotopic-labeled precursors and mass spectrometry-based metabolomics to determine the downstream metabolites derived exclusively from Phe and Tyr in sorghum. Several phenylpropanoids show bioactivity that might influence plant growth and development or might be beneficial for human health. El Houari et al. (in this volume) reviewed reports describing altered accumulation of bioactive phenylpropanoids (or phenylpropanoid-derived metabolites) as the causal factor for observed phenotypes of lignin mutants in Arabidopsis. Cappellini et al. (in this volume) reviewed the recent progress in understanding the anthocyanin biosynthetic pathway in plants, with special emphasis on the differences in molecular mechanisms between monocot and dicot plants, and discuss the biological activities of anthocyanins as beneficial components of the human diet. Similar to anthocyanins, tannins form another group of phenolic compounds with beneficial effects on human health. Wang et al. (in this volume) performed a genome-wide analysis of the tannase gene family to identify candidate genes responsible for tannin metabolism in three nut tree species in the Juglandaceae family: walnut, pecan, and Chinese hickory.The biosynthesis of phenylpropanoids is often triggered by environmental stimuli. To this end, the effect of chilling treatment on the accumulation of phenylpropanoids and on antioxidant activity in seedlings of two rice varieties (contrasting for chilling tolerance) was studied by Tang et al. (in this volume) leveraged single-molecule real-time sequencing technology to elucidate flavonoid synthetic pathways in blueberries. Their transcriptome analyses led to the discovery of a R2R3 MYB transcription factor that can positively regulate anthocyanin synthesis in fruits. 5-aminolevulinic acid (ALA) is a plant growth regulator that induces fruit coloration and thereby finds potential applications in modern fruit production. A transcriptome study by Zheng et al. (this volume) identified the differentially expressed genes associated with ALA-induced anthocyanin accumulation in apple, including two R2R3-MYB transcription factors involved in flavonoid accumulation. A study by Ani\u010di\u0107 et al. (this volume) investigated flavonoid metabolism during fruit development in rockrose, a traditional medicinal plant rich in bioactive phenylpropanoids, using comparative metabolomic and transcriptomic approaches. This work highlights correlations between expression patterns of biosynthetic genes and the content of proanthocyanidins. Phenolic compounds are modulated by biotic and abiotic stresses, and a study by Laou\u00e9 et al. (in this volume) used quantitative trait locus (QTL) mapping and RNA-Seq to explore the complex polygenic network underlying the constitutive production of specific stilbenoids, flavonoids, and lignans in white spruce. Understanding the formation of secondary cell walls (SCWs) and their lignification has important agro-industrial applications. Hixson et al. (this volume), by undertaking an integrated analysis of the metabolome, transcriptome, and proteome of Arabidopsis lines mutated in arogenate dehydratase genes, exposed the involvement of novel proteins and additional post-transcriptional and translational processes that govern phenylpropanoid/lignin biosynthesis. As a proxy to study SCW formation in the bioenergy crop sugarcane, Sim\u00f5es et al. (this volume) established a lignifying cell culture system that they probed with transcriptomic and metabolomic analyses to illuminate the molecular mechanisms involved in this differentiation process, leading to the discovery of regulatory modules that control SCW deposition.The identification of genes and transcriptional networks responsible for specific accumulation patterns of phenylpropanoids during a physiological development process or a stress response is essential to elucidate and harness the fine regulatory mechanisms involved in these patterns. Recent advancements in omics technologies enable integrated approaches to unravel these mechanisms at the transcriptomic, proteomic, and metabolomic levels. These studies provide platforms to guide future research on improving crops for human health and wellness. Chen et al. (in this issue) identified two non-selective uridine diphosphate (UDP) glycosyltransferases (UGTs) from Isatis indigotica Fort. that catalyze the addition of a sugar molecule onto several structurally diverse lignin acceptor substrates. Shi et al. (in this issue) sought to explore the transcriptional regulatory mechanisms of anthocyanin and proanthocyanidin biosynthesis in Chinese bayberry, of which the fruit is considered an important dietary source of natural antioxidants. They identified a MrMYB6 gene that is highly upregulated during the latter stages of fruit development and determined it is a negative regulator of anthocyanin and proanthocyanidins through formation of a complex with two transcription factors, bHLH and WD40. Busche et al. (in this issue) carried out a study five 2-oxoglutarate-dependent dioxygenases involved in the formation of the flavonoid aglycon in banana (Musa): flavanone 3-hydroxylase, flavonol synthase and anthocyanidin synthase. Biochemical analysis of several recombinant candidate proteins showed that MusaF3H1 and MusaF3H2 act as flavanone 3-hydroxylases, MusaFLS1 and MusaFLS3 both function as flavonol synthases, and MusaANS has anthocyanidin synthase activity. Elucidating the activity of these genes will facilitate the development of bananas with higher nutritional value. Hydroxycinnamoyl acid amides, such as clovamide, are phenylpropanoid metabolites that play roles in protecting plants from biotic and abiotic stresses. Sullivan and Knollenberg (this issue) identified, cloned and biochemically characterized a hydroxycinnamoyl-CoA:L-DOPA hydroxycinnamoyl transferase (HDT) from red clover that is capable of synthesizing clovamide and related hydroxycinnamoyl amides in vitro. Characterization of this enzyme activity expands our knowledge of the poorly characterized family of BAHD hydroxycinnamoyl-CoA transferase enzymes and will aid in future studies aimed at understanding the molecular basis of substrate specificity within this important family.The phenylpropanoid pathway in plants plays a major role in the synthesis of a wide variety of secondary metabolites. Metabolites originating from this pathway are frequently involved in plant structure or chemical signaling and defense, including flavonoids, lignins, hydroxycinnamic esters, flavonoids, anthocyanins and tannins. Dietary flavonoids, anthocyanins, proanthocyanidins, hydroxycinnamoyl acid amides and lignans are bioactive compounds that have been shown to exhibit multiple health promoting and antioxidant activities. Lignans are plant secondary metabolites composed of a core scaffold that is formed by two or more phenylpropanoid units that can adopt a spectrum of different structural forms. Lin et al. (in this issue) provide direct evidence that two key enzymes involved in monolignol biosynthesis, 4-Coumaric acid:CoA ligase (4CL) and 4-hydroxycinnamoylCoA:shikimic acid hydroxycinnamoyl transferase, form a Ptr4CL-PtrHCT complex in Populus trichocarpa and its formation is a potential mechanism to modulate metabolic flux during secondary cell wall synthesis. The brown midrib (bmr) phenotype found across several C4 grasses has been critical for identifying mutants compromised in lignin synthesis. Tetreault et al. (in this issue) used a combined bulk segregant analysis (BSA) and next-generation sequencing (NGA) approach to show that bmr30 encodes a chalcone isomerase (CHI) and is involved in synthesis of the flavonoid tricin and not a monolignol. In Populus species, lignin can also be further modified by acylation with p-hydroxybenzoate. Zhao et al. (in this issue) used wild type (WT), lignin p-hydroxybenzoate deficient, and p-hydroxybenzoate overproduction plants to investigate the role of this modification in the response of plants to gravitropic/mechanical stress. They showed that lignin-bound p-hydroxybenzoate content increased during tension wood formation. This increase is correlated with a significant induction of expression of a gene encoding a BAHD family acyltransferase, namely, p-hydroxybenzoyl CoA: monolignol p-hydroxybenzoyltransferase 1 (PtrPHBMT1) whose gene product preferentially conjugates p-hydroxybenzoate to S-lignin monomer sinapyl alcohol.Lignin is a heterogeneous phenolic polymer that is highly abundant in the secondary cell walls of all land plants and is composed of three major monolignol subunits: 4-hydroxyphenyl (H), guaiacyl (G), and syringyl (S). The monolignol building blocks of lignin are synthesized by enzymes acting in concert that catalyze sequential reactions. Ferreira and Antunes (this volume) reviewed current progress on synthetic biology and highlighted the application of biosensors for re-engineering and autonomously controlling plant phenylpropanoid metabolism. Lam et al. (this volume) reviewed the understanding and bioengineering of the biosynthesis of tricin, a type of plant flavonoid that is an essential plant defense chemical and a promising nutraceutical. Sullivan et al. (this volume) established a de novo hydroxycinnamoyl-malate ester biosynthetic pathway in alfalfa via heterologous expression of a red clover gene and enhanced alfalfa post-harvest protein protection. A transcriptomic study of transgenic tomato plants by Zhao et al. (this volume) defined a GATA transcription factor mediating the co-regulation of drought stress response and phenylpropanoid biosynthesis. Genetic, biochemical and physiological studies from Lee et al. (this volume) found that Arabidopsis needs optimal anthocyanin content for better growth under high nitrate and high salt conditions. A study by Roldan et al. (this volume) using transgenic white clover with high levels of foliar condensed tannins discovered that condensed tannins bind to forage proteins to reduce anthropogenic greenhouse gas emission. Huber et al. (this volume) chemoenzymatically synthesized a series of new phenylpropanoid derivatives and studied their structures and biological effects. Using qualitative and quantitative phytochemical analyses, Gampe et al. (this volume) demonstrated that Ononis hairy root cultures produce isoflavonoids with less chemical divergence and in higher quantity, suggesting a promising system for large-scale isoflavonoid production.Plant phenylpropanoids and their derivatives are essential for plant growth, stress responses, and health benefits for humans. A comprehensive understanding of the biosynthetic mechanisms and transcriptional regulatory network(s) of phenylpropanoid metabolism in various plant species is central for developing biotechnological approaches to produce economically desirable traits and products. Additionally, advancements in synthetic biology and biosensor technology illuminate the potential of real-time control of phenylpropanoid metabolism in the future. Systems biology and biotechnology have largely contributed to enhance our understanding on the molecular mechanisms underlying the biosynthesis of phenylpropanoids in plants, as well as to manipulate the phenylpropanoid metabolism to exploit its economic, medicinal and nutraceutical potential. Articles in this volume further contribute to these goals, covering different aspects and branches of the pathway. Novel insights and exciting biotechnological strategies involving the phenylpropanoid pathway are expected in the years to come.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.IC is indebted to Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo (FAPESP) for the Research Grant No. 2019/25587-0 and to Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq) for the research fellowship 302927/2018-2. MX is supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research, as part of the Quantitative Plant Science Initiative at Brookhaven National Laboratory. BU is supported by the Center for Bioenergy Innovation (CBI), a U.S. Department of Energy Bioenergy Research Center supported by the Office of Biological, Environmental Research in the DOE Office of Science.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The encapsulation of seeds in hard coats and fruit walls (pericarp layers) fulfils protective and dispersal functions in many plant families. In angiosperms, packaging structures possess a remarkable range of different morphologies and functionalities, as illustrated by thermo and hygro\u2010responsive seed pods and appendages, as well as mechanically strong and water\u2010impermeable shells. Key to these different functionalities are characteristic structural arrangements and chemical modifications of the underlying sclerenchymatous tissues. Although many ecological aspects of hard seed encapsulation have been well documented, a detailed understanding of the relationship between tissue structure and function only recently started to emerge, especially in the context of environmentally driven fruit opening and seed dispersal (responsive encapsulations) and the outstanding durability of some seed coats and indehiscent fruits (static encapsulations). In this review, we focus on the tissue properties of these two systems, with particular consideration of water interactions, mechanical resistance, and force generation. Common principles, as well as unique adaptations, are discussed in different plant species. Understanding how plants integrate a broad range of functions and properties for seed protection during storage and dispersal plays a central role for seed conservation, population dynamics, and plant\u2010based material developments. In fruits and seeds, tissue hardening is often a result of lignification, but hard secondary cell walls may also consist mainly of polysaccharides. A good example are the hard, nonlignified endosperm cell walls in many palm seeds \u2013 for example, date palm (Phoenix dactylifera) or the tagua nut (Phytelephas macrocarpa) \u2013 which serve simultaneously as storage and protective tissues  against physical, chemical, and biological damage Fig.\u00a0. In hardBertholletia excelsa; Sonego et al., Ibicella lutea; Horbens et al., Hamamelis mollis; Poppinga et al., Based on their performance, we classify sclerenchymatous encapsulations as either static, meaning dimensionally stable and indehiscent , Proteaceae  and woody cones in the Pinaceae (e.g. Pinus spp.) and Cupressaceae (e.g. Sequoiadendron giganteum), which may all reduce seed loss or damage from granivores, desiccation, and fire  die and typically dry together with the embyro(s) inside. After this point, seed viability depends strongly on the hydration level. Therefore, a major function of many hard encapsulation tissues is to retain a low moisture content inside the seed. A low seed moisture content may increase the desiccation tolerance of the embryo and induces dormancy in a large number of species Werker, . In addiet al., et al., et al., et al., et al., et al., et al., et al., et al., In static encapsulations, waterproofing may only be beneficial until conditions are suitable for germination. As germination requires water uptake by the embryo (imbibition), all covering layers play a central regulatory role in this step Fig.\u00a0. In addiet al.  represents a unique adaptation for epizoochorous dispersal via trample\u2010burrs. The tissue is entirely fibrous  for separation and are often simply realized by means of a locally reduced tissue and cell wall thickness, and/or lignification gaps . This i, et al. , known a, et al.  and dry  et al., . These p et al., , for exawns Fig.\u00a0 that alset al., et al., Aethionema arabicum), which consequently show different modes of dispersal and different levels of physical dormancy , plants develop follicles (responsive systems) with different valve curvatures along a climatic gradient, which results in higher levels of serotiny and higher opening temperatures in drier regions , four genes related to the flavonoid metabolism and seven peroxidases and thio/peroxiredoxins have been associated with differential dormancy along an aridity gradient  have far\u2010reaching consequences for dispersal, protection, and germination. They may occur within the lifetime of an individual  and eastern black walnut (J. nigra). In both species, the seed is surrounded by an ellipsoidal hard shell and partly separated by a septum. However, the septum in J.\u00a0regia is thin and mechanically insignificant, whereas in J.\u00a0nigra it is extremely thick and reinforces the shell internally . Interestingly, they also occur in many species of the palm family (Arecaceae); for example, in the Borneo giant fan palm , the Bismarck palm (Bismarckia nobilis), and in Eugeissona palms (Eugeissona spp.) . Shell geometry is particularly important to resist shell cracking by granivores via compression loading, for example. Owing to a higher rigidity, small spherical shells are more advantageous than elongated shells of similar size and thickness (Huss et al., et al., et al., et al., et al., Hard encapsulations for seed protection and dispersal are morphologically extremely diverse. On a general basis, the functionality of packaging structures arises from characteristic modifications of the tissues surrounding the embryo. Despite large genetic and ecological differences, many encapsulations share rather common features, such as predetermined breaking points, employment of fibres for force generation, and the incorporation of flavonoids for long\u2010term storage and protection. However, many questions still remain open. In the context of cell shapes, for example, it is unclear why 3D puzzle sclereids are rather rare in static structures despite their high strength (Huss"}
+{"text": "Oxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy.The protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (\u226536\u2009weeks\u2019 gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals.p\u00a0<\u20090.00001).We included data from seven studies  of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36\u2009weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.The online version contains supplementary material available at 10.1186/s12884-021-04216-3. Clinical administration of exogenous Oxytocin is the most common way to induce and augment labour as it increases the frequency, duration and strength of uterine contractions . Recent Intra-partum Oxytocin administration has been shown to reduce the mean duration in labour in several clinical trials . This isImproper use and administration of high doses of Oxytocin has been found to precede perinatal sentinel events such as uterine rupture, cord prolapse or placental abruption as a result of uterine hyperstimulation, leading to fetal asphyxia . InapproThe protocol for this study was registered with PROSPERO (ID: CRD42020165049). Any amendment or modification to the original protocol during the course of the review was submitted to PROSPERO. The Cochrane handbook for systematic reviews of interventions was used to frame this review. One investigator (CB) searched the published literature between January 1970 to May 2021 on Medline (Ovid), Embase (Ovid) and Web of Science Core Collection  databases to access relevant studies. The years were limited to 1970 to reflect current clinical practice as much as possible to allow the translation of findings. We searched for the concepts (1) encephalopathy/HIE, (2) oxytocin/uterotonic, expanded with risk factors and intrapartum injections/treatment/intervention/management/surveillance to find papers not explicitly mentioning oxytocin and (3) newborn infants/newborn infant diseases and obstetric, using controlled terms (i.e. MeSH-terms in MEDLINE) and words in title and abstract. , quasi RCTs, non-randomised prospective cohort studies and retrospective studies reporting intrapartum use of Oxytocin.Primigravidae and multiparous women giving birth at or after 36\u2009weeks\u2019 gestation.Intra-partum Oxytocin for induction (continuous and discontinuous) and augmentation of labour through intravenous and intramuscular routes at all doses. We excluded studies where Oxytocin was used after the delivery of the baby for prevention of post-partum bleed.Women who did not receive Oxytocin or any other uterotonic drug during labour.Babies with signs of neonatal encephalopathy following Oxytocin administration during labour. Neonatal encephalopathy was defined as the need for prolonged resuscitation at 5\u2009min of age and/or a 5-min Apgar score\u2009<\u20097  or lack of crying by 5\u2009min of age for babies born at home.2 index. An I2 value of size 0\u201340% was considered a low, 30\u201360% as moderate, 50\u201390% as substantial and 75\u2013100% as considerable heterogeneity according to the Cochrane Handbook [2 index. A Chi2 test was conducted to determine subgroup differences. Lastly, the overall effect was presented using a Z-test. All statistical analyses were performed on the RevMan V.5.1.4 software.Raw data was extracted from the selected studies on Excel spreadsheets by two independent investigators (CB/MM) and cross-checked by a third investigator (PM). Any disagreement during study selection or data extraction and analysis were resolved by consensus or by involving a senior reviewer when no consensus was reached. Risk of bias was assessed for each study by one investigator (CB) using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool, which evaluates risk of bias in estimates of the effectiveness or safety (benefit or harm) of an intervention. The RoB 2.0 tool was used to assess the risk of bias of randomised studies. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess certainty in the body of evidence. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals. Heterogeneity between studies was assessed to determine variability in the data using the IWe identified seven studies following full text screening, of which one had its data collected during a previous community-based cluster randomised controlled trial. These seven studies included neonatal encephalopathy as an outcome, of which 6 were case controls and 1 was a cluster randomised trial \u201317 , asphyxiated infants (Apgar score of <\u20096 at 1\u2009min) with no sign of encephalopathy (n\u00a0=\u20091 study) or term infants with a Thompson score\u2009<\u20093 (n\u00a0=\u20091 study). Data from the remaining study compared women with no injections during labour and women with injections during labour. Three of the included studies were undertaken in HICs, 4 in LMIC settings and all reported Oxytocin use and the prevalence of neonatal encephalopathy in newborns (Supplementary Table\u00a0Inclusion criteria for participants in selected studies were comparable: (1) a gestational age of at least 36\u2009weeks with 2) a classification of the baby into mild, moderate or severe neonatal encephalopathy according to Sarnat scoring and (3) administration of Oxytocin for induction and/or augmentation of labour. Studies compared neonatal encephalopathy infants with term infants with no sign of encephalopathy at birth . The Committee defines neonatal encephalopathy as a clinically defined syndrome of disturbed neurological function within the first week of life in term infants , manifested by difficulty initiating and maintaining respiration, depression of tone and reflexes, subnormal level of consciousness, and often, seizures. Upon further reading, we established that the PMMRC defines moderate and severe neonatal encephalopathy as Sarnat stages 2 and 3 [Two of the studies, however, did not use Sarnat scoring to determine neonatal encephalopathy severityis et al  assessednn et al  employedny et al  considerFarquhar  et al de 2 and 3 .Risk of bias was evaluated for 6 studies using the ROBINS-I tool, which is used in observational studies comparing health effects of interventions. The RoB 2.0 tool was used to assess for of bias of the cluster-randomised study. Selected studies ranged from low to severe risk of bias due to confounding domain and co-interventions, as these were not assessing specifically the effect of Oxytocin on neonatal outcomes  [Ellis et al, Futrakul et al, Mullany et al, Tann et al) [Farquhar et al [, Hayes et al [Milsom et al [, Ellis et al [, Futrakul et al [, Mullany et al [Tann et al [Pooled data from HIC studies  \u201313 revean et al) \u201317 reporar et al , Hayes ees et al  and Milsis et al , Futrakuul et al , Mullanyny et al  and Tannp\u00a0=\u20090.02). Furthermore, the subtotal difference in the onset of neonatal encephalopathy between the Oxytocin  and the Oxytocin-free  groups was significantly different in studies from LMICs . The overall effect combining results from both HICs and LMICs demonstrates a significant difference between the Oxytocin  and Oxytocin-free group  in the onset of neonatal encephalopathy . Subgroup differences analysis (I2) revealed that 72.2% of the variability in effect estimates from both groups is due to subgroup differences rather than sampling error  was available for 158 infants in the Oxytocin group and 175 infants in the Oxytocin-free group in high-income settings. Pooled data from HIC studies showed a significant difference in the subtotal for the onset of neonatal encephalopathy between the Oxytocin  and Oxytocin-free 175/600; 29%) groups . The heterogeneity amongst subgroups was of 44% for HIC studies and 51% for LMIC studies.The included studies had an overall substantial heterogeneity  and LMICs  that included intra-partum Oxytocin use in mothers of term infants with neonatal encephalopathy. Our main finding was an association between Oxytocin use and the onset of neonatal encephalopathy, which was significantly higher in term babies of women induced/augmented with Oxytocin compared to Oxytocin-free women . Moreover, this was found to be even higher in LMICs  compared to HICs . A higher percentage of heterogeneity across LMIC studies may be linked to variability in social environment as well as settings where studies were taking place such as home births in rural areas of southern Nepal [We assessed a total of seven studies from HICs  summary. Supplementary Table\u00a04. Risk of bias for Mullany et al., 2013 (RoB 2.0). Supplementary Table\u00a05. Summary of Findings table (GRADE)."}
+{"text": "Fueled by advances in computing power, algorithms, and big data, the last decade has witnessed widespread applications of artificial intelligence (AI) in every major field, including medicine and healthcare. Generally speaking, AI is expected to help realize the promise of precision medicine in three major areas: (1) disease prevention, (2) personalized diagnosis, and (3) personalized treatment. In this Research Topic, \u201cArtificial Intelligence for Precision Medicine,\u201d we aim to set up an open stage in the community where breakthrough application examples of AI for precision medicine are presented. We envisage that AI technologies, if applied openly, fairly, robustly, and in close collaboration with human intelligence, will open new doors for effective and personalized healthcare worldwide.Hart et al.- AI-aided diagnosis and early detection of diseases: Chen et al.; Jensen et al.; Mistro et al.; Wang et al.- AI-enhanced treatment and delivery: Barua et al.- Clinical decision support with AI techniques: Luo- Enhancing patient care via AI applications: Zhang et al.- Radiomics and quantitative imaging: Kapelner et al.; Namdar et al.- Bioinformatics for more effective healthcare: Chan et al.- Innovative AI applications for patient safety: Hart et al. developed seven machine learning algorithms based solely on personal health data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and compared them with 15 practicing physicians in stratifying endometrial cancer risk for 100 women. The results indicate that their random forest model achieves a testing AUC of 0.96, 2.5 times better at identifying above-average risk women with a 2-fold reduction in the false-positive rate. A novel concept named \u201cStatistical Biopsy\u201d was proposed for the first time.In their work, Chen et al. reported their development of a deep-learning convolutional neural network (DCNN) for enhanced organ-at-risk (OAR) segmentation on cone beam computed tomography (CBCT), trained with forty post-operative head and neck cancer patients. The developed DCNN improved CBCT in terms of Hounsfield unit (HU) accuracy, image contrast, and OAR delineation accuracy.Jensen et al. demonstrated that their novel machine learning model can be used to quickly estimate the Pareto set of feasible dose objectives in cancer radiotherapy, which may directly accelerate the treatment planning process and indirectly improve final plan quality by allowing more time for plan refinement. Their model outperforms the existing machine learning techniques by utilizing optimization priorities and output initialization.Using a cohort of 100 prostate cancer patients, Mistro et al. have demonstrated that knowledge models can be effectively used as teaching aid to bring inexperienced planners to a level close to experienced planners in fewer than 2 days. The proposed tutoring system can serve as an essential component in an AI ecosystem that will enable clinical practitioners to use knowledge-based planning effectively and confidently for personalized radiation treatment.As a first attempt, Wang et al. have demonstrated a novel deep learning framework for pancreas stereotactic body radiation therapy (SBRT) planning, which can predict a fluence map for each beam, hence bypassing the lengthy inverse optimization process.Based on 85 training cases and 15 test cases, Barua et al. demonstrated that a Multivariate Functional Principal Component Analysis (MFPCA) approach can be used to characterize the temporal trajectories of mandibular subvolumes receiving radiation. Their work suggests that temporal trajectories of radiomics features derived from sequential pre- and post-RT CT scans correlate with radiotherapy-induced mandibular injury, which may be used to aid in earlier management of osteoradionecrosis, a major side-effect in radiation therapy of oropharyngeal cancer patients.In their work, Luo summarized three major approaches currently employed in predicting cervical cancer outcomes: statistical models, medical images, and machine learning, and discussed some of the challenges in making clinical outcome prediction more accurate, reliable, and practical.In a mini-review, Zhang et al. proposed a transfer learning-based prognostication model for overall survival in pancreatic ductal adenocarcinoma patients. The model achieved the area under the receiver operating characteristic curve (AUC) of 0.81, significantly higher than that of the traditional radiomics model of 0.54. Their result suggests that transfer learning-based models may significantly improve prognostic performance in typical small sample size medical imaging studies.Kapelner et al. introduced and discussed a novel R package called \u201cPersonalized Treatment Evaluator (PTE)\u201d developed by them. They combined randomized comparative/controlled trial (RCT) data with a statistical model of the response to estimate outcomes under different treatment allocation protocols. Their PTE package can be used to evaluate personalization models in medicine as well as fields outside of medicine.To evaluate the overall effectiveness of personalized medicine, Namdar et al. presented first a comprehensive review of AUC metric, and then proposed a modified version of AUC that takes confidence of the model into account and incorporated AUC into Binary Cross Entropy (BCE) loss function. They demonstrated the validity of the new concept on MNIST, prostate MRI, and brain MRI datasets.In their paper, Chan et al. discussed and summarized the various applications of machine learning approaches in machine-specific and patient-specific quality assurance (QA), a key component in safeguarding patient safety during the radiation treatment of cancer patients.In a review paper, Precision medicine is an evolving healthcare approach focused on tailoring medical decisions, treatments, practices, and products to individual patients based on their genetic, environmental, lifestyle, and other factors. In this Research Topic, eleven teams reported promising results from their experience in applying AI for precision medicine. Moving forward, we anticipate that more work needs to be done to eliminate biases in the AI models and make these models interpretable, therefore ultimately achieving the promise of precision medicine, i.e., delivering the right treatment to the right patient at the right time.JD drafted the editorial. JD, TH, EC, JC, and FE-S revised and approved the final version. All authors contributed to the article and approved the submitted version.Research reported in this publication was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R01EB022589, by the National Science Foundation under Award Number DMS 1918925, by the National Cancer Institute under Award Number 21X130F, and by the Department of Energy under Award Number DE-SC0021655 to JD. EC was supported by the grant NSF 19-500 under Award Number DMS 1918925 and 1922843 in years 2019-2022.The content is solely the responsibility of the authors and does not necessarily represent the official views of those institutions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A study of natively iodinated bovine thyroglobulin demonstrates that structural details of biologically important chemical reactions can now be visualized by electron cryo-microscopy. Its circulation regulates metabolism and many other fundamental processes, including neuronal tissue growth (Caravalho & Dupuy, 2017Acta Cryst. D (Kim et al., 2021et al., 1989et al., 2020in vivo conditions and those made available under the in vitro conditions of iodination assays (Coscia et al., 2020et al. did not observe the presence of mono-iodinated tyrosine residues in the bovine TG structure. Similarly, biochemical assays performed by Coscia et al. did not reveal the presence of T3, the active form of thyroxine hormone. Hence, direct synthesis of T3 still needs to be demonstrated. The bovine TG structure exposes another interesting issue potentially related to the regulation of the redox potential of thyroid follicles. TG structures contain numerous cysteine residues, many of which are present in the cysteine-rich thyroglobulin type domains. In the human TG structure, all cysteine residues are linked by disulfide bonds. Due to the limiting resolution of density maps, this conclusion was often only supported by their proximity. In contrast, the bovine TG structure contains cysteine residues not involved in disulfide bridges despite their proximity, as described by Kim et al.In the cryo-EM structure of bovine TG from natural sources presented in this issue of et al., 1985et al., 1999et al., 1996et al., 2020et al. stated, the bovine TG material at first also appeared unstable on the grids. They hypothesized that the instability was caused by the inter\u00adactions at the solvent\u2013air interface and that a small addition of detergent already successfully applied in other studies (Noble et al., 2018et al., 2019et al. is a triumph of sample preparation and the maturation of electron cryo-microscopy. The structure demonstrates that structural details of bio\u00adlogically important chemical reactions can now be visualized by electron cryo-microscopy.Although TG has been extensively studied, its three-dimensional structure could not be determined for decades. Isolation of purified TG (Heidelberger & Palmer, 1933"}
+{"text": "Inspired by how the human brain works, neurocomputing algorithms, including deep learning, reinforcement learning, and neurodynamic optimization, have achieved tremendous success in various applications across many domains, e.g., visual object tracking, speech recognition, human-level control, text understanding, and real-time optimization.Various types of intelligent equipment and hardware devices have been developed to implement neurocomputing models for engineering systems. Deep learning has been employed for industrial robotic applications, including stereo reconstruction, object pose recognition, and product quality check. With the advent of the Internet of Things and edge computing devices, deep reinforcement learning has become popular in the predictive maintenance of engineering equipment. Embedded convolutional neural networks are widely utilized for autonomous vehicle control. The success of applying neurocomputing approaches and related hardware implementations in different engineering domains, such as intelligent manufacturing, energy internet, and smart healthcare, has proven the potential of employing neurocomputing for solving real problems in various engineering fields.In recent years advances in sensor and data storage technologies have enabled the accumulation of a large amount of data from engineering systems. Driven by big data generated from engineering systems, neurocomputing, and its hardware implementation will continually transform engineering systems into more intelligent forms.This Research Topic aims to provide a forum for researchers to present the latest research on applications of neurocomputing algorithms and neurocomputing-based hardware in engineering systems. It brings together 14 high quality papers reporting on the latest applications of neurocomputing in transportation, manufacturing, biomedical engineering, electrical engineering, and knowledge management.Self-Triggered Consensus of Vehicle Platoon System With Time-Varying Topology,\u201d Wang et al. designed a secure event-triggered controller considering the safe distance for the vehicle platoon system. Based on the new event-triggered function, a more energy efficient self-triggered control strategy was developed by using the Taylor formula. The new self-triggered control strategy could avoid continuous calculation and measurement of vehicles.In the paper entitled \u201cIndustrial Control Malicious Traffic Anomaly Detection System Based on Deep Autoencoder\u201d by Wang et al. proposes a method of detecting abnormal traffic in industrial control networks based on autoencoder technology. The Kullback\u2013Leibler divergence was added to the loss function of the proposed model to improve the ability of feature extraction and the ability to recover raw data. The gas pipeline dataset was used to verify the performance of the proposed method.The paper on \u201cData-Driven Hybrid Equivalent Dynamic Modeling of Multiple Photovoltaic Power Stations Based on Ensemble Gated Recurrent Unit\u201d Long et al. report on a data-driven hybrid equivalent model for the dynamic response process of the multiple PV power stations. The data-driven hybrid equivalent model contained the simple equivalent model and data-driven error correction model. The simulation results validated the super-performance of the proposed model both in response speed and accuracy.In a contribution on \u201cSun et al. contribute a paper on \u201cAutoPath: Image-Specific Inference for 3D Segmentation,\u201d which introduces AutoPath, an image-specific inference approach for more efficient 3D segmentations. The proposed AutoPath dynamically selected enabled residual blocks regarding different input images during inference, thus effectively reducing total computation without degrading segmentation performance. Experimental results on a liver CT dataset showed that the proposed approach not only provided an efficient inference procedure but also attained satisfactory segmentation performance.Boosting Knowledge Base Automatically via Few-Shot Relation Classification\u201d by Pang et al. investigated a fully automatic method to train a relation classification model which facilitates to boost the knowledge base. In the proposed method, various multiple instance learning methods were incorporated into the classic prototypical networks, reducing sentence-level noises.A paper on \u201cGu et al.'s article \u201cInvestigating the Impact of the Missing Significant Objects in Scene Recognition Using Multivariate Pattern Analysis\u201d adopted multivariate pattern analysis to explore the object-scene association in scene recognition when different amounts of significant objects were masked. The analysis results suggested that the lateral occipital complex was sensitive to the loss of significant objects and mainly involved in scene recognition by the object-scene semantic association.Machine Learning Models to Predict Primary Sites of Metastatic Cervical Carcinoma From Unknown Primary,\u201d Lu et al. conducted a series of bioinformatics analyses based on a dataset from The Cancer Genome Atlas (TCGA) RNA-Seq data of squamous cancer and TCGA Pan-Cancer data. Three machine learning models, random forest, neural networks, and support vector machine, were developed to explore potentially effective tools to distinguish these squamous cancers.In the paper \u201cA Manufacturing-Oriented Intelligent Vision System Based on Deep Neural Network for Object Recognition and 6D Pose Estimation\u201d Liang et al. present a new two-stage intelligent vision system based on a deep neural network with RGB-D image inputs for object recognition and 6D pose estimation. A dense-connected network fusing multi-scale features was first built to segment the objects from the background. The 2D pixels and 3D points in cropped object regions were then fed into a pose estimation network to make object pose predictions based on the fusion of color and geometry features.In their contribution examining \u201cArtificial Intelligence-Based Application to Explore Inhibitors of Neurodegenerative Diseases\u201d by Deng et al. explores an integrated new approach for finding lead compounds that inhibit galectin-3, by combining universal artificial intelligence algorithms with traditional drug screening methods. Manifold artificial intelligence algorithms were performed to validate the docking results and further screen compounds.The paper titled \u201cEnergy Investment Risk Assessment for Nations Via Seq2seq Model\u201d Liang et al. propose a sequence to sequence model to evaluate the energy investment risk of 50 countries. Bi-long-short term memory was used as an encoder to process the historical statistics in the proposed method.In their \u201cA Relational Adaptive Neural Model for Joint Entity and Relation Extraction\u201d by Duan et al. describes a relational-adaptive entity relation joint extraction model based on multi-head self-attention and densely connected graph convolution network. In the model, the multi-head attention mechanism was specifically used to assign weights to multiple relation types among entities to ensure that the probability space of multiple relations was not mutually exclusive.The paper on \u201cClassification of Metastatic and Non-Metastatic Thoracic Lymph Nodes in Lung Cancer Patients Based on Dielectric Properties Using Adaptive Probabilistic Neural Networks\u201d by Lu et al. proposes a classifier to identify metastatic and non-metastatic thoracic lymph nodes in lung cancer patients based on dielectric properties. Compared with the other methods, the proposed classifier achieved a higher classification accuracy based on dielectric property data collected from lung cancer patients.An article on the \u201cXiang et al.'s contribution on the \u201cPrediction of Dangerous Driving Behavior Based on Vehicle Motion State and Passenger Feeling Using Cloud Model and Elman Neural Network\u201d presentes a new method for dangerous driving behavior prediction using a hybrid model consisting of cloud model and Elman neural network based on vehicle motion state estimation and passenger's subjective feeling scores.A New Way of Airline Traffic Prediction Based on GCN-LSTM\u201d by Yu employed graph convolutional neural network and long short memory network to construct an airline traffic prediction system with short-term prediction ability.The paper titled \u201cThese successful applications of neurocomputing in various domains demonstrate the significant potential of applying neurocomputing approaches to solving complex engineering problems. With the help of big data and increasing computing power, neurocomputing will play a vital role in future engineering systems.LW wrote the manuscript. ZZ, ZS, and CH edited the manuscript. All authors contributed to the article and approved the submitted version.This work was supported in part by the National Natural Science Foundation of China under Grant 62002016, in part by the Guangdong Basic and Applied Basic Research Foundation under Grants 2020A1515110431 and 2019A1515111165, and in part by the Fundamental Research Funds for the Central Universities and the Youth Teacher International Exchange & Growth Program under Grant QNXM20210037.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The 2021 Nobel Prize in Physiology or Medicine honors the discoveries of the temperature or mechanically activated channels, whose structural studies provided insights of channel gating at atomic level. Using capsaicin, a natural pungent agent that induces pain in our skin similar to that induced by heat, David Julius identified the TRPV1 ion channel as a heat-activated nociceptor in the peripheral nervous terminus  Unexpectedly, the atomic structures of these channels were all determined by single-particle cryo-electron microscopy (cryo-EM), a structure determination technique that does not require crystallization but, instead, images individual biological molecules embedded in a thin layer of vitreous ice using an electron microscope followed by extensive computational image analysis (Cheng, 2018et al., 2013et al., 2013et al., 2016Interestingly, progress in structural studies of TRPV1 and the technological developments and advancements of single-particle cryo-EM were tightly entwined. With the methodological breakthroughs in single-particle cryo-EM, the first structure of TRPV1 was determined in 2013 (Cao etc. These exogenous stimuli generate pain that serve as a warning signal for avoidance. TRPV1 activation can also be modulated by endogenous stimuli, such as extracellular protons generated by tissue acidosis associated with inflammation. Potentiation of TRPV1 by extracellular protons causes heat hypersensitivity. Without the restriction of crystallization, single-particle cryo-EM not only enabled atomic structure determination of TRPV1 (see Fig. 1et al., 2013et al., 2016et al., 2021As a polymodal signal detector, TRPV1 can be activated by exogenous stimuli, such as heat, capsaicin, plant toxins and peptide toxins from spider et al., 2015et al., 2019et al., 2018As for Piezo1/2, soon after its initial discovery, structural biology had entered this new era of single-particle cryo-EM. As such, structural studies of Piezo channels were carried out exclusively using this method and comprehensive structural studies have progressed rather rapidly (Ge The major goals of structural biology go beyond knowing the atomic structures of these channels and what they look like, but address the harder questions of how they work to generate physiological responses. In this regard, there are still many unanswered questions concerning these channels. Among them, the mechanisms of temperature activation, such as TRPV1 by heat or TRPM8 by cold, and the mechanism of mechanosensing by Piezos, remain among the most pressing unanswered questions. Recognition of the Nobel Prize not only honors the seminal discoveries of these channels, but also stimulates excitement among structural biologists to continue pursuing these burning questions."}
+{"text": "Sci., 2020, DOI: 10.1039/d0sc04044d.Correction for \u2018Direct synthesis of the organic and Ge free Al containing BOG zeolite (ITQ-47) and its application for transformation of biomass derived molecules\u2019 by Qintong Huang  In the original manuscript, the affiliations of authors Anmin Zheng and Avelino Corma were displayed incorrectly. The corrected affiliations are as displayed above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder, affecting the cerebral cortex and hippocampus in human brain , presenilin-1 (PSEN1), and presenilin-2 (PSEN2) are associated with early-onset AD (EOAD), developing in fourth or fifth decade of life  can be observed already 15\u201320 years prior to the onset of the clinical symptoms  and meta-analyses combining multiple GWAS dataset (n = 21) in AD risk evaluation were included (n = 16) were analyzed separately (n = 13) combined identified genotype alterations in GWAS and meta-analyses with changes in AD-related biomarkers  enrichment analysis was performed, using Cytoscape plug-in ClueGO . This toIn our dataset of genes related to AD risk, we observed significant enrichment for four major GO biological process categories: cellular process, metabolic process, biological regulation, and localization .APP, PSEN1, and PSEN2 genes result in overproduction of the hydrophobic A\u03b240 and A\u03b242 peptides, leading to aggregation and formation of insoluble plaques  family that includes PS1 and PS2  have increased risk for early development of memory impairment  E4 allele (APOE4), which is associated with more extensive A\u03b2 deposition is considered a major risk factor for LOAD  and rs7412 (p.Arg158Cys) define polymorphic alleles APOE2, APOE3, and APOE4 that encode three respective protein variants: apoE2 , apoE3 , and apoE4  , followed by APOE4 (5\u201335%) and APOE2 allele (1\u20135%)  gene were associated with AD. PICALM rs3851179 was associated with decreased AD risk  rs744373 SNP was associated with risk for LOAD  was associated with AD  family  were linked to AD. Rs11136000 was associated with decreased risk for AD  or increased (rs9331888) risk for AD  were associated with AD and type 2 diabetes (T2D), indicating potential shared molecular pathways between the diseases /proton (H+) exchanger in the Golgi, important in maintenance of homeostasis  cluster encodes a family of cell surface proteins that participate in the regulation of calcium signaling  and was shown to considerably increase AD risk , important for tau phosphorylation and NFT formation in CNS . Rs1466662 within this DCHS2 was associated with AD  is a gene, encoding for poliovirus receptor 2, immunoglobulin expressed in neuronal cell tissues, that is important in T-cell activation  were identified as novel AD related risk alleles  forms one of the primary pores via which proteins can readily enter the mitochondria. The TOMM40 gene is the only gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction   locus, contributing to the diverse and specific Ig forming in the adaptive immunity  and blood plasma biomarker levels can predict neurodegenerative changes in AD progression and memory decline and are often used in clinical diagnostics. Except for their diagnostic potential, biomarkers can be applied in studies of AD molecular mechanisms and could be used to monitor the biochemical effects of potential disease intervention  linked to molecular pathways identified in this review  were associated with CSF A\u03b2 and tau levels , important mediator of immune system, were associated with CSF A\u03b2 and tau levels , were associated with LOAD protein expression in CSF [271]. Furthermore, association of rs2228145 with CSF and serum IL6R levels revealed the effect on age of onset in AD [171]. GLIS3 rs514716 association with CSF A\u03b2 and tau levels was observed  were associated with CSF levels of ACE gene product  and APOE-containing lipoproteins  that were associated with CSF A\u03b2 levels in AD subjects  gene, is important enhancer of immune response  encodes ATIP3, inhibitor of extracellular signal-regulated kinase 2 (ERK2) and cell proliferation. Similarly, rs3092960 within CCR2 encoding for CCL2 receptor was also associated with significant levels of CCR2 protein in CSF  were associated with CCRL2 protein expression in CSF as well  were associated with biomarker levels, with rs573521 being the best predictor of MMP3 protein expression in CSF in LOAD  as a novel AD-related locus (Zhong et al., BCAM was associated with CSF levels of phosphorylated tau181 and A\u03b242 (Huang et al., BCAM is a gene encoding Lutheran blood group glycoprotein, an immunoglobulin important in laminin recognition (Parsons et al., ARHGAP24 rs111882035 was associated with memory tests outcomes in MCI individuals (Chung et al., ARHGAP24 is important in actin cytoskeleton remodeling and specifically suppresses Rac1 and Cdc42 activity (Lavelin and Geiger, Although not enriched in GO analysis, many other genes were manually annotated cellular processes and are also summarized in Genes and key SNPs, involved in biological regulation, associated with biomarkers in GWAS and their meta-analyses, are summarized in CD1A polymorphisms: rs16840041, rs2269714, and rs2269715 were associated with increased plasma neurofilament light level, a potential protein biomarker for AD (Wang et al., Three ATP6V1H rs1481950 was associated with higher CSF BACE activity (Hu et al., Additionally, one biomarker associated gene was manually annotated to biological regulation . A polymGenes and key SNPs, involved in localization, associated with biomarkers in GWAS and their meta-analyses, are summarized in GRIN2B rs10845840 was reported as a risk loci for AD, associated with temporal lobe atrophy (Stein et al., GRIN2B encodes the NR2B subunit of NMDA receptor that mediates a Ca2+ dependent synaptic transmission in the CNS (Hu et al., MAPT rs242557 was associated with plasma tau levels (Chen et al., MAPT encodes for tau, the prominent component of NFTs. H2 haplotype is associated with MAPT expression and LOAD risk (Allen et al., BCHE rs509208 with PET imaging of cortical A\u03b2 in AD subjects was revealed (Ramanan et al., Genes and key SNPs, involved in neurological system process, GO term specific for biomarker gene set, are summarized in Among all AD related biomarker loci, obtained from GWAS and meta-analyses that were not enriched in GO analysis, additional 18 were manually annotated.The remaining seven genes could not be associated with any of the seven main enriched pathways, even though they were linked biomarker changes in AD GWAS and meta-analysis. Although some of them were linked to a specific function in the literature, they have not been annotated with any of the GO terms. Genes and key SNPs with no known function associated with AD biomarkers in GWAS and meta-analyses are summarized in CCDC134 rs7364180 was associated with CSF A\u03b2 levels in AD subjects (Kim et al., CCDC134 is a proliferation promoting molecule, driving cytokine-like activation of CD8+ T-cells (Huang et al., ECRG4 rs34487851 was observed (Chung et al., ECRG4 encodes a peptide hormone that is involved in NFT formation, age-related senescence of precursor cells in the CNS and activation of microglia and peripheral mononuclear leukocytes (Kujuro et al., FRA10AC1 as a novel risk locus (Li et al., FRA10AC1 gene are potential cause of folate-sensitive fragile site FRA10A expression (Sarafidou et al., LUZP2 was also proposed as a novel AD risk locus as rs7943454 was associated with higher plasma neurofilament light levels (Li et al., LUZP2 gene (Stepanov et al., ZNF804B, is not known yet, a ZNF804B rs73705514 was associated with memory tests outcomes in MCI individuals (Chung et al., Alzheimer's disease is the most prevalent neurodegenerative disorder worldwide. A lot of research focuses on the identification of genetic factors that may contribute to the development and progression of the disease. Numerous GWASs and meta-analyses reported different genetic factors associated with AD risk or biomarker levels. A cumulative effect of small but significant contributions of numerous genetic factors can at least in part elucidate the LOAD progression. The pathogenic processes in AD may be influenced on a personalized basis by a combination of variants in key genes and pathways. Apart from serving as a hallmark of the disease, polymorphisms in various genes might help in early diagnostics and prediction of disease progression. Integration of genetic factors and biomarker status may increase the predictive value of diagnostic or prognostic models.Through the GO analysis we compiled a list of the most enriched pathways, associated with AD pathology. Among four GO parental categories in AD risk gene set, immune response, APP metabolism, cholesterol metabolism, endocytosis and biological regulation on different levels can be exposed as important AD related biological processes. Furthermore, enrichment analysis on smaller AD biomarker gene set pinpointed three additional parental categories. Besides neurodegeneration, numerous research evidence link AD with neuroinflammation, lipid metabolism as well as receptor mediated endocytosis, supporting scientific background of our analysis. Several identified genes were associated with more than one biologic process, represented in various GO categories. The intersection of different biological processes creates a complex interconnected network, suggesting multi-pathway approach in AD genetic background evaluation is needed. Additionally, manual annotation of genes that were not associated with the most significant pathways in GO analysis, could help to elucidate their function in AD pathogenesis.This comprehensive summary of genetic variants identified by GWAS studies and their meta-analyses can also provide background for identification of novel molecular targets, and the results may be important for development of personalized medicine. However, GWAS and meta-analyses cannot explain the molecular mechanisms of the contribution of a novel susceptibility locus to the overall genetic risk. Therefore, our compiled and annotated results may serve as a basis for the functional studies of pathophysiological mechanisms of risk genes, identified on a genome-wide scale. Furthermore, better characterization of risk genes functions could enable the stratification of AD patients according to the main molecular mechanisms of pathogenesis, supporting development of tailored and personalized treatment of the disease.The original contributions presented in the study are included in the article/DV performed literature search and gene enrichment analysis. DV, KG, and VD participated in writing and editing of manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The development of bioactive biomaterials is an important component in the general field of tissue engineering, specifically for the success of tissue repair and regeneration approaches . BioactiEngineered bioactive materials involve conventional biomaterials, such as bioactive glasses and ceramics, as well as biopolymers based on proteins. Polysaccharides and biomoleculecontaining biomaterials . In receSprio et al. reviewed the application of biomorphic transformations to obtain nanostructured 3-D bioceramics. Yanmei Tang et al. reviewed the advances of polydopamine nanoparticles in tissue engineering applications, including the repair of bone, cartilage, skin, heart, and nerve. Fujian Zhao et al. reported tantalum-gelatin methacryloyl-bioactive glass (Ta-GelMA-BG) scaffolds which could enhance osteointegration at the early stage of implantation. Haiping Lu et al. developed Ag and MSCs-derived exosomes-contained PCL scaffold for regulating immune cells and MSCs proliferation and differentiation. Haiping Lu et al. introduced the broad application of \u03b2-TCP in tissue engineering and discussed different approaches to enhance and customize \u03b2-TCP scaffolds, including physical modification.This Research Topic is the second part on the \u201cMultifunctional Bioactive Nanomaterials for Tissue Regeneration\u201d series, which includes several papers demonstrating the main advances of multifunctional nanomaterials in tissue engineering. In this topic, Multifunctional Bioactive Nanomaterials for Tissue Regeneration Part 2\u201d will contribute to inspire future developments of advanced bioactive nanomaterials for regenerative medicine to close the gap between research and clinical applications.The editors hope that the current topic \u201c"}
+{"text": "In last few decades, organic materials  including polymers have received much attention for their potential applications in electronics, because they have outstanding advantages such as high processibility, mechanical flexibility, and low weight. Extensive research efforts have thus been devoted to the development and advancement of organic materials for various applications, covering a wide range from molecular design to device-fabrication methods. In addition, it has been recognized that surfaces and interfaces play a crucial role in the operation and performance of the devices. For instance, various interactions at organic\u2013metal interfaces are of great importance in organic epitaxy, and also have a strong correlation with intermolecular structures and their electronic properties.In this context, the main focus of this Special Issue was collecting scientific contributions addressing surface and interface engineering with organic materials, and related applications. The diversity of contributions presented in this Special Issue exhibits the potential of organic materials in a variety of applications that are not limited to the fabrication of organic devices. This Special Issue contains eight featured original research papers as regards nanoarchitecture based on organic elements , physicaIn the contributed article entitled \u201cInvestigation on the Adsorption-Interaction Mechanism of Pb(II) at Surface of Silk Fibroin Protein-Derived Hybrid Nanoflower Adsorbent\u201d , Xiang LByung Soo Hwang et al. provided an outlook for the development of stimuli-responsive functional materials through their study of gelation behaviors of hydrogels in the contributed article entitled \u201cThermogelling Behaviors of Aqueous Poly(N-Isopropylacrylamide-co-2-Hydroxyethyl Methacrylate) Microgel\u2013Silica Nano-particle Composite Dispersions\u201d [Peng Xiao et al. presented a facile method for the fabrication of liquid metal electrodes using polydimethylsiloxane, and also demonstrated solar-blind photodetection via surface exfoliation in a series of contributed articles entitled \u201cFabrication of a Flexible Photodetector Based on a Liquid Eutectic Gallium Indium\u201d , and \u201cFlIn the contributed article entitled \u201cCrack-Assisted Charge Injection into Solvent-Free Liquid Organic Semiconductors via Local Electric Field Enhancement\u201d , Ju-HyunIn the contributed article entitled \u201cCesium Doping for Performance Improvement of Lead(II)-acetate-Based Perovskite Solar Cells\u201d , Min-SeoHyeok Jo Jeong et al. reported the sigmoidal concentration dependence of electrical conductivity of poly:poly(styrene sulfonate) processed with linear glycol-based additives in the contributed article entitled \u201cSigmoidal Dependence of Electrical Conductivity of Thin PEDOT:PSS Films on Concentration of Linear Glycols as a Processing Additive\u201d . It was In the contributed article entitled \u201cThe Methods and Experiments of Shape Measurement for Off-Axis Conic Aspheric Surface\u201d , Shijie Materials. I am personally grateful to Ms. Freda Zhang, Managing Editor of this Special Issue.In conclusion, the contributed articles in this Special Issue demonstrate relevant progress and the potential of organic materials in a variety of applications. I wish to thank and acknowledge all the authors for their priceless contributions and the editorial members of"}
+{"text": "The bladder exstrophy\u2013epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current knowledge on this multifactorial disorder, including phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components. Congenital anomalies of the lower urinary tract (CALUT) are a group of birth defects of the ureter, bladder, and urethra, which includes bladder exstrophy\u2013epispadias complex . BEEC is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine . The sevEpispadias is rare, with incidences of one in 101,000 live births in males and one in 1,300,000 in females ,8. CBE hEpispadias is generally diagnosed at birth, although its presentation is dependent on severity and sex. It consists of a dorsal located ectopic urethral meatus as a result of non-closure of the urethral plate during embryological development . In bothCBE presents as a protrusion of the urinary bladder through a defect on the infraumbilical abdomen, in association with a diastasis of the pubic symphysis with distally divergent rectus abdominis muscles A 3]. Pu. Pu3]. PCE is a major birth defect in which the bladder is widely open on the infraumbilical abdominal wall and is separated into two distinct halves. It is often associated with omphalocele, separated pubic bones, short-gut syndrome, and other malformations, including talipes and spina bifida B 1,11].,11.1,11]The vast majority of BEEC cases are non-syndromic, however, a number of cases have been reported whereby BEEC has also been associated with various other syndromes, malformations, and congenital diseases . There aThe majority of individuals affected by BEEC have no positive family history of BEEC. However, even though familial occurrence is rare, 30 multiplex families have been described ,19,20,21n = 28) and triplets (n = 2), including monozygotic (n = 20), dizygotic (n = 3), trizygotic (n = 2), and unknown zygosity (n = 5). Of the CE anomalies within the 20 monozygotic twins, 9 were concordant and 11 were discordant. The higher incidence of CE in monozygotic twins compared to dizygotic twins could suggest a possible genetic contribution to the occurrence of these anomalies. Fullerton et al., 2017 [Reutter et al., 2007  reportedl., 2017  reportedThere is an extensive history of successful disease gene discovery made through the characterization of individuals with chromosomal abnormalities. These chromosomal changes provided a shortcut to identify relevant chromosomal loci for positional cloning approaches before next generation sequencing techniques transformed disease gene discovery over the past decade. Translocations disrupting disease-associated genes and deletions harboring the causative gene led to some of the earliest disease gene identifications in the last century.Cytogenetic analyses have identified a number of chromosomal anomalies in individuals with BEEC, summarized in Multiple autosomal chromosome anomalies have been reported in association with BEEC. Zaki et al., 2012  identifiBoyadjiev et al., 2005  identifiEl-Hattab et al., 2010  reportedThauvin-Robinet et al., 2004  reportedA study undertaken by Harrison et al., 2014  of 17 feDraaken et al., 2010  performeFrom a cohort of 244 BEEC cases, Lundin et al., 2010  reportedA comparison of eight previously reported 22q11.21 duplications in individuals with CBE revealed a 414 kb \u201cphenocritical\u201d region, encompassing 10 candidate protein coding genes . Within In contrast to the potential high penetrance effect of chromosomal changes, candidate and genome wide association studies (GWAS) investigate the contribution of more common variants, conferring a smaller effect size. Both association study approaches seek to genotype large cohorts of individuals with BEEC and compare allele frequencies of SNPs in these against ethnically matched controls.p = 0.026, odds ratio (OR) = 18.33) whereas a four-base-pair insertion was associated with an increased risk in non-Caucasian patients OR = 4.58. Using luciferase assays, they showed a consistent statistically significant reduction in transcriptional efficiencies of the promotor sequences containing indel polymorphisms, suggesting that indel polymorphism of the deltaNp63 promoter leads to a reduction in p63 expression which could potentially lead to BEEC.To date, only a small number of candidate gene association studies have been undertaken, the first of those by Wilkins et al., 2012  to invesReutter et al., 2014  conductep = 2.22 \u00d7 10\u22128). Meta-analysis of rs6874700 from this study and the previous study by Draaken et al., 2015 [p = 9.2 \u00d7 10\u221219). Analysis of ISL1-expressing cells by a lineage tracer mouse model showed ISL1-expressing cells in mouse model in the urinary tract E10.5 and distributed in the bladder E15.5. In zebrafish larvae, staged 48 HPF ISL1 expression was detected in a small region of the developing pronephros. This association together with functional studies in mouse embryos and zebrafish larvae suggest ISL1 as an important susceptibility gene for CBE and as a regulator of urinary tract development.Draaken et al., 2015  performeThe lack of large multiplex families has made traditional positional cloning approaches to disease gene discovery incredibly challenging in BEEC. Ludwig et al., 2009  conducteThe introduction of exome and genome sequencing technologies and large sequence variant databases in healthy controls have opened opportunities to determine the effects of rare variants that may be enriched in individuals with BEEC. Reutter et al., 2016  were theThe application of array-based, GWAS, and next generation sequencing techniques in large BEEC cohorts has helped to identify putative disease-causing genes and chromosomal regions in the human genome for both Mendelian and multifactorial BEEC. Functional analysis of embryonic pathways provides a better understanding of the molecular biological mechanisms underlying normal, urorectal, and genitourinary malformations within the embryology of the human urogenital system.It is reasonable to propose that both inherited and de novo highly penetrant variants could be relevant to the etiology of BEEC as they have been shown for many genetically heterogeneous congenital birth defects such as congenital heart disease.New approaches such as gene and pathway enrichment analyses of high-impact de novo variants from whole exome or whole genome data in parent-offspring trios will likely aid in the identification of novel genes and/or pathways to better understand the underlying genetic mechanisms of BEEC, and the potential to use these data to develop therapeutic approaches to help children affected by this devastating congenital disorder."}
+{"text": "Mental health problems early in life can negatively impact educational attainment, which in turn have negative long-term effects on health, social and economic opportunities. Our aims were to: (i) estimate the impacts of different types of psychiatric conditions on educational outcomes and (ii) to estimate the proportion of adverse educational outcomes which can be attributed to psychiatric conditions.N = 2511) were from a school-based community cohort of Brazilian children and adolescents aged 6\u201314 years enriched for high family risk of psychiatric conditions. We examined the impact of fear- , distress-  and externalising-related conditions  on grade repetition, dropout, age-grade distortion, literacy performance and bullying perpetration, 3 years later. Psychiatric conditions were ascertained by psychiatrists, using the Development and Well-Being Behaviour Assessment. Propensity score and inverse probability weighting were used to adjust for potential confounders, including comorbidity, and sample attrition. We calculated the population attributable risk percentages to estimate the proportion of adverse educational outcomes in the population which could be attributed to psychiatric conditions. Analyses were conducted separately for males and females.Participants (p < 0.05) and grade repetition , respectively. Externalising conditions were associated with grade repetition in males  and females , as well as age-grade distortion in males  and females . Externalising conditions were also associated with lower literacy levels  and bullying perpetration  in females. If all externalising conditions were prevented or treated, we estimate that 5.0 and 4.8% of grade repetition would not have occurred in females and males, respectively, as well as 10.2  and 5.3%  of age-grade distortion cases and 11.4% of female bullying perpetration.Fear and distress conditions in males were associated with school dropout (odds ratio (OR) = 2.76; 95% confidence interval (CI) = 1.06, 7.22; The study provides evidence of the negative impact of psychiatric conditions on educational outcomes in a large Brazilian cohort. Externalising conditions had the broadest and most robust negative impacts on education and these were particularly harmful to females which are likely to limit future socio-economic opportunities. The global prevalence of these conditions in young people is around 13.4%  on a range of educational indicators beyond attainment  in young males and females separately, while implementing robust adjustment for confounders  and a random subsample based on all eligible children (n\u00a0=\u00a0958). These families (n\u00a0=\u00a02511) were selected for full household assessment by lay interviewers (parent interview) and trained psychologists (child interview) at baseline (6\u201314 years) and at follow-up . Participation was associated with higher maternal education, socioeconomic group (SEG), living in Porto Alegre, and anxiety-related conditions at baseline  and 3-year follow-up (2013\u20132014) data from the Brazilian High-Risk Cohort Study for Psychiatric Conditions (BHRCS), a large school-based community cohort enriched for high family risk for psychiatric conditions , University of S\u00e3o Paulo and Federal University of Rio Grande do Sul ethics committees. Written informed consent was obtained from parents and participants that were able to read, write and clearly understand the written consent.et al., et al., Current psychiatric conditions were assessed at baseline using parent-report on the Brazilian\u2013Portuguese version of the Development and Well-being Assessment (DAWBA)  were excluded due to divergent literature as to which broad group they might belong.Based on previous literature . Age-grade distortion was calculated for participants reporting grade repetition, dropout or expulsion since baseline, but still enrolled in education. For these participants, age-grade distortion was measured in years and calculated by subtracting the participant's current age from the expected age range for the current school grade. For example, if a child was 12\u201313 years and enrolled in 5th grade (expected age 10\u201311 years), we estimated an age-grade distortion of 2 years. For subjects not currently enrolled in school but reporting grade repetition or dropout since baseline, to be conservative, we attributed the value of 1 year.et al., Reading and writing literacy was measured via the School Performance Test (\u2018Teste de Desempenho Escolar\u2019 \u2013 TDE) ; intelligence (IQ); study site  and the dummy comorbidity variable described above.SEG was assessed using the classification from the \u2018Associa\u00e7\u00e3o Brasileira de Empresas de Pesquisa\u2019 (Brazilian Association of Research Companies) ABEP, . ClassifIQ was assessed by trained psychologists with the vocabulary and block design subtests of the Wechsler Intelligence Scale for Children, 3rd edition \u2013 WISC-III .We estimated the impact of baseline psychiatric conditions on educational outcomes at 3-year follow-up using unadjusted and adjusted regression models and using schools as the primary sampling units. Maternal education, any anxiety condition and study site predicted response at follow-up in the present sample , based on weighted predicted probabilities from regression models. \u2018Punaf\u2019 generates estimates based on two scenarios: first, using predicted probabilities from the model and second, if all participants did not have a psychiatric condition. The ratio of predicted prevalence estimates from the two scenarios was then used to calculate PARPs. As we aimed to generalise to the Brazilian population, we included an additional sampling weight for PARP calculations. This sampling weight fully accounted for the family liability oversampling (see sample description). The methods and results can be found in the Supplemental material in Martel et al.  due to psychiatric condition category. Estimated PARPs can be interpreted as a percentage of adverse educational outcomes in the total population attributable to psychiatric conditions . The PARP was computed using l et al. . This alFor educational outcomes, we used data from the National Institute of Educational Studies and Research database to estimate the number of Brazilians to which PARPs would translate. Details of estimates are described in online Supplementary material.Potential confounders were adequately balanced (standardised mean difference <0.2) between weighted groups following application of PSWs .Among males, fear-related conditions were associated with higher odds of school dropout, and distress-related conditions were associated with higher odds of grade repetition . ExternaComorbidity between fear-, distress- and externalising-related condition categories was included as a covariate in regression models and associated estimates are presented in online Supplementary Tables S6a to S8b. Females with a comorbid condition in addition to fear-related or distress-related condition had higher odds for school dropout and age-grade distortion, respectively (online Supplementary Tables S5a and S6a). Males with fear-related or distress-related conditions who met criteria for at least one other condition category had higher odds of bullying perpetration and low literacy levels respectively (online Supplementary Tables S5b and S6b).Applying school participation estimates for 2014 in Brazil, described in online Supplementary material (p. 3), we estimate that for the Brazilian population, 154\u00a0000 cases of grade repetition , 591\u00a0000 cases of age-grade distortions  and 236\u00a0000 cases of bullying perpetration  would have been avoided if externalising conditions were prevented or treated. As hypothesised, some differences according to gender were found, et al., et al., et al., Psychiatric conditions can have multiple short- and long-term impacts on individuals and society  were more likely to experience school dropout and grade repetition, respectively. This further increases the gender disparity already experienced by males who have lower educational attainment than females OECD, . Previouet al., et al., et al., et al., To contextualise the population impact of psychiatric conditions, we calculated PARPs for each educational indicator. Previous research has estimated that up to 10.2% of early school termination could be attributed to psychiatric conditions (Vander Stoep et al., et al., et al., As a practical application of our estimates, we consider the case of ADHD in Brazil. Among those with ADHD, it is estimated that only 20% receive medication treatment (Mattos et al., et al., This study has some limitations. First, cohort participants came from two large urban areas and thus findings are more generalisable to urban areas, where more than 80% of the Brazilian population lives OECD, . TherefoIn conclusion, the current study estimated the impact of psychiatric conditions on educational outcomes, including examining different condition categories with several widely used educational indicators. The United Nation Sustainable Development Goals recognise education as \u2018one of the most powerful vehicles for sustainable development\u2019. Our findings provide support that treatment and prevention of psychiatric conditions could prevent around 4.9% of grade repetition and 7.7% of age-grade distortion in males and females, and 11.4% of bullying perpetration behaviour and low literacy performance in females with prior externalising-related conditions. Thus, policies which encourage early intervention and collaboration between education and health sectors to support the mental health of schoolchildren can have profound consequences for lifetime opportunities and socioeconomic well-being."}
+{"text": "Retinal vein occlusion (RVO) is a differential diagnosis for Coats\u2019 disease due to retinal arterial Leber\u2019s aneurysms. Occasionally, RVO shows a Coats-like appearance. The differential diagnosis between Coats\u2019 disease and RVO is essential for clinical therapy, especially for those obsolete RVOs with collateral vessels and without retinal hemorrhage. In this case report, we describe and discuss the imaging characteristics of bilateral RVO-simulated Coats\u2019 disease with tortuous retinal arterioles and its prognosis after anti-vascular endothelial growth factor therapy, which will be beneficial for its definite diagnosis and aid further investigation. Coats\u2019 disease was first reported in 1908 as an ocular disorder with retinal telangiectasis and massive intraretinal and subretinal exudation . RetinalA 52-year-old woman was presented to the ophthalmology department of First Hospital of China Medical University complaining of blurred vision in her left eye for two months. She had amedical history of hypertension and no diabetes. The best-corrected visual acuity was 60/60 in her right eye and 15/60 in her left, and the intraocular pressure was 17mmHg in both eyes. Slight cataracts were found in both eyes, and other anterior segment examinations were normal. Wide-field fundus imaging showed bilateral tortuous retinal arterioles with retinal hemorrhage, as well as tortuous and dilated retinal veins in the supratemporal quadrant. Heavy hard exudates were found in the macula of the left eye. The middle phase of fluorescein angiography revealed numerous miliary aneurysms in both eyes and patchy, blocked fluorescence in the left eye. Peripheral fluorescein angiography demonstrated the \u201cfishing net\u201d appearance of retinal capillaries and non-perfusion regions in both eyes . Multico4 and Schatz et al [Herein, we described a bilateral branch RVO with a Coats-like appearance and tortuous retinal arterioles. Hypertension may be a risk factorfor RVO. In contrast to reports by Scimecaetaltz et al , no secotz et al , which iFamilial retinal arteriolar tortuosity is characterized by tortuosity of the second- and third-order retinal arterioles . Khan etIn conclusion, this was the first report of bilateral RVO-simulated Coats\u2019 disease with tortuous retinal arterioles. A definitive diagnosis is crucial for further investigation and treatment."}
+{"text": "Proteins as molecular machines have dynamic structures sampling various conformational states, which determine their functionality, ligand binding, and allosteric properties. Allosteric communication as an intrinsic property of proteins  simulations, elastic network models (ENM), hybrid and integrated methods, and protein structure networks (PSN).Khan et al., performed an integrated computational study on the estrogen receptor alfa (ER\u03b1), which have been observed to be recurrent in metastatic breast cancer patients. The impact of experimentally-reported ER\u03b1 polymorphisms was studied using techniques such as mCSM stability and binding affinity analysis  has become a promising therapeutic approach in cancer immunotherapy. In Liu et al.'s work, the binding features of PD-1 with Nivolumab, a humanized IgG4 antibody approved by the US FDA, were investigated using MD simulations. The computational analysis suggested that the N-terminal loop of PD-1 serves as an important gatekeeper for the anti-PD-1 antibody binding, which might be a potential target for anti-PD-1 antibody design.MD simulation is the most popular computational method used in complementing experimental techniques as it captures the behavior of proteins in full atomistic detail for understanding binding and allosteric events  complex was generated as a potential therapeutic target for inflammatory bowel disease. Eight \u201chot spots\u201d residues and six potential binding sites at the OSM-OSMR interface were predicted using computational alanine scanning and FTMap , and identified potential key binding sites. Besides, some possible tunnel pathways of the inhibitors in these CYP51-inhibitor complexes were proposed. Using MD simulations, Du et al. gave a detailed analysis of thermostability factors of barley limit dextrinase, including eight salt-bridges.In the brief research report by Dudas et al. used the hybrid MDeNM    enzyme and its allosteric properties. In particular, large fluctuations of the N-terminal domain and its allosteric role were discussed in the context of infectious disease treatment.Normal mode analysis based on ENM facilitates the study of protein dynamics and allosteric effects in a high-throughput manner   as the case study. Based on available experimental structures conformationally most variable region of HA was identified as a potential target for diverse ligands. Furthermore, the empirical contact potentials including an ENM-based entropy term were found successful in ranking the free energies of peptide/proteins designed against HA.Halder et al., gave a thorough presentation on the network-dynamical systemic approach to protein function. In addition, their work highlighted the advantages of the side-chain network analysis in studying subtle conformational changes with an emphasis related to allostery. Gosu et al., used PSN to study the MD ensemble of Myeloid differentiating factor 88 (Myd88) and AlloSigMA  that could serve as a potential binding site. Yan et al. designed the ANCA webserver for constructing and analyzing PSN for interpretation of functional residues and allosteric regulation.Topological description of protein structures has become a popular tool to quantify protein structures and dynamics  is a technique that measures the thermodynamics of binding reactions and reaction kinetics. The review by All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "While vaccines traditionally have been designed and used for protection against infection or disease caused by one specific pathogen, there are known off-target effects from vaccines that can impact infection from unrelated pathogens. The best-known non-specific effects from an unrelated or heterologous vaccine are from the use of the Bacillus Calmette-Gu\u00e9rin (BCG) vaccine, mediated partly through trained immunity. Other vaccines have similar heterologous effects. This review covers molecular mechanisms behind the heterologous effects, and the potential use of heterologous vaccination in the current COVID-19 pandemic. We then discuss novel pandemic response strategies based on rapidly deployed, widespread heterologous vaccination to boost population-level immunity for initial, partial protection against infection and/or clinical disease, while specific vaccines are developed. Since the introduction of the smallpox vaccine in 1796, and the Bacillus Calmette-Gu\u00e9rin (BCG) vaccine in 1921, vaccination-related reductions in non-specific morbidity and mortality have been described. Carl N\u00e4slund was the first to establish the concept of non-specific immunological vaccine effects, also known as heterologous effects of vaccination (HEV), when BCG vaccination started in Sweden (Aaby and Benn Measles vaccination (MV) can also have non-specific effects. After the introduction of MV in Guinea-Bissau, there was a significant decrease in childhood mortality . Since its introduction in South America, reports revealed an interference with the replication of other enteroviruses, resulting in fewer diarrheal deaths , but the primary data in fact only supports the conclusion of increasing risk with decreasing number of DPT innoculations.Until recently, the lack of studies evaluating the underlying mechanisms of HEV has been a major obstacle in recognizing and taking advantage of these effects during a pandemic. In this mini-review, we review the immunological mechanisms and the development of the idea of Heterologous Vaccine Intervention (HVI), referring to the exploitation of heterologous or non-specific effects of current approved vaccines against one or more unrelated pathogens. This novel pandemic \u201cearly response\u201d intervention, that could be rolled out in parallel with non-pharmaceutical interventions (NPIs) could be used for the current COVID-19 pandemic and for future pandemics to come.+ monocytes and imprints a persistent transcriptomic myeloid bias on human hematopoietic stem and progenitor cell compartment in the bone marrow  after a primary exposure, such as an infection or vaccination, that leads to an altered response towards a second exposure after the return to a non-activated immune state, is termed \u2018trained immunity\u2019(Netea et al. Other innate immune cells that can contribute to protective HEVs include NK cells by increased cytokine production (Rozot et al. Less well studied mechanisms in BCG and other live vaccines are from viral interference (Sepp\u00e4l\u00e4 et al. In addition to the effect of a heterologous vaccine on innate immune mechanisms, vaccines can also alter adaptive immune responses to unrelated pathogens and antigens. Two different mechanisms have been described: cross-reactivity and bystander activation. The classical adaptive immune response corresponds to T cells that respond to antigen presentation, but these T cells may cross-react with a different antigen with amino acid similarity (Frankild et al. Toxoplasma gondii in adults are stimulated through bystander activation, upon immunization with tetanus toxoid (Goodridge et al. An illustrative example of cross-reactivity resulting from molecular mimicry is the existence of memory T cells specific to viral antigens in unexposed adults, such as herpes simplex virus, cytomegalovirus and HIV-1, possibly as a consequence of cross-reactivity with antigens in the environment. Furthermore, the seasonal influenza vaccine can stimulate T cells specific for a cross-reactive bacterial homologue (Su et al. The durability of the heterologous effects after vaccination is unknown, although vaccinia and BCG vaccinations are associated with better long-term survival during a 40-year follow up (Rieckmannet al. Several ecological studies have suggested a negative association between different vaccines and the prevalence or mortality of COVID-19. Escobar et al. attempted to mitigate potential confounding factors and reported a strong correlation between their BCG index and COVID-19 mortality in different socially similar European countries, specifying that every 10% increase in the BCG index was associated with a 10.4% reduction in COVID-19 mortality (Escobar et al. An inverse association between influenza vaccination coverage rate in the elderly, at a county or region level in the US (Zanettini et al. Using the quadrivalent inactivated influenza vaccine applied in the Netherlands in the 2019\u20132020 influenza season, Debisarun et al. demonstrated the induction of trained immunity response in an in vitro model, including improvement of cytokine responses, after stimulation of human immune cells with SARS-CoV-2 (Debisarun et al. The concept of Heterologous Vaccine Intervention is being developed with BCG vaccination, and several randomized trials are underway to study if BCG vaccination reduces the incidence or severity of COVID-19 in different countries (NIH U.S. National Library of Medicine Although specific COVID-19 vaccines have been released and given emergency use approval, they are still in limited supply and the slow pace of COVID-19 vaccination is a global challenge. Public health policies against pandemics may derive benefit from the concept of HVI, authorizing the early use of non-specific vaccines either generally as a boost, second dose after the COVID-19 vaccine prime (Hupert et al."}
+{"text": "Focused electron beam (FEB) and focused ion beam (FIB) technologies have opened novel paths for material science research and technology at the micro and nano scales in recent decades. These technologies are highly adaptable, and flexible tools are used successfully in fundamental and applied research projects allowing visualization, elemental and structural analysis, and additive and subtractive manufacturing, as well as efficient modification of materials. All of this can be done on scales ranging from hundreds of \u03bcm to one nanometer. The unique flexibility of focused beams enables them to be used for rapid prototyping as well as nanostructure editing and analysis. Today, these technologies play an important role in the development of new integrated circuits based on miniaturized electronic devices.Concerning the additive nanofabrication, the use of gas injection systems with advanced programs  allow to grow in single-step nanostructures in three dimensions by the partial decomposition of a precursor material produced by the effect of the beam scanning. This technique is called focused ion/electron beam-induced deposition (FIBID/FEBID). Nanostructures grown using this additive manufacturing technique can have arbitrary shapes, both in-plane  and out-of-plane , and also can host insulating, metallic, ferromagnetic, or superconducting properties.+ FIBID deposits with in situ heating ,  nan nan+ FIBs [+ FIB ,8.1) Purification of FEBID nanostructures: Markus Rohdenburg et al. [ Purifica2) High-resolution nanostructures using FEBID: Sangeetha Hari et al. [ High-res3) A new approach for the nanofabrication of metallic nanostructures based on FEB: Luisa Berger et al. [ A new ap4) Tuning of diameters in 3D FEBID nanostructures: Lukas Seewald et al. [ Tuning o5) Evolution of the microstructure and resistivity in Pt FIBID deposits with in situ heating: Chaorong Zhong et al. [ Evolutio+ FIB-induced processing for photonic applications: Mariachiara Manoccio et al. [6) Nanofabrication using Ga Nanofabr+ FIB: Alex Belianinov et al. [7) Fabrication of 3D FIBID nanostructures using He Fabricatv et al.  have repI would like to thank all authors who submitted their papers to this Special Issue. I would also like to thank all the reviewers for dedicating their time to provide careful and timely reviews to ensure the quality of this Special Issue."}
+{"text": "Tinel et\u00a0al.; Aschauer et\u00a0al.; Wu et\u00a0al.; Okamura et\u00a0al.) and three comprehensive Review articles  on immunogenomics of SOT and HSCT that include both animal and human studies.Alloreactivity is caused by the extensive difference in polymorphic genes between allogeneic donor and recipient, primarily in the major histocompatibility complex (MHC). As key mediators of alloresponses, alloreactive T cells are educated by self MHC and thus acquire the ability to recognize non-self MHC, leading to graft rejection and graft-versus-host-disease (GVHD), in solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT), respectively . ThroughShi et\u00a0al. provides an insightful review of genomic-based approaches to the study of transplant rejection, including microarray, RNA sequencing (RNA-seq), and spatial transcriptomic techniques. This review traces the developmental history of these approaches and extends it to the current fast-paced field of emerging technologies, which includes the integration of single cell RNA-seq with T cell receptor (TCR) and B cell receptor (BCR) sequencing to profile immune repertoires, with mass cytometry and featured barcode antibodies to measure protein expression, and with chromatin sequencing to explore gene regulatory networks. The authors discuss the advantages and limitations of each approach. Application of these analysis tools will contribute to a fundamental understanding of the alloresponse and likely promote novel therapeutic options to overcome rejection and GVHD.Tinel et\u00a0al. performed miRNA and mRNA profiling of kidney allograft biopsies to reveal new pathways involved in microvascular Inflammation (MVI), the main histological injury associated with AMR. This study identifies six differentially-expressed miRNAs that are correlated with the intensity of MVI. mRNAs/miRNAs interplay analysis further elucidates the crosstalk between renal-resident and allograft-infiltrating cell subsets and suggests that epithelial, rather than endothelial, metabolism modifications occur during AMR. This study illustrates the great potential of multi-omics to decipher rejection mechanisms.To investigate the role of microRNAs (miRNAs) in antibody-mediated rejection (AMR) after SOT, Tian et\u00a0al. reviews recent advances in TCR-seq and computational tools and discusses the potential of using TCR-seq to profile alloreactive T cell repertoires. Defining and tracing donor- and recipient-reactive TCRs may reveal the fingerprint of alloreactive T cells, providing valuable indication of graft rejection, acceptance and treatment response after SOT.TCR repertoire diversity and turnover dynamics are related to rejection and tolerance in SOT . The preAschauer et\u00a0al. analyzes donor-reactive TCRs in pre-transplant blood and post-transplant kidney biopsies in the presence and absence of TCMR to find little repertoire overlap in these two sites. While circulating donor-reactive repertoire is increased in both groups, donor-reactive T cells in kidney are only enriched during a TCMR episode with substantially diverse TCRs, indicating the capability to respond against a variety of epitopes in the allograft.Frequencies of circulating donor-reactive T cells were elevated in kidney transplant patients receiving conventional immunosuppression , 7. HoweFu et\u00a0al. further discusses the use of TCR-seq to discern the factors behind human T cell repertoire development and how this approach can be used in combination with human immune system mouse models to understand human repertoire selection. The article explains current understanding of the propensity of alloreactive TCRs as a consequence of thymic selection. It also notes the limitations of techniques historically used to study human TCR repertoires and provides descriptions of innovative tools the authors are utilizing  TCR diversity is narrowed in allogeneic T cells; 2) top dominant T cell clones are highly shared across circulation and GVHD target organs in allogeneic recipients; 3) clonal expansion of rare rearrangements from pre-transplant donor T cells may account for the sharing of a few clones among allogeneic recipients. Their findings illustrate immune repertoire sequencing-based methods as a novel personalized strategy to guide diagnosis and therapy in GVHD.T cells are considered as not only the main culprit behind TCMR after SOT, but also the driving force of GVHD after allogeneic HSCT . RecoverOkamura et\u00a0al. reports that high levels of complement factor Ba a week after HSCT predict the occurrence of TA-TMA and related non-relapse mortality. This finding, once confirmed in a broader cohort, will lay the groundwork for highly-tailored and complement-targeted therapeutics. C5 blockade\u2014which already revolutionized outcomes of atypical hemolytic uremic syndrome  is also a life-threatening medical condition. Although pathogenic variants in complement regulatory genes have been reported as genetic susceptibility to TA-TMA in only a minority of patients , 20, grosyndrome , anothersyndrome .This Research Topic of articles provides an in-depth review of current understanding of alloresponses after transplantation\u00a0in preclinical and clinical settings from the immunogenomics perspective and encourages future investigations in this field.YW, JZ, and JF collected articles and wrote the editorial review. All authors contributed to the review and approved the submitted version.YW was supported by R01 CA258440 from NIH/NCI (PI: Xue-Zhong Yu). JZ was supported by the Fondation Emmanuel Boussard, IMAGINE Institute, DIM-Th\u00e9rapie G\u00e9nique/R\u00e9gion Ile-de-France, Agence de la Biom\u00e9decine, and Agence Nationale de la Recherche . JF was supported by a Congressionally Directed Medical Research Program (CDMRP) Discovery Award W81XWH-20-1-0159 funded by the Department of Defense (DoD), a R21 grant AI166069 supported by NIH/NIAID and Nelson Faculty Development Awards UR011630-01 and UR011630-02 from the Nelson Family Transplantation Innovation Award Program at Columbia University Irving Medical Center.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Bipolar disorder is associated with premature mortality, but evidence is mostly derived from Western countries. There has been no research evaluating shortened lifespan in bipolar disorder using life-years lost (LYLs), which is a recently developed mortality metric taking into account illness onset for life expectancy estimation. The current study aimed to examine the extent of premature mortality in bipolar disorder patients relative to the general population in Hong Kong (HK) in terms of standardised mortality ratio (SMR) and excess LYLs, and changes of mortality rate over time.This population-based cohort study investigated excess mortality in 12 556 bipolar disorder patients between 2008 and 2018, by estimating all-cause and cause-specific SMRs, and LYLs. Trends in annual SMRs over the 11-year study period were assessed. Study data were retrieved from a territory-wide medical-record database of HK public healthcare services.Patients had higher all-cause [SMR: 2.60 (95% CI: 2.45\u20132.76)], natural-cause [SMR: 1.90 (95% CI: 1.76\u20132.05)] and unnatural-cause [SMR: 8.63 (95% CI: 7.34\u201310.03)] mortality rates than the general population. Respiratory diseases, cardiovascular diseases and cancers accounted for the majority of deaths. Men and women with bipolar disorder had 6.78 (95% CI: 6.00\u20137.84) years and 7.35 (95% CI: 6.75\u20138.06) years of excess LYLs, respectively. The overall mortality gap remained similar over time, albeit slightly improved in men with bipolar disorder.Bipolar disorder is associated with increased premature mortality and substantially reduced lifespan in a predominantly Chinese population, with excess deaths mainly attributed to natural causes. Persistent mortality gap underscores an urgent need for targeted interventions to improve physical health of patients with bipolar disorder. Specifically, we adopted two mortality metrics, namely SMR  and LYLs to quantify the magnitude of excess mortality among patients with bipolar disorder compared with the general population. Changes in SMRs across the study period were also assessed to clarify whether the mortality gap improved or worsened over time.et al., et al., et al., et al., Population statistics and information on all registered deaths in HK between 2008 and 2018  were obtained from the Census and Statistics Department. Data of the patient cohort were extracted from the Clinical Data Analysis and Reporting System , and aged \u2a7e15 years during the study period as the study population. Diagnosis of bipolar disorder was recorded and verified by the International Classification of Diseases, 10th revision (ICD10 codes: F30 and F31). Final diagnostic ascertainment took into consideration the longitudinal illness course (Chang Causes of death were classified according to ICD10 codes (online Supplementary Table S1), and were divided into natural and unnatural causes. Natural causes were categorised into infectious and parasitic diseases (A00\u2013B99), neoplasms (C00\u2013D48), cardiovascular diseases (I00\u2013I99), respiratory diseases (J00\u2013J99), digestive diseases (K00\u2013K93) and genitourinary diseases (N00\u2013N99). An array of specific natural causes was also identified for analyses. As data on specific unnatural causes (V01\u2013Y98) were not available, we treated unnatural deaths as a single category for analyses.P exact tests. To assess trends in all-cause, natural-cause and unnatural-cause SMRs over time, joinpoint regression analysis was performed which estimated the optimal number of linear slopes and joinpoints with modified Bayesian information criteria  for all-cause and cause-specific deaths were calculated as the primary mortality measures to quantify the relative mortality rate between patients with bipolar disorder and the general population. First, number of observed deaths and person-years of follow-up were computed for each calendar year (2008\u20132018), sex and age category  for the patient group. The number of person-years for each stratum was multiplied by the corresponding mortality rate in the general population to produce expected number of deaths, indirectly standardising overall mortality ratio by age, sex and calendar year. SMRs were estimated by dividing the observed number of deaths by the expected number of deaths. Crude mortality rates (CMRs) per 100\u00a0000 person-years as well as SMRs for all-cause and cause-specific deaths of the patient group over the whole study period, stratified by sex and four broader age groups , were then calculated, with 95% confidence intervals (CIs) of SMRs being derived by mid-et al., et al., et al., et al., et al., et al., lillies  for all-cause mortality were also calculated as a complementary mortality measure. Following the method adopted in previous research for LYL estimation  with 106\u00a0147 persons-years of follow-up , and a total of 1042 deaths, of which 821 (78.8%) had a known cause. The numbers of person-years and cause-specific death counts for each demographic subgroup of patients are listed in online Supplementary Table S2.All-cause SMR for bipolar disorder was significantly increased in the total sample  and in each demographic subgroup relative to the general population  and 2. ASMRs for natural and unnatural causes were significantly increased in the total sample  and in each demographic subgroup of patients with bipolar disorder, except the youngest age-group who showed no significant increase in natural-cause SMR  and 2. BNatural causes accounted for most of the known-cause deaths in patients. Approximately two-thirds of all known-cause deaths were attributed to respiratory diseases, cancers and cardiovascular diseases (online Supplementary Table S2). Respiratory diseases represented the leading cause of death and accounted for around one-thirds of all known-cause deaths. Cancers and cardiovascular diseases contributed to about 1 in 5 and 1 in 7 known-cause deaths, respectively. Unnatural causes accounted for approximately one-fifths of known-cause deaths. Men had generally higher CMRs for most listed causes of death than women . MortaliAs shown in Joinpoint regression fitted a linear model of all-cause, natural-cause and unnatural-cause SMRs with no joinpoints over time for the total sample, men and women subgroups. As shown in To our knowledge, this is the first study using LYLs complementary with relative mortality risk measure (SMR) to evaluate the excess mortality associated with bipolar disorder. Our results showed that patients with bipolar disorder had 2.6-fold increased mortality risk compared with the general population. Both men and women with bipolar disorder exhibited a substantially shorter lifespan than the general population, with approximately 7 years of excess LYLs. Natural causes, specifically respiratory diseases, cardiovascular diseases and cancers, accounted for the majority of known-cause deaths, while unnatural cause had markedly elevated SMR, particularly among patients aged <35 years. Generally, the mortality gap persisted over 11 years, albeit slightly improved in men with bipolar disorder.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Our finding on all-cause SMR for bipolar disorder is broadly consistent with the literature which reported 2\u20133 times greater overall mortality risk than the general population (Chang et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Until now, very few studies have comprehensively examined cause-specific SMRs for natural deaths in bipolar disorder. Consistent with the literature (Crump et al., et al., et al., et al., Patients with bipolar disorder had approximately 8 times greater risk of dying from unnatural causes than the general population. This finding is concordant with the unnatural-cause summary SMR of 7.42 reported by a recent meta-analysis (Hayes et al., et al., et al., et al., et al., Although our analysis suggested small, albeit statistically significant, reduction in annual all-cause mortality rate over time in men with bipolar disorder, the overall mortality gap remained largely unchanged over 11 years. Both natural-cause and unnatural-cause mortality differences also showed no significant improvement across the study period in either sex or in the overall sample. Our results thus agree with most previous studies (Medici et al., et al., et al., Several study limitations should be noted. First, several demographic variables including educational level, socioeconomic or employment status and a number of premature mortality risk factors such as unhealthy lifestyles and obesity were not adequately recorded in medical database and thus were not included in the analysis. Second, missing data on patients\u2019 death causes may compromise the accuracy in evaluating cause-specific SMRs. Third, as information on specific unnatural causes was not available, we were not able to investigate mortality risk for individual categories of unnatural deaths including suicide and accidents. Fourth, the study data did not contain information denoting the disorder subtypes, precluding us from examining potential differences between bipolar I and II disorders in mortality rate and life expectancy. Fifth, patients\u2019 age of illness onset was defined by age of first-recorded diagnosis of bipolar disorder. However, previous studies showed that there could be significant delays between illness onset and ascertainment of bipolar disorder diagnosis (Dagani In conclusion, this large population-based study indicates that bipolar disorder patients have increased mortality risk and markedly reduced life expectancy in a predominantly Chinese population, with excess mortality being primarily attributable to natural causes. Our findings of persistent mortality gap across the study period highlights an urgent need for further research to identify its underlying causes and to implement multi-level, targeted interventions to promote physical health of bipolar disorder patients so as to significantly reduce their risk of preventable physical morbidity and premature mortality."}
+{"text": "The increase in number of people suffering from neurodegenerative dementia (ND), such as Alzheimer's disease (AD) and Parkinson's disease (PD), has placed a huge burden on society. Precise detection of ND in an early phase is still challenging in daily clinical practice , 4-[(E)-2-(6-{2-[2-(2-(18F)fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)ethen-1-yl]-N-methylaniline (18F-AV45), and 7-(6-(18F)fluoropyridin-3-yl)-5H-pyridoindole (18F-AV1451) have been widely used in research and diagnostic imaging of ND. Development of bioinformatics analysis and artificial intelligence methods has significantly facilitated advances in research of ND. Nowadays, researchers are facing difficulties in choosing the best method in order to conduct research in a comprehensible fashion with estimates of accuracy and reproducibility.In addition to metabolic changes such as altered glucose metabolism, alterations of amyloid-beta and tau protein are biomarkers associated with pathology of AD, whereas alpha-synuclein is proven to be related to PD and other NDs  e4 allele might affect the relationship between serum lipid levels and cognitive impairment. In addition, Hu, Li, Zhao, et al. provided evidence that the combination of telmisartan and rosuvastatin might be an effective prevention and/or treatment strategy for cognitive impairment and dementia, especially in hypertensive patients with the APOE e4 allele. Kuang et al. demonstrated that the e4 genotype leads to distinct default mode network (DMN) functional alterations in early phases of AD using persistent homology approach. Lin investigated whether CDGSH iron-sulfur domain 2 (CISD2) gene attenuation had an influence on anti-inflammatory effects and M1-M2 polarization in microglia. This study promised a potential therapeutic target for ND.Based on univariate and multivariate analyses, Jiao et al. focused on plasma biomarkers which are less expensive and invasive than those necessitating a spinal fluid sample. The results of their study showed that the multifactor model of plasma amyloid-beta 42 and total-tau in combination with Montreal Cognitive Assessment (MoCA) could be a viable model separate health and AD subjects in clinical practice. Gao et al. characterized the relationship between plasma amyloid-beta levels and cognitive decline in 1,240 cognitively normal participants. The relationship between plasma amyloid-beta 40 and cognitive decline was an inverted-U shape in a cognitively normal population. None of relationship between plasma amyloid-beta 42, amyloid-beta 42/40, and cognitive decline was found during a 2-year follow-up. Lin et al. enrolled cognitively normal amyloid-beta-positive participants from 2 cohort studies, all types of resilience to cerebrospinal fluid (CSF) amyloid-beta could predict longitudinal cognitive decline.For clinical diagnosis of AD, Yu et al. identified 16 hub genes correlated to the neuropathological stage and 35 potential biomarkers for the diagnosis of AD. Yuen et al. demonstrated a systematic workflow for evidence synthesis of transcriptomic studies using both meta-analysis and bioinformatics methods to identify potential pathogenic factors. The results showed that reduced amyloid-beta clearance in AD pathogenesis was associated with genes encoding Fyn and EGFR, which were key receptors in amyloid-beta downstream signaling. Robin et al. comprehensively profiled phenotypic features over time in one commercially-available induced Pluripotent Stem Cell (iPSC)-derived human neuron cell line. This study provided a tool to investigate neurodegenerative and other central nervous system (CNS) diseases. Deng et al. applied multivariate model to estimate the association between leukocyte telomere length (LTL) and cognitive performance. Their results suggested that LTL might be a biomarker of cognitive aging.Identification of novel molecular biomarkers for diagnosis and treatment of AD is urgently demanded. Based on bioinformatics analysis, Kong et al. explored the links between diabetes and AD by studying the advanced glycation end products (AGEs) and the receptors for AGEs (RAGE). The results of their study suggested that patients with diabetes were at a higher risk of developing AD. They further reviewed the interaction between RAGE and amyloid-beta as well as tau, which highlighted the potential of RAGE to be used as an effective target for AD diagnosis and treatment. Ho et al. explored type 2 diabetes mellitus (T2DM) pathogenesis in the amyloidogenic evolvability. A better understanding of the role of T2DM in amyloidogenic evolvability might reveal new targets for therapeutic intervention in AD patients who are comorbid with T2DM.Li et al. found that T2DM could give rise to the white matter atrophy of several brain regions, including left posterior cingulate, precuneus, insula, and right rostral middle frontal gyrus. In addition, they investigated the white matter structural network disruption in T2DM patients with MCI. Chen et al. developed MR glucose chemical exchange saturation transfer (glucoCEST) imaging in a rat model of AD. The findings from their study showed that this method could explore the occurrence and progress of diabetes-related AD or dementia.Using magnetic resonance (MR) imaging, Feng et al. explored the role and underlying mechanism of calcium-sensing receptor (CaSR) in cognitive deficits in AD mice. Their study might provide novel insights on the potential of CaSR as a therapeutic target for AD. Wu et al. examined whether steroid receptor coactivator 1 (SRC-1) is involved in pathogenesis of AD. Tyagi et al. reviewed the role of cyclooxygenases (COX) and mammalian/mechanistic target of rapamycin (mTOR) and potential therapeutic approaches targeting COX-2 and mTOR in AD and cancer.Based on live-cell imaging combined with behavioral tests, Bjorkli et al. reviewed the preclinical and clinical investigations of commonly used biomarkers in animal models of AD and AD patients respectively. They also provided recommendations for standardization of procedures in sample collection to enhance the translational validity of preclinical study using AD animal models.Zhang, Chen, et al. reviewed the researches about TDP-43 and its relationship with limbic-predominant age-related TDP-43 encephalopathy (LATE).TDP-43 is a protein related to amyotrophic lateral sclerosis (ALS) and many cases of tau-negative frontotemporal lobar degeneration. Zhang, Xie, et al. reported prospects of 2 kinds of reprogramming technologies for neurodegenerative diseases: (1) convert adult somatic cells to iPSCs and (2) directly reprogramming adult somatic cells to induced Neurons (iN).In an effort to develop neurodegenerative disease model at cellular level, Jang et al. provided updates on current progress in stem cell-derived dopaminergic neuron transplantation as a therapeutic alternative for PD. Yang, Zhang, et al. aimed to uncover the metabolic pathways across anatomical regions in the brain of PD and levodopa-induced dyskinesia (LID). Based on principal component analysis (PCA) and multivariate general linear model, the midbrain and right cortex were identified as the primary regions of metabolic abnormalities in PD and LID rats. In addition, PD and LID rats exhibited lower levels of synaptophysin (SYP). All results provided key insights for developing targeted therapies in PD. Harsanyiova et al. discussed the relationship between gastrointestinal tract and the pathology or treatment of PD symptoms.Bao et al. surveyed the various positron emission tomography (PET) radiotracers available for AD imaging and discussed their clinical applications especially in terms of early detection and cognitive relevance. Based on [18F]-APN-1607 PET tracer, Lu et al. detected tau deposition in AD and reported that individual tauopathy is correlated with impaired cerebral glucose metabolism and cognitive function. Using combined PET and MR imaging, Kim et al. investigated the effect of conductive hearing loss in an AD mouse model. The findings from their study indicated that even partial hearing loss could aggravate memory impairment in AD.11C-PE2I is a PET radiotracer targeting neuronal dopamine transporters (DaT). Ivanidze et al. investigated neurovascular unit (NVU) integrity by using arterial spin labeling (ASL) MR imaging and correlated the findings of NVU integrity with striatal DaT density from 11C-PE2I PET imaging. This exploratory research could serve as a foundation for further development of combined NVU and striatal DaT density as early disease biomarkers and potential new therapeutic targets. Based on 11C-CFT and 18F-FDG PET imaging data, Fei et al. studied the relevancy between UPDRS motor scores and PDQ39 mobility sub-scores.31P MR spectroscopy of parieto-occipital lobes with 7-Tesla MR imaging, Das et al. accurately quantified high-energy phosphate and membrane phospholipid metabolites in amnestic MCI (aMCI). Furthermore, they have also found that brain energy metabolism and membrane phospholipid indexes were related to cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills using aMCI.Based on partial volume-coil Liu, Jiang, et al. explored functional and structural properties of abnormal brain networks associated with PD. The authors showed that both the expressions of metabolic and structural patterns in PD patients were significantly higher than healthy controls, and verified their results in connectome analysis, which provided new information for elucidating the neuropathological mechanisms of PD. Shu et al. developed an integrative nomogram based on white matter radiomics biomarkers and nonmotor symptoms for the identification of early-stage PD.Tsai et al. explored the skull score (SS) distribution of tremor patients, and correlated the SS with image feature from customized skull density ratio (cSDR). This study provided useful information for clinical study of MR-guided focused ultrasound thalamotomy. Chiu, Tzeng, et al. found that the patients with tremor and vascular cognitive impairment (VCI) had high possibility of mixed pathology of PD and Lewy body disease (LBD).Ye et al. investigated the volumetric changes in thalamus and hypothalamus in ALS. The results from their study revealed no significant difference of the volume in thalamus and hypothalamus between ALS patients of normal frontotemporal function and healthy controls.Yu et al. identified the brain function activity differences between MCI patients with depression and MCI patients without depression using resting state MR imaging measurements. This study provided useful information for a better understanding of the relationship between depressive symptoms and memory deficits. Xing et al. explored the alterations in intra- and inter-network functional connectivity of multiple networks in presbycusis patients, suggesting that functional network connectivity can be used to predict potential cognitive impairment in their early stage.Wan et al. compared the changes in subcortical nuclei in older adults with cognitive frailty (CF) and studied their relationship with cognitive decline and physical frailty. Their results showed significant volume reductions in five subcortical nuclei, including the bilateral thalami, left caudate, right pallidum, and accumbens area in older adults with CF. Lee et al. used surface-based analysis to evaluate subcortical structural characteristics and its relationship with early onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). The results from their study demonstrated that EOAD and LOAD might have different courses of pathomechanism.Qiao et al. examined the neural substrates and mechanisms that generate memory deficits, seizures, and neuropsychiatric abnormalities in encephalitis with leucine-rich, glioma-inactivated 1 (LGI1) antibodies. The results showed that neural disorder and behavioral deficits of anti-LGI1 encephalitis might be associated with extensive changes in brain connectivity and microstructure.Bruchhage et al. performed machine learning to assess the contribution of volume fraction myelin and gray matter volume. They proposed a refined model of cerebellar contribution to early AD development. The results from their study showed higher anterior cerebellar contribution to MCI and higher posterior cerebellar contribution to mild/moderate stages of AD for each tissue property. Ma et al. proposed a generative adversarial network (GAN) framework to distinguish brain images of human subjects of normal brain aging from those of human subjects with AD and frontotemporal dementia (FTD). The results from their study showed an accuracy of 88.28% in distinguishing human subjects of normal brain aging from those of human subjects with AD and FTD based on GAN framework derived from brain image.Hu, Li, Zhang, et al. found that periodontitis was associated with learning and memory impairment, probably induced by neuroinflammation via activating the toll-like receptor 4/Nuclear factor kappa B signaling pathway. Ding et al. aimed to evaluate the value of odors in olfactory identification (OI) test and other known risk factors for predicting incident dementia. The results from their study suggested that peppermint smell capability might be one of the useful indicators for predicting dementia. Nie et al. assessed the differences of eye movement parameters between healthy elderly individuals and patients with MCI. They found that cognitive deficits and eye movement indexes were correlated, which could be further explored as early markers for MCI.Yang, Huang, et al. proposed a neuroimaging approach to identify MCI using a deep learning method and functional near-infrared spectroscopy (fNIRS). Their results indicated that fNIRS imaging approach based on temporal feature maps as a promising diagnostic method for early detection of MCI and clinicians might use it as a tool for evaluation of MCI.The paper by Tseng et al. used multivariate time-series electrocardiogram (ECG) analysis to diagnose cardiovascular diseases. They investigated various ECG features and found some associations between features of ECG and medical records .Chiu, Hung, et al. studied the relationship between freezing of speech (FOS) and dementia with Lewy bodies (DLB). They designed a freezing of speech single questionnaire (FOSSQ) and compared the association factors of FOS in non-demented participants, patients with AD, vascular dementia (VaD), and DLB. The results of their study supported validity of the FOSSQ for discriminating DLB from individuals with non-demented or other forms of dementia. Similarly, Wang, Hung, et al. designed a novel questionnaire for visuospatial dysfunction (VSD) in DLB.Gupta et al. proposed different neuroimaging modalities combined with APOE genotype to form a multimodal system for discrimination of AD to increase the classification accuracy.To distinguish stable MCI (MCIs) from converting MCI (MCIc), Lin et al. developed an extreme learning machine (ELM)-based grading method to predict MCI-to-AD conversion. The method was validated by Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, with an accuracy of 84.7% in prediction of MCI progression to AD within 3 years.In order to determine whether a MCI patient is at high risk of progressing to AD, Wang, Wei, et al. conducted a systematic review and meta-analysis to assess the available preclinical evidence and possible mechanisms of baicalein for animal models of PD. Li et al. investigated the efficacy and safety of 3 Erinacine A-enriched Hericium erinaceus mycelia (EAHE) capsules for the treatment of patients with mild AD. The study lasted for 49 weeks and the results showed that EAHE was well-tolerated without significant side effects. Flavonoid containing natural products, Myricetin (MYR) and Dihydromyricetin (DMY) are abundant in fruits and vegetables. Liu, Guo, et al. reviewed the benefits of MYR and DMY in AD patients at molecular level, including effects on amyloid-beta protein imbalance, neuroinflammation, dyshomeostasis of metal ions, autophagy disorder, and oxidative stress.Lai et al. compared and ranked 9 treatment methods for MCI in AD based on meta-analysis. They pointed out that music therapy might be the best treatment for MCI followed by acupuncture, among the nine treatment methods included for their meta-analysis. Similar to those non-pharmacological interventions, Pei et al. proposed a neurofeedback training based on mismatch negativity to regulate sensory ability and memory.The early intervention for MCI could decrease the rate of conversion from MCI to AD. Stuckenschneider et al. investigated the effects of a 12-month structured exercise program on the progression of 183 amnestic MCI patients. No significant improvement of cognitive performance was found based on the results from their study. In another study based on event-related measurement of auditory memory, Laptinskaya et al. found no improvements of cognitive performance in a 10-week unimodal cognitive or physical training and an active lifestyle for older adults at risk for dementia. In the narrative review by Meng et al., patients with AD who presented with long-term exercise interventions appeared to have improved blood flow, increased hippocampal volume, and improved neurogenesis. These results indicated that exercise intervention might be an important moderator to prevent long term disease progression.Kumar et al. reviewed and discussed nano-enabled drug delivery systems and their current and potential applications for the treatment of various NDs, including AD and PD, in studies to overcome the limits of blood-brain barrier (BBB). Huang et al. developed a medical red light treatment (RLT) device to treat older adults with mild to moderate AD. They planned a study protocol to verify the safety and efficacy for a 24 weeks period. On the other hand, Zhu et al. found that there was more efficacy via tele-health interventions in lowering depression for careers of dementia patients based on meta-analysis.Luo et al. reviewed the therapeutic effect of DBS in AD, and analyzed its stimulation parameters and potential mechanism of action. Tan et al. used a convolutional neural network (CNN) to classify handwritten digits and letters and applied dropout at different stages to simulate DBS effects on engrams. The results of their study showed that dropout of engram nodes might be a possible mechanism by which neuromodulation techniques could disrupt or enhance memory. Hwang et al. pointed out the applications of phase amplitude coupling-based phase-dependent DBS technique in PD, which aimed to deliver timed stimulation pulses to a specific phase precisely to modulate pathological network activities and behavior in real time.Deep brain stimulation (DBS) is widely used in the field of mental and neurological diseases. Tang et al. investigated the effect of electroacupuncture (EA) on cognitive impairment and the role of c-Jun N-terminal kinase (JNK) signaling pathway in AD model mice. The results of their study showed that EA could reverse cognitive deficits and substantially lower the burden of amyloid precursor protein. In another study, Hongna et al. demonstrated the improvements of locomotor function by promoting autophagy flux and inhibiting necroptosis in rats with spinal cord injury treated with Jia-Ji electro-acupuncture.In summary, large number of articles collected in this Research Topic reflected recent advances in mechanistic study of pathophysiology of AD and PD, development of biomarkers and molecular imaging techniques for diagnosis and treatment of AD and PD. We hope that publications of this Research Topic will not only report recent advances in ND research, but also facilitate translation of new discovery to development of new diagnostic tests and therapeutic agents for early diagnosis and treatment of ND, including AD and PD.JJ and KS wrote the draft. FP copyedited for the language. C-YH and W-MK reviewed and revised the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Neurodegenerative diseases, including Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD) and amyotrophic lateral sclerosis (ALS), are typically characterized by progressive neuronal loss and neurological dysfunctions in the nervous system, affecting both memory and motor functions. Neuregulins (NRGs) belong to the epidermal growth factor (EGF)-like family of extracellular ligands and they play an important role in the development, maintenance, and repair of both the central nervous system (CNS) and peripheral nervous system (PNS) through the ErbB signaling pathway. They also regulate multiple intercellular signal transduction and participate in a wide range of biological processes, such as differentiation, migration, and myelination. In this review article, we summarized research on the changes and roles of NRGs in neurodegenerative diseases, especially in AD. We elaborated on the structural features of each NRG subtype and roles of NRG/ErbB signaling networks in neurodegenerative diseases. We also discussed the therapeutic potential of NRGs in the symptom remission of neurodegenerative diseases, which may offer hope for advancing related treatment. Neurodegeneration is characterized by the progressive loss of neuronal structure and function, including the death of neurons, which deteriorates over time and eventually leads to dysfunction of the nervous system. Neurodegenerative diseases, including Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), Huntington\u2019s disease (HD), amyotrophic Ilateral sclerosis (ALS) and spinocerebellar ataxia  belong to the epidermal growth factor family of extracellular ligands, participating in the regulation of normal cells and tumor cell growth and survival through the ErbB family receptor tyrosine kinases  is a family of growth factors that plays multiple roles in many neurological disorders, including ALS  has been differently named as neu differentiation factor , heregulin , acetylcholine receptor-inducing activity , glial growth factor , and sensory and motor neuron-derived factor  was originally found in DNA sequence databases and DNA libraries when screening for genes with sequence similarities to members of the NRG1 family  was originally detected in adult pancreas and muscle and was initially identified as a necessary factor for tissue growth  is a neurodegenerative disease with insidious and progressive onset, mainly in the elderly, and its incidence increases with age  is a continuously progressive disease clinically characterized by changes in cognition or behavior  is pathologically characterized mainly by: (1) senile plaque formed by abnormal deposition of \u03b2-amyloid protein outside neurons; and (2) NFTs formed by abnormal phosphorylation of tau protein   such as the C-terminal fragments of APP (APP-CTs) have been reported to exert cytotoxic effects in neuronal cells  represents a potential treatment for AD, and lots of BACE inhibitors are progressing through clinical trials at present  increase the levels of pErbB4 receptor and pAkt, and increase the level of Bcl-2 both in in vitro studies and APP/PS1 transgenic mice  family, NRG2 can bind directly to ErbB3 and ErbB4, thus transactivating ErbB2 , a specific ligand for ErbB4 and a neuronal-enriched neurotrophin, has been identified as a protein structurally related to the NRG1. It is involved in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including AD, autism and schizophrenia  and the risk of AD development  and in the family sample (p = 0.0166), indicating that genetic variants in the NRG3 gene play a role in AD and SNPs in the NRG3 genes and were more strongly associated with AAO of AD  follows AD as the second severe neurodegenerative disease  toxin-based mouse model of PD, researchers also found that systematic administration of NRG1\u03b21-ECD can rescue nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase , also known as motor neuron disease (MND) or Lou Gehrig\u2019s disease, is a disease that causes the death of neurons controlling voluntary muscles  of spinal motor neurons (Lasiene et al., In a recent study on the relationship between ErbB4 and ALS/FTD, ErbB4 mutation was found for the first time in ALS/FTD and that its mutation reduced auto-phosphorylation of upon NRG1 stimulation (Sun et al., Schizophrenia is one of the serious psychiatric diseases whose etiology is not fully elucidated. The main clinical characteristics of schizophrenia are perception, thinking, emotion and behavioral disorientations (Owen et al., NRG1 (Harrison and Weinberger, NRGs and the increased risk of schizophrenia development may be determined by the wide-ranging effects of NRGs on brain functions (Wang et al., Studies suggest that NRG1/ErbB4 interactions play a vital role in the pathological mechanism of schizophrenia (Li et al., NRG1 or ErbB4 gene in some schizophrenia patients (Walss-Bass et al., NRG1 or ErbB4 may only account for a small part of schizophrenia cases (Harrison and Weinberger, The direct and chronic disturbance of NRG1/ErbB4 signal transmission, such as the mutation of NRG3 are associated with cognitive and psychotic symptom severity, which is accompanied by increased expression of prefrontal cortical NRG3 (Meier et al., In order to reveal the role of NRG2 in the modulation of behaviors with relevance to psychiatric disorders, Vullhorst et al.  found a Although scientists are looking forward to finding cures for neurodegenerative diseases with complex and unclear pathogenesis, no comprehensive and effective treatments and drugs have been developed. The results of a growing number of studies suggest that NRG1 regulates cell maintenance, differentiation, proliferation, migration, and survival or apoptosis in both neuronal and nonneuronal cell types (Mei and Xiong, Current evidence has indicated that NRGs play important roles in neurological disorders such as brain trauma (Fricker et al., In order to strengthen the understanding of NRGs in neurodegenerative disease prevention and treatment, further relevant mechanisms need to be clarified in the future. More in-depth future research on NRGs is necessary to improve diagnostic solutions for neurodegenerative diseases, thereby reducing the burden on both patients and families.W-jZ: conceptualization. W-jZ, G-yO, and W-wL: writing\u2014original draft preparation. W-jZ and G-yO: writing\u2014review and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sci., 2021, 12, 14432\u201314440, DOI: 10.1039/d1sc04138j.Correction for \u2018Plasticizer and catalyst co-functionalized PEDOT:PSS enables stretchable electrochemical sensing of living cells\u2019 by Jing Yan  The authors regret that there was an error in the equation of the calibration curve of PPL/PDMS in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Helicobacter pylori) has been classified by the International Agency for Cancer Research as carcinogenic in humans but many other are the subject of intense research. Most studies on the role of microbiota in GI tract oncogenesis focus on pancreatic and colorectal cancers with the following three species: Helicobacter pylori, Escherichia coli, and Porphyromonas gingivalis as likely causative factors. This review summarizes the role of bacteria in GI tract oncogenesis.Disturbances in gastrointestinal (GI) microbiota could play a significant role in the development of GI cancers, but the underlying mechanisms remain largely unclear. While some bacteria seem to facilitate carcinogenesis, others appear to be protective. So far only one bacterium ( Cancer is currently a major world-wide health problem: it is estimated that approximately 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred in 2018 alone, and there is a 20% risk of developing cancer before turning 75\u00a0years old, and 10% risk of dying from it   correlated positively with tumor development, while members of the Clostridiales, especially Clostridium Group XIVa, were associated with decreased cancer risk, probably due to the production of butyrate, which has anti-inflammatory and anti-tumorigenic properties  mouse model in which gut microbiota changes, which occurred during tumorigenesis, supported increased tumorigenic process in the later stages , which develop spontaneous colitis due to microbial-induced activation of effector T cells , Firmicutes (mainly Streptococcus), and Actinobacteria (mainly Rothia) , while Firmicutes predominated in saliva and mouthwash (predominant taxa Streptococcus and Prevotella). Interestingly, Acinetobacter and Fusobacterium, which were enriched in the neoplastic tissue, remained increased in the late stage of OSCC facilitating cancer progression by their ability to cause local inflammation. Zhang et al. (F. nucleatum infections may cause cancer through their effect on MMP9 pathways and upregulation of cytokines such as tumor necrosis factor (TNF)-\u03b1, IL-1\u03b2, and IL-6 (Whitmore and Lamont 2014).Zhang et al.  examinedg et al.  performeg et al. . These ag et al. . It was Streptococcus  has become the focus of extensive microbiota analysis , but infection alone is not sufficient   dying within 5\u00a0years of initial diagnosis 2. Furthermore, the authors found that hypoxia, a dominant feature of the PDAC microenvironment, greatly enhances P. gingivalis intracellular survival , complement activity and TLR4 activation. These effects facilitate local inflammatory responses that contribute to progression of periodontitis  is currently the third leading cause of cancer-related death worldwide . Although HCC is closely related to chronic infection with hepatitis B virus and hepatitis C virus as well as to chronic liver damage   increased intestinal permeability caused by alterations in the tight junctions between enterocytes allowing for the inflow of such harmful substances as LPS into portal blood. (2) Modification of specific receptor activity which consequently allows for passage of microbial metabolites into circulation. (3) Increased secretion of biochemically active factors  was proposed by Ni et al  and 13 potentially harmful bacteria, which are often increased in these patients   is the second leading cause of cancer death in the USA  showed that B. fragilis was proposed as a likely carcinogen because of its ability to produce metalloprotease in CRC patients  are also likely to be important for colonic tumorigenesis  through TLR4 expression on CRC cells F. nucleaKanazawa et al.  studied Bacteroides fragilis toxin which decreases E-cadherin on the surfaces of epithelial cells loosening intercellular junctions and thus allowing for an increased inflow of harmful substances and antigens from the gut (Sears et al. Several mechanisms have been proposed to explain the effect of bacteria on CRC development. The \u201calpha-bug\u201d hypothesis assumes that bacteria induce CRC by a specific action such as the one described for E. coli and B. fragilis already at an early noncancerous stage (Dejea et al. Interestingly, the colonic mucosa biofilm in patients with familial adenomatous polyposis was reported to be composed mainly of F. nucleatum has been confirmed in studies involving global cohorts. However, this biomarker is not sufficiently specific and sensitive to allow for non-invasive CRC diagnosis (Chang et al. Streptococcus bovis, which has been associated with colon cancer (Tjalsma et al. S. bovis antigen profiles could distinguish 11 out of 12 colon cancer patients from 8 control subjects, whereas E. coli antigen profiles were not useful (Tjalsma et al. S. bovis antigen profiles were also detected in patients with polyps, suggesting that this infection occurs in the early stage of carcinogenesis. This could be a promising diagnostic tool for the early detection of human colon cancer (Tjalsma et al. Based on metagenomic analyses a number of microbes have been proposed as biomarkers of CRC, but only Probiotics show promise as agents of host\u2013microbiome modulation therapies for several diseases, including CRC (Torres-Maravilla et al. Although the overwhelming majority of studies support the role of the microbiome in cancer, some authors did not find significant associations. For example, in the study by Olson et al.  there weA large number of studies have been devoted in recent years to the analysis of the role of microbiota in GI oncogenesis. New treatments such as fecal transplantation, phage-based therapy, antibiotics, and probiotics therapies are currently tested in clinical settings to detect, prevent or improve the clinical course of various cancers. There is also a concerted effort to develop a fast, non-invasive, sensitive, and specific cancer detection test. However, these novel treatment interventions and diagnostic tests require validation in rigorous clinical trials before they could enter clinical practice."}
+{"text": "Dauncey et al., Chem. Sci., 2019, 10, 7728\u20137733.Correction for \u2018A dual photoredox-nickel strategy for remote functionalization  The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Obesity is the result of an energy imbalance caused by an increased ratio of caloric intake to energy expenditure. In conjunction with obesity, related metabolic disorders, such as type 2 diabetes mellitus, dyslipidemia and hypertension, have become global health problems . ReducinGanoderma lucidum inhibits differentiation and lipid accumulation of 3T3-L1 adipocytes via reducing the expression of genes responsible for lipogenesis and the phosphorylation of mitogen-activated protein involved in cell proliferation and differentiation and is, thus, a promising natural agent for obesity and related metabolic diseases. Lee et al. [Schisandra chinensis ameliorates lipid accumulation and induces a brown fat-like phenotype through AMP-activated protein kinase in 3T3-L1 adipocytes. The authors also described that gomisin N inhibits adipogenesis and lipogenesis by enhancing fatty acid oxidation and thermogenesis and may have a potential preventive and therapeutic agent to combat obesity. Lee et al. [In studies using cell and animal models, Jeong and Park  providede et al.  showed te et al.  demonstrIn a human study, Auguet et al.  reportedIn a recent review, Kury\u0142owicz and Puzianowska-Ku\u017anicka  summarizThis Special Issue offers interesting findings from cell, animal and human studies on medicines for the treatment of obesity and suggests strategies for the development of future antiobesity therapies."}
+{"text": "Chinese university students are at high risk for depressive symptoms and the ongoing coronavirus disease 2019 (COVID-19) pandemic may have exacerbated the mental health of university students. However, existing studies on depressive symptoms in Chinese university students during the COVID-19 pandemic reported a wide range of prevalence estimates, making mental health planning for this population difficult. The objective of this study was to conduct a systematic review and meta-analysis of surveys that assessed the prevalence of depressive symptoms in Chinese university students amid the COVID-19 pandemic.Major Chinese  and English  databases and preprint platforms were searched to identify cross-sectional studies containing data on the prevalence of depressive symptoms in Chinese university students during the pandemic. Two authors independently retrieved the literature, evaluated the eligibility of potential studies, assessed the risk of bias (RoB) of included studies, and extracted data. RoB was assessed with the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data.I2 = 99.9%, p < 0.001). The pooled prevalence of depressive symptoms was 26.0% (95%CI: 23.3\u201328.9%), which was significantly higher in female than in male students , in postgraduates than in undergraduates , in students living inside than in those living outside the COVID-19 epicentre , in students from universities at the epicentre than in those from universities outside the epicentre , in students who had close contact with COVID-19 than in those who did not , and in students who had acquaintances or relatives infected with COVID-19  than in those who did not. Five sources of heterogeneity were identified from the subgroup analysis: survey period, % of males among the survey sample, scale of depressive symptoms, cutoff score of the scale and level of RoB.In total, 1177 records were retrieved, and 84 studies involving 1 292 811 Chinese university students during the pandemic were included. None of the included studies were rated as completely low RoB. Statistically significant heterogeneity in the prevalence estimates of included studies was detected (Over one-fourth of Chinese university students experienced depressive symptoms during the COVID-19 pandemic. Mental health services for this population should include periodic evaluation of depressive symptoms, expanded social support and psychiatric assessment and treatment when necessary. It is also necessary to design depression prevention programmes that target higher-risk cohorts of university students. The transition is challenging because of the high level of academic and employment stress and the prevalent interpersonal, romantic and emotional problems in this particular stage for university students  pandemic has caused a global mental health crisis. Lessons learned from the 2003 severe acute respiratory syndrome (SARS) epidemic in China suggest that depressive symptoms are one of the most common mental health problems among university students; for example, during the SARS epidemic, 25.4\u201329.6% of the Chinese university students had depressive symptoms  guidelines, and the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD 42020206666.The inclusion criteria for eligible studies were (a) cross-sectional surveys or baseline surveys of cohort studies with meta-analysable data ; (b) study subjects were Chinese university students, including overseas students and postgraduates; (c) the presence of depressive symptoms was assessed with standardised instruments and (d) the study was conducted during the COVID-19 pandemic (since 1 January 2020). We excluded studies with mixed samples that did not present results separately for university students and studies that assessed depressive symptoms with unstandardised instruments .We searched potential studies published between 1 January 2020 and 10 February 2021 in both Chinese and English bibliographic databases: China National Knowledge Infrastructure, Wanfang data, VIP Information, PubMed, Embase and PsycInfo. Key terms used were: (adolescen* OR teenager* OR youth* OR student* OR young adult* OR undergraduate* OR universit* OR college*), (coronavirus disease 2019 or severe acute respiratory syndrome coronavirus 2 or COVID-19 or COVID) and (depress*). To avoid missing relevant studies, reference lists of the retrieved reviews and included studies were also hand-searched. Preprint servers were also searched to retrieve grey literature: medRxiv, bioRxiv, PsyArXiv, ChinaXiv and Research Square. The literature search was ended on 12 February 2021. Detailed search strategies are provided in online Supplementary Table 1.By using a predesigned electronic form, the following variables were extracted from included studies: first author, study site, study period, characteristics of the study sample, sampling method, sample size, survey method, assessment of depressive symptoms and rates of depressive symptoms. According to the State Council Information Office of the People's Republic of China  Critical Appraisal Checklist for Studies Reporting Prevalence Data (abbreviated as \u2018JBI checklist\u2019 hereafter) to assess the RoB of included studies , a fixed-effect model was used to generate the pooled estimates; otherwise, the random-effect model was used. The pooled rates of various cohorts were compared by using the Z test. We used subgroup analysis to explore the source of heterogeneity in the prevalence estimate of depressive symptoms. The Q-value test was used to test the significance of differences in prevalence rates between subgroups. Publication bias was assessed with funnel plots and Begg's test, since Begg's test is fairly powerful for large meta-analyses that include 75 or more original studies  for the prevalence of depressive symptoms in the whole sample and in various cohorts of the sample. Forest plots were adopted to display the prevalence rates and pooled estimates. We used the et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., n\u00a0=\u00a037), followed by Zung's Self-rating Depression Scale (SDS) (n\u00a0=\u00a022), the depression subscale of the Symptom Checklist-90-Revised (SCL-90-R) (n\u00a0=\u00a08), the depression subscale of the Depression, Anxiety and Stress Scale \u2013 21 Items (DASS-21) (n\u00a0=\u00a07) and the Center for Epidemiologic Studies \u2013 Depression Scale (CES-D) (n\u00a0=\u00a07). The average and median reported prevalence rates of depressive symptoms were 27.3% and 25.8%, respectively. Other detailed characteristics of the included studies are shown in The process of study inclusion is shown in n\u00a0=\u00a062) and problematic sampling method (n\u00a0=\u00a058) (online Supplementary Table 2).In total, 31 studies had a RoB score of \u20180\u20133\u2019, 42 had a RoB score of \u20184\u20136\u2019 and 11 had a RoB score of \u20187\u20138\u2019. No study was scored nine. The two most common methodological issues were inappropriate sample frame  . Pooled v. 28.6%, p\u00a0<\u00a00.001), in students with siblings than in only child students , in overseas than in domestic students , in postgraduates than in undergraduates , in students living in Hubei than in those living in provinces other than Hubei , in students from universities of Hubei than in those from universities of other provinces , in students who were in close contact with COVID-19 than in those who had no history of COVID-19 contact , and in students who had friends, classmates or relatives infected with COVID-19 than in those who did not   .Table 2p value of the Begg's test was 0.169. No statistically significant publication bias was detected across the 84 included studies.As shown in v. 21.8%, p\u00a0=\u00a00.015), in studies with a percentage of males <50% than in those with a percentage of males \u2a7e50% , in studies assessing depressive symptoms with CES-D than in those using SCL-90-R , in studies defining the presence of depressive symptoms as \u2018PHQ-9\u00a0\u2a7e\u00a05\u2019 than in those defining it as \u2018PHQ-9\u00a0\u2a7e\u00a010\u2019 , and in studies with a high RoB than in those with a low RoB .Five factors were identified as sources of heterogeneity across included studies : survey v. males), in students with siblings (v. only children), in overseas students (v. domestic), in postgraduates (v. undergraduates), in students living within the COVID-19 epicentre (v. those living outside), in students from universities at the epicentre (v. those from universities of provinces other than Hubei), in close contacts of COVID-19-infected persons (v. those without a history of COVID-19 contact) and in students who had COVID-19-infected friends, classmates or relatives (v. those who did not). In addition, 1.69% of Chinese university students had severe depressive symptoms.This systematic review and meta-analysis summarised studies estimating the prevalence of depressive symptoms among Chinese university students amid the COVID-19 pandemic. We found an overall prevalence rate of 26.0% of depressive symptoms in Chinese university students and significantly higher rates in female students   .et al., et al., et al., One possible explanation for the higher risk of depressive symptoms in overseas than in domestic students is the status of ethnic minority groups in foreign countries , the sample representativeness of overseas students may be limited in our study. Finally, patterns of utilisation of mental health services among depressed students are very important for mental health planning and policy-making in the context of the COVID-19 pandemic, but the included studies provided little information on service use.This study has some limitations. First, none of the included studies were rated as completely low RoB. Subgroup analysis according to RoB level found a significantly higher prevalence of depressive symptoms in studies with a high level of RoB, so it is possible that the reported overall pooled estimate overestimates the true prevalence. Second, because several included studies used strict criteria to define the presence of depressive symptoms (i.e. PHQ-9\u00a0\u2a7e\u00a010), we may have underestimated the prevalence of depressive symptoms. Given the above two limitations, it is difficult to assess the magnitude and direction of bias in the prevalence estimate. Cautions are needed when generalising our findings. Third, even after stratifying the studies, high levels of heterogeneity were still kept within each strata of study in the subgroup analysis, so there remained other factors associated with the risk of depressive symptoms that were not identified. The heterogeneity of the results suggests that further rigorously designed studies using widely accepted assessments of depressive symptoms and representative samples of Chinese university students amid the COVID-19 pandemic are warranted to arrive at accurate estimates. Fourth, because of the small number of studies during the postoutbreak period, longitudinal data are needed to examine the trajectory of depressive symptoms in Chinese university students in the postpandemic era. Fifth, since the sample size of overseas students was relatively small  indicate that cohort-specific prevention programmes, which are probably cost-effective, need to be designed.China is a mental health services resource-poor country, so university managers and staff, including campus psychological counselors, should have a critical role in depression prevention; for example, they could provide expanded social support to students at risk, engage in follow-up care, mental health education and periodic screening of depressed students and promote social connectedness between students. Although the pandemic increases physical distances between staff and students, support services can be easily provided to students via smartphones.In addition, the 28.9% prevalence of depressive symptoms during the postoutbreak era in this study  and some"}
+{"text": "There is growing evidence that damage to spermatozoa by reactive oxygen species (ROS) play a key role in male infertility. The aim of the present study was to assess seminal plasma levels of total antioxidant capacity (TAC), free 8-Isoprostane and activities of catalase and superoxide dismutase (SOD) in men with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia compared with normozoospermic males.The patients consisted of 46 men with seminal parameters abnormalities. The patients were grouped into asthenozoospermic (n = 15), asthenoteratozoospermic (n = 16) and oligoasthenoteratozoospermic (n = 15). The control group consisted of 16 healthy males with normozoospermia. Catalase activity was measured by Aebi spectrophotometeric method. Levels of TAC and SOD were measured by commercially available colorimetric assays. Level of free 8-Isoprostane was assessed by commercially available enzyme immunoassay (EIA) method. Differences between groups were assessed using Mann-Whitney U test and Kruskal-Wallis test. Coefficients of correlation were calculated using Spearman's correlation analysis. All hypothesis tests were two-tailed with statistical significance assessed at the p value < 0.05 level with 95% confidence intervalsLevels of catalase and TAC were significantly lower in patients than the control group. No significant changes were seen in SOD activities. Levels of free 8-Isoprostane were significantly higher in patients than the control group. Furthermore, asthenozoospermic, asthenoteratozoospermic and oligoasthenoteratozoospermic groups had significantly lower values of catalase activity and TAC when compared to normozoospermic males. Levels of free 8-Isoprostane were significantly higher in all patients subgroups than the control group. Levels of catalase and TAC were positively correlated with sperm motility and morphology. Free 8-Isoprostane levels showed an inverse correlation with sperm motility and morphology.Decreasing seminal plasma antioxidants levels, especially catalase and TAC, could have significant role in etiology of impaired sperm function. Measurement of 8-Isoprostane may be used as a specific biomarker for assessing oxidative stress on sperm. In the etiology of male infertility, there is growing evidence that damage to spermatozoa by reactive oxygen species (ROS) play a key role ,2. Spermet al study showed statistically significant change in activity of SOD in infertile men compared to normozoospermic samples. They also observed that the SOD activity exceeds values obtained for normozoospermic samples only in oligozoospermic males [et al investigated activities of SOD and catalase in men with asthenozoospermia, teratozoospermia and oligozoospermia compared to normozoospermic males. Their study showed a significant elevation in intracellular activity of SOD and decreasing in catalase activity in infertile samples [et al study showed that seminal plasma activity of SOD in infertile men is significantly grater than in fertile men while catalase activity is not different between these groups [et al showed seminal plasma enzymatic  and nonenzymatic (TAC) antioxidant capacities do not alter in the asthenozoospermic specimens, whereas SOD activity is lower in oligoasthenozoospermic samples than normozoospermic males [et al investigation showed that there is not a significant difference in seminal plasma or sperm SOD activity between normozoospermic and oligo- or asthenozoospermic males [et al observed that whole semen SOD activity is higher in men with oligoszoospermia than those with normozoospermia [et al study showed that seminal plasma TAC in infertile asthenozoospermic and asthenoteratozoospermic males is lower than fertile men [The findings on the seminal plasma catalase and SOD activities and total antioxidant capacity (TAC) are controversial. Sanocka ic males . In anot samples . Zini ete groups . The stuic males . Hsieh eic males . This grospermia . Koca ettile men . They alAvailable data on the impact of oxidative stress on sperm are based on the measurement of seminal plasma and sperm levels of malondialdehyde (MDA) by the thiobarbituric acid-reacting substance (TBARS) assay -25. ReceThe aim of the present study was to assess seminal plasma levels of TAC and free 8-Isoprostane and activities of catalase and SOD in men with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia compared to normozoospermic males.6/ml of ejaculate and specimens with hyperviscosity were excluded from this study. The criteria for sperm normality were as follows: sperm concentration \u2265 20 \u00d7 106/ml of ejaculate, sperm motility \u2265 50% and normal sperm morphology \u2265 30% [A case-control study was designed. Following Institutional Review Board approval, the semen samples were collected from the case and the control groups. All specimens were collected into sterile plastic containers by masturbation after an abstinence period of 3\u20135 days, and were analyzed within 1 h of collection. After allowing at least 30 min for liquefaction to occur, semen analysis was performed to measure sperm concentration, sperm motility and sperm morphology using Sperm Quality Analyzer IIC  ,30. Sampgy \u2265 30% ,29,30. Tgy \u2265 30% ,31. The 2O2 (250 \u03bcmol/L) was then added to all tubes, and absorbance (A2) was read exactly after 3 minutes. The difference between A2 and A1 (\u0394A) was calculated. The TAC of the sample was then calculated by the following formula: TAC = Concentration of the Standard \u00d7 (\u0394A Blank - \u0394A Sample)/(\u0394A Blank - \u0394A Standard). The results were expressed as mM.TAC was measured by colorimetric assay ,33. We u10 of standards and SOD activity was expressed as U/ml.SOD activity was measured by colorimetric assay ,31. We uCatalase activity was estimated by the method of Aebi . CatalasWe assessed free form of 8-Isoprostane and only the fraction shedded to seminal plasma from cell membranes.Free 8-Isoprostane was purified by affinity chromatography method . We usedAt first, the elution solution was evaporated to dryness using a vacuum centrifugation. Then, the concentration of free 8-Isoprostane was measured by enzyme immunoassay (EIA) method . We usedDifferences between groups were assessed using Mann-Whitney U test and Kruskal-Wallis test. Coefficients of correlation were calculated using Spearman's correlation analysis. All hypothesis tests were two-tailed with statistical significance assessed at the p value < 0.05 level with 95% confidence intervals. The data were expressed as the mean \u00b1 SEM. Statistical computations were calculated using SPSS 11.5 for windows software .Seminal parameters of the subjects are reported in Table Then, we examined the correlation between seminal parameters and seminal plasma levels of 8-Isoprostane, TAC, SOD and catalase in total case group. Levels of TAC showed a positive correlation with sperm motility  and morphology . We also observed a direct correlation between catalase activity and sperm concentration , sperm motility , and sperm morphology . Seminal plasma levels of free 8-Isoprostane showed an inverse correlation with sperm motility  and sperm morphology . Levels of SOD did not show any correlation with seminal parameters.The most relevant findings of this study were (i) significant elevation of seminal plasma levels of free 8-Isoprostane and decreasing of catalase and TAC levels in asthenozoospermic, asthenoteratozoospermic, oligoasthenoteratozoospermic samples compared with normozoospermic men (ii) both catalase and TAC showed a positive correlation with sperm motility and morphology while an inverse correlation was seen with free 8-Isoprostane levels.et al [et al results about catalase activity in infertile men [et al. evaluated antioxidant capacity of seminal plasma in asthenozoospermic and oligoasthenozoospermic specimens with normal viscosity and hyperviscosity [et al., we observed a significant decrease in catalase activity and TAC in men with asthenozoospermia compared to normozoospermic men. Our finding about SOD activity in asthenozoospermic men was similar to Siciliano et al study. In another study, Hsieh et al evaluated SOD activities in seminal plasma and spermatozoa in infertile men with normozoospermia and oligoasthenozoospermia [et al also observed that SOD activities of seminal plasma and sperm are positively but nonsignificantly correlated with sperm motility and concentration. Our results about the SOD activity of the seminal plasma in oligoasthenozoospermic men were similar to Hsieh et al study. Koca et al evaluated TAC in infertile asthenozoospermic and asthenoteratozoospermic men compared to normozoosperic fertile men [et al study also showed that TAC correlates positively to sperm motility. We also observed these findings. Tkaczuk-Wlach et al evaluated activity of SOD in the whole semen of patients with oligozoospermia compared to patients with normozoospermia [et al study was limited by the fact that they used whole semen sample, because the membrane-bound oxidases or antioxidants associated with cellular debris and/or organelles can influence activities of antioxidant enzymes such as SOD and catalase [Our findings about activities of SOD were contradicted the results of Sanocka et al ,11. Our iscosity . Their sospermia . They obtile men . Their sospermia . Their scatalase .et al study [et al also observed that there is an inverse significant correlation between seminal plasma TAC and ROS levels. They suggested that the inverse correlation between TAC and ROS might be associated with an increase in the consumption of soluble, non-enzymatic antioxidants in seminal plasma which is resulted from over production of ROS. In our study the correlation between TAC and sperm morphology was positive. According to Gil-Guzman et al study, this finding could be interpreted that in semen with high rate of abnormal forms, because of high levels of ROS production, consumption of non-enzymatic antioxidants will be higher.Immature spermatozoa with abnormal morphology and cytoplasmic retention are the most sources of ROS production in semen. This has been confirmed by Gil-Guzman al study . Their set al [et al and our study might suggest that the higher level of antioxidant status prevents lipid peroxidation in spermatozoa and therefore results in higher sperm motility. Hsieh et al observed a slightly positive correlation between seminal plasma SOD activity and sperm concentration [et al. Immature spermatozoa generate primary superoxide anion. This anion is dismuted to hydrogen peroxide by SOD activity. Detoxification of hydrogen peroxide is carried out by catalase activity. Hydrogen peroxide is the primary toxic ROS for human spermatozoa that its high concentration induces lipid peroxidation and results in cell death. Therefore, the balance of the SOD and catalase activities in semen is important for maintaining sperm motility [The inverse correlation between lipid peroxidation and sperm motility has been shown by Keskes-Ammar et al . In our ntration . Their imotility .Our results are agreed with some previous studies that show increasing of lipid peroxidation by measuring MDA in sperm and seminal plasma in males with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospemia ,23. SimiMDA is widely used index of lipid peroxidation due to its simplicity. The TBARS test application to body fluids and tissue samples is unreliable. Application of a gas chromatography/mass spectrometry (GC/MS) assay for MDA has indicated that the commonly used TBARS assay overestimates the actual MDA levels by more than 10-fold, possibly resulting from cross reactivity with other aldehydes and the harsh conditions used in sample preparation .sn-2 position of phospholipids by phospholipase A2, isoprostanes are formed initially in situ, where they may contribute to the effects of oxidative stress on membrane biophysics. Measurement of 8-Isoprostane may provide a reliable marker of lipid peroxidation in vivo, because, it is a stable compound. In addition, 8-Isoprostane is specific product of free radical-induced lipid peroxidation. 8-Isoprostane has also been found to be present in detectable quantities in all normal biological tissues and in free form in all normal biological fluids. This is important because it allows the definition of a normal range such that small increases in its formation can be detected in situations of mild oxidant stress. Finally, the levels of 8-Isoprostane is unaffected by lipid content of the diet [Recent studies have focused on 8-Isoprostane, as an index of lipid peroxidation. Isoprostanes are formed in situ in cell membranes; following free radical attack on the arachidonic acid. Unlike prostaglandins, which are formed from arachidonic acid following its release from the the diet ,28.Evidence is beginning to emerge suggesting that isoprostanes are not only markers of oxidative injury, but active participants in the pathophysiology of some disorders. The capacity of isoprostanes to readily esterify to cell lipid membranes, and the resulting marked distortion of membrane structure and function, undoubtedly contribute to their pathophysiologic potential. As well, the existence of specific receptor for isoprostanes has been proven . So, becIt is concluded that decreasing seminal plasma antioxidant status, especially catalase activity and TAC, may have significant role in the etiology of impaired sperm function. Measurement of 8-Isoprostane may be used as a specific biomarker for assessing oxidative stress on sperm. However, further studies with a larger sample size are required to confirm these findings.The author(s) declare that they have no competing interests.Ali Khosrowbeygi carried out all of the experiment and participated in data analyzing and writing the manuscript.Nosratollah Zarghami designed the study and participated in data analyzing and writing the manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Several authors advocate spleen preserving distal pancreatectomy, because of the increased complication rate after splenectomy.Postoperative complications and survival after distal and total pancreatectomy, were recorded and retrospectively analyzed according to spleen preservation. Patients, who underwent distal and total pancreatectomy without histologically proven adenocarcinoma, or extrapancreatic disease, were included in the cohort which was divided into splenectomy and no splenectomy groups. Statistical analysis was performed using Fisher's test.The study group consisted of 62 patients who underwent distal and total pancreatectomy between 26/11/1987 to 6/1/2006. Splenectomy was performed in 35 out of 62 patients (56.5%), distal pancreatectomy was performed in 49 out of 62 patients (79%). Morbidity rate was 28.6% in splenectomy group and 14.8% in the no splenectomy group (p = 0.235), while 30 days mortality rate was 2.9%; one patient died in the splenectomy group (p = 1).Spleen-preservation did not influence the outcomes after distal and total pancreatectomy in our series. Pancreatectomy may be accompanied with splenectomy in distal and total pancreatic resections. Elective peripheral pancreatectomy is safer than pancreaticoduodenectomy, but carries a high morbidity rate -4; intraIn our study, postoperative complications after distal and total pancreatectomy, were recorded and analyzed according to spleen preservation, in patients with pancreatitis (chronic and acute), benign neoplasms and other benign diseases.th of November 1987 and 6th of January 2006. Patients with histologically proven adenocarcinoma, patients with cystadenocarcinoma, patients who underwent completion pancreatectomy after postoperative complication of pancreaticoduodenectomy, patients who underwent pancreatectomy because of abdominal trauma, patients who had hepatic metastases in laparotomy, patients who had cancer in the pancreatic head or lower common bile duct and patients who had additional procedures such as gastrectomy and colectomy were excluded from the study. The patients were divided into splenectomy and no splenectomy group. The following parameters were recorded and analyzed for each of the above mentioned groups: sepsis (SIRS and MODS), acute renal failure, pulmonary complications , ARDS , cardiac complications , central nervous system complications , intra abdominal abscess (defined as an infected fluid collection identified by CT or ultrasound scan-guided needle aspiration and microbiologic culture), postoperative primary intra abdominal hemorrhage , postoperative primary gastrointestinal hemorrhage (1ry GI), delayed gastric emptying, wound infection, wound dehiscence, first 30 postoperative days mortality.Prospective collected data were retrospectively analyzed for patients who underwent distal or total pancreatectomy with or without splenectomy between 28\u00ae, Chicago, IL, USA). A p value less than 0.05 was considered significant.Statistical analysis was performed using Fisher's two-tailed test, in the \"Statistical Package for the Social Sciences\" version 12 for Windows . After fulfilling the exclusion criteria, our study group consisted of the rest 62 patients who underwent total and distal pancreatectomy with or without splenectomy. The demography, types of operations and final diagnoses are shown in Tables Hospital data included 160 patients who underwent distal and total pancreatectomy between 28Using the Fisher's test no studied factor was correlated with splenectomy vs no splenectomy groups Table . InteresThe two cases of intra abdominal access were treated by the radiologist with a CT guided drainage. The only case of primary postoperative hemorrhage needed a reintervention after a failed embolization.The 30 days mortality rate in the study group of patients was 2.9%. One patient died (stroke) in the splenectomy group (p = 1). There was not recorded any postoperative death due to postsplenectomy sepsis.et al., [et al., [et al., [et al., [et al., [Spleen preserving distal pancreatectomy has been advocated by many authors, because of splenectomy associated immunologic alterations and septic postoperative complications ,16,24,25et al.,  and Beno[et al.,  studied [et al.,  studied [et al., ,27. Aldr[et al.,  in a gro[et al.,  demonstr[et al.,  studied [et al., , in a co[et al., ,4,28 aftThe authors conclude that spleen preservation does not influence the outcome after distal or total pancreatectomy, in benign diseases and selected benign neoplasms.The author(s) declare that they have no competing interests.IK: Designed the study, performed bibliographic research, drafted and revised the manuscript.AT: Carried out the data and participated in the writing process.RB: Participated in the design of the study, helped to draft the manuscriptand and performed the statistical analysis.SB, JB, DM: Participated in manuscript revision process.All authors read and approved the final manuscript."}
+{"text": "The importance of prophylactic aspirin use in both developed and developing countries can hardly be overemphasized. I am troubled, however, by Stafford and colleagues' failure to cite and discuss United States studies that show much higher rates of antithrombotic use than they report . Using aTwo factors probably account for these differences. First, Stafford et al.'s federal surveys of ambulatory care encounters miss a significant proportion of aspirin use. Studies in a variety of populations that used direct patient surveys and other methods, some of which are cited in Brown et al. , have foThe experience of the nonprofit-integrated systems is also important because it calls into question Stafford et al.'s suggestion, emphasized in PLoS's accompanying synopsis, that direct-to-consumer advertising of statins explains the 1997\u20132000 dip in aspirin use in their data. Kaiser Permanente and HealthPartners members were equally exposed to direct advertising, but maintained high aspirin use during this period\u2014despite probably also using statins (and angiotensin converting enzyme [ACE] inhibitors) at higher rates than individuals in other US care-delivery settings.The US nonprofit HMO experience nevertheless reinforces the authors' main conclusion that \u201caggressive and targeted interventions are needed to enhance provider and patient adherence to consensus guidelines for CVD risk reduction\u201d . Aggress"}
+{"text": "The condition appears to be inherited in an autosomal dominant mode, although sporadic cases have been reported. It is a rare disease, a few families have been described in the literature. In the British family, the locus for oculo-oto-dental syndrome was mapped to 20q13.1 within a 12-cM critical chromosomal region. Dental management is complex, interdisciplinary and will include regular follow up, scheduled teeth extraction and orthodontic treatment. Hearing checks and, if necessary, hearing aids are mandatory, as well as eye examination and ad hoc treatment if necessary.The otodental syndrome also named otodental dysplasia, is characterised by a striking dental phenotype known as globodontia, associated with sensorineural high frequency hearing loss and eye coloboma. Globodontia occurs in both primary and permanent dentition, affecting canine and molar teeth ( The Otodental syndrome has been described under various names:\u2022 Otodental dysplasia ,2;\u2022 Familial otodentodysplasia ;\u2022 Globodontia; the term globodontia refers to the enlarged bulbous fused malformed posterior teeth with almost no discernable cusps or grooves -6;\u2022 In some families, an associated ocular phenotype was recognized  and it wThe condition has been described in at least 9 families. The first case of otodental syndrome was described in Hungary in a mother and her son by Denes and Csiba, 1969 ,8, a girThe otodental syndrome, also named otodental dysplasia, is characterised by a striking dental phenotype known as globodontia, associated with sensorineural high frequency hearing loss and eye coloboma.per se diagnostic. It consists mainly of enlarged canine and molar fused teeth  both in the primary and in the permanent dentition. The incisors are not affected. In a few cases described in the literature the condition was discovered in young children (around 3 years of age) [The dental phenotype is  of age) ,11 consuSensorineural high frequency hearing loss and coloboma was reported in the British family only ,8.et al., 1976 [et al., 2002 [et al., 1975 [Some authors have reported dysmorphic facial features. Witkop l., 2002  had alsol., 1975  had symmet al., 1975 [Constitutional short stature was diagnosed in a patient followed by Levin l., 1975 . HoweverThe association of sensorineural hearing loss and dental anomalies can be found in other syndromes:\u2022 autosomal recessive sensorineural hearing impairment, dizziness and hypodontia ;\u2022 bilateral sensorineural hearing loss and multiple anterior dens invaginatus ;\u2022 Kantaputra and Gorlin, 1992 [et al., 2002 [OOD was mapped to 20q13.1 within a 12-cM critical chromosomal region.The condition appears to be inherited on an autosomal dominant basis. In the British family described by Vieira l., 2002 , the locet al., 2002 [Sensorineural hearing loss of about 65 dB is found at all frequencies but is more pronounced at about 1000 Hz. It usually plateaus by the fourth decade . The agel., 2002 . Speech Frequent ear abscesses were noted in one patient .Differential diagnostic audiometric test suggested a cochlear site of lesion .et al., 2002 [Eye phenotype was described by Vieira l., 2002 . AbnormaThe gingiva was described as inflamed and enlarged in a patient . GingivaThe oral/dental anomalies affect both the primary and the permanent dentition and could be classified as anomalies of eruption, number, size, shape and structure.There was a significant delay in eruption of the primary and permanent dentition ,16, espeet al., 1988 [Missing teeth, especially premolars, were reported . The prel., 1988 .Large bulbous canines and molars crowns can summarize the clinical intraoral findings.globodontia [et al., 1981 [et al., 1975 [Permanent molars are malformed with fusion of cusps. The crowns of the canines and posterior teeth are enlarged, bulbous and malformed with multiple prominent lobules. The deciduous dentition is more severely involved. The relation between cusps and the major groove is eliminated hence the use of the term bodontia . Cook etl., 1981  describel., 1975  noted laThe canines have been described as large with a marked bulbous cingulum . Based oet al., 1971 [et al., 2001 [The average size premolars had convex occlusal surfaces with no developmental grooves or fossae . In the l., 1971  premolarAn enamel defect (hypoplasia) was frequently found on the buccal surface of canines .et al., 2002 insisted that the incisors were not normal, demonstrating also the yellowing and pitting enamel defects [The teeth might be prone to decay . The ena defects .The molars displayed taurodontism (an inverted crown-body/root ratio). The roots were short and tapered and some were taurodont in configuration . The decet al., 2002 described also the enlarged pulp chambers, the pulp stones and the abnormal root defects [Vieira  defects .et al. [Various malocclusions were described in the family members examined by Vieira et al. . Case 1 et al., 1988 [The boy presented by Chen et al., 1984 [Odontomas, the most common type of odontogenic tumors, were reported by Beck-Mannagetta l., 1984  in the pet al., 1984 and Toledo et al., 1971 [The histological findings described by Beck-Mannagetta l., 1971 ,20 showeIn the area of hypoplastic enamel, slightly reduced enamel thickness and alterations existed with prominent enamel rods, irregular incremental lines and rod sheath area containing voids, defects very similar to those observed in hypomaturation enamel defects. The amelodentinal junction in these areas was displaced towards the surface of the tooth and the subjacent underlying dentin had scanty irregular tubules .Genetic counselling is important. Inheritance is clearly autosomal dominant with complete  to variaad hoc treatment if necessary.Dental management is complex, interdisciplinary and will include regular follow up, scheduled tooth extraction and eventually orthodontic treatment. Hearing check and, if necessary, hearing aids are mandatory; as well as eye examination and The identification of the gene involved in this disease is of importance in our understanding of the development of various tissues and organs ."}
+{"text": "Editorial on the Research TopicYing and Yang Members of the Tumor Necrosis Factor Superfamily: Friends or Foes in Immune-Mediated Diseases and CancerBalomenos et al.; Chakrabandhu and Hueber; Roberts et al.; Saxena et al.; Volpe et al.; Yamada et al.; Yolcu et al.; O\u2019Reilly et al.). Unfortunately, other critical members of the TNF superfamily, including CD40L/CD40, GITR, BAFF, APRIL, TACI, and GITR were beyond the scope of this research topic. However, we refer the reader to scholarly reviews about other members of TNF/TNFR superfamilies that have not been covered here, including their roles in rheumatic diseases , and general aspects of their signaling pathways (Tumor necrosis factor (TNF) and TNF-receptors (TNFR) superfamilies represent one of the earliest immunological systems to be targeted for immunotherapy as typified by the use of anti-TNF\u03b1 agents for treating Crohn\u2019s disease in patients refractory to corticosteroids and conventional immunosuppressives . It is adiseases , neuroinpathways .The articles published under this research topic help to provide a better understanding of the roles of some of the major members of the TNF/TNFR superfamily in the pathogenesis of several diseases and generate considerable hope that their manipulation could lead to therapeutic interventions:Hamad\u2019s paper on the \u201cExpansion of FasL-Expressing CD5+ B Cells in Type 1 Diabetes Patients\u201d discusses a newly identified subpopulation of FasL+ CD5+ CD19+ B cells that was significantly elevated in Type 1 Diabetes (T1D) subjects. In contrast, to IL-10+ CD5+ B cells that do not express FasL but produce IL-10, FasL+ CD5+ cells do not produce cytokines and are more resistant to activation-induced cell death (AICD). These intriguing findings could lead to better understanding of the mechanisms underlying the pathogenic role of FasL in T1D and cell types expressing it , 5.Yamada et al.; Hamad et al.).Yamada\u2019s group\u2019s paper on the \u201cDual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance\u201d uses data from research studies on Fas/FasL gene mutations in mice and humans to discuss the dual function of the Fas pathway signaling leading to apoptosis or cell proliferation of immune cells depending on local environmental circumstances, and how mutations and disruptions of this process leads to the pathogenesis of autoimmunity .Yolcu\u2019s paper on \u201cFas/Fas-Ligand Interaction As a Mechanism of Immune Homeostasis and \u03b2-Cell Cytotoxicity: Enforcement Rather Than Neutralization for Treatment of Type 1 Diabetes\u201d focuses on the immunogenic activities of Fas/Fas-L interactions, as well as how TNF functions in both apoptosis and growth signaling, thereby regulating both immune reactions and injury repair. The paper further details how these processes may be involved in the pathogenesis of T1D and presents arguments for and against therapeutic neutralization of Fas and/or FasL to potentially abrogate T1D .Balomenos\u2019s paper, \u201cOn How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in Volpe et al.).Volpe\u2019s paper, \u201cFas-Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis,\u201d discusses Fas\u2013Fas ligand interactions, and their involvement in Activation Induced Cell Death (AICD) and negative selection to destroy autoreactive lymphocytes in the context of autoimmune disease and cancer. In particular, this article focuses on the Fas\u2013FasL pathway and how defects in its interaction involving Th17 and Treg can contribute to the pathogenesis of multiple sclerosis (Chakrabandhu and Hueber).Chakrabandhu\u2019s paper, \u201cFas Versatile Signaling and Beyond: Pivotal Role of Tyrosine Phosphorylation in Context-Dependent Signaling and Diseases,\u201d discusses the role of the Fas/FasL system as an apoptosis activator as well as a source of non-death signals that can promote survival, proliferation, migrations, and cell invasion. This article focuses on the recent identification of tyrosine phosphorylation in the death domain as a regulator of the reversible signaling switch between the two seemingly opposite roles of Fas/FasL, the factors and context that contribute to the switch, and how pathologies can develop in the signaling pathways . Interestingly, upregulation of IL-10 as a result of FasL blockade plays a critical role in preventing islet insulitis in NOD mice bearing a loss-of-function gld mutation of FasL .O\u2019Reilly\u2019s paper \u201cThe Janus Face of Death Receptor Signaling during Tumor Immunoediting\u201d addresses the issue of tumor cells\u2019 ability to proliferate and evade immune-mediated elimination by resisting the death ligand-induced apoptotic pathway through cleavage and mutations in death ligand receptors, or overexpression of decoy receptors and pro-survival proteins. The article discusses the role of death receptor signaling, and the early elimination and escape phase of tumor immunoediting as it relates to the tumor cells\u2019 ability to resist cell death and metastasize. The article also discusses the opportunities and challenges of developing death receptor agonists for cancer therapeutics (In summary, diversity of these studies reveal the complex tasks carried out by TNF superfamily members, which provides a great opportunity for identifying therapeutic targets and at the same time, underlines the challenges.AG and RA read and summarized manuscripts published under the Research topic. AH, HY served as associate editors for the Research Topic and TD read, commented, and edited the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Inflammation has been widely demonstrated to be involved in various stimuli, such as oxidative stress, bacterial and virus infection, and some physiological process, while a chronic and excessive inflammatory response is a significant risk factor for developing various human diseases .An increasing number of compelling reports are recently published suggesting that some nutrients, like amino acids, oligosaccharides, and short-chain fatty acids, exhibit anti-inflammatory effect , 3, whicThe articles contained in this special issue include 4 review papers and 10 original research papers that are focused on characterizing the contribution and molecular mechanisms associated with nutrients and inflammation. A brief description of these 14 works is detailed below.Amino acids and their metabolites have been widely demonstrated to exhibit anti-inflammatory effect on various inflammatory models, such as inflammatory bowel disease. X. Bao et al. provide a detailed review of the literature on the relationship between amino acids and inflammatory bowel disease in their paper titled \u201cRoles of Dietary Amino Acids and Their Metabolites in Pathogenesis of Inflammatory Bowel Disease.\u201dIn the paper titled \u201cRole of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis,\u201d A. Kushiyama et al. outline the molecular mechanisms underlying inflammation occurrence in relation to uric acid metabolism.Inflammation contributes to the development of various metabolic diseases, such as obesity and diabetes. S. Chen et al. review the anti-inflammatory properties of quercetin in relation to obesity and type 2 diabetes in the paper titled \u201cTherapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes.\u201dIntestinal microbiota is highly involved in host physiology and pathology through activity of the microbiome and its metabolic products. \u201cDiet-Intestinal Microbiota Axis in Osteoarthritis: A Possible Role\u201d by Y. Li et al. concludes that intestinal microbiota is a major hidden risk factor for osteoarthritis and an important explanation for person-level risk factors.Four groups from R. Garib et al., H. Xiao et al., H. Ni et al., and M. Li et al. investigated the anti-inflammatory effects of amino acids on different inflammatory models. The papers include \u201cEffect of Previous High Glutamine Infusion on Inflammatory Mediators and Mortality in an Acute Pancreatitis Model,\u201d \u201cN-Acetyl-L-cysteine Protects the Enterocyte against Oxidative Damage by Modulation of Mitochondrial Function,\u201d \u201cEffects of Glutamate and Aspartate on Serum Antioxidative Enzyme, Sex Hormones, and Genital Inflammation in Boars Challenged with Hydrogen Peroxide,\u201d and \u201cHigh-Methionine Diet Attenuates Severity of Arthritis and Modulates IGF-I Related Gene Expressions in an Adjuvant Arthritis Rats Model.\u201d\u03baB signaling pathways involve in the mechanism of anti-inflammatory effects of fatty acids from royal jelly.In the article \u201cIn Vitro Anti-Inflammatory Effects of Three Fatty Acids from Royal Jelly,\u201d Y.-F. Chen et al. evaluate and compare the in vitro anti-inflammatory effects of three fatty acids on lipopolysaccharide-stimulated RAW 264.7 macrophages and find that MAPK and NF-Escherichia coli, G. Liu et al. find that dietary chitosan markedly alleviated intestinal inflammation. The paper is titled \u201cChitosan Modulates Inflammatory Responses in Rats Infected with Enterotoxigenic Escherichia coli.\u201dIn rats infected with enterotoxigenic Veronicastrum axillare were collected: \u201cCurcumin Alters Neural Plasticity and Viability of Intact Hippocampal Circuits and Attenuates Behavioral Despair and COX-2 Expression in Chronically Stressed Rats\u201d by G.-Y. Choi et al. and \u201cVeronicastrum axillare Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Suppression of Proinflammatory Mediators and Downregulation of the NF-\u03baB Signaling Pathway\u201d by Q. Ma et al.Traditional medical plants and plant extracts have been widely explored to treat inflammatory diseases. In this issue, two articles about curcumin and A clinical trial titled \u201cThe Effect of Immunonutrition on the Postoperative Complications in Thymoma with Myasthenia Gravis\u201d by Y. Xin et al. concludes that preoperative immunonutrition support is effective in reducing postoperative complications in patients of thymoma with myasthenia gravis.High-mobility group box 1 protein (HMGB1) and autophagy are vital to maintain cellular homeostasis and protect against inflammatory response. In the paper titled \u201cRegulation of Autophagy-Related Protein and Cell Differentiation by High Mobility Group Box 1 Protein in Adipocytes\u201d by H. Feng et al., it focuses on the relationship between HMGB1 and autophagy in adipocytes."}
+{"text": "As members of the Ca2+ permeable transient receptor potential (TRP), five of the channels (TRPV1-4 and TRPM2) are activated by different heat temperatures, and two of the channels (TRPA1 and TRPM8) are activated by cold temperature. Accumulating evidences indicates that antagonists of TRPA1 and TRPM8 may protect against cisplatin, oxaliplatin, and paclitaxel-induced mitochondrial oxidative stress, inflammation, cold allodynia, and hyperalgesia. TRPV1 was responsible from the cisplatin-induced heat hyperalgesia and mechanical allodynia in the sensory neurons. TRPA1, TRPM8, and TRPV2 protein expression levels were mostly increased in the dorsal root (DRG) and trigeminal ganglia by these treatments. There is a debate on direct or oxaliplatin-induced oxidative cold stress dependent TRPA1 and TRPV4 activation in the DRG. Involvement of molecular pathways such as cysteine groups, glutathione metabolism, anandamide, cAMP, lipopolysaccharide, proteinase-activated receptor 2, and mitogen-activated protein kinase were also indicated in the oxaliplatin and paclitaxel-induced cold allodynia. In this review, we summarized results of five temperature-regulated TRP channels  as novel targets for treating chemotherapy-induced peripheral painAbnormal Ca Chemotherapeutic agents such as taxanes  and platinum analogs  are used in treatment of several cancer types. Taxanes inhibit progression of mitosis through stabilization of tubulin in the treatment of solid tumors  overload plays an important role. Ca2+ enters into cells by different ways including cation channels. Voltage gated calcium channels (VGCC) and chemical channels  are well-known calcium channels  neurons have important roles in the pathobiology of neuropathic pain. There is no barrier between the DRG and blood, and compounds with a high molecular weight can easily diffuse into the DRG  channels .Excessive reactive oxygen species (ROS) and low levels of antioxidants play a pivotal role in the pathobiology of cancers  has a significant role in the development and maintenance of neuropathic pain. The involvement of TRPA1 through activation of p38 MAPK in oxaliplatin-induced acute cold hypersensitivity in mice DRG neuron was recently reported  is a member of PAR subfamily of G protein-coupled receptors and activation of these receptors regulates several pathophysiological processes including inflammation and pain , menthol, icilin  and low-voltage-activated (LVA) channels  are very selective to CaTRPV1 is a member of vanilloid subfamily of the TRP superfamily. The channel was firstly expressed in rats through activation of high temperature and pungent hot chili pepper component (capsaicin) in mice DRG (Caterina et al., ROS are produced in physiological levels as part of normal mitochondrial function and phagocytic activity. During the removal of bacteria and viruses, ROS are produced by anti-inflammatory cells such as macrophages microphages and microglia. Therefore, there is direct relationship between increased levels of ROS and inflammatory hyperalgesia (Oehler et al., Cisplatin-induced TRPV1 channel expressions were investigated in DRG neuron by Hori et al.  and theyReports on cisplatin-induced thermal sensitivity in rodents are conflicting. For example, cutaneous mechanical allodynia and hyperalgesia but not noxious thermal sensitivity was reported by cisplatin treatment (Hori et al., In a study, diameters of TRPV1 remained unchanged in mice DRG neurons following cisplatin treatment, although the occurrence of TRPV1 in the neurons was increased by cisplatin treatment (Khasabova et al., 2+ concentrations induced release of excessive substance P from the central and peripheral nerve terminals of DRG neurons in response to noxious stimuli (Sacerdote and Levrini, Increased intracellular CaThe involvement of oxaliplatin on the release of calcitonin gene-related peptide from rat sensory neurons in culture was recently reported (Pittman et al., Another member of TRP superfamily is the TRPV2 and the channel is also a member of thermosensitive TRP channels and it is activated by a very high-threshold heat temperature (>52\u00b0C; Ahluwalia et al., As a member of TRP superfamily, TRPV4 was firstly described with mammalian osmotransducer property (Liedtke et al., Induction of hyperalgesia through activation of \u03b12\u03b21 integrin and Src tyrosine kinase pathways in rat DRG neuron was reported in the TRPV4 knockout mice by paclitaxel treatment (Alessandri-Haber et al., Accumulating evidence suggests that neuropathic pain and painful neurotoxicity in the rodents are increased by selected chemotherapeutic agent through increased sensitization of TRPA1, TRPM8, and TRPV1. In addition, antagonists of TRPA1 and TRPM8 were able to attenuate cisplatin, oxaliplatin, and paclitaxel-induced mitochondrial oxidative stress, inflammation, cold allodynia, and hyperalgesia, although TRPV1 was responsible for cisplatin-induced heat hyperalgesia and mechanical allodynia in sensory neurons. TRPA1, TRPM8, and TRPV2 protein expression levels were mostly increased in the DRG and trigeminal ganglia neurons by chemotherapeutic agents. There is a debate on direct or oxaliplatin-induced oxidative cold stress dependent TRPA1 and TRPV4 activation in the DRG. Involvement of molecular pathways such as cysteine group, GSH, anandamide, cAMP, lipopolysaccharide, proteinase-activated receptor 2, and mitogen-activated protein kinase were also indicated in oxaliplatin and paclitaxel-induced cold allodynia. Therefore, there is growing evidence for the potential role of TRP channel inhibitors as modulators of chemotherapy-induced neuropathic pain in the clinic.A new member of the TRP superfamily is TRPM2. The enzyme ADPR pyrophosphatase in the C-terminal domain of TRPM2 is sensitive to ROS and RNS (Wehage et al., MN formulated the present hypothesis and he was responsible for writing the report. NB made critical revision for the manuscript. The original figures were produced by MN.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Editorial on the Research TopicSelf-Eating on Demand: Autophagy in Cancer and Cancer TherapyThe field of autophagy has grown enormously over the past 10\u201315\u2009years, with rapid advances in our understanding of the regulatory mechanisms that control autophagy pathways in mammalian systems, and an improved understanding of the physiological influences of autophagy in health and disease. Supporting such progress, there has been substantial diversification in assessment and modulation tools . SponsorTransAutophagy comprises five different thematic Working Groups with activities designed to synergize and support translation of our ever-advancing basic autophagy knowledge into biomedical and biotechnological applications . TargetiMathiassen et al. (Cecconi\u2019s lab) discusses mounting evidence for new regulatory intersections between autophagy and the cell cycle, which need to be urgently validated in vivo. At the mechanistic level, the tumor suppressor role of autophagy has been ascribed to its vital cell-autonomous functions in mitigating damage and maintaining cellular integrity during metabolic stress. An emerging and intriguing link, which is discussed in the review of Kania et al. (Bultynck\u2019s/Parys\u2019s labs), is the regulation of autophagy in cancer cells through Ca2+ transfer from the ER to mitochondria via the inositol 1,4,5-trisphosphate receptor (IP3R) at ER\u2013mitochondria contact sites. In a developing research area with enormous potential, the impact of miRNA-mediated autophagy regulation on the tumor microenvironment and cancer growth, and their potential as cancer biomarkers and therapeutic targets, is discussed in the review of Gozuacik et al. (Gozuacik\u2019s lab).The review of Viry et al. (Janji\u2019s lab), cancer cell-associated autophagy in hypoxic tumors plays a crucial role in modulating immunosurveillance and in fostering the immunosuppressive tumor microenvironment, by suppressing key mechanisms of innate and adaptive antitumor immunity, thus favoring tumor outgrow and dissemination. Consistent with this pro-tumorigenic role, advanced tumors often display an \u201cautophagy-lysosomal addiction,\u201d which appears to be required to maintain their energy balance through the recycling of intracellular components into biosynthetic pathways or ATP synthesis and to regulate secretion of pro-tumorigenic factors. In the review of New et al. (Tooze\u2019s lab), the idea that advanced and aggressive mutant KRAS-driven tumors  exploit a heightened autophagy\u2013lysosomal pathway under the transcriptional control of the MiF/TFE factors to support energy metabolism and to allow growth under conditions of energy deficit and metabolic stress is discussed (Iovanna (Iovanna\u2019s lab) highlights the key role played by the pancreatitis-associated vacuolar protein 1 (VMP1) in pancreatic acinar cells and how its elevated expression drives early autophagy and cooperates with the KRAS oncogene to promote carcinogenesis in the pancreas.In established tumors, elevated levels of autophagy are often associated with poorly oxygenated regions where the demand for nutrients and the need to withstand diverse metabolic stresses are increased. As further discussed in the review of iscussed . FurtherKeulers et al. (Rouschop\u2019s lab), is the ability of advanced cancer cells to use autophagy as a trafficking and export mechanism of pro-tumorigenic factors, such as pro-inflammatory/pro-angiogenic cytokines or chemotactic/pro-invasive molecules. This cancer cell-autonomous trait further illustrates the plasticity of tumor-associated autophagy, which can enable and modulate the crosstalk between cancer and stromal cells thereby affecting the tumor microenvironment, a property that needs to be taken into consideration when considering therapeutic approaches. Based on the growing relevance of tumor-associated autophagy, many labs are developing and testing the effects of autophagy modulators in cancer therapy. The recognition of the prevalent\u2014albeit not unique\u2014cytoprotective and stress adaptation roles of autophagy in advanced cancers has led to the assumption\u2014as supported by in vitro and preclinical data\u2014that blocking cancer cell-intrinsic autophagy may curtail cancer cell resistance to chemotherapy, thereby improving therapy outcome. Thus, the first-generation autophagy blockers, e.g., chloroquine and its derivative hydroxychloroquine (Fulda (Fulda\u2019s lab). Finally, although autophagy is a highly dynamic process, the expression of certain autophagy genes in aggressive tumors like melanoma, may provide novel independent prognostic biomarkers for early stage neoplasms, as discussed in the review of Tang et al. (Lovat\u2019s lab). This may help to identify patients at risk of disease progression, thus facilitating earlier patient therapeutic intervention and stratification for personalized therapeutic approaches.Another emerging aspect linking autophagy to tumor progression, discussed in the review of oroquine , 7 are cAuthors contributed equally.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "International Journal of Molecular Sciences on 11 May 2017 [We read with great interest the article \u201cCirculating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy\u201d published by Coco, S. et al. in The authors chose a device  which is simple, inexpensive and allows to study the biological characteristics of CTCs isolated from 3 ml of blood. Nevertheless, Haematoxylin\u2013Eosin (H&E) staining alone does not allow a correct enumeration of CTCs, which would necessitate further molecular characterization for cancer-specific biomarkers, such as, in this case, thyroid transcription factor 1 (TTF-1) for adenocarcinomas and high-molecular weight (HMW) keratins (CK5/6) for squamous-cell carcinomas . Indeed, as early as 2013, El-Heliebi et al. reported that reliable detection of CTCs should be confirmed by immunocytochemical and/or molecular biological methods [Furthermore, the association between a higher number of CTCs and better prognosis is definitely uncommon and would deserve further discussion. Our feeling is that, similarly to what is reported by Juan et al. , the autAs a suggestion, the authors could perform a leukocytes depletion before detecting CTCs by using a ScreenCell Cyto kit  and subsWe hope that our observation and advice will be accepted as a productive analysis."}
+{"text": "Editorial on the Research TopicCD4 T Follicular Helper Cells in HIVFH cells could also hold clues to a functional cure for HIV; as reservoirs of latent HIV during antiretroviral therapy (ART), TFH cells facilitate HIV persistence. This special topic \u201cCD4 TFH cells in HIV\u201d synthesizes reviews from experts in the field to explore, discuss, and share recent discoveries on the intricate relationship between TFH cells and HIV. This special topic also seeks to offer perspectives on areas needing further inquiry in this rapidly evolving field.CD4 T follicular helper cells are vital for induction of long-lived humoral immunity; this specialized function makes them highly desirable immunological targets for designing an effective HIV vaccine. Intriguingly, TFH cells during HIV infection. Leong et al. delineate potential cell intrinsic and extrinsic factors driving viral replication within TFH cells during HIV infection. These include lack of cellular host restriction factors within TFH cells, exclusion of cytolytic CD8 T cells from B cell follicles within germinal centers (GCs), and trapped virus on GC follicular dendritic cells; a constellation of factors that create a perfect storm to promote unfettered viral replication within GC TFH cells.Despite the success of ART, achieving a functional cure for HIV, i.e., sustained viral suppression after ART interruption, remains a challenge due to persistence of viral sanctuaries under ART. As a result, there is a critical need to understand the reservoir to devise effective strategies to purge the latent virus and eliminate life-long dependence on ART. In this special topic, experts in the HIV field synthesize and evaluate recent discoveries in humans and non-human primate model systems to understand the complex dynamics of TFH cells are not depleted as dramatically as other CD4 T cell subsets. Zaunders et al. report a clear increase in proportion of TFH cells compared to other CD4 T cell subsets in serial fine-needle aspirates from lymph nodes of SIV-infected macaques. Miles et al. reveal that an increase in interleukin 6 and interferon gamma and a corresponding reduction in IL-2 could promote TFH proliferation. Hong et al. and Wang et al. argue that a relative increase in TFH cell proportions occurs in the face of net decrease in TFH cells numbers. They attribute the decrease in TFH numbers to increased expression of programmed death-ligand 1 on dendritic cells following infection. Hong et al. also state that an increase in transforming growth factor-b-mediated collagen deposition and fibrosis and loss of fibroblastic reticular cells drives disruption of the lymphoid architecture impairing TFH cell numbers and function. Miles et al. state that an increase in T follicular regulatory cells impairs TFH function in HIV infection. While these observations may seem at odds with each other, given the complex immunopathology of HIV infection and progression to AIDS, it is highly likely that TFH cell numbers and function vary widely over the course of infection and between infected animals and humans. Ultimately, B cell responses are impaired with aberrant B cell activation and hypogammaglobulinemia in the face of poor HIV-specific antibody responses. Chiodi et al. raise the possibility that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on TFH cells leading to abnormal B cell differentiation and apoptosis.Surprisingly, despite being hotbeds for viral replication, TZaunders et al. contend that not all immune responses are impotent but that effective immune responses drive virus evolution resulting in Envelope divergence and diversification. The generation of neoantigens in the infected host could recruit naive CD4 T cells, which upon activation drive viral replication leading to eventual depletion of CD4 T cells.However, antibody responses are not compromised in all HIV-infected individuals. In some infected individuals, broadly neutralizing antibodies that have acquired extensive hypermutation and even deletion/insertion mutations appear several years after initial infection. Graff-Dubois et al. assert that TFH cell frequency varies widely according to (i) the stage of HIV/SIV infection, (ii) the severity of the disease, and (iii) the ability to develop broadly neutralizing antibodies highlighting that a blanket increase or decrease in TFH cells is not a unifying characteristic of all HIV/SIV infections. Given the intricate link between virus and lymph node cells, blocking HIV replication in lymphoid tissues might be a prerequisite for induction of effective TFH responses and anti-HIV antibodies and could have the benefit of dramatically decreasing seeding of the latent reservoir. While the lymph node has received a great deal of attention, other compartments are also emerging as critical parameters deserving of attention.In their review, Thornhill et al. review what is known about peripheral(p) TFH cells, which are now emerging as valuable surrogates for GC TFH cells and indicate that the preservation of pTFH cells during HIV infection by early ART initiation is associated with better viral suppression and lack of B cell dysfunction. Moukambi et al. highlight the importance of TFH cells in the spleen, the primary organ for B cell activation and differentiation. Their recent observations indicate early and profound loss of splenic TFH cells. There is also emerging interest in studying TFH cells in mucosal compartments\u2014this understanding of the TFH cell response in distinct tissue compartments with differences in viral dynamics will undoubtedly shed further insights in the relationship of CD4 TFH cells and HIV. Thus, there remains a great deal to learn about TFH cells, and as with HIV, these cells are likely to attract the attention of immunologists and virologists alike.The author confirms being a contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Molecular Psychiatry, Huang et al. heroically investigated the cortical functional changes following methamphetamine abuse both in animal model and human addicts -induced motor evoked potential (MEPs) (Huang et al., Motor cortex is commonly a neglected region in addiction field. However, neuroimaging findings demonstrated that craving evoked by drug-associated cues involved motor and sensory regions (Yalachkov et al., Cortical plasticity is affected by a number of factors, such as genetic susceptibility to activity-dependent plasticity, trophic factor expression, neurotransmitters (Li Voti et al., Cortical plasticity impairment, however, is not limited to addiction. Previous studies reported that schizophrenia (Fitzgerald et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer\u2019s, Parkinson\u2019s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer\u2019s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer\u2019s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases. A central role of mitochondria in age-related metabolic and neurodegenerative diseases has long been proposed, and an association between mitochondrial dysfunction and Alzheimer\u2019s disease has been long proposed across multiple investigative strategies from analysis of human tissue to cell model systems Beal, . The \u201cmiHere we review the link between mitochondrial dysfunction and the risk of AD, the contribution of mitochondrial genetic variances to the risk, and how the risk is modulated by other factors, such as apolipoprotein E (APOE) genotype and sex differences.Unlike many other organelles, mitochondria have their own genome. The human mitochondrial genome is a circular set of 16,569 base pairs encoding 37 genes. Thirteen of these genes encode protein subunits required for four of the five electron transport chain complexes: complex I (NADH ubiquinone oxidoreductase), complex III (cytochrome bc1 complex), complex IV (cytochrome c oxidase), and complex V (ATP synthase); two encode rRNAs for mitochondrial ribosomes 12S and 16S), and 22 encode tRNAs  activity was observed in both platelets and postmortem AD brain  cycle enzymes was observed in AD brain. Autopsy-confirmed AD brain had significantly reduced activity in pyruvate dehydrogenase complex, isocitrate dehydrogenase, and \u03b1-ketoglutarate dehydrogenase complex, whereas the activity of succinate dehydrogenase and malate dehydrogenase were increased  than non-J participants  and total energy expenditure (TEE) were measured in 294 participants in the health, aging and body composition study . Different sets of haplogroups are identified in different studies and different studies could identify opposite effects of the same mitochondrial haplotype on risk of LOAD. Moreover, multiple studies involving Caucasians of European descendant  did not detect associations between any haplogroup and AD (Chinnery et al., APOE\u03b54 genotype is a widely recognized risk factor for AD, and has been repeatedly confirmed in the studies reviewed herein (Corder et al., In longitudinal studies, APOE\u03b54 carriers had significantly greater rCMRglc decline in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus (Reiman et al., In vitro studies also suggested that truncated APOE\u03b54 fragment can interact directly with mitochondria and cause mitochondrial dysfunction and neurotoxicity (Chang et al., At the cellular level, APOE\u03b54 gene expression in human was associated with down-regulation of genes involved in mitochondrial oxidative phosphorylation and energy metabolism (Xu et al., After stratifying by APOE\u03b54 status, three interesting modes of interactions between APOE\u03b54 status and mitochondrial haplogroups in modulating the risk of AD were apparent (see Table The first mode is a neutralizing effect of mitochondrial haplogroup on the effect of APOE\u03b54 on risk of AD (see Table The second mode is an enabling effect of APOE\u03b54 on mitochondrial genetic variances as risk factors for AD (see Table A synergistic effect was also observed between APOE\u03b54 and mitochondrial haplotypes (see Table As with the association between mitochondrial haplotype and the risk of late onset AD, the interaction between APOE\u03b54 and mitochondrial genetic variances in modulating the risk of late onset AD remains debatable. Multiple studies failed to identify any correlation between mitochondrial haplogroup and APOE\u03b54 status or failed to identify an interaction between the two on the risk of developing AD (Zsurka et al., Females are at greater lifetime risk for LOAD, and also have higher prevalence and incidence rate than all age-matched males (Brookmeyer et al., While almost all the reviewed studies recognized sex differences on risk of LOAD, only a few studied the effects of mitochondrial genetic variances in each sex (van der Walt et al., In contrast, some variances affected only males (see Table These results indicate that previously observed associations between mitochondrial haplogroups and AD could be driven by sex. Conversely, the effects observed in one sex could be diluted in the whole population, or be neutralized by the other sex, resulting in non-significant associations.Mounting evidence suggested a central role of mitochondrial dysfunction in the etiology of late onset AD. As reviewed above, disruption of mitochondrial bioenergetics, structure and dynamics have all been indicated in AD patients. Given the maternal pattern of inheritance of late onset AD and mitochondrial genome, herein we reviewed the association of mitochondrial genetic variances on bioenergetics, respiratory phenotypes and risk of developing LOAD. While the outcomes remain debatable, a large body of science supports an association between mitochondrial genetic variances and differences in bioenergetics and AD susceptibility. Several factors can help explain the disagreement. First, although most studies were conducted in descendants of European origin, the geographic distribution of participants were drastically different, which could result in diverse nuclear genetic background. Since mitochondria communicate extensively with the nucleus, uncontrolled nuclear background can potentially mask effects of mitochondrial genetic variances. Second, as we have reviewed, observations could be driven by certain subhaplogroups, thus results obtained from different populations may be biased by their dominant subhaplogroup. Third, given the heteroplasmic nature of the mitochondrial DNA, accumulated mutations throughout aging may be haplotype and tissue specific Wallace, , which cThe data also indicate that mitochondrial haplotype is one factor among several that impacts risk of AD. This is consistent with the multifactorial nature of aging trajectories and risk for LOAD. A systems biology approach that integrates mitochondrial genetic variances and risk factors such as APOE\u03b54 genotype and sex is a step towards resolving disparities across studies of mitochondrial haplotype and risk of neurodegenerative diseases associated with mitochondrial dysfunction (see Figure YW and RDB wrote and reviewed the manuscript together.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Saccharomyces cerevisiae  biosynthesis in heterologous robust hosts to produce a wide array of compounds  use of fluorescent compounds as acceptor substrates whose fluorescence signal decreases upon sugar conjugation (Gantt et al., E. coli, S. cerevisiae, and Streptomyces. These biosynthesis approaches include de novo pathway engineering, central carbon flux redirection for co-factor or precursor synthesis, the selection of alternative enzymes, protein engineering/mutagenesis, precursor directed mutasynthesis, modular metabolic engineering, system and synthetic biology tools, such as codon optimization, vector, promoter, ribosome binding site engineering, and the engineering and manipulation of other non-protein-coding sequences (Pandey et al., E. coli. This hurdle can be addressed by regulating intermediate consuming pathway genes in the chromosome of host organisms. Several studies have been reported by our group (Malla et al., E. coli by constructing background E. coli mutants (Kim et al., Recently, advances have been made in the construction of robust microbial cells for the synthesis of several biomolecules in in vivo fermentation approach for producing NP glycosides is inadequate for producing a significant amount of glycosides by simple fermentation even though the process can be easily subjected to industrial scale up. To produce future NP glycosides by fermentation, a robust system should be developed that is capable of producing diverse NDP-sugars in the cell cytosol while engineering promiscuous GTs for sugar transfer to acceptor molecules. High level production of target non-natural NP glycosides can be achieved by simple microbial fermentation upon proper implementation of recently developed system/synthetic biology tools for the engineering of microbial host cells. Cumulatively, this approach of GT-mediated exchange of microbial non-natural glycones with exogenous aglycones offers huge combinatorial potential for the biosynthesis of novel future molecules for human use.The RP and JS wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Innate lymphoid cells (ILCs) are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed. ILCs have the property of classic lymphoid cells but lack rearranged antigen-specific receptors  NKp46  cells, ILCs are conventionally divided into three groups based on their differential expression of effector cytokines and developmental requirements for transcription factors  cells were also described   and Peyer\u2019s patches has long been recognized (De Togni et al., + ILC3s, can induce inflammation in the intestines of both mice and humans (Bernink et al., Although ILCs normally play host-protective roles, dysregulated activation of ILCs could lead to inflammatory diseases (Artis and Spits, Chronic ILC2 activation was reported to contribute to a large variety of tissue inflammatory disorders such as asthma in the lung and atopic dermatitis in the skin, which are generally associated with over-production of the type 2 inflammatory cytokines such as IL-4, IL-5, and IL-13. ILC2s expand and produce the type 2 cytokines in mice with allergic lung inflammation (Chang et al., \u2212 cells within human colorectal carcinoma tumors (Kirchberger et al., ILC3s could contribute to inflammatory diseases and tumorigenesis in various tissues. IL-17- and IL-22-producing ILC3s have been linked with the inflammatory skin disease psoriasis, inflammatory bowl disease, obesity-associated asthma, and multiple sclerosis (Buonocore et al., in vitro development analysis (Scoville et al., Specific functions of ILCs in homeostasis and inflammation are associated with their unique localization in peripheral tissues. Recently, several groups reported that ILCs are predominantly tissue-resident cells that do not circulate in the body. In parabiotic studies, helper-like ILCs in both non-lymphoid tissues and lymphoid organs such as the small intestine, salivary gland, lung, mensenteric lymph node, and adipose tissue of two joined adult mice with shared blood circulation systems remain locally and do not move from one mouse to another (Gasteiger et al., + ILC1-type cells although their origin and lineage association are not known (Almeida et al., + and NCR\u2212 subsets, account for about 50% of total skin ILCs in humans (Dyring-Andersen et al., Skin is the outmost barrier tissue constantly exposed to assaults of various foreign agents. Skin is enriched with ILCs and ILCs of all the three groups could be found in the skin (Yang et al., + dendritic cells are involved in the programming of skin-homing CCR10+ ILCs in skin-draining lymph nodes (Yang et al., Since ILCs share many common regulatory pathways with helper T cells for their development and function, we investigated whether skin-specific ILCs are programmed in skin-draining lymph nodes to acquire their skin-homing property for establishment of their skin residency, paralleling the process by which the skin-homing property of conventional \u03b1\u03b2 T cells is imprinted in skin-draining lymph nodes (Yang et al., + ILCs in skin-draining lymph nodes, local inflammatory conditions suppress programming of skin-homing CCR10+ ILCs (Yang et al., Dependent on environmental cues of lymphoid organs in which T cells and ILCs are activated, they could be also imprinted to acquire homing properties to other distinct peripheral tissues (Campbell and Butcher, Compared to the healthy skin, ILC2s are increased in the skin of patients with atopic dermatitis (Kim et al., + ILC3s are increased in both lesional and non-lesional skin and NKp44\u2212 ILC3s have the potential to differentiate to NKp44+ ILC3s in response to stimulation of IL-1\u03b2 and IL-23 (Teunissen et al., + ROR\u03b3t+CD56+ ILC3s were found in the psoriatic skin in a separate study (Dyring-Andersen et al., Increasing evidence implicates involvement of ILC3s in psoriasis, a skin inflammatory disease largely resulting from overproduction of Th17-associated cytokines such as IL-17A (Dyring-Andersen et al., While ILCs are relatively well studied for their participation in development of skin inflammatory diseases, their physiological role in maintenance of the skin homeostasis and host protection is still poorly understood. Since ILC2s are capable of producing amphiregulin, a member of epithelial growth factor family, they could potentially contribute to wound healing (Salimi et al., + T cells and dampen their responses to microbiota (Hepworth et al., + ILCs and T cells plays a critical role in maintaining the immune homeostasis of the skin (Yang et al., Rag1\u2212/\u2212 mice that lack T and B cells, there are significantly reduced CCR10+ ILCs in the skin, while transfer of CD4+ T cells could partially restore the homeostatic presence of CCR10+ ILCs (Yang et al., Il2rg\u2212/\u2212Rag2\u2212/\u2212 mice, which lack all ILCs as well as T/B cells, donor CD4+ T cells in skin of hosts contain significantly higher percentages of IL-17A-producing Th17 and IL-5-producing Th2 cells but much lower percentages of IFN\u03b3-producing Th1 cells than those transferred into Rag1\u2212/\u2212 recipients that have ILCs (Yang et al., Skin ILCs interact with other skin-resident immune cells to maintain the immune homeostatic condition. In the steady-state skin, the preferential interaction of ILC2s and mast cells has been detected (Barnig et al., The research over past several years has started to reveal roles of ILCs in the skin and unravel mechanisms regulating establishment and function of the skin-resident ILCs. However, several major questions remain to be addressed. First, physiological functions of skin-resident ILCs in host protection and immune homeostatic maintenance are still poorly understood. While ILCs have been generally implicated in protection against infection, control of commensal bacteria and regulation of immune activation in various barrier tissues, the function of resident ILCs specifically in the skin is not well studied. Considering that ILCs are maintained locally in different barrier tissues, functions and regulation of ILCs in the skin and other barrier tissues are likely regulated differently with local environmental cues. For example, the CCR10/CCL27 axis is involved in the regulation of resident ILCs in the skin but not other sites (Yang et al., + ILCs are dominant in the healthy skin where they promote balanced maintenance of resident T cells (Yang et al., \u2212/\u2212, Foxp3\u2212/\u2212 or topical Calcipotriol-treated wild-type mice, CCR10+ ILCs are decreased while CCR10\u2212 ILCs are increased in the skin (Yang et al., + and CCR10\u2212 ILCs might be differently involved in skin immune homeostatic regulation and activation (Fig.\u00a0+ and CCR10\u2212 skin ILCs are regulated and function should help understand basic biology of the skin-specific ILCs in the health and disease.Second, mechanisms regulating differential involvement of ILCs in the skin homeostasis and inflammation are largely unknown. Studies of ILCs of the skin and other barrier tissues have showed that ILCs could be involved in both homeostatic regulation and tissue inflammatory processes. However, it is currently unknown whether and how ILCs involved in homeostatic regulation are different from ILCs involved in immune inflammatory processes in the skin. Our studies have found that CCR10+ ILC1s to ILC3s (Bernink et al., Third, the involvement of ILCs in promoting diseases has raised interest in modulating ILC functions for the treatment of diseases. In other tissues, antibodies against ILC2-activating cytokines, such as IL-25 and IL-33, as well as those targeting ILC2-produced cytokines, including IL-5 and IL-13, have been found to suppress ILC2 proliferation and function in tissue inflammatory diseases in the lung (Gauvreau et al.,"}
+{"text": "Phospholipids represent the highly conserved structural basis of biological membranes from bacteria to humans. However, plants and other photoautotrophic organisms are unique in using non-phosphorus galactolipids as primary components of their photosynthetic membranes. In light of the biomass of green tissues as compared with that of the overall plant body and the highly stacked thylakoid membrane structures in chloroplasts, galactolipids are the most abundant membrane lipids on the earth. Historically, the roles of galactolipids have been studied mainly in relation to photosynthesis, and recent advances in molecular biology with Arabidopsis and other model organisms have revealed an essential role of galactolipids in photosynthesis. However, these galactolipids are also abundant in non-photosynthetic organs, especially flowers, which suggests their distinct role apart from photosynthesis. The aim of this mini-review is to describe distinct biochemical properties of flower galactolipids and possible new roles, with a summary of the current understanding of galactolipid biosynthesis in Arabidopsis.The online version of this article (doi:10.1186/1999-3110-54-29) contains supplementary material, which is available to authorized users. Its activity was initially observed as a major DGDG synthetic activity in isolated chloroplasts or envelope preparations (van Besouw and Wintermans, SENSITIVE TO FREEZING 2, a gene essential for freezing tolerance in Arabidopsis, encodes a processive galactosyltransferase that produces oligogalactolipids by transferring galactose groups from MGDG (Moellering et al., Because of the odd enzymatic property of GGGT, its identity has long been an issue. Recently, Moellering and the Benning group found that Petunia hybrid to explore yet-unknown roles of galactolipids in flowers (Figure\u00a0Given that chloroplasts are differentiated as a form of plastids, an important question was whether galactolipids are unique in chloroplasts or are widely found in different plastids. Biochemical studies found significant levels of MGDG and DGDG in non-photosynthetic organs (Kleinig and Liedvogel, s Figure\u00a0 (Nakamurs Figure\u00a0; (Nakamus Figure\u00a0; (Nakamus Figure\u00a0.Figure 3The level of MGDG in petals is about one third of that in leaves (Nakamura et al., 2003dad1, which is deficient in anther dehiscence, is mutated in a gene encoding lipase that liberates 18:3 fatty acid from the glycerlipid backbone for jasmonic acid synthesis (Ishiguro et al., Among the 3 floral organs, stamens show the highest MGDG levels and the level is about half that in leaves (Nakamura et al., Pistils are the most unique among the floral organs we discuss in terms of predominant DGDG levels relative to that of MGDG (Nakamura et al., Galactolipids can be utilized even during pollen tube growth. Glycerolipid profiling of lily pollen tubes before and after elongation revealed a 5.7-fold increase in DGDG level and 2.8-fold increase in MGDG level (Nakamura et al., mgd1 mutant is challenging because it has a lethal phenotype (Kobayashi et al., Galactolipid biosynthesis is well understood in the model system Arabidopsis. Meanwhile, ample biochemical data from different botanical flowers show intriguing features of galactolipid biosynthesis in floral organs. Although the functional difference between type A and B MGD is clear and type B is more involved in MGDG synthesis in flowers, double knockout of MGD2 and MGD3 does not result in defective flower development nor MGDG level (Kobayashi et al.,"}
+{"text": "Neuroinflammation plays a critical role in the onset and progression of many neurological disorders, including Multiple Sclerosis, Alzheimer's and Parkinson's diseases. In these clinical conditions the underlying neuroinflammatory processes are significantly heterogeneous. Nevertheless, a common link is the chronic activation of innate immune responses and imbalanced secretion of pro and anti-inflammatory mediators. In light of this, the discovery of robust biomarkers is crucial for screening, early diagnosis, and monitoring of neurological diseases. However, the difficulty to investigate biochemical processes directly in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory responses have been identified in different body fluids, such as blood, cerebrospinal fluid, and tears. In addition, progress in micro and nanotechnology has enabled the development of biosensing platforms capable of detecting in real-time, multiple biomarkers in clinically relevant samples. Biosensing technologies are approaching maturity where they will become deployed in community settings, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight both clinical and recent technological advances toward the development of multiplex-based solutions for effective neuroinflammatory and neurodegenerative disease diagnostics and monitoring. Neurological disorders account for an increasing number of disability-adjusted life-years worldwide, especially in high-income countries. Alzheimer's disease, Parkinson's disease and Multiple Sclerosis are the most prevalent causes of neurological disability  cleavage of amyloid precursor protein] and its clearance, leading to the formation of toxic oligomers (A\u03b2O), subsequent synaptic dysfunction and neuronal cell death  the formation of amyloid plaques is promoted by an increased production of A\u03b21\u221242, while in sporadic AD it is mainly due to impaired A\u03b2 clearance  is a neurodegenerative disorder primarily affecting neocortical regions and characterized by progressive episodic memory loss leading to significant behavioral changes  deposition  imaging. Biomarker analysis, including \u03b1-syn, in serum or CSF, is not performed in standard clinical practice , GBA (glucocerebrosidase), PRKN (parkin), and LRRK2 (leucine-rich repeat kinase 2) which are expressed in microglia , the second most common neurodegenerative disorder, is characterized by the early and progressive loss of dopaminergic neurons in the Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the CNS of unknown etiology but with a genetic predisposition and environmental influence  or \u201cinside-out\u201d (CNS-intrinsic initiation of the inflammatory cascade) models  which specifically recognizes the biomarker  of interest and a transducer which converts biochemical interactions into a quantifiable electrical signal proportional to biomarker concentrations. Biosensors are commonly classified in electrochemical, optical, piezoelectric, or magnetic, based on the signal transduction mechanism. These technologies have broad applications in health  provided by the use of gold nanoparticles (NPs) , which mediates the neuronal binding and toxicity of A\u03b2O, was used as a recognition element for the specific detection of the oligomers. The biosensor presented a LOD of 0.5 pM and successfully detected cell-derived A\u03b2O from conditioned media of 7PA2 Chinese Hamster Ovary (CHO) cells that naturally secrete A\u03b2O  based on its oxidation and subsequent aggregation into NPs (polydopamine) (Yildirim and Bayindir, 2 nanotube arrays for sensitive \u03b1-syn quantification with a detection limit of 34 pg/mL (An et al., substancia nigra (Choi et al., 2 NPs (Heydari-Bafrooei et al., Although \u03b1-syn has been the most intensely studied and recognized biomarker for PD, its application in biosensing is very limited. A photoelectrochemical biosensor was developed by An et al. based on Au-doped TiOThe heterogeneous nature of MS, characterized by distinct patterns associated with the demyelination process, makes it highly improbable that a single diagnostic marker is capable of covering the full spectrum of MS subtypes (Lucchinetti et al., in situ early diagnostics of neuroinflammatory and neurodegenerative diseases. Altogether, these advantages will surely bring great benefits for both academic and medical fields.An increasing number of studies are uncovering the beneficial and detrimental roles of microglia in neurodegenerative disease onset and progression. Pro-inflammatory cytokines can be used in combination with classical biomarkers for neurodegenerative and neuroinflammatory disease diagnostics and monitoring of disease progression. Technologies for simultaneous detection and quantification of different biomarkers are rapidly developing and future devices are aimed at bringing valuable advantages, specifically related to lower sample volumes, detection time and limits, higher specificity and sensitivity. Decreasing the need for biological samples processing, while integrating biosensing platforms in portable lab-on-a-chip systems would, in turn, allow point-of-care use by semi-skilled operators toward real-time and All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The explosive growth of health-related data presented unprecedented opportunities for improving health of a patient. Machine learning plays an essential role in healthcare field and is being increasingly applied to healthcare, including medical image segmentation, image registration, multimodal image fusion, computer-aided diagnosis, image-guided therapy, image annotation, and image database retrieval, where failure could be fatal.The purpose of this special issue is to advance scientific research in the broad field of machine learning in healthcare, with focuses on theory, applications, recent challenges, and cutting-edge techniques.The quality level of the submissions for this special issue was very high. A total of 24 manuscripts were submitted to this issue in response to the call for papers. Based on a rigorous review process, 8 papers (33%) were accepted for the publication in the special issue. Below, we briefly summarize the highlights of each paper.One of the papers of this special issue, \u201cDiagnosis of Alzheimer's Disease Based on Structural MRI Images Using a Regularized Extreme Learning Machine and PCA Features,\u201d R. K. Lama et al. proposes a method and compared Alzheimer disease (AD) diagnosis approaches using structural magnetic resonance (sMR) images to discriminate AD, mild cognitive impairment, and healthy control subjects using a support vector machine (SVM), an import vector machine (IVM), and a regularized extreme learning machine (RELM). By means of experiments on the ADNI datasets, it has been concluded that RELM with the feature selection approach can significantly improve classification accuracy of AD from mild cognitive impairment and healthy control subjects.S. Alam et al. presented a method for distinguishing AD from healthy control using combination of dual-tree complex wavelet transforms, principal coefficients from the transaxial slices of MRI images, linear discriminant analysis, and twin support vector machine in their article \u201cTwin SVM-Based Classification of Alzheimer's Disease Using Complex Dual-Tree Wavelet Principal Coefficients and LDA.\u201dA semisupervised learning approach for cell detection is presented in the third article of this special issue by N. Ramesh et al. in their paper entitled \u201cCell Detection Using Extremal Regions in a Semisupervised Learning Framework.\u201d The method requires very few examples of cells with simple dot annotations for training.In the paper entitled \u201cPatient-Specific Deep Architectural Model for ECG Classification\u201d by K. Luo et al., a method for ECG classification is proposed. The method is based on time-frequency representation and patient-specific deep learning architectural model, and it uses deep neural network classifier.An automatic method for segmentation of 3D magnetic resonance imaging (MRI) data, useful in the clinical diagnosis of brain tumor, named as Glioma is presented by Z. Li et al. in the article \u201cLow-Grade Glioma Segmentation Based on CNN with Fully Connected CRF.\u201d The method combined a multipathway convolutional neural network (CNN) and fully connected conditional random field (CRF). Experimental results have shown that the method is useful for low-grade glioma.A general system for hybrid disease diagnosis adopting classifier optimization procedure using evolutionary algorithms is presented by M. R. Nalluri et al. in their article \u201cHybrid Disease Diagnosis Using Multiobjective Optimization with Evolutionary Parameter Optimization.\u201dY. Chou et al., in their paper \u201cA Real-Time Analysis Method for Pulse Rate Variability Based on Improved Basic Scale Entropy,\u201d proposed a method named sliding window iterative base scale entropy analysis by combining base scale entropy analysis and sliding window iterative theory for analyzing heart rate variability signal.Another paper of this special issue by J.-S. Park et al. titled \u201cR Peak Detection Method Using Wavelet Transform and Modified Shannon Energy Envelope\u201d presents an R peak detection method using the wavelet transform and a modified Shannon energy envelope for rapid ECG analysis.These 8 selected contributions basically can reflect the new achievements in the machine learning applications in healthcare, and we hope they can provide a solid foundation for future new approaches and applications."}
+{"text": "Iron (Fe) is an essential plant micronutrient but is toxic in excess. Fe deficiency chlorosis is a major constraint for plant growth and causes severe losses of crop yields and quality. Under Fe deficiency conditions, plants have developed sophisticated mechanisms to keep cellular Fe homeostasis via various physiological, morphological, metabolic, and gene expression changes to facilitate the availability of Fe. Ethylene has been found to be involved in the Fe deficiency responses of plants through pharmacological studies or by the use of ethylene mutants. However, how ethylene is involved in the regulations of Fe starvation responses remains not fully understood. Over the past decade, omics approaches, mainly focusing on the RNA and protein levels, have been used extensively to investigate global gene expression changes under Fe-limiting conditions, and thousands of genes have been found to be regulated by Fe status. Similarly, proteome profiles have uncovered several hallmark processes that help plants adapt to Fe shortage. To find out how ethylene participates in the Fe deficiency response and explore putatively novel regulators for further investigation, this review emphasizes the integration of those genes and proteins, derived from omics approaches, regulated both by Fe deficiency, and ethylene into a systemic network by gene co-expression analysis. Iron (Fe) is an essential element for living organisms including plants. Fe-containing proteins play a variety of vital roles in cellular respiration, intermediary metabolism, oxygen transport, and DNA stability and repair, as well as photosynthesis in plants. In human beings, Fe deficiency causes severe healthy problems, including anemia, which affects billions of people worldwide . The first step in this strategy is the acidification of the rhizosphere mediated by the H+-translocating P-type ATPase AHA2  transcription factor FER-LIKE Fe DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) , have been carried out in a broad range of plant species, including model strategy I plant Arabidopsis, Medicago, soybean, as well as Strategy II plant rice and others  from the four data sets, herein named Fe deficiency-response core genes, with 61 being up-regulated and 10 down-regulated  from S-adenosylmethionine (SAM), underlying the importance of controlling the expression of NAS genes including NAS1 gene  recycling for ethylene synthesis, is encoded by single gene in Arabidopsis genome, indicating the importance to tightly control its expression  oxygenase family; proteins in this family is generally considered to possess oxidoreductase activity catalysing the 2-oxoglutarate- and Fe(II)-dependent oxidation of an organic substrate using a dioxygen molecule. Previous study showed that the ethylene synthesis protein ACC oxidase also belongs to 2OG-Fe(II) oxygenase superfamily , functioning as ferric iron binding and participating in the cellular iron ion homeostasis, are essential to protect cells against oxidative damage and flowering  was the gene AT3G13610 encoding a Fe (II)- and 2-oxoglutarate-dependent dioxygenase family gene F6'H1  and Fe (II)-dependent oxygenase superfamily protein putatively assumed to be involved in hormone metabolism by MapMan analysis. The gene co-expressed with AT3G12900 is AT5G38820, whose expression is also regulated by ethylene     , and this study does have uncovered new layer of regulation in gene activity in response to Fe deficiency  that were induced in Brassica napus phloem sap upon Fe deficiency, which is consistent with the decrease of ACC content (Gutierrez-Carbonell et al., Medicago truncatula under Fe limitation (Rodriguez-Celma et al., Although nearly no protein with changes in abundance upon Fe deficiency has been uncovered across a wide range of plant species, a comprehensive comparison of these studies indeed has revealed some common elements in proteome under Fe limitation. In brief, proteins associated with \u201coxidative stress and defense,\u201d \u201cC metabolism,\u201d \u201cN metabolism,\u201d \u201ccell wall,\u201d \u201csecondary metabolism, particularly the phenylpropanoid metabolism,\u201d \u201cenergy and ATP-coupled transport processes,\u201d and \u201cprotein metabolism\u201d have been identified as differentially accumulated proteins among plant species, which is well-summarized in an excellent review published in 2013 (Lopez-Millan et al., Omic approaches have been widely employed to explore the responses of plant to Fe deficiency, and have uncovered diverse metabolic adaptations upon Fe starvation. A subset of conserved Fe-responsive genes and some common metabolic pathways have been revealed by transcriptome and proteome across a range of plant species. It has been clear that the concordance between the abundance of mRNA and their related proteins is not strong correlated (Lan et al., All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Stroke is an important cause of morbidity and mortality as well as functional impairment particularly in the elderly people . PredictSeveral previously published studies found an association between high serum CRP level and development of stroke , 8-10. RSimilarly, Ridker et al., found a positive correlation between serum hsCRP and severity of stroke . In a pr"}
+{"text": "Over the last decade, an increasing number of reports underscored the importance of epigenetic regulations in brain plasticity. Epigenetic elements such as readers, writers and erasers recognize, establish, and remove the epigenetic tags in nucleosomes, respectively. One such regulation concerns DNA-methylation and demethylation, which are highly dynamic and activity-dependent processes even in the adult neurons. It is nowadays widely believed that external stimuli control the methylation marks on the DNA and that such processes serve transcriptional regulation in neurons. In this mini-review, we cover the current knowledge on the regulatory mechanisms controlling in particular DNA demethylation as well as the possible functional consequences in health and disease. Among several other epigenetic tags, methyl tags on the DNA were generally considered as repressive marks. However, an increasing number of studies showed that the DNA methylation at intergenic regions as well as gene regulatory regions might enhance gene expression  in vivo  45 proteins (GADD45A and GADD45B) that in neurons take part in active DNA demethylation processes  was first described in the 1972  or apolipoprotein B mRNA editing complex (APOBEC) is an alternative path to successive oxidation reactions by TET enzymes for the initiation of DNA demethylation Figure . The modBdnf gene that is quite well investigated in the context of synaptic plasticity and learning , methyl CpG binding protein 2 (MeCP2), histone deacetylases (HDAC) 1 and 2. The repressor complex dissociates following phosphorylation of MeCP2 and nitrosylation of HDAC2 in response to Ca+2 influx (Chen et al., Bdnf IV in a stimulus-dependent manner (Ratnu et al., In the long-lived nature of postmitotic neurons, genomic stability needs to be maintained for decades while at the same time their remarkable plasticity has to be kept at a poised state ready to respond (Baker-Andresen et al., Gadd45b gene expression (Keeley et al., Unfortunately, conflicting reports have been published on the role of GADD45B in learning and memory processes. Fear conditioning induces Interestingly, 5hmC is not only an intermediate DNA demethylation form but also an epigenetic mark on its own, which is enriched within promoters and gene bodies (Kaas et al., Another critical issue is cell-type specificity of DNA demethylation. In most studies brain tissue that contains different neuronal and glial cell types was used. The current knowledge on how the DNA demethylation machinery functions in different cell-types and responds to neuronal activity is therefore very limited. DNA methylation patterns vary between neurons and non-neuronal cells. Ventromedial prefrontal cortex neurons have higher global DNA methylation levels compared to non-neuronal cells (Li et al., Bdnf IX promoter was found, which is in line with reduced Bdnf IX expression (Gavin et al., Arc was also associated with reduced levels of GADD45B and DNA demethylation in this stress model (Grassi et al., Bdnf IX promoter methylation level is abolished and mRNA expression is perturbed (Ma et al., Bdnf gene expression (Dong et al., Given the principal functions of chromatin modifications in regulating gene transcription programs, it\u2019s not surprising that the number of studies, which report the involvement of DNA demethylation machinery in neurological disorders, is steadily increasing. Enhanced GADD45B levels were reported in two different cohorts of major psychotic patients (Gavin et al., Based on the initial GADD45B-dependent demethylation hypothesis (Gavin et al., GB and MK are invited to contribute to the article collection for the special issue of the \u201cEpigenetic Mechanisms Regulating Neural Plasticity\u201d. GB outlined the mini review and GB and MK wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical  Proper brain function relies on appropriate connectivity between specific neuronal populations. An essential cellular process underlying such connectivity involves the generation and continued maintenance of molecular constituents within axons and dendrites , frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD)  and glial cells (tufted astrocytes and coiled bodies)  is characterized by severe atrophy of the frontal, temporal, and parietal lobes. Cytoplasmic neuronal tau inclusions known as Pick bodies represent the major neuropathological hallmark of PiD, and these are typically found in the dentate gyrus of the hippocampus and frontal and temporal cortices  promoter, which provides relatively selective expression of tau in forebrain neurons  vectors encoding P301L tau into the EC (Siman et al., Collectively, data from various animal models of tauopathy reveal axonal degeneration as a prominent pathological feature, and further suggest there is a contribution to this phenotype from glial cells. Based on their resemblance to this specific aspect of human tauopathies, these animal models may help define mechanisms and specific molecular components mediating the toxic effect of pathogenic tau on axonal maintenance and function.in vitro (Weingarten et al., in vivo has yet to be provided.The initial discovery of tau protein was based on biochemical procedures that revealed its ability to associate with purified microtubules and modulate their dynamic growth behavior in vivo. Furthermore, axonal development is normal in cultured primary neurons obtained from some tau knockout mice (Harada et al., Collectively, data from the available four transgenic tau knockout mouse lines (reviewed in Ke et al., Available experimental evidence suggests that tau performs functions other than microtubule stabilization in neurons. Numerous studies suggest a role for tau in multiple cellular processes and compartments, some of which may not include microtubule interactions. The functional repertoire of tau includes microtubule-actin cytoskeleton interactions (Selden and Pollard, In vitro studies using purified components of the AT system further supported a model where tau would elicit this effect by competing with conventional kinesin heavy chain subunits for microtubule binding (Seitz et al., in vivo extend the conclusions from squid axoplasm studies to mammalian neurons, showing normal AT rates in the optic nerve of tau-overexpressing mice (Yuan et al., The dependence of axons on proper anterograde and retrograde AT is evident because mutations in selected conventional kinesins or cytoplasmic dynein subunits suffice to promote dying-back degeneration of neurons (Morfini et al., in vitro and in situ also appears inconsistent with the notion that tau physically blocks motor proteins (Samsonov et al., The highly dynamic nature of the interaction between tau and microtubules The major motor proteins responsible for AT, conventional kinesin and cytoplasmic dynein, are regulated by specific protein kinases providing a novel mechanism linking pathological forms of tau to deficits in AT (Kanaan et al., 2+ dysregulation may negatively impact axonal connectivity (Figure 2+ from the endoplasmic reticulum, leading to inhibition of synaptic vesicle exocytosis and synaptic transmission through a mechanism involving PAD exposure and GSK3 activation (Figure 2+ imbalance and cell death in induced pluripotent stem cells (Imamura et al., 2+ levels by directly inhibiting plasma membrane Ca2+ ATPase (Berrocal et al., 2+ buffering in cells (Werth and Thayer, 2+ levels (reviewed in Eckert et al., 2+ levels may promote abnormal activation of calcium-activated proteases and proteolysis of critical cytoskeletal protein components (Figure In addition to the mechanisms above, mechanisms linking pathological tau to Cay Figure . For exan Figure . Oligomen Figure  and longn Figure  in cultun Figure . Studiess Figure . Consists Figure , and inhs Figure . Interess Figure . Collect2+ homeostasis, altered glial function, and others (Figure The landscape of tauopathies is marked by significant heterogeneity in clinical presentation, cellular topography, and neuropathological features. Despite this diversity, an examinations of human brains and animal models of tauopathies reveal axonopathy as a common feature of these diverse diseases (Hyman et al., s Figure . DevelopAK, BC, KC, GM, and NK all contributed equally with writing, editing and figure preparation for the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Malaria has remained a greatest health and socioeconomic burden in the tropical and subtropical regions of the world. According to World Health Organization, approximately, 429,000 deaths with 212 million cases were reported from malaria in the world , China , and Pakistan  and it shares the shortest land border with Afghanistan (106 Km)  among all the bordering countries of India , China (79%), Nepal (78%), and Bhutan (60%) while its prevalence in Myanmar and Bangladesh is 34 and 7%, respectively  followed by Myanmar (66%), Bhutan (40%), Nepal (22%), Pakistan (19%), China (11%), and Afghanistan (5%)  in the northeast region of India  of hanistan 06 Km  gene in this fatal human malaria parasite  gene  gene amplification were characterized by increased susceptibility to chloroquine but decreased susceptibility to mefloquine (Imwong et al., pvmdr1 in conferring resistance to chloroquine is still elusive and controversial (Faway et al., pvmdr1 gene copies correlated with mefloquine use history, in vivo data showing a direct relationship between mefloquine resistance and pvmdr1 gene amplification form mefloquine-treated patients are needed (Khim et al., P. vivax.i et al. . Howeveri et al. . AccordiKinley Wangdi and colleagues have highlighted the malaria elimination efforts carried out by the neighboring countries, however, they did not mention the Malaria Control Programme of Pakistan bordering Gujarat and Rajasthan, the high malaria transmission western states of India (Wangdi et al., Wangdi and colleagues have overlooked the malaria deaths and prevalence in children. According to WHO, \u201cA child dies of malaria every 2 minutes\u201d (World Health Organization, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Shen Yuan et al.  highlighIn the discussion, the authors state: \u201cOur study is the first meta-analysis investigating the protective role of chocolate consumption against diabetes.\u201dHowever, this represents a slight imprecision; in 2011, Buitrago-Lopez et al. [Another interesting difference between the two studies is that Shen Yang et al. found a chocolate protective effect occurred in the category of moderate chocolate consumption (<6 serving/week), while Buitrago-Lopez et al. found that a higher chocolate consumption (definitions of which vary from the number of servings per week or grams per day) confers the lowest incidence of diabetic and cardiometabolic events. Such differences deserve a detailed exploration in order to delimitate the ideal chocolate recommendation which provides optimal flavonoid amounts for a cardiometabolic protective effect  without"}
+{"text": "Tsianos et al.  demonstrThe possibility of combining neuroimaging and/or eye-tracking with visual search paradigms offers a promising avenue for cognitive style research. Visual search tasks can investigate the allocation of attention during task completion (i.e., Galpin and Underwood, We also argue that future cognitive styles research would benefit from not only adopting a mixed method experimental approach, but also from investigating other dimensions of cognitive style beyond the visualizer\u2013verbalizer dimension. For instance, it has been shown that individual differences in brain structure and function are related to preferences in field-dependence/field-independence (Hao et al., Whilst some authors argue that cognitive styles are more dynamic than static, so can change or alter Zang, , others A decade has passed since Coffield et al.'s  heavy crRB, opinion concept, main conclusions, article drafting; AG, LM, and SC verification of opinion concept, main conclusions, article drafting.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "IUCrJ (2017), 4, 108\u2013118] discuss progress on using in-cell NMR in prokaryotic and eukaryotic cell preparations.High-resolution NMR provides increasing possibilities to probe biomolecular structure in the native state. In this issue, Luchinat and Banci [ One of the unique properties of magnetic resonance (MR) has been its ability to non-invasively yield molecular information from the test tube to applications in cells, tissue and even entire organisms. In the context of MR imaging (MRI) or spectroscopy (MRS), water or other small molecules including metabolites can be used as MR-active probes to infer localized chemical information at the micrometre scale.in vitro solution-state or, more recently, solid-state NMR conditions. Applying the full and growing arsenal of such NMR methodology for studying larger molecules in a native  setting has, however, required the development of novel and tailored NMR-based cellular structural biology concepts. Compared to the in vitro case, NMR studies under native conditions have to simultaneously address several challenges. Firstly, adequate spectroscopic sensitivity is of utmost importance as the native cellular environment is usually far more complex than what can be mimicked under well defined test-tube conditions. Another challenge relates to the fact that NMR signals of interest must be detected in a complex, usually dominating, molecular background. In practice, concepts suppressing signals of the surrounding molecular background so far have employed a combination of tailored biochemical, cell biology and spectroscopic methods. Thirdly, studying \u2018live\u2019 cell preparations furthermore calls for NMR approaches that allow NMR data to be rapidly acquired or involve instrumental setups that keep cells viable by allowing exchange of nutrients and removal of metabolic byproducts.In parallel, nuclear magnetic resonance (NMR) spectroscopy has become a well established structural biology approach to comprehensively study (at the atomic level) three-dimensional molecular structure and dynamics under IUCrJ, E. Luchinat and L. Banci  and in human cells. In the latter case, Luchinat and Banci discuss various protein delivery methods that allow proteins or other biomolecules to be incorporated into cells as well as intracellular protein expression approaches. With these developments, solution-state NMR has become a powerful tool for studying three-dimensional molecular structure and the effect of molecular crowding at the atomic level. In addition, their review highlights elegant studies probing post-translational modifications and (mis)folding of proteins in living cells.In their review in this issue of et al., 2015et al., 2015et al., 2014et al., 2015et al.  native conditions. Again, promising applications have been seen in recent years. Next to the work discussed by Luchinat and Banci, such studies have targeted large protein complexes embedded in bacterial cell envelopes (Kaplan in vitro and in vivo NMR can be of great value in dissecting molecular structure and interactions in the native state. For example, successful demonstrations included the use of cell lysates (Frederick et al., 2015et al., 2015in vivo extracts (Qiang et al., 2017Finally, hybrid approaches that bridge the gap between"}
+{"text": "Recen in vivo . Further in vivo  has, howTanda and his colleagues further assessed specificity of the blocking effects ofthe TLR4 antagonists on self-administration of remifentanil or cocaine . ConsistThe more recent results by Tanda et al.  indicate"}
+{"text": "Sorop Figure 1). However, not all patients have all comorbidities and the unpredictable interplay between different comorbidities is likely to result in multiple HFpEF phenotypes. Indeed, unbiased cluster analysis of densely phenotyped HFpEF patients suggests the presence of distinct \u2018phenogroups\u2019 with different clinical characteristics and outcomes.A substantial proportion of patients with heart failure have a left ventricular (LV) ejection fraction (EF) in the \u2018normal\u2019 range, a form of the syndrome that is termed heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have significant morbidity and mortality but unlike heart failure with reduced EF, there are currently no effective validated therapies. HFpEF is therefore an important area for further research. Patients with HFpEF have cardiac and extra-cardiac manifestations, including LV diastolic dysfunction, abnormal heart rate and rhythm, microvascular dysfunction, increased aortic stiffness, and abnormal ventriculo-vascular coupling, which impair systolic and diastolic reserve capacity upon exercise.Clinical studies to investigate the pathomechanisms involved in HFpEF have typically involved small numbers of highly selected patients subjected to invasive physiological assessment and cardiac biopsy-based analyses. A recent extensively-promoted model based on such studies posits that comorbidities induce systemic inflammation and vascular endothelial dysfunction as a consequence of an abnormal balance between reactive oxygen species (ROS) production and nitric oxide (NO) bioavailability.et al.Experimental animal models that allow deeper analysis of the pathogenesis of HFpEF would clearly be valuable. Rodent models that have been employed include the DOCA-salt model of hypertension and models of obesity and/or diabetes.et al.,,et al.et al.\u2019s findings that cardiomyocyte size and body weight were both reduced in their model rather than being increased as might be expected. With regard to inflammation, the authors measured systemic TNF\u03b1 levels but it would have been informative to also quantify myocardial cytokines and inflammatory cell infiltration.Sorop et al.et al.Figure 1).A more general critique of the model reported by Sorop The work was supported by the British Heart Foundation (BHF CH/1999001/11735) and the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy\u2019s & St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London and King\u2019s College Hospital NHS Foundation Trust.Conflict of interest: none declared."}
+{"text": "Hair cells in the inner ear convert mechanical stimuli provided by sound waves and head movements into electrical signal. Several mechanically evoked ionic currents with different properties have been recorded in hair cells. The search for the proteins that form the underlying ion channels is still in progress. The mechanoelectrical transduction (MET) channel near the tips of stereociliary in hair cells, which is responsible for sensory transduction, has been studied most extensively. Several components of the sensory mechanotransduction machinery in stereocilia have been identified, including the multi-transmembrane proteins tetraspan membrane protein in hair cell stereocilia (TMHS)/LHFPL5, transmembrane inner ear (TMIE) and transmembrane channel-like proteins 1 and 2 (TMC1/2). However, there remains considerable uncertainty regarding the molecules that form the channel pore. In addition to the sensory MET channel, hair cells express the mechanically gated ion channel PIEZO2, which is localized near the base of stereocilia and not essential for sensory transduction. The function of PIEZO2 in hair cells is not entirely clear but it might have a role in damage sensing and repair processes. Additional stretch-activated channels of unknown molecular identity and function have been found to localize at the basolateral membrane of hair cells. Here, we review current knowledge regarding the different mechanically gated ion channels in hair cells and discuss open questions concerning their molecular composition and function. Hair cells of the inner ear are specialized mechanosensory cells, which convert mechanical stimuli provided by sound waves (cochlea) or head movement (vestibular system) into electrical signals. Hair cells are highly polarized cells with extraordinary morphological specialization for sensing mechanical stimuli. The most prominent morphological specialization of a hair cell is the hair bundle. It protrudes from the apical surface of a hair cell and is formed by an array of F-actin based stereocilia that are arranged in a staircase of decreasing heights Figure . The senBesides the sensory MET channels at tip links, a second mechanically activated channel was recently identified in hair cells that is located at their apical cell surface where stereocilia emanate from the cell body Figures . This MEHair cells in the mammalian cochlea come in two flavors, outer hair cells (OHCs) and inner hair cells (IHCs). OHCs have an important function in amplifying input sound signals while IHCs transmit sound information to the CNS  and low in Ca2+ (0.03 mM; Bosher and Warren, +. However, Ca2+ profoundly affects channel function where channel activity is increased when the external Ca2+ is decreased from a mM to a \u03bcM concentration (Corey and Hudspeth, The MET channel is non-selective for cations (Corey and Hudspeth, 2+ selectivity and single-channel conductance also show tonotopic characteristics in OHCs but not in IHCs. In 20 \u03bcM external Ca2+, single-channel conductance varies from 145 to 210 pS for OHCs along the tonotopic axis but is about 260 pS for IHCs along the entire length of the cochlea (Beurg et al., The organ of Corti in mammals has the ability to separate sound frequencies along its length\u2014high-frequency tones at the proximal end and low-frequency at the distal end of the organ. The Ca2+ either to the MET channel itself or to a binding side near the channel. Slow adaptation is thought to be regulated by a myosin motor complex at the upper insertion site of tip links (Crawford et al., 2+ (Peng et al., 2+ entry and voltage, while channel open probability is modulated by divalent ions interacting with the local lipid environment (Peng et al., 2+ influx (Corns et al., 2+ selectivity (Effertz et al., Sensory MET channels in hair cells adapt to mechanical stimuli, which leads to a decrease in current during a constant stimulus but additional stimulation again increases current. Adaptation is thought to set the resting tension of the transduction channel to position the channel near the most sensitive point of activation, and is important for providing amplification for mechanical signals (reviewed in LeMasurier and Gillespie, 2+, and sensitivity to channel blockers are similar but not identical between the two channels (Beurg et al., 2+ and ~90 pS at 0.07 mM Ca2+ (Beurg et al., During the early development of hair cells, their hair bundles are less directionally sensitive. Transducer currents can be observed by deflection of the hair bundle both towards the shortest and longest stereocilia (Waguespack et al., + and Na+ (Iwasa et al., \u2212, which is thought to regulate prestin function (Oliver et al., Several studies identified stretch activated MET currents in the basolateral membrane of hair cells, but the properties of these currents differed between reports. At least three different currents that are affected by mechanical force have been reported in OHCs. One type of current was activated by stretch and a single-channel conductance of 38\u201350 pS was determined for the underlying channel. This ion channel was non-selective to cations and had a reversal potential ~ \u221212 mV (Ding et al., 2+ imaging, it was demonstrated that the sensory MET channel is localized near the lower end of tip links (Beurg et al., The search for the molecular constituents of the MET channel in stereocilia has been in progress for decades. Using high speed CaTmc1 and Tmc2 are members of a gene family consisting in mammals of eight genes (Keresztes et al., Tmc1 and Tmc4 are the main family members that are expressed in adult cochlear hair cells, while Tmc2 is only transiently expressed in the cochlea during early postnatal development but can be detected in vestibular hair cells into adulthood (Kawashima et al., Tmc3 belongs to the same gene subfamily as Tmc1 and Tmc2, it does not appear to be essential for MET by hair cells (Beurg et al., Tmc1/2 deficient hair cells (Kawashima et al., 2+ selectivity and adaptation time constant in developing hair cells lacking either TMC1 alone or TMC2 alone differ (Kim and Fettiplace, 2+ selectivity of IHCs and OHCs lacking TMC2 but not TMC1 is significantly reduced (Kim and Fettiplace, Tmc1 has been reported to reduce Ca2+ permeability and single-channel conductance in IHCs (Pan et al., 2+ selectivity of the MET channel can be explained by variations in the stoichiometry of TMC1/2 (Pan et al., Tmc1 reduces single-channel conductance (Beurg et al., Tmc1 and Tmc2 can be caused by modulating the concentration of PIP2 in hair bundles (Effertz et al., tmc ortholog in the worm has been reported to relate to sodium-sensitive channel for salt sensation (Chatzigeorgiou et al., C. elegans (Zhang et al., Drosophila, TMC was found to play a function in providing sensory feedback for laval locomotion (Guo et al., Drosophila TMC (Zhang et al., However, whether TMC1 and TMC2 form the channel pore is still under debate. It was proposed that the tonotopic gradient in the conductance and CaTmhs/Lhfpl5 mutations cause deafness and lead to a dramatic reduction in mechanotransduction currents in cochlear hair cells of mice (Xiong et al., Tmhs/Lhfpl5-deficient hair cells. Single channel recordings demonstrated that in the absence of TMHS/LHFPL5 the conductance of the MET channel is affected as well as its activation and adaptation kinetics (Table TMHS/LHFPL5 is a second protein that has been implicated to be an integral component of the mechanotransduction channel in hair cells. TMHS/LHFPL5 is a member of a small subfamily within the large superfamily of proteins with four transmembrane domains (Petit et al., cs Table . The toncs Table . Taken tcs Table . Since scs Table . HoweverTmie-deficient cochlear hair cells, no MET currents can be detected, even though tip links remain intact and all known components of the MET machinery including TMC1/2 can travel into stereocilia (Zhao et al., TMIE is a protein with two transmembrane domains and linked to deafness in both human and mice (Mitchem et al., 2+ concentration (Wu et al., The similarities in single-channel conductance and pharmacological properties of the normal and reverse-polarity current in hair cells initially suggest that these two mechanically gated currents are carried by the same channel pore (Kim et al., \u2212 influx through a stretch-sensitive channel in the basolateral membrane of OHCs was reported to allosteric modulate prestin, thus potentially functioning in OHC amplification (Oliver et al., Piezo2-deficient hair cells demonstrated that PIEZO2 is not essential for electromotility (Wu et al., We still know next to nothing about the molecular composition of ion channels that carry the stretch activated currents in the basolateral membrane of OHCs (Ding et al., Recent studies have provided compelling evidence that hair cells express several molecularly distinct ion channels with different function. The best studied of these is the sensory MET channel at tips of stereocilia. Substantial evidence suggests that TMC1/2, TMHS and TMIE are integral components of the sensory MET channel Figure  but whicXQ and UM wrote the manuscript. Figures were designed by XQ.UM is a co-founder of Decibel Therapeutics. The other author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Drosophila melanogaster have uncovered that DANs in the fly brain are also spontaneously active, and that this activity reflects the behavioral/internal states of the animal. Strikingly, genetic manipulation of basal DAN activity resulted in behavioral alterations in the fly, providing critical evidence that links spontaneous DAN activity to behavioral states. Furthermore, circuit-level analyses have started to reveal cellular and molecular mechanisms that mediate or regulate spontaneous DAN activity. Through reviewing recent findings in different animals with the major focus on flies, we will discuss potential roles of this physiological phenomenon in directing animal behaviors.Dopamine modulates a variety of animal behaviors that range from sleep and learning to courtship and aggression. Besides its well-known phasic firing to natural reward, a substantial number of dopamine neurons (DANs) are known to exhibit ongoing intrinsic activity in the absence of an external stimulus. While accumulating evidence points at functional implications for these intrinsic \u201cspontaneous activities\u201d of DANs in cognitive processes, a causal link to behavior and its underlying mechanisms has yet to be elucidated. Recent physiological studies in the model organism  Animals need to modify behaviors according not only to the external world but also to their internal states, such as sleep need, hunger, or sexual motivation  was observed when animals are in REM sleep  has a central role in the regulation of the sleep-wake balance. A single pair of DANs projecting to the dFB promotes wakefulness, and dopamine receptors are necessary in the dFB neurons to process the waking signal  strongly correlates with the behavioral activity of rats    without external stimuli. In flies, repetitive training of paired presentations of odor cues and electric shocks with intervals (spaced training) is commonly used for the induction of aversive LTM , a gustatory center in the insect brain, is reported to control taste sensitivity to sucrose  cluster encode protein hunger : D1- to D5-type receptors (D1R\u2013D5R). It is commonly accepted that D1R and D5R mainly recruit the G\u03b1Drosophila, four dopamine receptors, DopR1 , Dop2R, DopR2  and DopEcR exist in the genome (Adams et al., Xenopus oocyte suggested it to be excitatory (Reale et al., in vitro but with different cell lines, and never been directly compared. It is thus important to measure the threshold of these receptors for correct interpretation of functional results.In Nonetheless, accumulating behavioral and physiological evidence suggests the critical role of DopR2 in the detection of spontaneous activity of DANs. DopR2 was shown to be critical in regulation of sleep in the dFB (Pimentel et al., in-vivo electrophysiology experiments demonstrated that DopR2 in the dFB neurons mediates the wake-promoting dopamine signaling (Pimentel et al., o and thereby hyperpolarizes the membrane potential through modulating specific K+ channels (Pimentel et al., in vitro (Han et al., Exquisite DopR2 in the MB is also responsible for detecting the spontaneous activity of MV1 or MP1 DANs during memory maintenance (Berry et al., Drosophila addressed intracellular signaling molecules that mediate the effect of spontaneous DAN activity (Cervantes-Sandoval et al., o family (Thambi et al., Xenopus oocyte system (Reale et al., Two of the recent studies in Drosophila studies. Importantly, different internal animal states, e.g., hunger, sleep need, or sexual drive, are represented by different yet partially overlapping DAN cell types. This combinatorial state coding is reminiscent of various reinforcement signals conveyed by different combinations of DANs (Aso et al., In this article, we have reviewed diverse functions of spontaneous activity of DANs, paying special attention to recent In some cases, spontaneous DAN activity functions as an information filter to enable animals to respond differently to the same sensory input, such as food, food-associated cues or potential mating partners, depending on the physiological state (Inagaki et al., TI, HT, and NY wrote the manuscript and designed the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Musculoskeletal pain due to ischemia is present in a variety of clinical conditions including peripheral vascular disease (PVD), sickle cell disease (SCD), complex regional pain syndrome (CRPS), and even fibromyalgia (FM). The clinical features associated with deep tissue ischemia are unique because although the subjective description of pain is common to other forms of myalgia, patients with ischemic muscle pain often respond poorly to conventional analgesic therapies. Moreover, these patients also display increased cardiovascular responses to muscle contraction, which often leads to exercise intolerance or exacerbation of underlying cardiovascular conditions. This suggests that the mechanisms of myalgia development and the role of altered cardiovascular function under conditions of ischemia may be distinct compared to other injuries/diseases of the muscles. It is widely accepted that group III and IV muscle afferents play an important role in the development of pain due to ischemia. These same muscle afferents also form the sensory component of the exercise pressor reflex (EPR), which is the increase in heart rate and blood pressure (BP) experienced after muscle contraction. Studies suggest that afferent sensitization after ischemia depends on interactions between purinergic (P2X and P2Y) receptors, transient receptor potential (TRP) channels, and acid sensing ion channels (ASICs) in individual populations of peripheral sensory neurons. Specific alterations in primary afferent function through these receptor mechanisms correlate with increased pain related behaviors and altered EPRs. Recent evidence suggests that factors within the muscles during ischemic conditions including upregulation of growth factors and cytokines, and microvascular changes may be linked to the overexpression of these different receptor molecules in the dorsal root ganglia (DRG) that in turn modulate pain and sympathetic reflexes. In this review article, we will discuss the peripheral mechanisms involved in the development of ischemic myalgia and the role that primary sensory neurons play in EPR modulation. Pain is a common clinical complaint resulting in a significant financial burden to both patients and society. In the U.S. alone, studies have estimated the mean cost of pain per patient at about $9K in adults and $12K in adolescents. The annual cost to society is over $635 billion  injury that is characterized by the generation of free radicals Debold,  and reacex vivo , a well-studied cardiovascular reflex arc that causes an increase in heart rate and blood pressure (BP) during exercise  and unmyelinated (C) neurons, whose cell bodies rest in the dorsal root ganglia (DRG), consist primarily of a long axon that gives rise to free nerve endings in the muscle tissue Stacey, . Some stInitially, group III and IV muscle afferents were studied to determine their roles in the generation of the EPR  were chemosensitive. In line with the work of Light et al. , as well as polymodal nociceptors have been extensively characterized electrophysiologically both t et al. , two dist et al. .The two previously mentioned sub-populations of metaboreceptors (\u201clow metabolite\u201d responders) and metabo-nociceptors (\u201chigh metabolite\u201d responders) along with their response properties are extensively altered following ischemic injury. Transient or prolonged ischemic insult to the muscles decreased mechanical thresholds and increased firing to mechanical stimulation in group III and IV muscle afferents (Ross et al., The increased mechanical sensitivity in primary afferents as well as the enhanced response to \u201clow metabolites\u201d, combined with the greater number of afferents responding to both noxious and non-noxious metabolite stimuli, correlate with increased behavioral responses after ischemic injury. In rats, models that cause ischemia-reperfusion via a hind limb tourniquet induced mechanical hyperalgesia and allodynia in the treated animals, accompanied by cold hyperalgesia (Coderre et al., After ischemic injury to the periphery, a diversity of channels and membrane receptors are upregulated in the DRGs Figure . Many ofin vitro from these animals showed increased responses to capsaicin, a TRPV1 agonist, compared to neurons from sham animals. Also in this model, there was an increase in the sympathetic response to arterial injection of capsaicin in the animals exposed to femoral artery occlusion compared to controls. In another femoral occlusion model, the pressor response evoked by intra-arterial injection of capsaicin into the injured hind limb more than doubled the response elicited by the same injection in the contralateral, uninjured limb (Tsuchimochi et al., TRPV1 has been associated with the development of ischemic pain in different models. Studies in humanized hemoglobin transgenic SCD mice have shown that TRPV1 plays a role in cutaneous afferent sensitization (Hillery et al., However, these findings are in contrast with other reports in which gene expression analysis in male mouse DRGs that innervate muscle tissue exposed to I/R or prolonged BAO injury did not show changes in TRPV1 mRNA expression 24 h after injury (Ross et al., There is ample evidence for the role of P2 receptors and how they affect afferent response to ischemia. As an example, the non-selective P2 receptor inhibitor PPADS, attenuates the EPR elicited by static contraction of the muscle (Kindig et al., ASIC and P2X receptors may also be key players in the afferent sensitization that is observed after ischemic injury (Dunn et al., The role of other P2X receptors in the development of ischemic myalgia is less clear. P2X3 is upregulated after I/R injuries and the total number of positive neurons in the DRG innervating ischemia-affected muscle tissue are also increased (Cairns et al., in vitro study showing that ATP enhances the response of ASIC3 to low pH. In this report, only the interaction between P2X5 and ASIC3 activation mimics the enhanced response to low pH and ATP that is observed in sensory neurons. Furthermore, about 25% of DRG neurons express P2X5 and of these neurons, about half co-express ASIC3 (Birdsong et al., in vivo or ex vivo is still required.P2X receptors also modulate the function of ASIC3, another key mediator of pain generation. Targeting this acid-sensing ion channel can effectively reduce muscle pain in different animal models (Sluka et al., In the specific context of ischemia, total DRG ASIC3 mRNA expression is increased in different injury models, and the total number of ASIC3 positive cells in the DRG increases (Queme et al., P2X receptors are not the only purinergic receptors that are relevant after ischemic injuries. In a prolonged ischemia model, expression of the ADP sensitive, P2Y1 receptor, was found to be upregulated in the DRGs (Ross et al., Ischemic injury alone does not likely drive all of the aforementioned changes in primary muscle afferents. Increased gene expression and concomitant afferent sensitization can also be linked to increased signaling from the damaged muscle tissue. Current evidence points at two important sources: cytokines and growth factors. These molecules are released into the intramuscular environment in response to the tissue damage caused by ischemia (Ascer et al., NGF has been frequently linked with the development of pain and hyperalgesia in various animal models and clinical conditions (Amaya et al., GDNF, another growth factor frequently tied to pain perception, is highly expressed in the muscles after ischemic injuries (Ross et al., One of the better characterized pro-nociceptive signals that is increased in injured muscles after ischemic injury is IL1\u03b2. This cytokine has been associated with pain development in multiple models ranging from muscle overuse (Noma et al., Another possible site of action for these various cytokines and growth factors is the DRG itself. Reports have highlighted the contributions of glial cells through cytokine release in models of neuropathic pain (Mika et al., Chronic pain conditions are more prevalent in women (Wijnhoven et al., in vivo behavioral results suggesting lower mechanical thresholds in females, mechanical thresholds were found to be significantly higher in females during patch clamp recordings of retrogradely labeled afferents (Hendrich et al., Recent studies have provided evidence for sex-dependent immune reactions that lead to differential brain and spinal cord sensitization mechanisms in a variety of rodent injury models (Sorge et al., In our own investigation of female muscle afferents, we have found distinct changes in gene expression within the affected DRGs following I/R. Whereas males show a robust upregulation of ASIC3 after I/R, which corresponded with alterations in behavior and afferent sensitivity (Ross et al., Interestingly, human and animal studies have shown that females also have decreased EPRs compared to males (Ettinger et al., Adequate management of the multiple complications in patients with ischemic injuries presents a variety of challenges. While patients with conditions like PVD and FM experience great benefits from an active lifestyle and physical therapy (Busch et al., SCD presents different challenges. Many patients with this condition are children and teenagers (Wilson and Nelson, Skeletal muscle ischemia is a strong driver of peripheral afferent sensitization, exerting robust effects through complex signaling cascades, resulting in the development of deep tissue pain and altered EPRs Figure . MultiplLFQ and MPJ planned the manuscript. LFQ and JLR analyzed the literature and wrote the manuscript with guidance from MPJ. All authors edited, read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting  NPC1 and NPC2 genes, resulting in functional defects in the lysosomal proteins NPC1 and NPC2, involved in cholesterol efflux from lysosomes.Niemann-Pick (NP) diseases encompass a group of autosomal recessive lysosomal storage disorders (LSD), characterized by the accumulation of diverse lipid species in lysosomes. While these diseases were initially considered a single entity with overlapping biochemical, pathological and clinical features, developing evidence demonstrated differential etiological causes phosphate, glucocerebroside, GM2 and GM3 gangliosides and sphingosine also accumulate in lysosomes  and NPC diseases are caused by defects in lysosomal homeostasis and function, there are significant differences between these diseases in relation to the degree of cholesterol trafficking to mitochondria, with the consequent impact in mitochondrial dysfunction and impairment in antioxidant defense strategies. In this review, we summarize the biochemical and genetic features of both diseases, highlighting their commonalities and differences regarding lysosomal-mitochondrial cholesterol trafficking and communication as the molecular basis to understand the differential involvement of mitochondrial dysfunction in NPC disease. Further understanding the lysosomal and mitochondrial liaisons in NP diseases may thus provide the opportunity to improve and expand the current armamentarium for the treatment of these lysosomal disorders.The clinical diagnosis of NPA and NPB diseases is mainly based on the presence or absence of neurological symptons , which is located on chromosome 11 locus 11p15.4-p15.1. More than 180 pathogenic mutations in the SMPD1 gene in patients with NPA and NPB have been identified, which are concentrated in exon two  and represent a valid model to examine lysosomal-mitochondrial communications that underlie the widespread defects in intracellular lipid transport.NPC1 is a multi transmembrane protein located in late endosomes and lysosomes  constitutes a highly dynamic membrane structure that plays a key role in the maintenance of cellular homeostasis, as well as in the digestion and recycling of cellular components and in lipid metabolism and trafficking  to the inner mitochondrial membrane (IMM), where it is converted to pregnenolone by P450scc Stocco, . MutatioThe trafficking of free cholesterol to OMM is mediated by several steps that involve various intracellular organelles, including lysosomes and lipid droplets (LD) and specific proteins, such as the translocator protein (TSPO) and voltage-dependent anion channel (VDAC) (Elustondo et al., Interestingly, 15 genes identified by sequence homology with the StAR hydrophobic lipid-binding pocket domain of approximately 210 amino acids have been described in human and mouse (Ponting and Aravind, The extramitochondrial source of the cholesterol pool that reaches mitochondria is not fully understood and could originate from LD, ER, the endosomal pathway or the plasma membrane (Rone et al., Another source of mitochondrial cholesterol is the ER. To reach mitochondria, cholesterol from the ER is transported by cytosolic proteins, such as the PAP7 protein, which interacts with TSPO and StARD proteins (Liu et al., Due to the relevance of lysosomal-mitochondrial liaisons in NPC, understanding the trafficking of lysosomal cholesterol to mitochondria may be essential for the pathophysiology of the disease. Interestingly, although astrocytes from NPC1 deficient mice exhibit decreased expression of StARD1 protein and mRNA levels (Chen et al., Mln64 mutant allele exhibited minor perturbations in the metabolism and in the intracellular distribution of cholesterol, questioning its contribution in the intramitochondrial trafficking of cholesterol (Kishida et al., critical role of this protein in steroidogenesis and hence in the trafficking of cholesterol to IMM for processing. Thus, although the understanding of the pathways of mitochondrial cholesterol trafficking and accumulation in NPC disease still remains elusive, this process is important for the progression of the disease and its further characterization may be key for the design of future therapies. Whether StARD1 in partnership with StARD3 are critical in this process remains to be fully established.Despite this evidence for a putative role of StARD3 in mitochondrial cholesterol trafficking, targeted mutation of the StARD3 StART domain has been shown to cause only modest alterations in cellular sterol metabolism and mice homozygous for the Mitochondria are double-membrane organelles that are essential for energy supply, metabolism, production of reactive oxygen species and apoptosis signaling Hatefi, . MitochoBesides Parkin and PINK1, which play a key role in mitophagy (McLelland et al., \u2212/\u2212 mice than in NPC fibroblasts (Ordonez, A considerable body of evidence suggests that impaired autophagy contributes to lysosomal lipid storage in LSDs through the accumulation of ubiquitinated proteins and dysfunctional organelles, including mitochondria (Platt et al., Ordonez, . MoreoveOrdonez, .Another factor that can contribute to impaired autophagy and defective clearance of dysfunctional mitochondria is the accumulation of sphingosine in lysosomes, which has been shown to disrupt calcium homeostasis (Lloyd-Evans et al., \u2212/\u2212 mice exhibit impaired autophagy flux determined by the combination of rapamycin with or without chloroquine, an effect that was accompanied by increased LC3BII and p62 levels. In addition, ASMase\u2212/\u2212 hepatocytes displayed impaired fusion of autophagosome-containing mitochondria with lysosomes in response to acetaminophen, which translated in increased susceptibility to acetaminophen-mediated liver injury by sustaining mitochondrial damage (Baulies et al., \u2212/\u2212 mice from acetaminophen-mediated liver injury. Moreover, human B lymphocytes from patients with NPB disease exhibit alterations in the rate of autophagic vacuole accumulation, mitochondrial fragmentation and mitophagy induction, indicating impaired clearance of damaged mitochondria (Canonico et al., In parallel with these findings in NPC, there is also evidence of autophagy defects in NPA/B diseases (Fucho et al., \u2212/\u2212 mice (Figure In contrast to defective autophagy, which is common to NPA and NPC, intracellular cholesterol trafficking and accumulation in mitochondria is a differential feature between NPA/B and NPC diseases Figure . Althouge Figure , and thie Figure . Moreovee Figure . The mece Figure . As acide Figure , it remae Figure , which ie Figure . As the e Figure .\u2212/\u2212 mice and in fibroblasts from NPC patients, leading to increased median survival and maximal life span of Npc1\u2212/\u2212 mice, protection against oxidative stress and oxidant-induced cell death and restoration of calbindin levels in cerebellar Purkinje cells, which improved locomotor impairment in Npc1\u2212/\u2212 mice. In addition, high-resolution respirometry analyses showed that GSH-EE treatment improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1\u2212/\u2212 mice (Torres et al., \u2212/\u2212 mice (Fu et al., \u2212/\u2212 mice (Mar\u00edn et al., Increased mitochondrial cholesterol content in NPC cells can lead to important functional consequences, such as decreased mitochondrial membrane fluidity (Colell et al., 2+ buffering capacity of mitochondria (Kiselyov and Muallem, 2+ homeostasis (Jennings et al., 2+ homeostasis preceded by the accumulation of sphingosine that impairs the endocytic pathway (Lloyd-Evans et al., 2+ content and function remains to be established. In addition, further work is needed to demonstrate a causal role for the disruption of Ca2+ homeostasis in the death of the Purkinje neurons in NPC disease, as shown in other related diseases (Girard et al., In addition to these events, mitochondrial cholesterol loading may impair mitochondrial dynamics reflected in the balance between fusion and fission events. Disruption of appropriate mitochondrial fluidity following cholesterol accumulation can prevent the fusion of mitochondria with adjacent healthy mitochondria (Baker et al., Although the genetic causes of NPA and NPC disease are well understood, the consequences at the level of disruption of intracelular trafficking and interorganelle communication is still incomplete, thus limiting the availability of effective therapy. Enzyme replacement therapy for ASMase and NPC1 deficiency is expected to successfully treat peripheral non-neuronal symptoms of both diseases (Schuchman and Desnick, ST, EB, SZ, CE, CG-R, and JF-C discussed findings, analyzed literature and wrote the manuscript. ST, CG-R, and JF-C designed the schematic Figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "An overview of the most relevant papers in the International Journal of Cardiovascular Imaging over the year 2016 for the different modalities. Relatively few manuscripts in the field of X-ray imaging were published in 2016. The far majorities were in MSCT, MRI and echocardiography, followed by nuclear cardiology and intravascular imaging, of which the last one is not included in this overview.Author He et al. described the use of the Myocardial Perfusion Frame Count (TMPFC) technique as an indicator to predict left ventricular systolic dysfunction in the sub-acute phase of STEMI . They coThe team of Starek et al. tested various acquisition protocols for the right atrium and the left atrium to create 3D models of the atria and esophagus using 3D rotational angiography . They usAnother topic that received attention was longitudinal stent deformation and the longer term clinical outcomes . Guler eTimmins et al. compared in a very small cohort of patients (n\u2009=\u20095) with non-obstructive coronary artery disease biplane angiographic versus intravascular ultrasound derived reconstructed coronary geometries, assessed wall shear stress and the association of wall shear stress and CAD progression after 6\u00a0months [Donmet et al. studied in a population of 81 patients the changes over time in non-culprit lesions in patients wih ST segment elevated myocardial infarction using QCA . They foIn 2016 different excellent paper in the field of nuclear cardiology were published in the journal. In this review we selected a few papers on technical advances, atherosclerosis imaging, imaging in heart failure and FDG PET/CT imaging in infective endocarditis.Perfusion SPECT imaging may be technically challenging in obese patients and data on its prognostic value in the obese are rather scarce. De Lorenzo et al.  studied High efficiency CZT cameras provide also an opportunity to lower the injected activities of radiopharmaceuticals for SPECT myocardial imaging. Kincl et al.  evaluateSeveral excellent reviews on the topics of atherosclerosis and multi-modality imaging were published in 2016. FDG-PET has shown promise in detecting metabolically active inflammatory cell infiltrates associated with vulnerable atherosclerotic plaque. In contrast to previous ex vivo studies incuatong plaque specimens with FDG after excision, Liu et al.  investigLeft ventricular dyssynchrony (LVD) is an independent predictor of adverse cardiovascular events and progression to heart failure. It can also be potentially corrected with cardiac resynchronization therapy. LVD can be diagnosed using phase analysis on myocardial perfusion imaging with ECG-gated SPECT. Tavares et al.  evaluateRecent studies have shown promising results using (18)F-FDG PET/CT for the diagnosis of prosthetic valve endocarditis (PVE) and the use of this nuclear imaging technique has been recently advocated in American and European guidelines on the management of endocarditis. However, negative controls were usually lacking in these studies. Fagman et al.  comparedIn the 2016 edition of the International Journal of Cardiovascular Imaging several interesting studies were published in the field of cardiac ultrasound. Some of them are discussed in this overview.The American and European scientific echo community have published an algorithm for the grading of diastolic function. However, the ability to use this algorithm effectively in daily clinical practice has not been investigated. Van Dalen et al. hypothesized that in some patients it may be difficult to grade diastolic dysfunction with this scheme, since there may be discrepancies in the assessed parameters . The ASE2 of 44.9% was obtained. When excluding either of LAVImin or E/e\u2032 the model fit was significantly reduced. In contrast, when LAVImax was excluded the model fit was preserved. To detect an NT-proBNP level of >125\u00a0ng/L, LAVImin yielded a significantly larger area under the receiver operating characteristic curve than LAVImax and E/e\u2032. In this community-based sample, LAVImin was more strongly associated with NT-proBNP than LAVImax. Moreover, the discriminatory power to detect an elevated NT-proBNP level was stronger in LAVImin than in LAVImax and E/e\u2032. These findings support previous data that LAVImin may be more closely related to left ventricular filling function than LAVImax.Previous data have demonstrated that left atrial (LA) minimum volume indexed for body surface area (LAVImin) is more strongly associated with the Doppler echocardiographic E/e\u2032 ratio than LA maximum volume index (LAVImax). Hedberg et al. sought to explore if LAVImin was more closely related to serum levels of NT-proBNP than LAVImax and E/e\u2032 in the community . A commuDe Groot-de Laat et al. assessed the incremental value of two-dimensional and three-dimensional transoesophageal echocardiography over two-dimensional transthoracic echocardiography in three reader groups with different expertise  in a total of twenty patients and five healthy persons . OverallParavalvular leak after transcatheter aortic valve implantation (TAVI) is challenging to quantitate. Transthoracic echocardiography is the main tool used for the assessment of paravalvular leak but is modestly reproducible. Abdelghani et al. sought to develop a reproducible echocardiographic approach to assess paravalvular leak in the post-TAVI setting . Four obDespite successful aortic coarctation (CoA) repair, systemic hypertension often recurs which may influence left ventricular function. Menting et al. aimed to detect early left ventricular dysfunction using left ventricular global longitudinal strain (GLS) in adults with repaired CoA, and to identify associations with patient and echocardiographic characteristics . In thisOxborough et al. simultaneously assessed longitudinal strain and left ventricular volume/ right ventricular area in 92 male athletes subdivided according to varying sporting demographics . AthleteSchinkel et al. wrote an interesting overview on the role of contrast-enhanced ultrasound (CEUS) in the evaluation of patients with known or suspected atherosclerosis . CEUS isThere were a number of interesting advancements in cardiovascular MRI (CMR) in 2016.Reval et al.  studied Improved border sharpness of post infarct scar was demonstrated by Rutz et al.  with a sThe prognostic value of stenosis class as measured by magnetic resonance angiography over traditional risk factors in patients with peripheral arterial disease was demonstrated by van den Bosch et al. . ImproveFaletti et al.  found th1-regularization (IS SENSE) was demonstrated [The performance of an accelerated CMR protocol using iterative SENSE reconstruction and spatio-temporal Lnstrated . In relanstrated  used thinstrated .The feasibility of heart deformation analysis for measuring regional myocardial velocity with CMR was tested in normal volunteers . CardiacMarkl et al.  performeA dose correction for post-contrast T1 mapping of the heart was proposed by Gai et al.  and applA semi-automated cardiac segmentation tool was found to improve the reproducibility and speed of right heart MRA .KnowledgIn 2016 a large number of original articles, covering a variety of topics related to CT, were submitted to the journal and underwent a rigorous review/selection process. While the submission, review, and editorial selection process has well-known biases, the articles published reflect current trends in computed tomography.Coronary artery disease is a major focus of cardiac CT. While clinical prevention guidelines suggest a limited role, coronary calcium scoring (CAC) remains a topic of ongoing research. Published papers describe the effective radiation exposure among participants from the MESA cohort , and disIn contrast to CAC, which identifies only calcified plaque, contrast-enhanced CTA can assess overall plaque burden and plaque characteristics. While it is not an indication for CTA itself, plaque burden is evaluated by experienced clinical readers in coronary CTA indicated for suspected obstructive CAD and is a topic of significant interest in research. Published papers describe a correlation between elevated HBA1c and higher frequency of obstructive CAD and vulnerable atherosclerotic coronary plaque characteristics (positive vessel remodeling and low-attenuation plaques) in patients with type 2 diabetes , 57 An oCT) has gained significant interest. One published study examined the feasibility of FFRCT in a small \u2018unselected\u2019 cohort of patients with suspected significant CAD [CTcould be measured in the majority of consecutive, patients who had suspected significant CAD by CCTA and demonstrated good diagnostic performance for detecting hemodynamically significant CAD even in patients with calcified vessels. Another important study demonstrated the impact of image resolution on geometrical reconstruction and subsequent FFR calculation with invasive and CT FFR [Based on the experience with invasive coronary angiography as well as CTA, the limitations of luminal stenosis assessment for the prediction of hemodynamic significance of CAD are well known. CT techniques to evaluate lesion functional significance are therefore a major focus of research. Among them, non-invasive fractional flow reserve measured by coronary computed tomography angiography  by micro-computed tomography (mCT) in a coronary bifurcation model . The traAn important focus of CT are indications in the context of structural heart disease intervention. For TAVR planning, one study evaluated an automatic aortic root landmarks detection method with automated determination of annulus radius, annulus orientation, and distance from annulus plane to right and left coronary ostia . Other sExciting progress is described in analysis of CT data. Published studies examined quantitative semi-automated methods for assessment of coronary luminal stenosis severity  and fullThe above selection of published articles about cardiovascular CT reflects current clinical use and research interests. Use of CT, like any other diagnostic test, has to balance anticipated benefit against potential risk, specifically for CT radiation exposure and contrast administration. This risk assessment takes into account the susceptibility of specific patient populations , 79. The"}
+{"text": "Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies.Loss of function mutations in the  RSK2 knock-out mice (RSK2\u2212) and mutants of the single RSK ortholog in Drosophila (D-RSK) were analyzed at the behavioral and neurophysiological level. We summarize findings with both animal models and their implications to better understand the neuropathophysiology of CLS.Coffin-Lowry syndrome  is a rare X-chromosome linked disorder with an incidence of 1:50,000\u2013100,000. Clinical characteristics are heterogeneous and variable in expressivity. They include facial dysmorphism, digit and skeletal abnormalities, and growth delay. Prominently, CLS patients suffer from severe mental disabilities (IQ: 15\u201360). Less frequently, stimulus-induced drop attacks, epileptic seizures and hearing loss are manifested. The risk to develop psychiatric diseases like depression and psychosis might be increased. No treatment exists for this disease  family. With the exception of a 140 amino acid N-terminal extension, D-RSK shows equal sequence similarities of about 70% to RSK1\u20134. Notably, all sequence motifs required for RSK activation are also present in D-RSK  belongs to the AGC kinase family and the C-terminal kinase domain (CTKD) is related to the CaK Figure . From biK Figure . HoweverDrosophila eye development, D-RSK acts as a cytoplasmic anchor for ERK, thereby inhibiting ERK nuclear translocation and phosphorylation of nuclear targets  carried a mutation in RSK2 and later on developed clearer characteristics of CLS, which generally resemble those of RASopathies  induces features of depression, expressed as general inactivity. Furthermore, activity recordings allow correlating disease associated genes with circadian and sleep disturbances as one characteristic of some mental illnesses.The similarities of molecular pathways controlling the generation and differentiation of neurons, neural circuit wiring and synaptic communication make animal models a powerful tool to characterize cellular and physiological processes and link them to human disorders. A more challenging task is to model mental disabilities or mental health disorders in animal systems because of the complexity of symptoms, the influence of genetic variation on disease outcome and species-specific characteristics at the molecular, neural circuit and behavioral level  and the habenula, playing a role in motivational and rewarding aspects of behavior  from CLS patients uncovered a reduction in total brain volume with a particular impact on temporal lobe, cerebellar and hippocampal volumes  but more pre-existing neurons (Castillon et al., RSK2\u2212 mice in a context-dependent manner.Do the behavioral phenotypes seen in mice and RSK2\u2212 mice (Mehmood et al., RSK2\u2212 animals showed a growth and developmental delay (Ammar et al., in vivo (Fischer et al., RSK2\u2212 behavioral deficits.Loss of RSK2 interferes at several levels with neuronal properties (Figure de novo synthesis, trafficking, variations in heterotetrameric subunit composition, posttranslational modifications and interaction with scaffold proteins at postsynaptic densities (Huganir and Nicoll, RSK2\u2212 mice, upregulated levels of the GluA2 subunit of AMPA-receptors at synaptic sites were observed (Mehmood et al., RSK2\u2212 mice or from hippocampal slices demonstrated decreased synaptic transmission, altered AMPA and NMDA receptor properties, but normal paired-pulse facilitation and long-term potentiation. Altogether, these findings argued for a postsynaptic function of RSK2 in neurotransmission (Morice et al., Accumulating data support the view that RSK2 influences ionotropic glutamatergic synapses. A focus of RSK2 research is the AMPA-subfamily of glutamate receptors because of their fundamental role in synaptic plasticity as a crucial step for learning and memory formation. The number of AMPA-receptors and their channel properties are influenced by RSK2\u2212 mice. Thus, RSK2 seems to mediate at least some of its effects by modulation of scaffold proteins of the postsynaptic density in an activity-dependent manner.Another function of RSK2 at the postsynapse is interaction with proteins of the Shank family, which act as major scaffolds for AMPA-, NMDR- and metabotropic glutamate receptors (Sala et al., RSK2\u2212 animals are increased with an accompanying up-regulation of dopamine receptor2 expression (Pereira et al., 2A receptor, thereby linking growth factor induced MAP-kinase signaling with regulation of a G-protein coupled receptor (Sheffler et al., RSK2\u2212 brains were detected (Pereira et al., Emotional behaviors like anxiety, depression or hyperactivity are regulated by the neurotransmitters dopamine and serotonin. Dopamine levels in the mouse cortex of Drosophila, analysis has focused on the larval neuromuscular system as a well-established model for synapse formation, neurotransmission and synaptic plasticity (Harris and Littleton, D-RSK mutants, overall bouton number is increased but this phenotype is counteracted by a much stronger decrease in synapse number per bouton (Fischer et al., Drosophila D-RSK is a postsynaptic requirement for efficient synaptic transmission.In Drosophila gave first insights into the impact of RSK2 on neuronal functions. In CLS patients it is still unknown, if similar neurite growth and synaptic defects exist like in animal models. Patient derived iPSCs could be differentiated into distinct neuron subtypes and analyzed at the molecular, biochemical and physiological level. Besides analysis of molecular interactions, a particular emphasis for further studies should be the analysis of RSK2 in experience-dependent synaptic changes. A good example for future research about CLS is the fragile-X mental retardation syndrome, where parallel experiments in animal models have paved the way to bridge the gap to better understand the human disease phenotypes. For example, metabotropic glutamate receptor and ERK-pathway dependent protein synthesis were affected, which led to clinical trials in patients with a mGluR5 antagonist, unfortunately turning out to be not effective (Berry-Kravis et al., RSK2/D-RSK phenotypes, our understanding of neuronal dysfunction is far from complete at all levels of analysis.While no information exists about the neuronal basis of the clinical phenotype in CLS patients, recent findings in mouse and MF and TR wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The earlier identification of selective inhibitors of fungal SL biosynthesis promised potent broad-spectrum anti-fungal agents, which later encouraged testing some of those agents against protozoan parasites. In this review we focus on the key enzymes of the SL de novo biosynthetic pathway in protozoan parasites of the Apicomplexa and Kinetoplastidae, outlining the divergence and interconnection between host and pathogen metabolism. The druggability of the SL biosynthesis is considered, alongside recent technology advances that will enable the dissection and analyses of this pathway in the parasitic protozoa. The future impact of these advances for the development of new therapeutics for both globally threatening and neglected infectious diseases is potentially profound.Sphingolipids (SLs) are an integral part of all eukaryotic cellular membranes. In addition, they have indispensable functions as signalling molecules controlling a myriad of cellular events. Disruption of either the  Protozoa (kingdom Protista) are single-cell organisms that can be free-living or parasitic in nature Baron, . Out of Trypanosoma brucei , Leishmania spp.  and Trypanosoma cruzi ; Sporozoa \u2013 the apicomplexan Toxoplasma gondii (toxoplasmosis), Cryptosporidium spp. (cryptosporidiosis) and Eimeria spp. (coccidiosis in poultry and cattle), Theileria spp. (East Coast Fever in cattle) and Plasmodium spp., including Plasmodium falciparum the causative agent of severe malaria and one of the \u2018Big Three\u2019 global infectious diseases alongside HIV and tuberculosis  or Neglected Zoonotic Diseases King,  and wereThis review presents sphingolipid (SL) biosynthesis and ceramide (CER) homoeostasis as a potential gold mine of tractable drug targets for these protozoan parasites.In general, available treatments for the diseases caused by the Kinetoplastidae and Apicomplexa are outdated (if not historic), with relatively few examples that were introduced recently, toxic and require a long treatment regimen, and therefore close monitoring of patients.The kinetoplastid pathogens in focus here all cause NTDs and as such there are significant problems with the available drug regimens:et al.et al.et al.et al.et al.et al.et al.et al.The treatment of leishmaniasis often requires a long course of intravenous pentavalent antimony drugs (e.g. Glucantime and Pentostam), aminosidine (paromomycin) or liposomal amphotericin B , and 660\u00a0000 (429\u00a0000 in 2015) associated deaths; although the actual numbers might be even higher , as the primary complex mammalian SL; and inositol phosphorylceramide (IPC) in fungi, plants and numerous protozoa  and ceramide-1-phosphate (C1P)  that can be protozoa . These ma et al.. Furthertrans double bond) affect their biophysical properties rendering these molecules different from their glycerolipid counterparts, i.e. SM vs phosphatidylcholine (PC)  to L\u03b1 (lamellar phase) transition near the physiological temperature of 37 \u00b0C, in contrast, this transition for naturally occurring glycerolipids is near or below 0\u00a0\u00b0C. Additionally, the long saturated alkyl chains of SLs allow them to pack tightly with sterols, stabilized by hydrogen bonding  of SPH allows it to remain partially uncharged at physiological pH retaining the ability to move across membranes  for new drug targets or regimens  via serine palmitoyltransferase (SPT), to produce dihydrosphingosine. The latter comprises first the formation of CER in the ER by the action of ceramide synthase (CerS), and then the formation of complex SLs in the Golgi. These products vary depending on the species, and are formed under the catalysis of what could be generically termed SL synthases: SM synthase in mammals and IPC synthase in fungi, plants and protozoa. It is worth mentioning that another Golgi localized metabolic pathway results in the formation of glycosylated CER species, and also contributes to the regulation CER levels  . However, clear divergence is observed in the second and the third steps, both of which represent a cell-fate modulator process. CerSs exhibit differential preferences for the chain length of the acyl-CoA substrate  around the PLP-binding lysine (in bold) -dependent . Subsequent minor metabolic differences are encountered across different species; mainly concerning the order of the hydroxylation (in fungi and higher plants) and acylation to produce CERs  has previously indicated the presence of CerS activity in transfer protein CERT in mammals  to produce IPC via IPC synthase  with respect to the animal SM synthases  and SLs ([phyto]ceramide and IPC/SM/EPC). Accordingly, these enzymes act as regulators of a delicate balance between pro-apoptotic CER and pro-mitogenic DAG , a depsipeptide, was first reported by Ikai et al.  and soon. et al.. The tarLeishmania major and T. gondii are not susceptible to AbA inhibition  compared with the single copy found, for example, in L. major and T. gondii , chain length variation, the hydrophobic nature of the involved enzymes and the presence of multiple pathways that can operate in parallel  subcellular localisation, (b) regulation (c) chain length specificity, (d) kinetics of trafficking and (e) mechanism of action. For example, phosphorylation of 1\u20133% cytosolic SPH may double the levels of S1P that acts on G protein-coupled receptor (GPCR) to elicit a specific response in a particular cellular locality for certain period of time , in the pursuit of identifying new compound scaffolds active against the Leishmania spp IPC synthase utilising yeast  and function makes SL biosynthesis highly alluring for drug intervention, after all, everybody needs SLs, right?"}
+{"text": "Atrial fibrillation (AF) is maintained by reentrant excitation forming stable or meandering rotors, leading circle reentry, or multiple circulating wavelets  repolarization in antiarrhythmic drug therapy. AF circuits were found to be less stable and more likely to self-terminate when APDINa blockade using Class I drugs has been extensively tested in clinical, experimental, and in silico studies. While these drugs are effective in treating paroxysmal AF, their efficacy may be related to suppression of triggered activity via non-canonical effects on RYR2 rather than INa (Salvage et al., INaK blockade impacts nodal cell firing via regulation of the so-called calcium clock (Sirenko et al., INaK blockade than a whole-heart virtual model that incorporates neural feedback and the conduction system, simulates the ventricular response rate to AF, and tests the potential risk of proarrhythmia by digitalis toxicity. Finally, the importance of IK1 in fibrillatory dynamics is well-established. Noujaim and colleagues (Noujaim et al., via its inhibitory effects on IK1. However, this strategy must be approached with caution since IK1 density is greater in ventricular compared to atrial myocardium. A notable concern is the potential for unmasking ventricular ectopy (Miake et al., This line of inquiry has clear implications for ion channel pharmacotherapy, an area of major challenge considering the suboptimal efficacy of many ion channel drugs against AF as well as their risk of inducing ventricular pro-arrhythmia. The focus on the aforementioned targets in an atria-only model is interesting from a theoretical perspective but less so from a pragmatic one. For example, in silico studies are always constrained by strong experimental and clinical measurements to guarantee their relevance for human AF.Nonetheless, the present work by Sanchez et al.  establisFA and CC drafted, revised, and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neurodegenerative diseases affect millions of individuals in North America and cost the health-care industry billions of dollars for treatment. Current treatment options for degenerative diseases focus on physical rehabilitation or drug therapies, which temporarily mask the effects of cell damage, but quickly lose their efficacy. Cell therapies for the central nervous system remain an untapped market due to the complexity involved in growing neural tissues, controlling their differentiation, and protecting them from the hostile environment they meet upon implantation. Designing tissue constructs for the discovery of better drug treatments are also limited due to the resolution needed for an accurate cellular representation of the brain, in addition to being expensive and difficult to translate to biocompatible materials. 3-D printing offers a streamlined solution for engineering brain tissue for drug discovery or, in the future, for implantation. New microfluidic and bioplotting devices offer increased resolution, little impact on cell viability and have been tested with several bioink materials including fibrin, collagen, hyaluronic acid, poly(caprolactone), and poly(ethylene glycol). This review details current efforts at bioprinting neural tissue and highlights promising avenues for future work. Neurodegenerative diseases affect over 55 million individuals annually in North America, creating a multi-billion dollar burden on the health-care industry due to the costs associated with treatment, and rehabilitation therapy , which are pluripotent stem cells derived from a human embryo; mesenchymal stem cells (MSCs), which are multipotent stromal cells that can differentiate into osteoblasts, chondrocytes, myocytes, and adipocytes; neural stem/progenitor stem cells, which are multipotent and can differentiate into neurons, astrocytes, and oligodendrocytes; and human induced pluripotent stem cells (hiPSCs), which are adult cells taken back to a pluripotent state   methacrylamide, and poly(a-hydroxy-acids)  from hESCs and hiPSCs, but they impose unnatural geometric constraints on the cells  uses a melted thermoplastic which is deposited layer-by-layer onto a flat substrate to build a 3-D construct  (Tan et al., Selective laser sintering uses a similar process as FDM, but SLS has a higher resolution (O\u2019Brien et al., Stereolithography is the highest resolution option for bioprinting (O\u2019Brien et al., Inkjet bioprinting uses a modified inkjet printer to deposit cells encapsulated in a bioink onto a chosen substrate (O\u2019Brien et al., Bioplotting using syringes to print tubes or spheroids layered on top of each other (O\u2019Brien et al., Microfluidic extrusion represents an extension of bioplotting (Pfister et al., Several groups have bioprinted neural tissue using various cell types with varying levels of success Table . In 2006In 2014, Lorber et al. inkjet printed retinal glial cells and disassociated retinal cells, resulting in 57% cell death in glial cells and 33% cell death in retinal cells compared with controls of unprinted cells grown on tissue culture plates (Lorber et al., Suri et al.  photopatCurley et al.  also useLee et al.  combinedGu et al.  extrudedin vivo study implanted 3-D printed constructs into cerebellum-lesioned zebrafish. Treated fish showed increased spontaneous coiling contraction and increased hatching rate compared with lesioned untreated fish, indicating cellular restoration.Similarly, Lozano et al.  extrudedLee et al.  used micThese studies differ greatly in the number of cells lost due to the stress of the printing process. Cell viability allows the user to seed at the correct cell density. However, some studies do not report cell death while others report up to 57% cell death during the printing (Lorber et al., Current work indicates that a wide variety of bioink materials may be suitable for 3-D printing neural tissue. However, more research needs to be done comparing the printability of each of these materials in terms of efficiency and ease-of-use, both which become important when scaling up production. This review has covered multiple methods of 3-D printing neural constructs. Inkjet bioprinting is the most well documented but is limited in both bioink material and geometries. Microfluidic extrusion has recently seen success in printing complex shapes with various neural cell types and remains an option of interest that needs further research in creating ideal bioink compositions. Other possibilities, such as stereolithography and SLS, remain underused for neural tissue applications.What remains to be done is finding a cohesive unit of bioink and bioprinting method which results in a high cell viability post-printing and is adaptable enough to print multiple different neural cell types with a bioink which has controllable elastic properties and porosity and can be loaded with factors to further control differentiation.In addition, most studies lack a hands-off manner of controlling bioprinting. Incorporating CAD and microtechnology into printing projects would help fully realize the high-throughput nature of 3-D bioprinting tissue, as the field is still largely limited by human-controlled systems. The use of CAD would further assist in increasing cell resolution within printed constructs. Advancing the resolution of bioprinting could also allow the printing of vascular networks within a designed tissue, something which would allow neural models to be scaled-up beyond a maximum achieved size of mm. This development would allow more physiologically relevant constructs to be printed for disease modeling and drug discovery.Bioprinting can change how neural tissue are engineered, moving it from a time consuming, hands-on process that can vary from lab-to-lab to a sterile, high-throughput process that can rapidly produce physiologically accurate brain constructs for applications in cell therapy and drug screening. The low throughout methods for engineering brain tissue limit their applicability for drug screening. Cell therapy has had limited success for the same reason: the number of cells required for injection requires lengthy culture time in addition to the difficulty controlling cell diffusion and differentiation. For bioprinting to succeed as the new standard for engineering neural tissue more bioinks must be done to accurately control brain region development, and the issue of vascularization must be solved to print accurate constructs suitable for long-term culture. However, such bioprinted neural tissues hold great promise for applications in both cell therapy and for drug screening.MT and SW both contributed to the authorship. SW proposed the topic and provided feedback through the writing process. MT wrote the initial draft and completed revisions based on feedback provided.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Protein kinases are major regulators of mitosis, with over 30% of the mitotic proteome phosphorylated on serines, threonines and tyrosines. The human genome encodes for 518 kinases that have a structurally conserved catalytic domain and includes about a dozen of cell division specific ones. Yet each kinase has unique structural features that allow their distinct substrate recognition and modes of regulation. These unique regulatory features determine their accurate spatio-temporal activation critical for correct progression through mitosis and are exploited for therapeutic purposes. In this review, we will discuss the principles of mitotic kinase activation and the structural determinants that underlie functional specificity. Protein phosphorylation is a key regulatory mechanism influencing various cellular processes such as cell growth, cell motility, cell differentiation and cell division. Most notably, protein phosphorylation peaks during mitosis and the timing coincides with the cell division-related chromosomal and cytoskeletal reorganization  and an \u03b1-helical C-terminal lobe  at each end  family . Though the activation loop auto-phosphorylation is sufficient for basal activity, facilitating the right conformation of the loop is required for full activation, and is achieved by the binding of TPX2 and INCENP to Aurora A and Aurora B kinases, respectively  and kinetochore-microtubule attachment Elowe, . Cdc20, CDK Activating Kinase belonging to the family of CDKs)  which is essential for their increased kinase activity  and the budding yeast Hrr25 (Casein kinase) critical for meiosis co-orientation of kinetochore do not require the activation loop phosphorylation and their kinase domains are constitutively active (Eswaran et al., Kinases achieve substrate specificity through multiple mechanisms in mitosis (Ubersax and Ferrell, in vitro and in vivo thus far has helped define kinase substrate specificity. Typically about 4-6 amino acids flanking the phospho-acceptor residue P can contribute to the selectivity of kinases for their substrate. The molecular basis for substrate recognition mainly comes from the structural work on CDK2/cyclin A bound to its substrate (Brown et al., Kinase substrate specificity is generally determined by the architecture of the substrate binding site, which might select negatively against certain residues flanking the phosphorylation site. The identification of substrates in vitro phosphorylation of kinetochore proteins by Bub1 followed by phosphorylation-directed staining and mass spectrometric analyses identified many prospective Bub1 substrates with a putative consensus motif \u03d5-X5-S/T (Breit et al., The identification of multiple budding yeast kinetochore Aurora B kinase substrates, allowed to define an Aurora consensus phosphorylation sequences (Cheeseman et al., in vivo (Dephoure et al., The use of peptide libraries against kinases has greatly contributed to the identification of optimal peptide sequence motifs and \u201canti-motifs\u201d for kinases (Hutti et al., Kinases may use docking sites or sites that are primed by another kinase to enhance their substrate selectivity. For example, to bind and to be phosphorylated by Plk1, a substrate generally needs to be primed by another kinase (Lee et al., CDK-cyclins also use docking sites to recognize and phosphorylate temporally their substrates. Certain cyclin partners have a hydrophobic docking patch that recognizes an \u201cRXL\u201d motif on substrates 40\u00c5 away from the catalytic site of the CDK active site (Schulman et al., Many mitotic kinases rely on spatial targeting to phosphorylate their specific substrates. This restricts the activity of the kinase to generate gradients of kinase activity. The most well characterized spatially-targeted kinases are Aurora A and B kinases and they appear to share the same substrate specificity (Fu et al., The molecular basis for the recruitment of Mps1 kinase to the outer kinetochore is also well established. Multiple kinases including CDK1, Aurora B, Plk1, and Mps1 itself are implicated in Mps1 kinetochore targeting (Morin et al., High resolution mechanistic understanding of kinase regulation is essential not only to define how kinases achieve error-free cell division, but also to exploit the differences in their regulatory mechanisms to specifically target them in mitosis-related human disorders. Structural studies of kinases thus far have provided key insights into the similarities and differences in the modes of activation and regulation of many mitotic kinases. Although kinases possess a broadly conserved catalytic core, their level of kinase activity and substrate specificity are determined by specific inter/intra molecular interactions and phosphorylation. In this review, we summarize how key structural regulatory elements such as the relative orientation of the C-helix, activation segment conformation and spatial regulatory elements responsible for correct kinase sub-cellular localization achieve accurate kinase function. However, there are still many open questions, particularly on factors determining the graded level of kinase activation and its implications on their mitotic role. More structural analyses of kinases in complex with their regulatory binding partners with and without bound substrates, and their functional implications in cells will undoubtedly further advance our mechanistic understanding of this essential class of mitotic regulators.JW and AJ have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A small proportion of patients with Parkinson\u2019s disease (PD), chronically under dopamine replacement therapy, may undergo an addiction-like behavioral disturbance, named dopamine dysregulation syndrome (DDS). This behavioral disorder is characterized by the increase of doses beyond those required for motor control, and its management remains difficult; thus, early recognition and careful monitoring of at-risk individuals are crucial. We report the cases of two PD patients with a previous unsatisfactory switching from an immediate release (IR) to an extended release (ER) pramipexole formulation who developed DDS. PD patients unsatisfactorily switched from an IR to an ER formulation of dopamine agonists should be considered as at-risk individuals for DDS development."}
+{"text": "The increasing use of nipple-sparing mastectomy (NSM) and skin-sparing mastectomy (SSM) in the treatment of nonmetastatic breast cancer is justified by considerations linked to their therapeutic index. In selected patients, efficacy results tend to be similar to those observed after radical modified mastectomy and at the same time, subcutaneous mastectomies preserve the patient\u2019s body image. Yet the oncologic safety of the two former surgical approaches is still a matter of debate, also in consideration of the almost complete absence of clinical studies directed to prospective, controlled comparisons between subcutaneous and radical modified mastectomies. In addition, no clear statement\u2014and consequently no consensus\u2014emerges from the rather rare reports addressing the issue of whether or not there exist robust algorithms for guiding decision-making in delivering postoperative radiotherapy after NSM or SSM. The objective of the present review article is to revisit the dataset recently provided by the literature, which might help oncology teams optimise local treatment in this patient population. Throughout the past two decades, both nipple-sparing mastectomy (NSM) and skin-sparing mastectomy (SSM) have been gaining ground in the surgical management of nonmetastatic breast cancer patients. The main reason for this trend relates to the therapeutic index elicited for NSM and SSM, which was shown to compare favourably with that observed for modified radical mastectomy (MRM). Indeed, the literature suggests that treatment outcomes of NSM, SSM and MRM tend to be similar as regards efficacy endpoints, and at the same time, patients draw a number of advantages from the two former surgical modalities, especially in terms of organ and body image preservation , 2\u20139.Whether to deliver postoperative radiotherapy (PORT) after NSM or SSM or not is nowadays an issue essentially addressed by multi-disciplinary tumour boards involving not only surgeons and radio-oncologists but also diagnosticians, pathologists and medical oncologists. Often, such a decision-making process turns out to be a challenging task, for no straightforward, prospective comparison between subcutaneous radical mastectomies and MRMs has emerged so far from reports analysing the exact relevance of PORT after NSM and SSM , 11.The objective of this review article is to revisit the messages recently provided by the literature which might help oncology teams optimise local treatment in this patient population.http://www.ncbi.nlm.nih.gov/pubmed).We used search strings on studies addressing the issue of interaction between NSM and SSM and adjuvant radiotherapy, via the following search terms: breast cancer, SSM, NSM, MRM, PORT, treatment outcome and late complications. This review article is essentially based on full articles published since 2000 and retrieved from the PubMed search engine  by tumour microfoci was demonstrated by Cense et al  in nearlet al . Neverthet al .et al [The persistence of mammary tissue after SSM or NSM obviously increases the risk of local failure if tumour cells are present in this residual tissue \u201319. In tet al , the locAfter SSM, the most significant risk factors for local recurrence identified in two studies are nodal involvement, tumour size, poorly differentiated carcinomas, and lympho-vascular invasion (LVI) , 21. In In 2007, Meretoja published a report on a cohort of 207 consecutive women who underwent, from 1992 to 2001, SSM and immediate breast reconstruction immediate breast reconstruction (IBR) without any adjuvant radiotherapy [et al [It has been repeatedly substantiated that PORT delivered to reconstructed breast carries a higher risk of complications compared to that of no PORT \u201326. Befoet al  showed tet al .et al [P = 0.03), nipple loss , and rates of reconstruction failure . On multivariate regression analysis, PORT , age >55 years , breast volume \u2265800 cm3 , smoking , and peri-areolar incision  were independent risk factors for complications. The authors concluded that despite higher complication rates after PORT, reconstruction failure and nipple/areola necrosis remained infrequent. Moreover, capsule formation can readily be treated with capsulotomy or capsulectomy [In a recent report published in 2015, Tang et al  analysedet al . Compareulectomy .et al [et al [et al [et al [et al [Out of 17 studies analysed by Janssen et al  in 2015,l [et al  and Burdl [et al  deliverel [et al  deliverel [et al , PORT wal [et al . The uneet al [n = 800) and those receiving delayed PORT (n = 201), on 5 days per week [At the European Institute of Oncology in Milan, Petit et al  performeper week , 32, 34.et al [Finally, an international survey, conducted by Marta et al , collect p < 0.001 for each of them).Answers to the questionnaire resulted in the identification of nine risk factors, practitioners include into the decision to deliver PORT or not after NSM/SSM and IBR. These factors were: 1) nodal involvement; 2) LVI; 3) grade III carcinomas; 4) triple negative histo-type; 5) young age; 6) positive surgical margins; 7) tumour size; 8) extracapsular extension (ECE) and 9) multi-centric presentation. As expected, radio-oncologists and surgeons did not fully agree on the magnitude of the risk level affecting each of these factors. For instance, the answers from the two professional disciplines most significantly diverged for the first five factors reported here above  than mastectomy patients.In a recent analysis of the current role of PORT after NSM, a total of 112,817 patients were isolated from the SEER database . Over thet al [Up until recently, the European Institute of Oncology in Milan recommended the use of intraoperative RT to the NAC in this latter patient population . In patiet al  indeed sRetrospective studies on NAC indicate that 10% to 30% of cases receive PORT , 39\u201346. There is also a grey zone in the literature as regards the specific impact of nodal status on treatment outcome after NSM or SSM. It is therefore legitimate to take into consideration the data retrieved from the Early Breast Cancer Trialists\u2019 Collaborative Group\u2019s meta-analysis . Compareet al [In the present state of knowledge, the current review strongly suggests that the recommendations by Marta et al  are in aFinally, this review confirms that, despite the fact that an increase in complications is documented in patients receiving PORT, immediate breast reconstruction using tissue expansion and implant is an acceptable option for women undergoing NSM and SSM for breast cancer .Whether SSM or NSM is safe in patients to whom no PORT is delivered remains a matter of controversy, especially in the absence of direct, controlled comparisons between patients with or without adjuvant radiotherapy. The literature on PORT after NSM and SSM continues to elicit rather large inconsistencies when treatment efficacy is the main endpoint. In particular, NSM, which spares a small amount of glandular tissue to protect the areola blood supply, raises concerns about the oncologic safety of this type of surgery, especially in high-risk patients. PORT is likely to reduce the risk of local failure in patients treated with subcutaneous mastectomy. Although some reasonable recommendations emerge from large-scale pooled analyses or surveys, the absence of prospective studies still prevents surgeons and radio-oncologists to identify those cases that are bound to draw a clear benefit from PORT after SSM or NSM. This definitely warrants the activation of randomised trials in these clinical settings.The author has no conflicts of interest and did not receive any funding to publish this review article."}
+{"text": "The induction of brown-like adipocyte development in white adipose tissue (WAT) confers numerous metabolic benefits by decreasing adiposity and increasing energy expenditure. Therefore, WAT browning has gained considerable attention for its potential to reverse obesity and its associated co-morbidities. However, this perspective has been tainted by recent studies identifying the detrimental effects of inducing WAT browning. This review aims to highlight the adverse outcomes of both overactive and underactive browning activity, the harmful side effects of browning agents, as well as the molecular brake-switch system that has been proposed to regulate this process. Developing novel strategies that both sustain the metabolic improvements of WAT browning and attenuate the related adverse side effects is therefore essential for unlocking the therapeutic potential of browning agents in the treatment of metabolic diseases. Adipose tissue is sensitive to changes in nutrient supply and ambient temperature: an evolutionary development that has allowed animal species to adapt to food shortage and cold temperatures. In higher vertebrates, white adipose tissue (WAT) primarily stores energy in the form of triglycerides in unilocular white adipocytes, which can then be released as fatty acids when food is scarce , as well as various peptides and hormones  adipocytes, the activation of which upregulates Ucp1 and other genes involved in energy expenditure in WAT. Browning of WAT is an adaptive and reversible response to environmental stimuli, including cold exposure, pharmacological agents such as \u03b2de novo differentiation   centers the browning transcriptional network. It has been proven to be necessary and sufficient for adipocyte differentiation and function Farmer . ChronicModulations of PPAR\u03b3 through ligands, posttranslational modifications, isoform distinction . Adipoq knock-out mice show increased thermogenic response , and fibroblast growth factor 21 (FGF21)\u2014are produced in response to \u03b2Besides the mainstreams of transcriptional and hormonal regulations, various mechanisms have been identified to regulate browning that include cytoskeleton remodeling  genetically obese mice resulted in reductions in total body weight and subcutaneous fat stores , an enzyme involved in prostaglandin synthesis, also induced browning of WAT and consequently increased energy expenditure and reduced adiposity  are PPAR\u03b3 agonists that were widely used as insulin sensitizers in the treatment of type 2 diabetes. In addition to their insulin sensitizing function, TZDs are well known to induce thermogenic gene expression in both white and brown adipocytes , whereas Fgf21-deficient mice show an impaired response to cold stress due to diminished thermogenic activity  emerges as an insulin-mimetic hormone that regulates systemic energy balance and has beneficial effects on body weight, insulin sensitivity, dyslipidemia, and pancreatic \u03b2-cell growth  mediate thermogenesis in BAT and lipolysis in WAT; thus, activating these receptors with selective pharmacological agonists is an attractive strategy for stimulating the browning of WAT. A number of \u03b23-AR agonists have been developed as anti-obesity agents. However, their harmful side effects have called into question whether the long-term stimulation of \u03b23-ARs is safe and beneficial. Himms-Hagen et al. demonstrated that chronic treatment with a \u03b23-AR agonist, CL 316,243, led to the appearance of multilocular brown adipocytes in WAT, promoted thermogenesis, and delayed the development of obesity in rats fed a high-fat diet  and T3 (triiodothyronine) are key regulators of metabolism and energy homeostasis, and have been shown to induce WAT browning , induced ectopic expression of UCP1 in rat abdominal WAT  T Moolman . THs hav Moolman , which d Moolman . This fuUcp1 and the appearance of brown adipocyte clusters  is a member of the superfamily of transforming growth factor-\u03b2. It has been shown to singularly promote the differentiation of mesenchymal progenitor C3H10T1/2 cells to a brown adipocyte lineage , and chronic diseases   and Parathyroid-hormone-related protein (PTHrP) have been implicated in the browning of WAT in cachexia. PTHrP was originally recognized for its beneficial effects on skin, cartilage, placenta, and bone development (Maioli et al. Burn trauma causes hypermetabolism due to marked increases in catecholamines, which have been reported years after the initial injury (Kulp et al. Foxa3 resulted in a lean, energy inefficient and more insulin sensitive phenotype in mice older than one year old (Ma et al. Aging is arguably a major risk factor for metabolic syndrome (Tchkonia et al. In recently years, significant progress has been made in identifying stimuli and signaling pathways that can induce browning of WAT and trigger adaptive thermogenesis. These advancements in knowledge have garnered great support in exploiting adipose tissue plasticity together with browning agents as therapeutic tools for obesity, albeit with side effects as discussed above. The revelation of the two sides of the coin regarding the browning of WAT\u2014namely, that it mitigates the metabolic consequences of obesity but propagates a hypermetabolic state in other pathologic conditions\u2014suggests that browning \u201cwastes energy\u201d and thus is not a favorable physiological state. Therefore, we hypothesized that the body needs to tightly regulate this browning process via a \u201cbrake-switch\u201d system to prevent the negative outcomes of both hyper- and hypo-activation of browning activity (Ferrannini et al. Prmd16 gene expression (Ng et al. Zfp423 in white adipocytes led to the accumulation of beige adipocytes in WAT in adult mice, while its gain-of-function converted brown adipocytes into a more white-like phenotype (Shao et al. This \u201cbrake-switch\u201d hypothesis is supported by the recent identification of HOXC10, a homeobox domain-containing transcription factor, as a negative regulator of browning of WAT (Ferrannini et al. The browning of WAT has become an increasingly favorable strategy for ameliorating the effects of obesity and subsequent metabolic dysfunction. However, it is energetically inefficient and thus is physiologically unfavorable. Furthermore, recent evidence has implicated browning in the development of cachexia, lipotoxicity, and other detrimental outcomes under acute and chronic hypermetabolic conditions (as summarized in Fig."}
+{"text": "Alcohol is one of the most commonly abused substances in the United States. Chronic consumption of ethanol has been responsible for numerous chronic diseases and conditions globally. The underlying mechanism of liver injury has been studied in depth, however, far fewer studies have examined other organs especially the heart and the central nervous system (CNS). The authors conducted a narrative review on the relationship of alcohol with heart disease and dementia. With that in mind, a complex relationship between inflammation and cardiovascular disease and dementia has been long proposed but inflammatory biomarkers have gained more attention lately. In this review we examine some of the consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver. The article reviews the potential role of inflammatory markers such as TNF-\u03b1 in predicting dementia and/or cardiovascular disease. It was found that TNF-\u03b1 could promote and accelerate local inflammation and damage through autocrine/paracrine mechanisms. Unraveling the mechanisms linking chronic alcohol consumption with proinflammatory cytokine production and subsequent inflammatory signaling pathways activation in the heart and CNS, is essential to improve our understanding of the disease and hopefully facilitate the development of new remedies. Alcohol is one of the most commonly abused substances in the United States. The effect of alcohol on organ systems of the body extends beyond the liver, where it is metabolized, to include the central nervous system, cardiovascular system, kidneys, lung, gastrointestinal tract, pancreas, and the immune system  is another recognizable complication of chronic excessive alcohol consumption  deficits. The severity of this damage depends on the duration, and frequency of exposure to ethanol during gestation. There is strong evidence that during prenatal development alcohol exposure has negative consequences, however, the causes ethanol-induced neurodegeneration are poorly understood. Alcohol has been linked to hyper-inflammation, reactive oxygen species (ROS) generation and ultimately neuronal death , which can increase the influx of proinflammatory mediators and leukocytes into the brain. The BBB consists of the mainly of specialized endothelial cells lining the cerebral blood vessels, surrounded by pericytes, astrocytical processes, and neurons. It is known that alcohol can directly pass through the BBB, ultimately reaching the brain cells and causing subsequent neuronal toxicity, however the underlying mechanism is not fully understood. It was indeed suggested that chronic ethanol exposure induces oxidative stress and neuroinflammation in part by affecting platelet endothelial cell adhesion molecule-1 (PECAM-1) expression.Endothelial PECAM-1 is a cell adhesion molecule that allows for the interaction of immune cells and the endothelium which facilitates the transmigration of leukocytes and thus contributes to the endothelial cell permeability barrier , not only is there abnormal production of TNF-\u03b1, but TNF-\u03b1 has also been linked to the pathological neuromodulation of the disease (McAlpine et al., Alcohol is well-known for its dysregulation of cytokines levels in several body organs such as the liver, brain, lung, and plasma. It has been postulated that such changes are responsible for undesirables CNS alterations, which results in long term effects in behavior and permanent neurodegenerative effect. Hence, understanding the role of such cytokines is essential to determine the exact pathogenesis of alcohol-associated neurological disorders (Achur et al., Along with other cytokines, TNF-\u03b1 was found to be dysregulated by alcohol-related tissue destruction as is evident by the abnormal levels of circulating cytokines in alcoholic patients (Achur et al., Alcohol can be beneficial or harmful and may affect the heart and whole cardiovascular system in many ways. Some of the cardiovascular diseases that are associated with heavy drinking are: cardiomyopathy, cardiac arrhythmias, hypertension, atherosclerosis and heart failure Table . In thisAccording to Djousse and Gaziano, approximately half a million Americans are diagnosed with heart failure each year and some of those cases are associated with alcohol consumption (Djousse and Gaziano, Cardiac disease remains an essential burden that causes death in chronic alcoholic population Kannel, . ExcessiDespite the lack of clear understanding of the exact mechanism by which chronic alcohol consumption causes heart failure, stroke volume reduction and low ejections fraction was found in alcoholic population (Patel et al., Recent evidence shows that cardiomyocyte apoptosis appears to play a major role in many alcoholic cardiomyopathies leading to heart failure (Fernandez-Sola et al., K, by IGF-1 mainly through PI-3K/Akt activation (Teos et al., K reported earlier maybe mediated by IGF-1-dependent signaling pathway.Sparagna et al. has shown that low-dose alcohol attenuates apoptosis in neonatal rat cardiocytes through Akt and AMP-activated kinase (Sparagna et al., Even though long-term alcohol abuse has been associated with defect in cardiac contractility and eventual development of dilated cardiomyopathy and low-output heart failure Table , interes2+ (2+ channels nor their inactivation parameters. Interestingly, no data is available on the electrophysiological effects of low alcohol exposure or on the exposure frequency. Clinically relevant concentrations of ethanol induced elevation of Ca,L (Brown et al., + currents of rats (Nakamura et al., 2+i in a concentration dependent manner (Ren, Most of the experimental evidence indirectly relates chronic alcohol-dependent changes in intracellular Caner Ren, . Interes Lieber, . Interes Lieber, .Although once thought of as part of inflammatory cells only, cytokines and chemokines are now recognized to play pivotal role in cardiac homeostasis and repair (Tarzami et al., in vivo study on pregnant Wistar Rats, the authors extrapolated that the inflammation and oxidative stress are the mechanisms of the destructive effect of ethanol on their hearts (Shirpoor et al., The relationship between inflammation and inflammatory markers with alcoholic heart disease has gained much attention lately. In an Among these inflammatory markers, TNF-\u03b1 was particularly interesting for its role in cardiovascular diseases Ferrari, . In addiThe locally produced autocrine TNF-\u03b1 was found to have a noticeable role in alcohol-related heart failure (Meldrum et al., Alcoholism is a multifactorial disorder that requires a multidisciplinary approach to treat depending on the organs affected. Heavy drinkers suffer from many organ damages; among the most effected organs are liver and kidney. As we mentioned before, heart and brain can be affected either directly or indirectly by alcohol and or its breakdown metabolites. So far, conventional treatment strategies have used a combination of a reduction of ethanol-dependent inflicted damage by control drinking and increasing local and systemic protective mechanisms of the body by using antioxidant supplementation (Mailloux, Other non-conventional suggested approaches included the use of microRNAs since they are shown to play an important role in multi-organ alcohol-induced damages including brain and heart (Natarajan et al., Alcohol consumption effects cardiovascular system and predisposes to the development of cardiac abnormalities such as cardiac remodeling, cardiac arrhythmia, cardiomyopathy myocardia infarction, and even SCD Table . ConsequHeavy drinking has been shown to increase the risk of heart failure, thus in addition to the conventional approach to control alcoholism, it is critical to focus on preventive measures that could reduce the risk to heart failure in these patients. It was reported that normal heart does not express TNF but failing heart procures robust amount of TNF-\u03b1, Hence, more studies are dedicated to understanding the role of TNF-\u03b1 in heart failure patients. It is known that TNF-\u03b1 is elevated in chronic heart failure patient in accordance with their functional class (Heberto Herrera Garza et al., Attempts to integrate TNF-\u03b1 antagonist into the realms of therapeutic medicine has been suggested, with possible effectiveness for symptomatic heart failure patients (Heberto Herrera Garza et al., Interestingly, in brain injury, TNF-\u03b1 has been postulated to potentiate glutamate-mediated cytotoxicity in astrocyte leading to neuronal degeneration (Pickering et al., SDF-1, otherwise known as CXCL12, plays a major role in regulating stem cell recruitments, inflammation and inflammation mediated injury (Doring et al., In the heart, various cells including cardiomyocytes, stromal cells, endothelial cells, fibroblasts, and dendritic cells express SDF-1 (Wei et al., Helicobacter Pylori induced peptic ulcer, rotator cuff disease, skin inflammation squamous cell carcinoma of the lung, renal ischemia-reperfusion injury, glioblastoma tumor, and AIDS-associated neurologic disorders (Han et al., in vitro, which indicates the pathological roles of SDF-1 in increasing the severity of neurological impairment due to increased astrocyte cell death (Table SDF-1 alpha has also been shown to play roles in other disease conditions that affect other systems in the body commonly affected by heavy alcohol exposure. SDF-1 has been shown to increase in toxic liver damage, neonatal sepsis, autoimmune, inflammatory diseases, th Table . Moreoveth Table . TogetheActivation of TNF-\u03b1 by SDF-1 has also been postulated to promote the reactivation of latent HIV in macrophages and microglial cells Table . Other pCollectively, these data suggest that the alcohol induced alteration in circulating chemokines is a major contributor in alcoholic mediated organ damages via both direct and indirect mechanisms Figure . The preIn conclusion, alcohol's action are complex, chronic alcohol consumption can increase the risk of heart disease, brain damage, dementia, neuropathy, metabolic disturbances, nutritional deficiencies, certain cancers, liver, and other faces of morbidity and mortality. In this review we have highlighted the contribution of inflammatory process in alcohol-mediated tissue damage and organ dysfunction. What is apparent from literature review is that the full understanding of the related cytokine signaling pathways in alcoholic injuries will be essential for further understanding of their potential contribution and their complex biological effects on alcohol-induced organ damage. Investigation of agents that interfere with inflammatory cytokine production is needed in order to enhance our understanding on their potential contributions into pathogenesis of diseases that are associated with excessive alcohol consumption.AO and AP: performed the literature search and designed the tables/figures and edited the manuscript; ST: wrote the manuscript; JL and GH: performed the literature search and discussed the content of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cancer is a leading cause of death worldwide, and its incidence is rising with numbers expected to increase 70% in the next two decades. The fact that current mainline treatments for cancer patients are accompanied by debilitating side effects prompts a growing demand for new therapies that not only inhibit growth and proliferation of cancer cells, but also control invasion and metastasis. One class of targets gaining international attention is the aquaporins, a family of membrane-spanning water channels with diverse physiological functions and extensive tissue-specific distributions in humans. Aquaporins\u22121,\u22122,\u22123,\u22124,\u22125,\u22128, and\u22129 have been linked to roles in cancer invasion, and metastasis, but their mechanisms of action remain to be fully defined. Aquaporins are implicated in the metastatic cascade in processes of angiogenesis, cellular dissociation, migration, and invasion. Cancer invasion and metastasis are proposed to be potentiated by aquaporins in boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with actin cytoskeleton, regulating proteases and extracellular-matrix degrading molecules, contributing to the regulation of epithelial-mesenchymal transitions, and interacting with signaling pathways enabling motility and invasion. Pharmacological modulators of aquaporin channels are being identified and tested for therapeutic potential, including compounds derived from loop diuretics, metal-containing organic compounds, plant natural products, and other small molecules. Further studies on aquaporin-dependent functions in cancer metastasis are needed to define the differential contributions of different classes of aquaporin channels to regulation of fluid balance, cell volume, small solute transport, signal transduction, their possible relevance as rate limiting steps, and potential values as therapeutic targets for invasion and metastasis. Xenopus laevis expression system, introduced AQP1 channels enabled high osmotic water flux across the plasma membrane as compared to non-AQP control oocytes  are a family of water channels that also include a subset of classes shown to mediate transport of glycerol, ions, and other molecules , which stimulates endothelial cell proliferation and angiogenesis in response to hypoxia , induce AQP1 expression in low oxygen conditions  occurs in normal physiological conditions such as implantation, embryogenesis, and organ development, as well as pathological processes such as cancer invasion and metastasis  degradation and retraction Figure . Cell poA migrating cell extends its leading edge into the ECM by assembling a branched network of intracellular actin filaments, predicted to yield a physical force that dynamically pushes the membrane out, alternating with relaxation and actin depolymerization Wang, . Membranin vitro, and augmented metastasis in a mouse model -mediated phosphorylation of AQP4 at serine 180 correlated with a decreased glioma cell invasion  have been shown to interact with adhesion molecules and to influence adhesive properties of migrating cells. Increased AQP1 in mesenchymal stem cells enhances migration by a mechanism involving \u03b2-catenin and the focal adhesion kinase (FAK)    chloride HgCl  cells (Gao et al., + is an inhibitor of voltage-gated potassium channels, calcium-dependent potassium channels, the nicotinic acetylcholine receptor, and it has also been shown to block AQP-1,\u22122, and\u22124 water permeability in Xenopus laevis oocytes and kidney derived cell lines (Brooks et al., + is variable, having been confirmed by some groups (Detmers et al., + in erythrocytes with native AQP1, or in epithelial cells transfected with AQP1, and suggested previous positive results might have been due to inhibition of K+ channels and altered baseline cell volume; however, the observation that site-directed mutation of AQP1 altered TEA sensitivity (Brooks et al., + block of AQP1 water permeability reduced cell migration and invasion in in vitro models of osteosarcoma and hepatocellular carcinoma (Pelagalli et al., + as a possible AQP1 inhibitor. However, given the variability in efficacy and cross-talk with other channels, TEA+ is not an ideal candidate for clinical development, although the targets causing the observed block of cancer cell migration and invasion might merit further investigation.TEAXenopus laevis oocytes (Migliati et al., in vitro (Dorward et al., 2, and NO (Nakhoul et al., 2 and cation transport properties (Yang et al., Xenopus oocytes stimulated with forskolin was first reported in 1996 (Yool et al., in vitro, but not in vivo (Klebe et al., in vitro remains to be determined.Bumetanide is a sulfamoylanthranilic acid derivative used clinically to increase diuresis by blocking sodium cotransporter activity at the loop of Henle in the nephron. Molecular derivatives of bumetanide have been synthesized and found to exhibit inhibitory effects on classes of AQP channels. For example, the bumetanide derivative AqB013 blocks osmotic water fluxes mediated by mammalian AQP1 and AQP4 channels expressed in Plant-based derivatives that reduce cancer cell migration and invasion include agents that have also have been found to inhibit AQPs. Bacopa monnieri is a perennial herb native to the wetlands of India that is used in alternative medicinal therapies. Chemical constituents bacopaside-I and bacopaside-II, were shown to block AQP1 but not AQP4 water channels (Pei et al., 2 (Zelenina et al., 4 (Zelenina et al., Mercury has classically been used as an AQP1 inhibitor. In the human AQP1 monomer, the NPA motif in loop E is near cysteine 189, which is the site at which mercury inhibits osmotic water permeability (Preston et al., Aquaporin-dependent mechanisms serve as key steps throughout the process of metastasis, in angiogenesis, cellular dissociation, cell migration and invasion. AQPs\u22121,\u22122,\u22123,\u22124,\u22125,\u22128, and\u22129 contribute to one or more processes, generally potentiating cancer invasion and metastasis by boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with the actin cytoskeleton, regulating proteases and ECM degrading molecules, contributing to the regulation of epithelial-mesenchymal transition in cancer cells, and interacting with specific signaling pathways important in cancer cell motility and invasions. Pharmacological agents for aquaporin channels have therapeutic promise for improving cancer treatment, and include derivatives of bumetanide, organic metal compounds, plant medicinal agents, and other small molecule compounds. Although conflicting evidence has been raised for some compounds, there is nevertheless a compelling need to continue identifying novel candidates for AQP-specific modulators relevant not only for the treatment of cancer, but other pathological conditions. In conclusion, although much remains to be defined for molecular mechanisms in cancer invasion and metastasis, the roles of AQP channel function in cancer progression will inspire new therapeutic targets for improving treatment of malignant and invasive carcinomas.MD: wrote the manuscript; AY: reviewed and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "AD is a multifactorial disease that occurs in familial and sporadic forms, but is always accompanied by neurotoxic accumulations of amyloid and tau proteins. The deposition of amyloid was postulated to be central for AD pathogenesis in the \u201camyloid cascade hypothesis\u201d , which belongs to a small family of transmembrane proteins together with amyloid precursor-like proteins (APLP) 1 and 2. APP can undergo distinct secretase-mediated cleavages, following either the \u201cnon-amyloidogenic\u201d or \u201camyloidogenic\u201d pathway. The first serves a range of important physiological functions, including regulation of transcription and synaptic plasticity (reviewed by M\u00fcller et al., In this commentary, we want to highlight two recent papers that addressed this question using overlapping and complementary methods: Puzzo et al.  and WangOn the other hand, Puzzo et al.  investigTaken together, the results from Wang et al.  and PuzzAnother important open question is whether similar results would have been obtained using mice with a more acute, conditional APP reduction, such as a tamoxifen-inducible APP-KO line (Callahan et al., The new pathological role for APP has implications for studies using transgenic AD mouse models, which typically overexpress human APP (recent overview in Jankowsky and Zheng, In conclusion, the studies by Wang et al.  and PuzzAS conceived the study and wrote the original draft with critical and substantial input from AU. AL-H provided valuable ideas and revisions. All authors reviewed relevant literature, participated in discussions, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Our understanding of reactive oxygen species (ROS)\u2014a group of highly reactive chemicals containing oxygen\u2014has changed in the last few years from ROS as just harmful substances to crucial intra- and extracellular messengers as well as important regulators controlling a wide spectrum of signaling pathways. Nevertheless, there are still many uninvestigated points and open questions regarding ROS, especially in pathophysiology. Delicately controlled ROS homeostasis is critical for maintaining normal cell functions and any disruption in the oxidation-antioxidation balance leads to oxidative stress associated with a wide spectrum of human disorders such as chronic inflammation, age-related diseases, and cancers. In health, the intracellular ROS level is tightly controlled by various antioxidants. In contrast, cancer cells have an abnormally high level of ROS due to an increased ROS production and/or impaired ROS detoxification that can damage intracellular macromolecules such as nucleic acids, proteins, and lipids. Elevated ROS production in cancer cells may result from an aberrant metabolic activity, mitochondrial dysfunction, disturbed cellular signaling, oncogene activity, and interaction with tumor infiltrating immune cells.2O2 has the opposite effects on cancer cell proliferation depending on its concentration and cancer type. G. Vilema-Enriquez et al. in their article \u201cMolecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications\u201d review effects of hydrogen peroxide on human lung cancer. The authors discussed effects of H2O2 on migration and invasion, calcium release, and other molecular features of cancer cells. Furthermore, they describe the link between hydrogen peroxide and inflammation. Finally, the authors hypothesize that novel therapeutic approaches against lung cancer may be based on the use of H2O2. Y.-C. Hung et al. in their review \u201cRoles of Reactive Oxygen Species in Anticancer Therapy with Salvia miltiorrhiza Bunge\u201d deal with Danshen as a drug of the traditional Chinese medicine and provide a systematic review of its antioxidant capacity and potential anticancer effects. Moreover, they conclude that based on the existed preclinical data this drug may be pipelined in clinical trials. A research paper by W. Li et al.  deals with hyperglycemia in pancreatic cancer cells. The authors succeeded in finding the link between hyperglycemia and epithelial-mesenchymal transition through the production of hydrogen peroxide. Another research report on breast cancer of D. M. Badr et al. (\u201cThe Combination of \u03b1-Tocopheryl Succinate and Sodium Selenite on Breast Cancer: A Merit or a Demerit?\u201d) shows in vitro and in vivo that sodium selenite antagonizes effects of \u03b1-tocopheryl succinate on apoptosis induction in cancer cells via inhibition of oxidative stress. An intriguing review came from France, authored by M. Assi and A. R\u00e9billard, and was devoted to the problem of cachexia in cancer patients (\u201cThe Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts\u201d). As regulators of catabolic pathways ROS are involved in muscle atrophy in cachectic cancer patients, the authors summarize and discuss contradictory data on the effects of antioxidants in such patients.The ultimate purpose of this special issue is to publish high-quality research communications as well as review articles dedicated to the role of ROS in cancer biology, anticancer therapy, and related topics. Five articles published in this special issue are devoted to reactive oxygen species in cancer biology. Presently, it is rather well known that HThe next topic highlighted in this issue is devoted to ROS in tumor immunology. A review by X. Chen et al. (\u201cReactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment\u201d) gives readers an overview of ROS in the tumor microenvironment and especially in the tumor-induced immunosuppression. The authors, based on improvement of anticancer T cell response, consider an antioxidant treatment as a promising option for cancer therapy. A. Scala et al. in their research article \u201cAlterations in Red Blood Cell Functionality Induced by an Indole Scaffold Containing a Y-Iminodiketo Moiety: Potential Antiproliferative Conditions\u201d deal with a prediction of the antiproliferative effects of heterocyclic scaffolds, which could be important for development of new therapeutic approaches against cancer.A research article by M. Weniger et al.  considers pancreatitis as a main risk factor for pancreatic cancer. The authors show an unexpected analgesic effect of the new antioxidant SkQ1 during pancreatic inflammation. The last article from this issue deals with the oxidative stress in cancer-prone diseases in pediatric age. S. Perrone et al. in \u201cOxidative Stress in Cancer-Prone Genetic Diseases in Pediatric Age: The Role of Mitochondrial Dysfunction\u201d review recent literature on such diseases and discuss molecular mechanisms of oxidative stress associated with mitochondrial dysfunction. They conclude that mitochondria-targeted medicines could be applied into the clinics to improve the quality of life of patients with cancer-prone genetic diseases.Summarizing, the wide spectrum of review and research articles presented in this issue provides recent interesting data on ROS in the context of cancer biology and anticancer therapy.Alexandr V. BazhinAlexandr V. BazhinPavel P. PhilippovPavel P. PhilippovSvetlana KarakhanovaSvetlana Karakhanova"}
+{"text": "Mandibular advancement surgery may positively affect pharyngeal airways and therefore potentially beneficial to obstructive sleep apnea (OSA).To collect evidence from published systematic reviews that have evaluated pharyngeal airway changes related to mandibular advancement with or without maxillary procedures.PubMed, EMBASE, Web of Science, and Cochrane Library were searched without limiting language or timeline. Eligible systematic reviews evaluating changes in pharyngeal airway dimensions and respiratory parameters after mandibular advancement with or without maxillary surgery were identified and included.This overview has included eleven systematic reviews. Maxillomandibular advancement (MMA) increases linear, cross-sectional plane and volumetric measurements of pharyngeal airways significantly (p<0.0001), while reducing the apnea-hypopnea index (AHI) and the respiratory disturbance index (RDI) significantly (p<0.0001). Two systematic reviews included primary studies that have evaluated single-jaw mandibular advancement, but did not discuss their effect onto pharyngeal airways. Based on the included primary studies of those systematic reviews, single-jaw mandibular advancement was reported to significantly increase pharyngeal airway dimensions (p<0.05); however, conclusive long-term results were lacking.MMA increases pharyngeal airway dimensions and is beneficial to patients suffering from OSA. However, more evidence is still needed to draw definite conclusion related to the effect of single-jaw mandibular advancement osteotomies on pharyngeal airways. Pharyngeal airway dimensions are inevitably affected by skeletal jaw movements during orthognathic surgery. Both one-jaw mandibular advancement, 2 and tSurgeons and orthodontists have gained increasing interest in pharyngeal airway evaluation, as it affects patients\u2019 health and quality of life. The effThe aims of this overview were to examine systematic reviews for changes in pharyngeal airway dimensions and/or respiratory parameters related to mandibular advancement osteotomies with or without concomitant maxillary osteotomies, and to critically appraise the quality of the reported systematic reviews.https://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42016046489).The reporting of this systematic review adheres to the Cochrane\u2019s recommendation on overview of systematic reviews and the rd April 2017. There was no search limitation set for publication language or dates. The search results were exported into Endnote X7  and duplicate articles were removed. Next, the title and abstract of all articles were screened for potential eligibility, and the full text of relevant articles was retrieved. Lastly, the reference lists of those relevant articles were manually searched to screen for further relevant articles. Both electronic and manual searches were performed independently by two authors (TSK and RAZ). Disagreement was resolved by discussion with the other authors.The electronic databases PubMed, EMBASE, Web of Science, Scopus and Cochrane Library were searched using the search strategy outlined in This overview has included systematic reviews that have assessed changes of pharyngeal airways related to mandibular advancement osteotomies with or without concomitant maxillary osteotomies. Eligible systematic reviews had to report outcome measures of pharyngeal airway dimensions and their post-surgical changes, i.e. linear, cross-sectional plane or volumetric measurements. Furthermore, data from reviews reporting on respiratory parameter changes have also been evaluated and included.Systematic reviews that have studied specific target group (i.e. edentulous patients and morbidly obese OSA patients), or pharyngeal airways in cleft lip and palate, syndromic or distraction osteogenesis patients have been excluded from this overview.Data from included systematic reviews was extracted independently by two authors  and inserted in pre-tabulated data sheets . Any disagreement related to data extraction was resolved by consensus in discussion with the other authors  to ensure consistency and reliability of extracted data. The data extraction included authors, publication year and title, methods of analyses, number and study design of included studies, sample population ; type of interventions, outcome measures and main findings, follow up period and meta-analyses\u2019 result when available.The methodological quality of the included reviews was assessed independently by TSK and RAZ using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. On the 2 test for heterogeneity (p = 0.1) and the \u03992 measure of inconsistency. A significant heterogeneity was considered when p< 0.1 for \u03c72 test or when \u03992> 50%. Treatment effects across the studies were combined using the fixed effect model when there was no heterogeneity observed (p> 0.1); in case of heterogeneity observed, the random effect model was applied. Funnel plot was used to assess publication bias, while Egger test for funnel plot asymmetry will be used when more than ten primary studies were included in an analysis[A narrative overview is provided summarizing the data gathered from included systematic reviews. Meta-analyses have been performed whenever possible by pooling the data across different reviews using the software \u201cReview Manager\u201d . The heterogeneity of trial results was assessed with the \u03c7 analysis, 24.An electronic search of the databases has generated an overall of 1642 articles. Titles and abstracts of 1211 articles were screened after removing the duplicates. The full texts of 23 relevant articles were retrieved and assessed for their eligibility of inclusion. No other relevant article was found while manually searching the reference lists of those 23 articles. Ultimately, 11 systematic reviews \u201318 have Two systematic reviews, 16 haveThe AMSTAR tool analysis revealed one systematic reviewwith a hiAlthough a self-declared no conflict of interest was found in eight systematic reviews, 16, 18,Eight out of eleven systematic reviews have analyzed the quality of evidence of their included primary studies. Three reviews, 9, 11 aet al[For the 38 primary studies that have been assessed based on risk of bias or methodology quality, only two were reported as low risk of bias or high methodological quality. Besides, half of them showed a moderate risk of bias or methodological quality. Zaghi et al did not The narrative information from the included systematic reviews is elaborated below. The results of the meta-analyses of included systematic reviews are shown in Although two systematic reviews, 16 inclMeta-analyses of three systematic reviews showed a significant increase of minimum cross-sectional area (CSA), pharynget al[et al[I2 = 0%), the fixed effect model was used. The meta-analysis indicated that MMA with or without genioplasty or genial tubercle advancement (GTA) lead to a significantly increased total pharyngeal volume  after the surgery (p<0.00001). Although there was no statistically significant different (p = 0.62) between the subgroups, MMA with genioplasty or GTA has higher increased total pharyngeal volume (mean = 8.73ml) in comparison with MMA alone  after the surgery. A symmetry funnel plot was noted suggesting a low risk of publication bias ..et al[etion bias et al[et al[et al[et al[Two primary studies reported by Butterfield et al, 43 were al[et al of the a al[et al meta-ana al[et al, 46 incl al[et al were fou al[et alwas eventMeta-analyses of post-MMA data reported by included systematic reviews in this overview revealed a significant reduction of the AHI, 18, Reset al[et al[Two systematic reviews, 18 haveet al reportedHsieh and Liao did not et al[et al[2 nadir (p = 0.04) to be associated with a higher post-MAA OSA cure rate (AHI<5/h).Univariate analysis of Holty et al suggesteet al. These r al[et al who haveThe here presented overview detected significantly reduced AHI after MMA with a relatively high treatment success rate (>85%) in OSA patients. This is comprehensible and in line with consistently increased post-MMA linear, cross-sectional area and volumetric pharyngeal airway measurements. The minimum CSA is one of the most commonly used airway measurements, and hasMandibular advancement with bilateral sagittal split osteotomies (BSSO) is a well-established procedure in the treatment for patients with retrognathic mandible, with concomitant beneficial effect on pharyngeal airways. However,et al[Based on CBCT analysis, Hernandez-Alfaro et alhave repoet al of MMA cet al, 18 withet al, 18 and et alare assocet al and OSA The maximum follow-up period varies across primary studies between 5 weeks to 12 years, with a vast majority of less than 5 years. Therefore, some of these follow-up periods were definitely too short since recurrence of OSA has been reported as late as 10 to 15 years after MMA. A standAround one third of the included systematic reviews have performed electronic search in only one database and therefore posed a significant threat to selection bias. Moreover, none of the included systematic reviews has disclosed the \u2018conflict of interest\u2019 status of their included primary studies. Besides, four systematic reviews did not describe the characteristics of their included primary studies. As the quality of systematic reviews is affected directly by the quality of its included primary studies, a thorough investigation and reporting of each included study are mandatory.et al[Publication bias is another critical aspect to be investigated in the systematic reviews. Only two, 18 out et al suspecteThe following shortcomings of this overview have to be highlighted. Most primary studies of the included systematic reviews were of moderate and only a few of high quality, which might have affected the quality of those systematic reviews. Besides, seven of the included systematic reviews\u201315, 17 hMaxillomandibular advancement (MMA) increases pharyngeal airway dimensions, providing positive post-surgical effects in patients suffering from OSA. However, still more evidence is needed to draw conclusions related to effect of single-jaw mandibular advancement osteotomies on pharyngeal airways.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file."}
+{"text": "Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases. Alternative splicing is a crucial step of post-transcriptional gene expression that substantially increases transcriptome diversity and is critical for diverse cellular processes, including cell differentiation and development as well as cell reprogramming and tissue remodeling. Our understanding of the physiological significance and disease implications of alternative splicing has been greatly improved by genetic approaches and RNA deep sequencing. In this review, we focus on alternative splicing in neuronal differentiation from stem/progenitor cells, neuronal migration and functional development of neurons Figure .trans-acting splicing regulators and cis-elements of pre-mRNAs   and muscleblind-like 1 (MBNL1) exhibit switched expression during heart development to regulate splicing of cardiac mRNAs  can be distinguished from neurons in the developing brain  promotes exon 10 inclusion of PTBP2 and thus maintains PTBP2 level in neurons  in NPCs and hence maintains apical progenitors. Genetic mutations that generate aberrant Flna splice isoforms in NPCs are linked to periventricular nodular heterotopia, a neuronal migration disorder. Thus, a better understanding of the mechanisms of neuronal alternative splicing may provide plausible treatment strategies for neuronal disorders.Among neuronal splicing regulators, PTBP1 is exclusively expressed in embryonic stem cells and NPCs, whereas PTBP2 and Rbfox proteins are mainly expressed in neurons. A recent report showed that PTBP1 and Rbfox antagonistically modulate neuronal fate via their roles in regulating alternative exon selection  splice isoforms, i.e., PKM1 and PKM2 in neurons and glial cells, respectively (Zhang et al., PKM1 and PKM2 isoforms result from mutually exclusive exon selection. Selective expression of PKM isoforms is also critical for regulating glucose metabolism in muscle and cancer (Christofk et al., Brain tissues comprise a variety of cell types including neural precursor cells, neurons, and various subtypes of neuroglia. Tantalizing issues remain as to whether and how alternative splicing influences neural fate determination and which splicing regulators are involved (Raj and Blencowe, Reeler mutant mice and mice with spontaneous or targeted mutations of Dab1 or either of the receptors exhibit similar phenotypes characterized by ataxia, tremors, and a reeling gait (D'Arcangelo et al., Dab1 occurs during brain development, resulting in multiple splice isoforms (Gao et al., Dab1 exon 9b/c (Yano et al., Dab1. Differential selection of exons 7 and 8 of Dab1 is also intriguing because these two exons encode a domain containing critical tyrosines that are targets of Reelin-mediated phosphorylation. Moreover, ApoER2 also undergoes alternative splicing. The exon 19-containing domain of ApoER2 is important for synapse formation and function via its interaction with PSD-95 (Beffert et al., ApoER2 and that blocking SRSF1-binding sites using an antisense oligonucleotide has therapeutic potential (Hinrich et al., The mammalian cerebral cortex has a highly organized six-layered structure consisting of a variety of neuron subtypes (Molyneaux et al., Scn9a mRNA increases the SCN9A level (Eom et al., Alternative splicing also regulates neurologic functions such as axon guidance and synaptogenesis. A number of neuronal mRNAs undergo alternative exon selection to generate isoforms in response to neuronal stimulation. Synaptic activity promotes exon 19 inclusion of ApoER2, which then binds Reelin and enhances long-term potentiation (Beffert et al., The combination of various genetic tools and RNA-seq has advanced our knowledge of the impact of alternative splicing on neural development and function. Recently, the use of cell-surface or genetically engineered fluorescent protein markers and fluorescence-activated cell sorting has enabled the isolation of stem/progenitor cells and specific neuronal types (Zhang et al., C-HS, DD, and W-YT: Jointly wrote this review; W-YT: Defined the scope of the review and edited the draft. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "At the cellular and subcellular levels, acid-base balance is achieved by ion exchange.Most physiological processes are sensitive to pH  and regulation of pH within tissues and body fluids represents a fundamental homeostatic process in living organisms. At the organismal level, acid-base balance is achieved by fast respiratory modulations of the partial pressure of CORecently in Current Biology, Jalalvand et al.  describein vitro spinal cord was studied. While mammals regulate arterial blood pH (pHa) at 7.4 at their normal body temperature of 37\u00b0C, Jalalvand et al. (a and CSF pH (pHCSF) increase by ~0.015 unit per \u00b0C when body temperature decreases in ectothermic vertebrates  upon intense and exhaustive exercise  that interfaces with neuronal membranes. Chesler , the Danish Natural Sciences Research Council (FNU) (TW), the National Institutes of Health- NS091836 to Sherif Elbasiouny (SD), and the National Science Foundation IOS-1257338 (LH) for funding.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Anterior shoulder instability has been successfully managed arthroscopically over the past two decades with refined \u201canatomic\u201d reconstruction procedures involving the use of anchors for the repositioning and re-tensioning of the antero-inferior capsuloligamentous complex, in an effort to recreate its \u201cbumper effect\u201d.Research and online content related to arthroscopic treatment of shoulder instability was reviewed and their results compared.The short- and mid-term results of this technique have been very satisfactory. The greatest number of recent reports suggests that long-term results (>5 years follow-up) remain rather satisfactory, especially in the absence of significant glenoid bone loss (>20-25%). In these studies recurrent instability, in the form of either dislocation or subluxation, ranges from 5.1 to over 20%, clinical scores, more than 5 years after the index procedure, remain good or excellent in >80% of patient population as do patient satisfaction and return to previous level of activities.As regards arthroscopic non-anatomic bony procedures (Latarjet or Bristow procedures) performed in revision cases or in the presence of >20-25% bone loss of the anteroinferior aspect of the glenoid, recent reports suggest that their long-term results are very satisfactory both in terms of re-dislocation rates and patient satisfaction.It appears that even \u201clege artis\u201d performance of arthroscopic reconstruction decelerates but does not obliterate the degenerative procedure of dislocation arthropathy. The presence and grade of arthritic changes correlate with the number of dislocations sustained prior to the arthroscopic intervention, the number of anchors used and the age at initial dislocation and surgery. However, the clinical significance of radiologically evident dislocation arthropathy is debatable. Despite prompt reduction and immobilisation for a reasonable but not excessive period of time before further rehabilitation, it can often lead to recurrent shoulder instability -3. It apet al. , Porcell [et al.  and Yian [et al.  have sug [et al. , 8.A Bankart lesion or various Bankart-variants appear to be the \u201cessential lesion\u201d in most instability cases and is most usually amenable to \u201canatomic\u201d procedures that aim to reconstruct and recreate the anatomy of the antero-inferior capsule-ligamentous complex. Over the past 10 years refined arthroscopic reconstruction techniques involving the use of suture anchors have been developed and offer very satisfactory short- and mid-term outcomes that are comparable to classic open techniques. On the other hand, \u201cnon-anatomic\u201d procedures such as the Latarjet or Bristow coracoid transfer or other \u201cbone-block\u201d procedures are being used all the more often to address patients with a combination of osseous and ligamentous injuries. These procedures have recently been performed arthroscopically by a number of experienced surgeons, with a very promising outcome -12. In t1 & 2). Therefore, only studies reporting on the long-term outcome following arthroscopic stabilisation with the use of anchors will be analysed in this review. Both metal and bio-absorbable anchors have been used very successfully in the treatment of shoulder instability, neither one providing superior clinical outcomes. However, the visibility of the drill holes was significantly greater after using poly-L-lactic acid polymer implants [Initial clinical studies on the long-term clinical outcome (>5-year mean patient follow-up time) following arthroscopic Bankart procedures describe the clinical outcome in patient series where techniques involving the use of tacks and trans-glenoid sutures were employed and report relatively high re-dislocation rates  and haveimplants .et al. [Kim et al.  report oRhee and colleagues  on the oUnlike Rhee and colleagues  Larain aCastagna and colleagues in 2010  analysedet al. in 2007 [Porcellini  in 2007  reportedPlath and colleagues  in a veret al. [Van der Linde et al.  report aet al.  for failet al. . It alsoArthroscopic or open techniques involving bone block procedures or coracoid transfer techniques are used more and more often in both revision and primary instability surgery, especially in the presence of >20-25% bone loss of the anteroinferior aspect of the glenoid , 22. Recet al. [et al. have also reported a low recurrence of instability (4 out of 68 shoulders- 5.9%) in their long term results study of open Latarjet procedure [Schmid et al.  have reprocedure .et al. [Dumont et al.  have repet al. in 1983, who introduced the term \u201cdislocation arthropathy\u201d for this pathology and classified it radiologically [et al. [Arthritic changes in the shoulder joint following shoulder dislocation were first described by Samilson ogically . The cla [et al.  and cons [et al. .No such evidence was available concerning the long term effect of arthroscopic anatomic procedures on the prevalence and evolution of dislocation arthropathy until recently, when a number of publications have demonstrated that the long-term incidence of moderate and severe dislocation arthropathy is similar to that reported following open anatomic procedures , 19, 28.et al. reviewed the long term results of 68 shoulders treated with the Latarjet procedure. One fourth of the patients  showed progression of arthritis [3).Mizuno rthritis . This perthritis  and the It appears that initial joint trauma sustained during anterior shoulder dislocation has long-term biologic effects on the shoulder joint cartilage and the joint physiology in general. Avoiding numerous pre-operative dislocations appears to prevent to some extent the occurrence and severity of post-operative dislocation arthropathy . One shoAnterior first time shoulder dislocation has significant short and long term effects on the shoulder joint. It can lead to anterior instability, loss of function and dislocation arthropathy. Open or arthroscopic anatomic procedures in the absence of severe glenoid bone loss provide good to excellent long term results even for the high demand athlete. Long term results of non-anatomic procedures in the presence of significant glenoid bone loss have been reported as satisfactory. Shoulders with a history of anterior dislocation are very likely to eventually develop some grade of arthritis even when they are treated surgically, however the presence of arthritis does not correlate with functional scores."}
+{"text": "Stem Cells International set out to publish a special issue focused on the \u201cEx Vivo and In Vivo Stem Cell-Based Tissue Engineering Strategies for Their Use in Regenerative Medicine.\u201d This special issue resulted in a collection of nine outstanding articles which include two reviews and seven original studies made by recognized researchers from seven countries across Europe, Asia, South America, and North America.Tissue engineering is an emergent discipline focused on the generation of bioartificial tissue-like substitutes through the combination of biomaterials, cells, and growth factors. In this context, stem cell-based strategies have made substantial contributions in the field. Researchers worldwide have demonstrated that stem cells have an extraordinary capability to differentiate into different cell lineages, promote tissue regeneration, release a wide range of growth factors, and modulate the host immune response. Based on the current impact of tissue engineering and stem cells in medicine, Concerning the review articles, M. Cimino et al. contributed with a complete review entitled \u201cXeno-Free Strategies for Safe Human Mesenchymal Stem/Stromal Cell Expansion: Supplements and Coatings,\u201d where authors suggest that culture/expansion of human mesenchymal stem cells under xeno-free conditions is still needed to improve their clinical translation. The review made by A. Owczarczyk-Saczonek et al. discussed \u201cThe Use of Adipose-Derived Stem Cells in Selected Skin Diseases ,\u201d highlighting that these stem cells are promising alternatives to generate new engineered or stem cell-based strategies to treat skin diseases.in vivo studies were published in this special issue. On the one hand, M. Mata et al. published the article entitled \u201cIn Vivo Articular Cartilage Regeneration Using Human Dental Pulp Stem Cells Cultured in an Alginate Scaffold: A Preliminary Study\u201d in which they demonstrated, through different histological approaches, that human dental pulp stem cells have a positive impact on the regeneration of articular cartilage in rabbits. On the other hand, V. Chapman et al. demonstrated that late passage marrow-derived mesenchymal stem cells were more efficient than early passage cells in the treatment of osteoarthritis on their article entitled \u201cTherapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis.\u201d These articles provide new evidence related to the usefulness of stem cells in cartilage tissue engineering.In the field of cartilage tissue engineering, two interesting Cryptomphalus aspersa's eggs induced the differentiation of adipose stem cells to myofibroblast on their study entitled \u201cHigh Sensitivity of Human Adipose Stem Cells to Differentiate into Myofibroblasts in the Presence of C. aspersa Egg Extract.\u201d In another interesting ex vivo approach, E. Oliveira et al. on their article \u201cInfluence of Different ECM-Like Hydrogels on Neurite Outgrowth Induced by Adipose Tissue-Derived Stem Cells\u201d demonstrated the synergetic effect of the correct combination of biomaterials and adipose stem cells to increase the neurite outgrowth from DRG explants. In these articles, the usefulness and versatility of adipose stem cells in tissue engineering were well demonstrated.Currently, adipose-derived mesenchymal stem cells are considered one of the most promising mesenchymal stem cells by several and well-supported reasons. Within this special issue, N. Garcia-Honduvilla et al. demonstrated that a natural extract purified from in vivo approach, M. Garrido et al. demonstrate the potential clinical application of amniotic membrane in digestive surgery on their article \u201cTransplantation of Human Amniotic Membrane over the Liver Surface Reduces Hepatic Fibrosis in a Cholestatic Model in Young Rats.\u201d These three articles highlight the potential clinical usefulness of extraembryonic-derived cells and scaffolds in tissue engineering.Extraembryonic tissues are an important source of stem cells and natural scaffolds. In this regard, G. P. Liao et al. successfully repaired diaphragmatic defects in rats by using decellularized rat diaphragm containing human amniotic fluid-derived stem cells on their article entitled \u201cTissue Engineering to Repair Diaphragmatic Defect in a Rat Model.\u201d In addition, in order to solve the problem associated to the expansion of epithelial cells, S. M. Nam et al. investigated the use two stem cells sources as feeder cells of corneal epithelial cells on their article entitled \u201cEx Vivo Expansion of Human Limbal Epithelial Cells Using Human Placenta-Derived and Umbilical Cord-Derived Mesenchymal Stem Cells.\u201d In an Finally, in these nine articles, authors rigorously discussed and demonstrated the high versatility of different kinds of stem cells to differentiate, promote tissue healing, modulate host immune response, and serve as feeder platform for the ex vivo expansion of differentiated cells. In conclusion, the articles published in this special issue provide new tissue engineered-based strategies and scientific evidence that support the potential clinical usefulness of stem cells in regenerative medicine.V\u00edctor CarrielStefano GeunaMiguel Alaminos"}
+{"text": "ICC) is the second most common primary hepatic malignancy with poor prognosis. Despite improvements in its diagnosis and therapy, the prognosis for ICC patients remains poor. An improved understanding of ICC pathogenesis and consequential identification of novel therapeutic targets would improve the prognosis of ICC patients. MicroRNAs (miRNAs) are a class of highly conserved, endogenous, small non\u2010coding RNA molecules of 18\u201323 nucleotides in length, which regulate gene expression through complementary base\u2010pairing with target messenger RNAs and subsequent gene silencing. Several studies have shown deregulated expression of miRNAs in ICC cell lines and tissues, in which these miRNAs play important roles in ICC apoptosis, cell proliferation, invasion, migration and metastasis. In this review, we illustrate the potential role of miRNA in the pathogenesis of ICC and explore the possibilities of using miRNAs as prognostic and diagnostic markers, as well as therapeutic targets in ICC.Intrahepatic cholangiocarcinoma ( Intrahepatic cholangiocarcinoma (ICC) originating from cholangiocytes is the second most common primary tumour of the liver MicroRNAs (miRNAs) belong to a new class of small non\u2010coding, endogenous RNAs comprising 18\u201323 nucleotides that negatively regulate gene expression through inducing mRNA degradation or repressing translation by annealing with the complementary sites in 3\u2032\u2010untranslated regions (3\u2032\u2010UTRs) of target mRNAs via exportin\u20105 Previous data showed that miRNA synthesis and maturation consists of a stepwise process that is compartmentalized between the nucleus and the cytoplasm et al. using 27 ICC tissues, 10 normal cholangiocyte samples and 8 normal liver tissues Deregulated miRNAs in ICC were listed in Table Further study on miRNAs expression profiling identified a number of significantly deregulated miRNAs in two ICC cell lines (HuCCT1 and MEC) as compared with a normal intrahepatic biliary epithelial cell line (HIBEpiC) et al. Oishi et al. Plieskatt et al. Wang et al. Karakatsanis et al. Recently, Zhang et al. Plieskatt via derepressing or suppressing important signalling mediators along specific signalling pathways pertinent to cancer development.A number of aberrantly expressed miRNAs have been reported to function as tumour suppressors or oncogenes in ICC Table  via dereet al. Hu et al. Wang et al. in vitro and impaired tumour growth in vivo. Furthermore, PTPN14 and PTEN were identified as direct and functional targets of miR\u201021. High expression levels of miR\u201021 were closely related to adverse clinical features, diminished survival and poor prognosis in ICC patients.Wang The biological functions and/or prognostic significance of two down\u2010regulated miRNAs, namely miR\u2010204 and miR\u2010320, have been studied in details et al. Twist, and decreased E\u2010cadherin levels by directly targeting the Twist gene. Oishi et al. Li et al. in vitro and reduced the protein levels of SMYD3 and downstream target genes . Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR\u2010124 overexpression.Hepatitis C virus core protein (HCVc) plays an important role in the development of ICC. Zeng et al. Iwaki et al. Qiu et al. Li et al.Bernuzzi The dismal prognosis and aggressive progression associated with ICC have led researchers and clinicians to explore new avenues of potential treatment for ICC patients The authors declare no conflict of interest."}
+{"text": "The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders\u2014such as rubella, human immunodeficiency virus, and herpesviruses\u2014and human distal-less homeobox (DLX) proteins expressed in developing brain\u2014namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity\u2014that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens. Infections, neuropsychiatric diseases, and language disorders are often concomitant pathological events that can have early etiological roots in fetal life and then become apparent in any stage across the life span of the individual, from the postnatal period to the late age  family\u2014namely DLX1, DLX2, DLX5, and DLX6\u2014that have been thoroughly investigated in numerous studies on neurodevelopment. Indeed, the four TFs are expressed during early fetal neurodevelopment , where DLX proteins may be expressed , DLX2 , DLX5 , and DLX6  were dissected into pentapeptides offset by one aa residue: MTMTT, TMTTM, MTTMP, and so forth. Then, each of the resulting pentapeptides was analyzed for matches to a sample library of 25 viral proteomes using the Protein Information Resource (PIR) match program (https://research.bioinformatics.udel.edu/peptidematch/batchpeptidematch.jsp)  was used as a control neural protein. Glutamate decarboxylases 1  and 2  were additionally investigated as DLX-related proteins.The primary amino acid (aa) sequences of human DXL1 : Borna disease virus ; Epstein-Barr virus ; Hendra virus ; Hepatitis B virus genotype C subtype ayr ; Hepatitis C virus genotype 1a ; Human cytomegalovirus ; Human herpesvirus 1 ; Human herpesvirus 2 ; Human herpesvirus 6A ; Human herpesvirus 6B ; Human immunodeficiency virus type 1 group M subtype A ; Human parvovirus B19 ; Influenza A virus, H5N5 ; Influenza A virus, H1N1 ; Influenza A virus, H7N7 ; Influenza B virus ; Influenza C virus ; Measles virus ; Rotavirus A ; Rotavirus C ; Rotavirus X ; Rubella virus ; Vaccinia virus ; Varicella-zoster virus ; and Zika virus .www.iedb.org) resource   and 4.4% of the DLX2 peptide sharing ;the extent of the peptide sharing is independent of the virus protein length. For example, Rubella virus  and the eleven times longer HHV3  share exactly the same number of pentapeptides\u2014namely, three\u2014with DLX1 protein;quantitatively, the extent of the peptide sharing is unexpectedly high compared to the mathematical expected value of the pentapeptide sharing between the five neural proteins and the 25 viral proteomes. The expected value can be calculated as follows: given two protein entities  and assuming that all aa occur with the same frequency, the expected probability for the two entities to share a pentapeptide is expressed by the formulam is the number of pentapeptides present in the DLX1 protein ; n is the number of pentapeptides present in the set formed by the 25 viral proteomes , and N is the number of all possible pentapeptides. Since each residue can be any of 20 aa, then N is 205 . Developing the equation, the expected pentapeptide sharing between DLX1 and the 25 viral proteomes is equal to 1,02668314453125e-5 or, practically, zero.where: www.immuneepitope.org; Vita et al., n < 12.The pentapeptide matching between viral and neural proteins illustrated in Table A comparative analysis of DLX expression in fetal and adult neurogenic areas of the human brain was conducted using the online database and resources of the Allen Institute for Brain Science (Lein et al., On the whole, Figure Actually, few data are available on DLX protein expression in humans. Rakic and Zecevic  studied https://www.proteinatlas.org/on DLX1 and DLX5 protein expression in the adult human brain. The data are shown in Figure Such experimental results obtained in human fetal developing brain are flanked by data collected from the Human Protein Atlas (www.proteinatlas.org; Uhl\u00e9n et al., In essence, we found a vast and unexpected peptide sharing between DLX proteins and numerous infectious agents that constellate human life, from prenatal time to adulthood. The peptide platform defined in Table In this context, different immunological pathogenic mechanisms might be theoretically account for the neuronal damage according to the type of immune response, i.e., humoral vs. cell-mediated, and the timing of infection-induce maternal immune activation in relationship to the expression patterns of DLX proteins in the fetus (see Figure On the other hand, a cell-mediated mechanism could also theoretically be implied in the cross-reactive immune-mediated subclinical damage of the fetal nervous systems, since memory T-cell trafficking between mother and fetus is also a well-known phenomenon (Jeanty et al., Based on data from Figure Functionally, infection-induced immune cross-reactions would affect two TFs that, according to numerous studies, are implicated in crucial functions and fundamental processes during neurodevelopment and adult neurogenesis, and are potentially relevant to language competence and other higher cognitive functions see Box ;Spatially, infection-induced immune cross-reactions would damage brain structures where adult neurogenesis occurs and that are involved in the neural circuitry of language and memory, and in cognitive and emotional functions (Ming and Song, Temporally, infection-induced immune cross-reactions suggest a two-hit model that, depending on the DLX protein expression profiles, comprehends targets allocated in two time-windows in the life of an individual with a subclinical damage in fetal life and clinical onset in adulthood.Box 1DLX1:regulates the development of the ventral forebrain, craniofacial patterning, and the early diencephalic subdivision (Eisenstat et al., regulates neurite maturation and migration (Cobos et al., regulates the fate switch between cortical and striatal interneurons: cells that ordinarily would become cortical interneurons transform toward a subtype of GABAergic striatal interneurons, thus reducing glutamatergic input to the hippocampus (McKinsey et al., its loss leads to subtype-specific loss of inhibitory interneurons with a reduction in inhibitory currents and generalized seizures in mice (Cobos et al., contributes to promote cortical interneuron migration from the basal forebrain by direct repression of the semaphorin receptor neuropilin-2 (Le et al., when altered, might be related to Mowat-Wilson syndrome (McKinsey et al., is downregulated or altered in autism spectrum disorders (ASD; Liu et al., has low thalamic expression in psychosis (Kromkamp et al., has been proposed as a language-associated protein (Boeckx and Ben\u00edtez-Burraco, DLX5:promotes neuronal differentiation in SVZ (Shu et al., its loss leads to defective neuronogenesis (Perera et al., contributes to convert fibroblasts into induced GABAergic interneurons (Colasante et al., regulates development of peripheral and central components of the olfactory system (Long et al., is a candidate genes for autism (Nakashima et al., is involved in Rett syndrome (Itaba-Matsumoto et al., participates to the regulation of the expression of the glutamic acid decarboxylases (St\u00fchmer et al., its loss preferentially reduces the number of mature parvalbumin- interneurons (Wang et al., in vivo, the possibility of obtaining animal models of neuropsychiatric disorders by immunizing pregnant animals with DLX proteins could be examined. Moreover, analyses of sera from human patients with neuropsychiatric diseases, for example schizophrenia, are warranted to measure immunoreactivity against the peptides shared between viruses and DLX proteins. Possibly, the results of these joint basic and clinical in vivo approaches might also help design new therapeutic approaches in neuropsychiatry.In synthesis, the present study confirms previous reports (Kanduc et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We are aware of concepts of osmotic and oncotic pressure in clinical physiology. Per Starling's law, the freely movable ions do not significantly contribute to the retention of vascular volume, or the maintenance of interstitial fluid pressure  was predicted for a long time (Stiernet et al., In the beta cells of the pancreas, the insulin granules are not freely soluble molecules in the cytosol but rather exists as packaged vesicles. Electron micrographs of beta cells and physiological experiments have revealed that these insulin granules undergo regulated exocytosis to a glucose load, rather than random secretion Dean, . PotassiRecently, it has been suggested that the exocytosis involving insulin granules resembles remarkable similarity to the pattern of inhibitory enteric neuromuscular neurotransmission (Chaudhury, \u2212/\u2212 mice, the number and appearances of secretory granules in islet \u03b2-cells of knockout mice were normal (Sakamoto et al., The SLC17A9 channel transports ATP within the insulin containing dense core vesicles (Sawada et al., Type II diabetes mellitus is characterized by progressive exhaustion of the beta cells of the pancreas (Butler et al., In this commentary, we advance the hypothesis that SLC17A9 dysfunction may contribute to the ongoing inefficacy of insulin exocytosis, leading to progressive diabetes. The lack of entry of ATP through a dysfunctional SLC17A9 (Sakamoto et al., What causes SLC17A9 dysfunction is not clear. Interestingly, SLC17A9 is gated by ATP itself (Sawada et al., There have been recent advances of novel markers that can tag synaptic proteins, especially those acting on the membranes. PET imaging may detect these global aspects of neurotransmission (Finnema et al., ArC, conceptualized and development of manuscript, drafted manuscript. CD, major intellectual contribution. VD, major intellectual contribution. CM, important discussion. NS, important discussion. WM, important discussion and conceptualizations. RR, important discussion. AM, important discussion, manuscript recheck. AdR, important discussion and prospects. All authors read and approved final version of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Helicobacter pylori-mediated inflammation has been implicated in gastric cancer in many previously established studies, and Fusobacterium nucleatum presence has been observed with greater intensity in colorectal cancer patients. Despite ambiguity in the exact mechanism, infection-mediated inflammation may have a link to cancer development through an accumulation of potentially mutagenic DNA damage in surrounding cells. The multiple DNA repair pathways such as base excision, nucleotide excision, and mismatch repair that are employed by cells are vital in the abatement of accumulated mutations that can lead to carcinogenesis. For this reason, understanding the role of DNA repair as an important cellular mechanism in combatting the development of cancer will be essential to characterizing the effect of infection on DNA repair proteins and to identifying early cancer biomarkers that may be targeted for cancer therapies and treatments.Pathogenic and commensal microbes induce various levels of inflammation and metabolic disease in the host. Inflammation caused by infection leads to increased production of reactive oxygen species (ROS) and subsequent oxidative DNA damage. These in turn cause further inflammation and exacerbation of DNA damage, and pose a risk for cancer development.  The significance of cancer as a disease that affects a large percentage of the world population is undeniable. It is one of the leading causes of death worldwide and according to World Health Organization, it causes 8\u20139 million deaths/year. In the United States alone, it is projected that 39.6% of the population will have some type of cancer during their life. Consequently, there are enormous expenditures in the field of cancer care. The expenditures for cancer care in the United States were nearly $125 billion in 2010 and could reach $156 billion in 2020; as mentioned in the website of National Cancer Institute. Infection and infection-associated inflammation is the major threat of cancer. Chronic inflammation from infection causes abnormal immune response, obesity, DNA damage and cancer. The best example is the inflammatory bowel disease where Ulcerative colitis and Crohn's disease develop colon cancer.Helicobacter pylori (gastric cancers), hepatitis B and C viruses (hepatic cancers), and Fusobacterium (Colon cancer). The detailed list of microbes that have been researched in relation to their effect on certain DNA repair proteins are added in the Table In 1863, Rudolf Virchow was the first scientist to link inflammation with cancer. He mentioned that the origin of cancer was at sites of chronic inflammation and a group of irritants with tissue injury causes cell proliferation  of innate immune system . The inflammatory cytokines have been reported to generate ROS and reactive nitrogen intermediates (RNI) using NADPH oxidase in phagocytic cells and epithelial cells  directly induces DNA damage. The versatility of different ROS is reflected in the wide array of DNA damage that they can cause. In general, the hydroxyl molecule (OH\u2212) is the most damaging form of ROS, but other forms like the oxygen molecule (O2), RO2, and RO are also capable of different types of damage. For instance, while OH\u2212 can react with all of the bases and the deoxyribose backbone of DNA, O2 preferentially targets guanine residues  that inflict damage on the host DNA such as DNA strand breaks that may affect tumor suppressors or oncogenes . The MMR, BER, and NER pathways respond to specific lesions in DNA residues. DSBs are particularly dangerous lesion and are repaired by two principal pathways: NHEJ pathway functions in all phases of the cell cycle, while the high-fidelity HR pathway requires a template for repair and utilizes available sister chromatids during the S and G2 phases of the cell cycle.Nucleotide excision repair, or NER, is a versatile repair pathway that recognizes bulky adducts and general base lesions that cause a distortion of the double-helix structure of DNA. The major sources of these types of DNA damage are ultraviolet radiation and various types of genotoxic chemicals  and transcription-coupled repair (TC-NER) pathways. In GG-NER, DNA damage is removed from the whole genome while TC-NER is primarily involved in repairing the damage on the coding strand of actively transcribed genes  is now considered a specialized sub-pathway of BER. They share several common proteins including APE1, Pol\u03b2, LIGIII\u03b1, along with the nick sensor poly (ADP-ribose) polymerase 1 (PARP1) and the scaffold protein X-ray cross-complementation group 1 (XRCC1) . On the other hand, the mammalian bifunctional DNA glycosylases have an associated AP lyase activity generating 3\u2032dRP  or 3\u2032-P (NEIL1 and 2) and 5\u2032-P. The DNA polymerase then fills in the gap using the template DNA strand and finally, DNA ligase seals the nick by completing the repair of the DNA duplex , RAD50, and NBS1 recruits ATM (ataxia telangiectasia mutated), generates DNA breaks followed by phosphorylation of histone H2AX (generating \u03b3H2AX) that amplifies the damage signal  and generate DSBs that ultimately progress to gastro-intestinal cancer  and Colibactin. Cdt is present in There are multiple mechanisms for bacterial infections to induce cancer, and we focused gastric cancer and colon cancer here. Further studies in this arena will give more in depth insight to the mechanisms of association between specific bacterial infections and cancers, but in the next section we will discuss the well-known and characterized bacterial-infection associated cancers especially through the lens of ROS induced DNA damage and alteration of DNA repair pathways.Chlamydia pneumonia and Mycobacterium tuberculosis  and failure in these bring DNA damage/mutation and genomic instability. Microbial infection is one of the major reasons of the failure of DDRs.Microbes such as bacteria, virus and parasites are able to activate or alter various signaling pathways that may lead to either activation of oncogenes or down-regulation of tumor suppressor genes in a contribution to cancer progression   is able to bind E-cadherin to induce greater \u03b2-catenin release and ultimately activate WNT signaling, which is oncogenic  and outer inflammatory protein A (OipA) are involved in epidermal growth factor receptor activation which leads to PI3K-AKT signaling and ultimately activates \u03b2-catenin , the major pathway that repairs small-scale mutations such as single base pair mismatches, is inhibited (Kim et al., H. pylori infection. Additional MMR proteins MLH1, MSH3, MSH6, PMS1, and PMS2 have also been shown to be down-regulated upon H. pylori infection of gastric cell lines AGS and BG (Machado et al., H. pylori infection are supposed to be repaired by the BER pathway in a normally functioning cell. In a cell infected with H. pylori, there is decreased expression of vital BER proteins. APE-1, an AP endonuclease, and YB-1, an early-stage repair protein of BER, are down-regulated upon H. pylori infection (Machado et al., H. pylori infection. Reduced expression of OGG1 allows for accumulation of abasic sites that would not be repaired by the other DNA repair pathways and lead to carcinogenic mutation-build up and cellular transformation (Kidane et al., An accumulation of DNA damage caused by chronic inflammation and resulting ROS has the potential to induce cellular transformation. In a normally functioning cell, the multiple DNA repair pathways are able to curb the accumulation of DNA mutations by addressing the damage as it occurs. In a cell infected by H. pylori induced gastric cancer has been. Certain pathogenic species such as enterotoxigenic Bacteroides fragilis and Escherichia coli strain NC101 have been linked to colitis-associated colon cancer (Wu et al., The association between bacterial infection and colon cancer has not been elucidated to the extent that Fusobacterium nucleatum in abundance in colorectal tumor tissues (Kostic et al., F. nucleatum is a gram-negative microbe more often associated with the oral cavity. However, the bacterial species have been identified in the early stages of cancer in colorectal adenomas as well as carcinoma samples (McCoy et al., F. nucleatum to mice was shown to speed up colonic tumorigenesis and induce a pro-inflammatory state through NF-\u03baB signaling (Kostic et al., F. nucleatum has also been positively correlated with mortality linked to colorectal cancer, meaning that greater abundance of the bacteria more likely resulted in mortality due to the cancer (Mima et al., F. nucleatum is a causative agent in colorectal carcinogenesis, but the preliminary studies have indicated the involvement of bacteria in the induction of cancer (Ray, One area of interest in this field is the presence of cer Ray, .F. nucleatum is a very invasive bacterial species due to its ability to adhere well to mucous surfaces (McCoy et al., F. nucleatum can therefore act similar to H. pylori and adhere to host cell surfaces to alter cellular pathways with its bacterial proteins. Once F. nucleatum adheres to host cells, bacterial FadA adhesin binds E-cadherin to activate \u03b2-catenin signaling to increase cell growth and proliferation as well as to regulate inflammatory response of the cell (Rubinstein et al., F. nucleatum has also been found to activate TLR4 and ultimately lead to NF-\u03baB activation (Yang et al., F. nucleatum to a pro-inflammatory state (Kostic et al., F. nucleatum in the colon (Rubinstein et al., F. nucleatum contributing to carcinogenesis and tumorigenesis by inducing genetic mutations as a result of prolonged inflammation and potentially the down-regulation of various DNA repair pathways, similar to what occurs in H. pylori-mediated inflammation leading to gastric cancer.In the oral cavity, H. pylori and Fusobacterium, Salmonella typhi infection has been associated with the development of gallbladder cancer (Mager, Other bacteria associated cancers: Other that r Mager, . All othHelicobacter pylori infection correlated to a lower risk for esophageal cancer development (de Martel et al., Streptococcus pyogenes and Serratia marcescens in the late 1800's to induce an initial fever followed by treatment for many different types of cancers (de Martel et al., Salmonella enterica serovar Typhi reduced tumor growth and enhanced survival in mice (Vendrell et al., Mycobacterium bovis, is used clinically for the treatment of high-risk urinary bladder cancer (Kucerova and Cervinkova, While a number of bacterial infections have been shown to increase the potential for carcinogenesis, recent developments in the field have provided evidence for a positive role of certain bacteria and toxins in cancer prevention and therapy Mager, . For exaH. pylori, Hepatitis B and C virus, and Human papilloma virus (Mantovani et al., F. nucleatum and colorectal cancer, on the functionality of the various DNA repair pathways, can lead to novel identification of various markers for early cancer detection as well as more effective therapies and treatments that can combat the loss in DNA repair function in host cells.About 20% of the global cancer burden is linked to infectious agents including, but not limited to, All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this mini-review we discuss the biological characteristics of studied material  and its handling  which influence results of histochemical staining with \u201cclassical\u201d fluorochromes. Future perspectives of ROS and RNS imaging with newly designed probes are briefly outlined.Developmental transitions and stress reactions in both eukaryotes and prokaryotes are tightly linked with fast and localized modifications in concentrations of reactive oxygen and nitrogen species (ROS and RNS). Fluorescent microscopic analyses are widely applied to detect localized production of ROS and RNS  Quite recently, peroxynitrite (formed upon NO reaction with superoxide anion) was shown as a positive regulator of plant cell signaling by tyrosine nitration in proteins  are generated and scavenged over the whole life span of all known types of aerobic organisms. In plants and fungi production of ROS, together with reactive nitrogen species (RNS), has been linked with almost all developmental processes from germination through reproduction until cell death Asada, . ROS andArabidopsis research. Cell-permeable fluorescence-based probes were subsequently introduced to detect tiny real-time changes in ROS and RNS levels within relevant cellular compartments, e.g., DCF DA and DHDCF DA for detection of ROS , proper sample washing, keeping constant time of staining/scanning within a set of experiments, using optimal pH and turgor pressure can contribute to obtaining of correct results. Still it should be emphasized that histochemical staining and subsequent microscopic detection cannot be used for accurate ROS/RNS quantification but the combinations of several different analytical methods can give more reliable estimation of their intracellular levels  for hydrogen peroxide , hydatodes (at leaf edge), or nectaria (in flowers) can enhance the introduction of fluorochromes into the living tissues of above-ground plant organs. The fluorochromes uptake in multicellular organs can thus be enhanced by increased external or decreased internal pressure, e.g., by syringe or vacuum infiltration, respectively (Figure Optimization of staining procedures for different photosynthetic and fungal organisms in our laboratory showed that results of ROS/RNS imaging in multicellular biological matrices are significantly influenced by the feasibility of material infiltration with the applied probes Figure . Currenty Figure . Moreovey Figure  but sevey Figure .in vivo patterns of ROS and RNS abundance within plant organs and meristems. Newly synthesized probes with increased specificity and improved photostability have been reported, such as Aarhus Sensor Green preferable to SOSG for singlet oxygen (Pedersen et al., Arabidopsis, both on cultured cells and on leaves (Ledoux et al., 2O2 endogenously produced in living macrophages (Yuan et al., Recognized drawbacks of commercially available fluorescence probes for ROS and RNS detection initiated a quest for improved tools to measure more accurately the differential 2O2 with good selectivity based on intramolecular charge transfer (Chen et al., in vitro. However, the \u201cclassical fluorescent probes\u201d based mainly on diaminofluorescein derivatives, still represent important tools to study ROS and RNS in plant science (Nie et al., 2O2, peroxalate esters, and fluorescent dyes as published for in vivo imaging of H2O2 in mouse model (Lee et al., Fluorescein derivatives have become replaced in animal ROS and RNS research by more specific molecular probes based on nanoparticles or redox-sensitive fluorescent proteins (for review see Guo et al., in vivo monitoring. The situation resembles a \u201cpopulation bottle-neck\u201d; only a reduced number of protocols are applicable to ROS and RNS microscopy in plant and fungal models and thus these few remain fixed in routine practice for a substantial period. With increasing knowledge on the importance of localized and tiny intracellular redox fluctuations the quantitative and spatio-temporal analysis of ROS and RNS levels in plant and fungal cells is still highly challenging.Although, a plethora of ROS and RNS sensing molecules have been designed, just a part of them has been confirmed experimentally to be suitable for ROS and RNS MS prepared manuscript based on long-lasting discussions and joint experiments with LL, it was approved and widely discussed by both authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "One rationale for the frequent use of MgSO4 in critical care is the high incidence of hypomagnesaemia in intensive care unit (ICU) patients. Correction of hypomagnesaemia along with the neuroprotective properties of MgSO4 has generated a wide application for MgSO4 in ICU.Magnesium (Mg) has been developed as a drug with various clinical uses. Mg is a key cation in physiological processes, and the homeostasis of this cation is crucial for the normal function of body organs. Magnesium sulfate (MgSO Magnesium (Mg) is one of the most abundant cations in the body, and is also a drug with numerous clinical applications. The body usually contains up to 28 g of Mg . Most ovia regulating intracellular calcium availability . Magnesani, 2011). Calciuani, 2011; Noronhaani, 2011). Influx and efflux of Mg plays an important role in different transcellular transports . MagnesOne of the key reasons for the wide use of Mg in critical care is the high prevalence of hypomagnesaemia in ICU patients  reduction of intestinal absorption of Mg, (2) increased loss of Mgbyrenal route, and (3) compartmental redistribution . The moIntravenous Mg supplementation rapidly increases serum Mg level following long-term use of PPIs and subsequent hypomagnesaemia. PPIs affect intestinal epithelial cell locally. Oral Mg is not effective in PPI's induced hypomagnesaemia. Discontinuation of PPI use will resultsin quick normalization of serum Mg levels , post-renal transplantation and drug-induced Mg wasting  are reasons for renal Mg loss . These Numerous roles for magnesium in critical care medicine have been suggested . Defici4) was used to prevent eclamptic seizures in Germany . Magnesal., 1985). MgSO4 hak, 2002; Ignatavhak, 2002). A numbhak, 2002; Gonzalehak, 2002). Hypomahak, 2002). MgSO4 ard, 1925; Pritchaard, 1925), and coNumerous mechanisms of action have been suggested for magnesium including 1) vasodilatory action, (2) blood-brain barrier (BBB) protection, (3) reduction of cerebral edema, and (4) central anticonvulsant action .4 as a treatment option for patients who are resistant to standard therapy , agonists of \u03b22-receptors, inhaled ipratropium bromide, corticosteroids, anticholinergic drugs and general managements . Researal., 2008; Gontijoal., 2008; Jones aal., 2008; Kew et al., 2008). Life-tal., 2000; Daengsual., 2000; Griffital., 2000; Kew et al., 2000; Kokturkal., 2000; Rowe, 2al., 2000; Rowe anal., 2000; Rower eal., 2000; Singh eal., 2000).+-Ca2+ pumps), (2) muscle relaxation , (3) reduction of inflammatory mediators (inhibition of degranulation of mast cells and T-cells stabilization), (4) depression of the irritability of muscle fibers, and (5) inhibition of prostacyclin and nitric oxide synthesis. These mechanisms lead to a reduction in the severity of asthma  reduction of intracellular calcium level .4 is used via intravenous and inhalation routes for the management of acute asthma  and peak expiratory flow rate (PEFR) were assessed in different clinical trials . Use ofal., 2000; Daengsual., 2000; Griffital., 2000; Kew et al., 2000; Kokturkal., 2000; Rowe, 2al., 2000; Rowe anal., 2000; Rower eal., 2000; Singh eal., 2000). In somnes, 2008). Unlikeal., 2000, 1996[29al., 2000; Porter al., 2000; Scarfonal., 2000). The imal., 2002; Boonyaval., 2002; Devi etal., 2002; Gallegoal., 2002; Green aal., 2002; Hughes al., 2002; Mahajanal., 2002; Silvermal., 2002; Tiffanyal., 2002). In chial., 2013; Liu et al., 2013). Up to al., 2013; Devi etal., 2013; Green aal., 2013; Singh eal., 2013; Tiffanyal., 2013). Howeveal., 2006; Gallegoal., 2006; Gandia al., 2006; Hill etal., 2006; Hughes al., 2006; Kokturkal., 2006; Mangat al., 2006; Nanninial., 2006; Nanninial., 2006; Rolla eal., 2006; Zandsteal., 2006). Respiral., 2006; Gandia al., 2006; Hill etal., 2006; Mangat al., 2006; Nanninial., 2006; Nanninial., 2006; Rolla eal., 2006; Zandsteal., 2006). In oneal., 2013). In 201al., 2016). In chial., 2016). Adversott, 2008). 4 has been well documented to be beneficial in the management of nervous system injuries especially in the ICU. These injuries include stroke, aneurysmal subarachnoid hemorrhage (ASAH), and traumatic brain injuries . 4 in ASAH in the last two decades  velocity and Glasgow Outcome Scale (GOS). The findings showed better outcome in patients with ASAH 90 days post-hemorrhage, but they did not find a significant difference in GOS between the control and treatment groups . Differal., 2002). Also, al., 2002) showed ues (2005) revealeal., 2006). High dal., 2008). MgSO4 al., 2013; Chen anal., 2013; Westermal., 2013). Despital., 2009; Wong etal., 2009). Friedlal., 2009) reporte4 24 hours post-stroke shows a significant decrease in the infarct volume based on the findings of MRI . Saver al., 2009). In theal., 2002). Singh al., 2002) showed al., 2013). It wasal., 2006). Concural., 2012; Zhu et al., 2012).4 on biomarkers in different neuropathies has been assessed in several studies . MgSO4 al., 2012). The inal., 2012; Mirrahial., 2012). The deal., 2012). S100B al., 2012; Lamers al., 2012). Increaal., 2012; Mizukosal., 2012). Increaal., 2012). 4 decreases inflammatory biomarkers such as nitric oxide, prostaglandin E2, interleukin 1\u03b2 and tumor necrosis factor-\u03b1 . Concural., 2013; Ovbiageal., 2013).TBI is an important health problem with high a mortality and morbidity rate . StudieNumerous studies have reported that Mg plays an important role in the prevention and treatment of central nervous system (CNS) injuries. Magnesium protects neurons from ischemic injuries and supports neuronal survival following TBI with different mechanisms such as: (1) blocking NMDA channels, (2) inhibition of presynaptic excitatory neurotransmitters, (3) inhibition of voltage-gated calcium channels, and (4) potentiation of presynaptic adenosine. Moreover, Mg can relax vascular smooth muscles and enhance cerebral blood flow. Serum total and ionized Mg levels are reduced after head injuries  .4 in diffuse axonal injury has been shown by Zhao et al. . The inal. (2016). The pral. (2016). The moal. (2016). 4 cannot improve the strength of respiratory muscles in the critically ill patients under mechanical ventilation . Serum al., 1993). The noal., 1993).4 is an important drug in the ICU. MgSO4 can increase brain tissue oxygenation index by 34 % after cerebral artery occlusion . As staal., 2005). Electrolyte imbalance following hypomagnesaemia has been reported by researchers in the ICU , coronary artery bypass surgery and heart valve surgeries . Kaplanal., 2003). Concural., 2012). In subal., 2012). Adminial., 2013).4 as a neuroprotective agent, current evidence suggests that MgSO4 is an important part of the management of ICU patients (Table 14 therapy in the ICU, serum Mg levels should be checked on a daily basis.Despite the controversial views on the effects of MgSOs Table 1. (RefereThe authors have no competing interests to declare."}
+{"text": "Editorial on the Research TopicHomeostasis and Allostasis of Thyroid FunctionA basic understanding of thyroid control involving pituitary thyrotropin (TSH) has become a cornerstone for the contemporary diagnosis of thyroid disorders. However, long-held simplistic interpretations of the classical feedback concept fall short of the elusive goal of a universally applicable and reliable diagnostic test. Diagnostic ambiguities may arise from the dynamic nature of thyroid homeostasis. Concentrations of TSH and T3 are governed by circadian  and, addConsequently, the clinical care of thyroid patients faces major challenges, foremost ill-defined reference ranges for TSH and thyroid hormones (THs), and persistently poor quality of life in a substantial subset of treated hypothyroid patients . Divergestability through change by modifying setpoints and parameters of feedback control  provides an overview of homeostatic mechanisms in the light of recent research. The classical \u201cshort feedback\u201d structure (Astwood-Hoskins loop) (A review article by the editors (ns loop)  is now cns loop) , 18, thens loop) \u201323.Hoermann et al.; .Newly identified non-classical processing structures add to the complexity of the control system. They explain both pulsatile thyrotropin release and significant deviations from a log-linear relationship between FT4 and TSH concentrations . In  et al.; , therebyrelational stability [Hoermann et al.; .The novel clinical concepts feed back to theory. \u201d models \u201335, demoLeow, extending implications to antithyroid treatment and LT4 substitution.Interpretation of thyroid function tests can be severely affected by homeostatic time constants resulting in hysteresis effects , as reviAlthough sensitive for primary hypothyroidism, TSH measurement has low specificity and is unable to detect dysfunctions of central origin. Isolated TSH measurements may be misleading in certain physiological  and alloDietrich et al.) for novel diagnostic approaches based on mathematical modeling, such as functional thyroid reserve capacity and step-up deiodinase activity. These calculated parameters deliver estimates for \u201chidden\u201d structure parameters of thyroid homeostasis and provide early indicators of thyroid failure. Reconstructing the individual equilibrium point  of thyroid homeostasis is facilitated by new tools and may prove useful as a personal target for L-T4 dosage titration , e.g., for therapy of stroke or in long-lasting space flights. Based on its pleiotropic effects they question if 3-T1AM can be a safe cryogenic drug. Some of the inconsistencies in reported serum concentrations may result from plasma protein binding, potential role of gut microbiota in the formation of thyronamines from iodothyronines or conversion of 3-T1AM to 3-iodothyroacetic acid (3-TA1), a possible major mediator of thyronaminergic signaling .The traditional view of pituitary\u2013thyroid feedback control holding T4 plasma concentration constant close to a fixed set point  has beenHoermann et al.).Deeper insights in the physiology of thyroid function and its homeostatic control warrant a rethinking of diagnostic practice. The old paradigm employing TSH in the center of diagnostic work-up has to be replaced by a relational concept, where TSH is interlocked with FT4 and FT3, and multivariable distributions represent homeostatic equilibria , 30. ThiJD, JM, and RH wrote some of the papers in this Research Topic and participated as guest editors for manuscripts, where they were not coauthors themselves. All authors listed have made a substantial, direct, and intellectual contribution to this editorial and approved it for publication.JD received funding and personal fees by Sanofi-Henning, Hexal AG, Bristol-Myers Squibb, and Pfizer and is co-owner of the intellectual property rights for the patent \u201cSystem and Method for Deriving Parameters for Homeostatic Feedback Control of an Individual\u201d . All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported."}
+{"text": "We recently elucidated several misperceptions in a field related to toxin/antitoxin (TA) systems, persister cell biology  field, born of controversy, is plagued by several prevailing misperceptions. For example, some TA systems stabilize plasmids and other genomic regions; however, the evidence of post-segregational killing by toxins of TA systems is weak. In addition, the evidence is weak for cell death via TA systems like MazF/MazE and weak for TA systems mediating death in phage exclusion systems. Although many aspects of the biological roles of TA systems remain enigmatic, there are now some clear, confirmed TA functions: (i) phage inhibition, (ii) plasmid maintenance, (iii) stress response (including regulation of loci distinct from the TA pair itself), (iv) biofilm formation, and (v) persistence. Therefore, this opinion piece aims to challenge the oft-repeated claims of cell killing related to TA systems with the goal of emphasizing their primary biological role: constraining metabolism in a reversible manner. Hence, their roles in their five confirmed functions all stem from their ability to rapidly and reversibly reduce metabolic activity.Historically, TA systems were deemed cytosolic (not secreted); hence, TA system toxins were considered primarily to affect the metabolism of the host that produced the TA system rather than as serving as a weapon against other cells, such as colicins , regardless of the gene order. In addition, we prefer naming the antitoxin with four letters ending with an \u201cA\u201d , where possible, to more readily identify the antitoxin.How TA systems are classified is also evolving and is based on the mechanisms by with antitoxins mask toxin activity. There are six well-established systems , was discovered in 1983, and was shown to maintain a mini-F plasmid , that also stabilized a plasmid (R1) , and R1 plasmids  have a copy number of 6  are also suspect. For example, although roughly 80% of vegetative Myxococcus xanthus cells undergo PCD during nutrient-limiting development , it was claimed that MazF mediated this killing  has been proposed as a quorum-sensing element for E. coli type I TA system Hok/Sok inhibits T4 phage propagation  was an \u201cantitoxin\u201d .Even this year it has been written that \u201cthe biological roles of many TA modules still remain elusive\u201d  eliminating nearly all mRMA via toxin MqsR cleaving 5\u2032-GCU sites and (ii) reducing ATP via toxin GhoT  and thereby reduces the translation of the RpoS transcript (Hu et al., S. aureus, the SavS/SavR TA system silences the virulence genes hla and efb by binding their promoters (Wen et al., This role of antitoxins controlling more than their own promoter was confirmed by antitoxin DinJ of the In addition, the TisB/IstR-1 type I TA system has been shown to have the physiological role of producing persister cells when the cell is stressed by ciprofloxacin (D\u00f6rr et al., mqsRA is not governed by conditional cooperativity (Brown et al., E. coli YafQ/DinJ TA system (Ruangprasert et al., Yersinia pestis HicA3/HicB3 TA system (Bibi-Triki et al., Proteus vulgaris HigB-HigA TA system (Schureck et al., It is frequently indicated that conditional cooperativity is the prevalent form of type II TA system regulation (Harms et al., Charles Darwin emphasized the importance of natural selection for beneficial mutations; i.e., changes that lead to improved reproduction will become dominant Darwin, . For bacTW conceived and wrote the manuscript. SS helped write the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Evidence from experimental and clinical studies have shown that oxidative/nitrosative stress and inflammation associated with metabolic disorders such as obesity, hypertension, and diabetes conduce to left ventricular hypertrophy, fibrosis, diastolic dysfunction, heart failure, and ischemia/reperfusion damage , 2.\u03baB, are shown. Information in this issue also includes findings on the relationship between ROS and the activation/maturation of dendritic cells (DCs) that might trigger cardiovascular and metabolic pathologies.In this special issue, original researches on the causative effect of oxidative stress and inflammation on pathologies such as mitral valve prolapse (MVP), arteriosclerosis, hypertension, and ischemia/reperfusion (IR) injury are presented. Also, the evidence of the effect of NLRP3-inflammasome and reactive oxygen species (ROS) production by Ca2+ overload on mitochondrial function, along with the demonstration of the regulatory properties of MG132, demetoxicurcumin, and lycopene on signaling pathways that activate either nuclear factor E2-related factor 2 (Nrf2) or NFThe strong association between osteoprotegerin (OPG) levels and oxidative stress status in patients affected by MVP with severe regurgitation opens its possible use as a serum marker of this pathology according to P. Songia et al. On the other hand, R. Mastrocola et al. demonstrate that the inhibition of NLP3-inflammasome reduces IR injury by activating prosurvival RISK pathway and preserving mitochondrial function. This is interesting and is related to the article presented by Y. Oropeza-Alamaz\u00e1n et al., which demonstrates that silencing of MCU decreases ROS production and mitochondrial dysfunction induced by Ca2+ overload in reperfusion injury.Pharmacological regulation of oxidative stress and inflammation is also included in this special issue. Y. Li et al. demonstrated that the downregulation of cyclooxygenase (COX-2) by demethoxycurcumin (DMC) favors nitric oxide (NO) production via e-NOS activation, preventing endothelial dysfunction, whereas L. Kong et al. demonstrated that MG132 administration inhibits Nrf2 and IkB proteolysis via the proteasome, preventing endothelial dysfunction associated with cardiovascular disease in animals with diabetic nephropathy. The antioxidant and anti-inflammatory properties of lycopene are shown to be related with the downregulation of Rho-associated kinases and the activation of key factor expression in the study described by Y. He et al., who propose that this compound might by a potentially effective method for transplant arteriosclerosis in clinical organ transplantation. Finally, J. Stein et al. show that Nox2-derivated oxidative stress and PKC activation play relevant roles in DCs activation and the atherothrombotic processes that might impinge on cardiovascular and metabolic pathologies.We hope that the research articles included in this issue contribute to the understanding of mechanisms related to the development of cardiovascular diseases and increase the possibility to find novel specific markers and the proposal of new potential therapeutic treatment with the use of new drugs that regulated pathway risk related with the trigger of cardiovascular disease."}
+{"text": "Recently, Mikheil Gogiashvili and colleagues from TU-Dortmund have published a study about the metabolomics heterogeneity of breast cancer . The ba1H NMR are still relatively rare in breast cancer. Therefore, the present study of Gogiashvili and colleagues represents an important milestone in this field of research. Currently, the majority of prognostic studies with cancer patients has been performed based on mRNA (Grinberg et al., 2017; 20159]9]; March"}
+{"text": "Studies in behavioral economics have shown that social punishment can explain why genetically unrelated individuals are often able to maintain high levels of socially beneficial cooperation  and parties that are financially unaffected (\u201cthird parties\u201d \u2014TPP)  and mentalizing  brain regions in TPP (Baumgartner et al., Pioneering behavioral studies have showed that strong emotions trigger the willingness to punish norm violators (Hirshleifer, Recently, Krueger and Hoffman  reviewedInterestingly, these three networks partially overlap with those underlying the detection of norm violations in other social contexts. There is a growing cognitive neuroscience literature on a neural mechanism that detects when individual behavior or beliefs differ from those of others (for reviews, see Izuma, However, amygdala activity was reported only in SPP and TPP studies (Buckholtz et al., Interestingly, TPJ activity during TPP is paralleled by an initial deactivation of the DLPFC (Buckholtz et al., These recent findings raise intriguing and testable questions for future research, e.g., in the use non-invasive brain stimulation to further verify fMRI findings. There is evidence suggesting that transcranial current stimulation could effectively modulate within- and between-network interactions. For example, transcranial alternating current stimulation induced oscillatory desynchronization between the medial frontal and parietal cortices and, therefore, affected value-based decisions but not closely matched perceptual decisions (Polan\u00eda et al., All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The IL-23/IL-23R is critical for pathogenic inflammatory Th17 cell differentiation. Experimental data in murine models of arthritis, colitis and encephalomyelitis corroborate these findings. This manuscript reviews the current knowledge on the effects of sodium chloride on innate and adaptive immunity. We also performed a systematic literature review for clinical studies examining the relationships between salt consumption and the development or the activity/severity of the most common IMDs mediated by the IL-23/Th17 pathway, i.e., rheumatoid arthritis (RA), multiple sclerosis (MS), and Crohn's disease (CD). Nine studies were found, 4 in RA, 4 in MS and 1 in CD. An association was found between developments of anti-citrullinated protein antibody (ACPA) positive RA in smokers and salt intake, but these results were not confirmed in another study. For MS, no association was observed in pediatric subjects while in adult patients, a link was found between salt intake and disease activity. However, this result was not confirmed in another study. These conflicting results highlight the fact that further evaluation in human IMDs is required. Moreover, physicians need to develop clinical trials with diet interventions to evaluate the impact of low salt intake on disease activity/severity of IMDs.Immune mediated diseases (IMDs) are complex chronic inflammatory diseases involving genetic and environmental factors. Salt intake has been proposed as a diet factor that can influence the immune response. Indeed, experimental data report the influence of sodium chloride on the differentiation of naive CD4 Immune-mediated diseases (IMDs) are complex chronic inflammatory disorders involving the contribution of different predisposing factors. Indeed, both specific genetic backgrounds and environmental factors participate in their pathogenesis. Environmental factors have been implicated according to the prevalence of these diseases in certain countries or geographical areas, and/or through exposure of the population to local factors, but lifestyle habits as well as diet are also involved. The most common IMDs are type I diabetes, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis, multiple sclerosis (MS), and inflammatory bowel diseases, such as Crohn's disease (CD). Contributing environmental factors are specific for each IMD, and for instance, smoking is a well identified factor for the development of RA or CD, while ultraviolet exposure is involved in SLE. The influence of diet has long been suspected as a contributing pathogenic factor for IMD. For instance, a Mediterranean diet is thought to influence the occurrence of RA  immune cells. For instance, sodium chloride favored the polarization of pathogenic CD4+ T cells toward a T helper 17 (Th17) phenotype , and especially ILC3 cells, and mucosal-associated invariant T (MAIT) cells  transcription factor . IL-23 has the capacity to induce and maintain the expression of SGK1 in Th17 cells. Using protein-protein interaction analysis from a large database, FOXO1 was identified as a transcriptional factor that had a downstream role in the expression of SGK1. SGK1 promoted phosphorylation of FOXO1, which led to reduced FOXO1 activity and increased IL23r mRNA expression and induction of ROR\u03b3t, a major regulator of Th17 differentiation  when cultured in a hypertonic milieu  has also been reported in normal subjects who have a high salt diet . Finally in a case-control study, sodium intake as evaluated by 24 h urinary sodium excretion was found to be increased in a small cohort of patients with early RA  in the colon (Aguiar et al., IL-10 deficient mice that were exposed to a high-salt diet developed also a more severe spontaneous colitis (Tubbs et al., Normal intestinal lamina propria mononuclear cells\u2014extracted from macroscopically and microscopically unaffected colonic samples of 9 patients undergoing resection for cancer colon- express high quantities of IL-17A, IL-23R, TNF-\u03b1, and ROR\u03b3t when exposed to increasing concentrations of sodium chloride (Monteleone et al., One study examined the relationship between salt consumption and CD (Khalili et al., + T cells markedly infiltrated the central nervous system (Kleinewietfeld et al., In EAE, mice that were fed with a high salt diet developed more severe disease. High salt consumption also accelerated the onset of disease. In this setting, IL-17A expressing CD4Our literature search found 4 papers analysing the effect of dietary salt in MS, namely 2 in adult patients and 2 others in pediatric subjects (Farez et al., We found neither experimental nor clinical data examining the relationship between salt consumption and psoriasis.via IL-23R promotion. Indeed, the studies by Wu et al. and Kleinewietfeld et al. both reported that an increased salt concentration promotes Th17 differentiation by SGK1 involvement (Capon et al., Sodium is an essential nutrient for the organism and is a major physiologic player. The description of its role as an environmental factor in inflammation, and especially in IMDs comes from several reports Arora, . Indeed,Lactobacillus murinus. Treatment of mice with L. murinus prevented salt-induced aggravation of actively-induced EAE by modulating Th17 cells. A moderate high-salt intervention in a pilot study in humans reduced intestinal survival of Lactobacillus spp. and increased Th17 cells. These results indicate that high salt intake is connected to the gut-immune axis (Wilck et al., One question is the consequence of a high salt diet on the blood or lymph node compartments. Indeed, besides the hypertonic and vasopressive effects on blood pressure, a high salt diet does not induce a high concentration in the blood or lymph nodes (van der Meer and Netea, Besides sodium chloride, are other salt components involved in the induction of the Th17 lymphocyte subset? For instance, potassium has been reported to be a protective cation for CD (Khalili et al., SGK1 gene polymorphism is another genetic background that merits investigation, despite negative findings in RA (Jiang et al., Despite strong experimental reports, clinical studies did not report consensual results. Indeed, clinical evidence for the relationships between sodium consumption and development and/or activity/severity of IMDs is limited. Three studies reported such a link in the setting of RA (Sundstr\u00f6m et al., The influence of the environment on the development and clinical expression of IMDs is an exciting and challenging issue. The role of sodium chloride in IMDs such as RA, CD, psoriasis and MS is a relevant question for the pathogenesis of these diseases but also for the management of patients. Current experimental data strongly support a link between salt intake and Th17 differentiation. However, the specific influence of dietary salt intake on the expression of IMDs in humans is still not demonstrated, and requires further studies, especially clinical trials with nutritional interventions aimed at comparing low vs. high salt diets. The interaction between salt and other environmental factors, as well as the genetic background, is a promising avenue for further research, in order to improve our understanding of the specific role of sodium chloride in the pathogenesis of IMDs.ET, MB, CV, and PS analyzed and discussed the literature and conceived the outline of the manuscript. ET and PS wrote the manuscript. All authors reviewed the manuscript and provided critical discussion and input.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Moreover, we measured the concentration of reduced and oxidized ascorbate and glutathione that are involved in ROS detoxification together with phenolics, anthocyanins and tocopherols. Among antioxidant enzymes, we analyzed the activities of ascorbate peroxidase , and the soluble and bound forms of polyphenol oxidase  and guaiacol peroxidase . The data reported in this paper are related to the research article \u201cMetabolic characterization and antioxidant activity in sweet cherry (Prunus avium L.) Campania accessions\u201d, authored by Mirto et al. (2018) In this article, we reported the original data obtained by the study of metabolites and enzymes involved in sweet cherry antioxidant system. We measured hydrogen peroxide (H Specifications TableValue of the data\u2022The data show the antioxidant metabolites and enzyme activities measured in sweet cherries fruits.\u2022The data highlight the differences among the different sweet cherries Campania accessions.\u2022The data are useful to identify the accessions more suitable for long-term storage.1Selecting fruit accessions rich in antioxidant can help delaying fruit senescence and better preserving its characteristics during postharvest. To this aim, we investigated antioxidant metabolites level and antioxidant enzyme activities in forty-three accessions of sweet cherry fruits from Campania region 2O2), as well as malondialdehyde (MDA) of sweet cherry fruit accessions. MDA is considered a useful index of general lipid peroxidation and a biomarker for oxidative stress In 2 (PPO) or H2O2 (POD), and their subsequent, polymerization to melanin. This phenomenon known as enzymatic browning, that occurs during fruit storage In 2To identify the accessions which better resist to oxidative stress and, therefore, are more suitable for the long-term storage, sweet cherry fruits of forty-three accessions from Campania region were harvested and collected at commercial maturity, in the regional experimental farm \u201cImprosta\u201d, Eboli Campania, Italy . One additional commercial accession (Bigarreaux) and two commercial cultivars (Del Monte and Ferrovia) were used as reference. The data were obtained by biological triplicates, each one constituted by twenty fruits from five plants, analyzed separately. The fleshy part of fruits was cut, frozen in liquid nitrogen, and powdered -1. Hydrogen peroxide (H2O2) malondialdehyde (MDA) were assayed according to Woodrow et al. Reduced and oxidized ascorbate (AsA+DHA) and reduced and total (reduced plus oxidized) glutathione (GSH) were extracted and evaluated as described in Annunziata et al. o-tolidine, used as substrate. PPO analysis was performed using catechol as substrate. Ascorbate peroxidase  was extracted and assayed according to Hediye Sekmen et al. Enzyme activity analyses were performed by spectrophotometer assays. Polyphenol oxidase  and guaiacol peroxidase  were simultaneously extracted by a two-step extraction protocol, that allowed the separation of both soluble and membrane bound isoforms"}
+{"text": "Alzheimer\u2019s disease (AD) is ultimately linked to the amyloid precursor protein (APP). However, current research reveals an important synaptic function of APP and APP-like proteins (APLP1 and 2). In this context various neurotrophic and neuroprotective functions have been reported for the APP proteolytic fragments sAPP\u03b1, sAPP\u03b2 and the monomeric amyloid-beta peptide (A\u03b2). APP is a metalloprotein and binds copper and zinc ions. Synaptic activity correlates with a release of these ions into the synaptic cleft and dysregulation of their homeostasis is linked to different neurodegenerative diseases. Metal binding to APP or its fragments affects its structure and its proteolytic cleavage and therefore its physiological function at the synapse. Here, we summarize the current data supporting this hypothesis and provide a model of how these different mechanisms might be intertwined with each other. Alzheimer\u2019s disease (AD) is a fatal neurodegenerative disorder and a severe burden of our aging societies  and several unstructured regions  in a slightly distorted square pyramidal geometry (a type 2 non-blue site) to three protein ligands  and two water molecules  almost as high as to CuBD. Copper-binding to the GFLD again correlates with the reduction of a neighboring disulfide bridge (Cys98-Cys105) pointing to redox-activity also of this site. Furthermore, the match of geometry and functionality is suggestive for a complementation of the two copper-binding sites by either a conformational change within the E1 domain into a \u201cclosed\u201d conformation  and with low affinity to zinc  harbors two or three different metal binding sites, here designated as M1\u20133  spread on three helices  to regulate homo- and hetero-dimerization with APP and APLP2  become progressively more acidic down to pH 6 in the trans-Golgi and <5 in lysosomes  in the amyloid plaques , ceruloplasmin, tyrosinase and dopamine \u03b2 hydroxylase , or WD. Loss of ATP7A function causes growth failure, brittle hair, hypopigmentation, arterial tortuosity and neuronal loss most prominent in the hippocampus and cerebellum  discussed involve S-nitrosylation, oxidation and allosteric modulation, increased anchorage of the neurotransmitter receptors to the membrane, and modulation of neurotransmitter receptor function  receptors), Glycine and other surface receptors, such as TrkB. Furthermore, zinc can bind to and regulate ProSAPs/Shanks scaffolding proteins of the postsynaptic density (PSD), involved in synaptic signaling. Indeed, in some cerebral areas nearly 50% of the glutamatergic synapses are actually \u201cglu-zinc-ergic\u201d (Watt et al., In contrast to copper ions there is a substantial amount of zinc loosely bound to biomolecules, designated as reactive or chelatable zinc, which is implicated in neuronal signaling. Reactive zinc is largely distributed within presynaptic vesicles in some axon terminals throughout the telencephalon and co-localizes with a subset of glutamatergic neurons (Frederickson et al., Synaptic function of APP is discussed in detail in other chapters of this special issue. Briefly, loss of APP function leads to a reduced number of dendritic spines (Watt et al., in vitro interaction of APP, and mutations, abolishing copper-binding to the GFLD, reduce APP synaptogenic activity in a cellular assay system (Baumk\u00f6tter et al., As pointed out before, copper binds APP at different sites within the E1 and E2 domain, causing structural changes and altered dimerization properties and heparin binding characteristics (Baumk\u00f6tter et al., in vivo conditions at the synapse. Consistently, addition of 50 \u03bcM zinc to cells expressing APLP1 caused a lateral concentration at cell-cell contact sites (Mayer et al., Different reports suggest binding of APP, APLP1 and to a minor extent also APLP2 to zinc with affinities in the low micromolar range (Bush et al., Despite some major gaps in our understanding of APP/APLPs synaptic function, the current data as presented in this review article strongly suggest that activity-dependent changes in zinc and copper concentrations in the synaptic cleft can be sensed by the APP/APLP family. In turn, they seem to modulate neurotransmission by different pathways including neurotrophic activity of sAPP\u03b1 or trans-cellular dimerization/signaling. However, one major gap in our current understanding, especially in respect to the function of copper, is the limitation of available sensitive sensors, allowing determination of local transient changes in copper concentration. In this regard, live-cell optical imaging with fluorescent sensors offers a potentially powerful approach for interrogating aspects of labile copper accumulation, speciation, trafficking, and redox function in living systems at the molecular level. Such reagents have greatly facilitated the study of calcium and zinc in cell biology, but analogs tools for cellular copper remain underdeveloped (Zeng et al., KW, AA, CUP and SK wrote this review article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Lin et al. reported that young, asymptomatic APOE4 targeted-replacement mice treated with rapamycin had restored CBF and BBB integrity to the level of wild-type controls [Alzheimer's disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. Inheritance of the Apolipoprotein \u03b54 (APOE4) allele is the strongest genetic risk factor for late-onset AD - APOE4 carriers accumulate beta-amyloid (A\u03b2) and neurofibrillary tau tangles earlier and with more extensive pathology compared to non-carriers. However, decades before the aggregation of A\u03b2 and tau, cognitively normal APOE4 carriers have developed neurovascular deficits, including reduced cerebral blood flow (CBF) and impaired bloodbrain barrier (BBB) integrity . The abocontrols . The preRapamycin is a drug approved by US Food and Drug Administration (FDA). It has been widely used in clinical settings and was originally used as an immunosuppressive agent to prevent rejection of organs in transplant patients. By 1991, Heitman and co-workers discovered a kinase, Target of Rapamyin (TOR) . In mammLin et al. demonstrated that mTOR inhibition reduced proinflammatory pathways in brain vasculature that otherwise impair BBB integrity in the APOE4 transgenic mice [Lin et al. previously reported that inhibition of mTOR activates endothelial nitric oxide synthase and causes the release of nitric oxide, a vasodilator, which in turn increases CBF [Lin et al. found that rapamycin restored their CBF and vascular density, which were associated with reduced accumulation of A\u03b2 and cerebral amyloid angiopathy, and improved memory [nic mice . Loss ofnic mice . Restorinic mice . In addiases CBF . In miced memory . CollectLin et al. further demonstrated that rapamycin restores and preserves neurovascular functions in the APOE4 transgenic mice using MRI. Their results may provide the basis for future AD prevention trials in human APOE4 carriers.In conclusion, mTOR inhibition has been shown to increase lifespan and healthspan in various species. Rapamycin  has been approved by the FDA since 1999 for various uses in humans, and these compounds have been given to cancer patients for relatively long periods of time with little change in the quality of life."}
+{"text": "Irradiated ice-covered ocean worlds with rocky mafic mantles may provide the conditions needed to drive the emergence and maintenance of life. Alkaline hydrothermal springs\u2014relieving the geophysical, thermal, and chemical disequilibria between oceans and tidally stressed crusts\u2014could generate inorganic barriers to the otherwise uncontrolled and kinetically disfavored oxidation of hydrothermal hydrogen and methane. Ionic gradients imposed across these inorganic barriers, comprising iron oxyhydroxides and sulfides, could drive the hydrogenation of carbon dioxide and the oxidation of methane through thermodynamically favorable metabolic pathways leading to early life-forms. In such chemostatic environments, fuels may eventually outweigh oxidants. Ice-covered oceans are primarily heated from below, creating convection that could transport putative microbial cells and cellular cooperatives upward to congregate beneath an ice shell, potentially giving rise to a highly focused shallow biosphere. It is here where electron acceptors, ultimately derived from the irradiated surface, could be delivered to such life-forms through exchange with the icy surface. Such zones would act as \u201celectron disposal units\u201d for the biosphere, and occupants might be transferred toward the surface by buoyant diapirs and even entrained into plumes. Key Words: Biofilms\u2014Europa\u2014Extraterrestrial life\u2014Hydrothermal systems. Astrobiology 17, 1265\u20131273. Such hydrogenations yield an ever-renewed stock of highly specified organic molecules\u2014the so-called CHNOPS with a typical bonding motif -C\u2013C(H2)\u2013N(H)\u2013C\u2013O  reactions as salty ocean waters are reduced to hydrogen and formate on gravitation into the primitive ultramafic crust  that are potentially more amenable as acceptors along metabolic pathways than just CO2 or carbonate  is a lower potential acceptor but has the advantage of also providing further carbon through a variant of the acetyl coenzyme-A pathway  from hydrothermal activity, and an ocean with dissolved oxidants providing a geochemical gradient, the first life-forms could potentially follow some of the same metabolic pathways known to be at, or near, the root of the earliest life on Earth, that is, acetogenesis and methanotrophy , leading to effective delivery through the ocean to the ice-water interface  along the ice-water interface to reach sites of down-welling convection in the ice that might bring radiolytically produced oxidants to the ocean  at the same time (Vargas et al.,et al.,et al.,et al.,et al.,et al.et al.,et al.,et al.,et al.,The dynamic communities comprising any sub-ice-shell biosphere could constitute a habitable zone, manifested as microbial mats concentrated around oxidant-rich ice-shell sites at the down-welling regions of thermally unstable regions at the ice-water interface (Goodman et al.,et al.,et al.,et al.,et al.,et al.,Future missions to search for life on Europa (Hand"}
+{"text": "Recently, Birte Hellwig and colleagues from the Department of Statistics, TU Dortmund University have published a study to predict late metastasis in breast cancer . In breIn the present study Hellwig et al. (2016) used a In recent years numerous studies have been performed to predict prognosis of cancer (Hammad, 2013; Hammad"}
+{"text": "Neutrophils are well known for their role in infection and inflammatory disease and are first responders at sites of infection or injury. Platelets have an established role in hemostasis and thrombosis and are first responders at sites of vascular damage. However, neutrophils are increasingly recognized for their role in thrombosis, while the immunemodulatory properties of platelets are being increasingly studied. Platelets and neutrophils interact during infection, inflammation and thrombosis and modulate each other\u2019s functions. This review will discuss the consequences of platelet\u2013neutrophil interactions in infection, thrombosis, atherosclerosis and tissue injury and repair. Platelets are anuclear cell fragments that circulate in healthy humans at about 150,000\u2013400,000 per microliter blood. Platelets are well known for their role in thrombosis and hemostasis. Inherited or acquired defects in platelet count and/or function can be associated with bleeding complications. Conversely, platelets are key players in thrombotic disease and drugs inhibiting platelet function are vital in treatment and prevention of arterial thrombotic diseases such as myocardial infarction and stroke. Recent studies show that platelets have many functions beyond physiological or pathological thrombus formation. They play a role in inflammation, are effectors of injury in a variety of pulmonary disorders and syndromes, facilitate tissue repair and act in the growth and development of metastases of various cancers  have been shown to crawl along and adhere to the surface of (activated) endothelial cells, eventually forming an almost continuous layer on the vascular endothelium (von Bruhl et al. At least three distinct mechanisms may be involved in platelet-dependent, neutrophil-mediated induction of thrombosis. First, neutrophils have been demonstrated to transfer tissue factor, the physiological initiator of coagulation, to platelets during thrombus formation in vitro (Giesen et al. The \u2018blood-borne\u2019 TF concept challenges the dogma that tissue factor is normally not located on cells in contact with blood and the source and quantity of blood borne TF is subject to ongoing debate (Butenas et al. A second mechanism by which the platelet\u2013neutrophil axis contributes to initiation and propagation of thrombosis is through generation of NETs (Fuchs et al. A third mechanism linking the platelet\u2013neutrophil axis to thrombosis relates to neutrophil constituents modulating hemostasis. For instance, neutrophil cathepsin G and elastase inactivate natural anticoagulant systems including tissue factor pathway inhibitor, thrombomodulin and antithrombin (von Bruhl et al. Platelets have long been implicated in acute coronary events. Their key role is evidenced by the success of platelet inhibitory drug in treatment and prevention of acute arterial thrombotic events (Jamasbi et al. Sterile tissue injury as for example encountered in injury by toxins (Miyakawa et al. For example, acetaminophen-induced liver injury results in an influx of platelets and neutrophils in the liver microcirculation (Miyakawa et al. Platelets and neutrophils have been implicated as drivers of ischemia/reperfusion injury in liver (Yadav et al. Platelets trigger the release of NETs in a model of experimental transfusion-associated acute lung injury and thereby aggravate disease (Caudrillier et al. Platelet\u2013neutrophil interactions have been shown to facilitate repair in a model of heat-induced liver injury (Slaba et al. Platelets are well known to be required for liver regeneration following partial hepatectomy and it has been suggested that growth factors stored within platelet granules drive platelet-mediated liver regeneration (Lesurtel et al. Finally, NETs have also been demonstrated to contribute to organ injury in sepsis (Czaikoski et al. Experimental and clinical evidence for a role of platelet\u2013neutrophil crosstalk in a variety of clinical conditions including inflammation, thrombosis, atherosclerosis and tissue injury is rapidly emerging. Agents blocking PSGL-1, P-selectin, or MAC-1 that have pleiotropic effects that include inhibition of platelet\u2013neutrophil interactions have been trialed in humans (Mertens et al. Inhibitors of PAD4 may have merit given the key role of PAD4 in NET formation and the intact NET-independent anti-inflammatory properties of PAD4-deficient neutrophils (Li et al. A clear advantage of targeting NETs in thrombotic syndromes is the lack of effect of the intervention on physiological hemostasis. As bleeding is an important side effect of current therapies for venous and arterial thrombosis and disseminated intravascular coagulation, the development of agents with a better risk/benefit ratio in terms of thrombotic potency versus bleeding risk would be a significant improvement.Although platelets are traditionally seen as key players in thrombosis and hemostasis and neutrophils as prime inflammatory cells, recent data demonstrate a complex interplay between these cells with important immune functions for platelets and a clear role of neutrophils in thrombotic diseases. The prime mode of interaction between platelets and neutrophils and the downstream effects of this interaction are summarized in Fig."}
+{"text": "HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer\u2019s disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches.There is widespread transcriptional dysregulation in Huntington\u2019s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant  HTT gene and is characterised by motor, cognitive and psychiatric features. Onset occurs around 45 years on average and inversely correlates with CAG repeat lengthHuntington\u2019s disease (HD), the most common monogenic neurodegenerative disorder in the developed worldHTT is ubiquitously expressed589101415519HD research has traditionally focused on the brain due to the presence of characteristic mutant huntingtin protein aggregateset al.2324et al.Transcriptional dysregulation is a central feature of HD pathogenesisIn the current study we present a transcriptomic analysis of whole blood in human HD using RNA sequencing (RNA-Seq). We studied differential expression of individual gene transcripts and enrichment of differential expression in gene sets in two independent cohorts from Track-HDPremanifest gene carriers had a mean total motor score (TMS) of 2 and total functional capacity (TFC) of 13  between premanifest and manifest HD in either the Track-HDHTT gene carriers were combined to increase the analytical power in a comparison of HD and controls. Once again there were no individually significant transcripts in independent or combined cohorts, but the differential expression analysis in the combined cohort is given in Attempting to identify both HD specific and stage-specific changes in gene expression (mRNA) level, we compared premanifest, manifest and control subjects, whilst controlling for age and gender. C) of 13 , indicatWe next asked whether networks of genes with similar functional annotation were dysregulated in HD relative to controls. Pathway annotations were collated from publicly available gene ontology databases to form a set of generic pathways using the same method as the recent HD genome-wide association study (GWAS) of modifiers of age at onsetGene set enrichment analysis (GSEA), with a false discovery rate  threshold of q\u2009<\u20090.05 to correct for multiple testing, identified 53 upregulated  and 14 det al.et al.Through RNA-Seq, Miller, et al.et al.A limitation of using curated pathways from databases is the incomplete or incorrect annotation. One way to overcome this is to use gene co-expression, because genes that are co-expressed often have related functions. WGCNA identifies clusters (modules) of genes with highly correlated expression, constructing original, unbiased gene co-expression networks based on observed dataGSEA for brain co-expression modules was applied to our combined Track-HD and Leiden blood expression dataset. Immune- and inflammatory-related brain modules were upregulated in HD blood, and notable downregulated modules included synaptic function, proteasomal degradation, mitochondrial function and transcription. The 10 most significantly up and downregulated modules in the combined dataset that were also nominally significant (p\u2009<\u20090.05) in both independent cohorts are given in \u20134) correlation between dysregulation p-value in the direction of interest (positive) in HD blood and degree of module membership (kME)The module membership (kME) of a gene is measured by the correlation of its expression with the eigengene, which is representative of all gene expression profiles in the module et al.et al.\u221216) excess , suggesting some concordance in signal at the individual gene level. Furthermore, a significant excess of generic pathways was found to be significantly (p\u2009<\u20090.05) dysregulated in both datasets, most markedly in the positive (p\u2009<\u20090.001) direction, but also negative (p\u2009=\u20090.028), thus showing an overlap in biological signal. Pathways significantly upregulated in both datasets are mainly related to immune response  in the 112 gene positive Track-HD subjects . After cWe then tested whether generic pathways that were significantly enriched for upregulated  or downr\u22127) and 66 , which were also dysregulated in the HD caudateSimilarly, we tested whether modules dysregulated in HD blood relative to controls  also coret al.\u22123). Using the same method as for concordance with Labadorf, et al.et al.\u22127). Thus, we conclude that analysis of TMS in the Track-HD cohort broadly supported the associations reported in Mastrokolias et al.Mastrokolias et al.\u22124).In Alzheimer\u2019s disease, an early inflammatory response involving microglia contributes to pathogenesis3637et al.yellow, being particularly highly enriched (combined Track-HD and Leiden p\u2009<\u20091\u2009\u00d7\u200910\u221216). Notably, this module has immune and microglia-specific functionset al.Zhang, HD research has focused on the brain as the most conspicuous clinical features can be clearly linked to progressive degeneration of specific brain regions45We conducted RNA-Seq of whole blood in two independent cohorts of HD patients. Using gene set enrichment analysis (GSEA) with publicly-available pathway databases and WGCNA modules from HD and control brain datasets, we identified dysregulated genes and gene sets in blood that replicated in both independent cohorts and correlated with clinical motor signs (TMS). These correspond to the most significantly dysregulated modules in caudate nucleus, the most prominently affected region in HD brain. This suggests mutant huntingtin drives a common pathogenic signature in both blood and brain.et al.944RNA-Seq more comprehensively and accurately quantifies mRNA than hybridisation-based microarrays or tag-based methodsDespite these limitations, gene set enrichment analysis identified significantly overlapping dysregulated pathways in the Track-HD and Leiden HD blood datasets, even though they differed in age and disease severity. Thus, through grouping transcripts into biologically relevant pathways and co-expressed transcripts, we could highlight areas of dysfunctional biology in HD. The observed upregulation of immune-related pathways is consistent with that previously identified in transcriptional and functional studies57910PGC-1\u03b1, a member of the dysregulated ATP metabolic process pathway  and 66 (CNneg1), were also significantly dysregulated in the same direction in both independent blood datasets. Compared with other brain regions, the caudate has the largest number of expression changes and the highest correlation with HDet al.et al.Our demonstration of a transcriptional signature common to both HD blood and brain supports the use of blood cells to study aspects of HD biology. HD model systems, such as mice, only recapitulate aspects of disease and must be compared to the relevant data in human tissue5519et al.et al.et al.In AD, amyloid plaques are surrounded by chronically activated microglia36All experiments we performed in accordance with the Declaration of Helsinki and approved by the University College London (UCL)/UCL Hospitals Joint Research Ethics Committee and the LUMC IRB. Peripheral blood samples were donated by genetically-diagnosed HD patients and controls, and all subjects provided informed written consent.Manifest subjects demonstrated motor abnormalities that were unequivocal signs of HD, as evidenced by total motor scores (TMS) over 5 on the Unified Huntington\u2019s Disease Rating Scale (UHDRS). Premanifest gene carriers had a burden of pathology score (age x [CAG \u2013 36.5))The Track-HD cohort consisted of 54 premanifest gene carriers, 63 manifest HD subjects and 23 controls. These were a representative sample from the Track-HD study , preseleThe Leiden cohortWhole blood was collected in two PAXGene Blood RNA tubes  per subject, and immediately placed upright at room temperature. They were checked at 5\u2009hours for incomplete mixing or separation, and any showing separation were remixed with a further 10 inversions. Tubes were stored overnight at \u221220\u2009\u00b0C and transferred to \u221280\u2009\u00b0C the following morning. They were sent on dry ice to Biorep within 30 days.TM method . Quality control measures were made on globin-reduced samples on the Bioanalyzer RNA 6000 Nano kit .Total RNA extraction was performed using the PAXGene Blood RNA kit , following the supplier\u2019s instructions. Each solution in the kit was divided into aliquots to process batches of 12 samples. Replicate tubes for each subject were processed on different days. RNA was stored at \u221280\u2009\u00b0C before proceeding with the quality measurements and further use. RNA was collected by centrifugation, washing with 70% ethanol, and resuspended in buffer. Quality measurements of total RNA were made using spectrophotometric analysis (Nanodrop), 260/280 ratio denaturing agarose gel, and the RNA 6000 Nano kit for the Agilent Bioanalyzer . Samples were globin reduced using the GLOBINclearTM Poly-A mRNA method (Illumina). In short, poly-A mRNA transcripts were captured from total RNA using poly-T beads and cDNA generated using random hexamer primingIndexed cDNA sequencing libraries were prepared using the TruSeqSequencing failed for six Track-HD samples, including four premanifest, one manifest and one control subject. Quality control analysis was performed using the RNA-SeQC packagehttp://www.ensembl.org/info/data/ftp/index.html, obtained in gtf format, genome build GRCh38.3, gene build updated in June 2015). To remove residual batch effects the R package svaseq was usedRNA-Seq data were aligned to the human reference genome hg19 using TopHat2Enrichment of differential expression among gene sets corresponding to biological hypotheses (pathways) was tested using the Gene Set Enrichment Analysis (GSEA) methodet al.The set of 124 HD brain expression modules derived by Neueder and Bateset al.A set of 117 co-expression modules derived from the Gibbs, We generated a set of 213 co-expression modules from Braineacet al.The set of 111 co-expression modules from Zhang, Weaknesses of relying on public databases to provide pathways for analysis include their restriction to prior biological knowledge and the poor annotation of many genes. To overcome this annotation gap, we also tested the following sets of gene co-expression modules for enrichment of dysregulation:et al.et al.Labadorf, et al. datasets.We used a similar method to test for concordance of fold change in genes between the Track-HD and Mastrokolias All data is deposited at the European Genome-phenome Archive (EGA) and accessible through the authors or the NeurOmics consortium.How to cite this article: Hensman Moss, D. J. et al. Huntington\u2019s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer\u2019s disease. Sci. Rep.7, 44849; doi: 10.1038/srep44849 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals. Gene transcription in eukaryotic cells is orchestrated through extremely complicated processes and multiple steps, including initiation, elongation, and termination, with the initiation being the most studied regulation step of gene expression. Disturbance of transcription initiation often results in serious diseases, such as cancer, in humans  has sharply increased in the past decades. Dysregulation of genes in the pathways controlling glucose and/or lipid metabolism is common in states of insulin resistance and T2D, especially when patients are also diagnosed with non-alcoholic fatty liver disease (NAFLD) or cardiovascular disease  and PGC1 families of transcription cofactors, MED1 contains two LXXLL motifs  that provide the binding surfaces for various nuclear receptors, and either one of the LXXLL motifs is sufficient for protein\u2013protein interactions -selective genes  and HMG-CoA synthase (Hmgcr) (Amemiya-Kudo et al. The functions of MED15 and other mediator subunits in worms have been recently reviewed (Grants et al. RhoA/MAL or Ras/ELK1, by directly interacting with them in response to upstream signals (Stevens et al. MED23 has been well studied in mammalian model systems. The importance of MED23 in viability has been shown with the embryonic lethality when MED23 was knocked out in mice (Balamotis et al. It is known that HNF4\u03b1 regulates a various set of genes that are not only involved in early development but also in liver and pancreatic cell differentiation, glucose metabolism, and lipid homeostasis (Odom et al. i.e., CDK19, MED12L, and MED13L (Daniels et al. Originally considered as a part of a transcriptional repressor in the large Mediator complex, the kinase module can repress or activate gene expression through kinase-dependent or kinase-independent mechanisms (Malik and Roeder The CDK8\u2013CycC dimer negatively regulates de novo lipogenesis by reducing nuclear SREBP-1a or SREBP-1c protein stability (Zhao et al. In addition to CDK8 function in the negative regulation of de novo lipogenesis through its kinase activity, it has been shown that CDK8 has a positive role in response to serum, likely at the elongation step instead of the initiation step where CDK8 is a negative regulator (Donner et al. Through MED13, the MED12\u2013MED13 dimer links the small mediator as well as the CDK8\u2013CycC dimer (Tsai et al. To date, not much information is available on the functions of MED12L and MED13L. Expressed in both heart and brain, MED13L is associated with early development of both heart and brain since its missense mutations and gene interruption are found in patients with congenital heart defect, learning disabilities, and facial anomalies (Muncke et al. Since the discovery of the Mediator complex as a transcription cofactor of eukaryotes, its subunits have been associated with various biological processes and several diseases ranging from developmental defects to cancer in animal models and humans. The metabolic functions of the Mediator complex have become increasingly significant. In most cases, the Mediator complex functions as a bridge to connect and integrate specific transcription factors to the basal transcription machinery, resulting in expression changes of a selective set of genes. In addition to the presence of many subunits, tissue-specific expression and possible diverse assembly states at different physiological conditions further complicate the biological functions of the Mediator complex. Future studies on the role of the Mediator complex in metabolism may include identification of how the metabolic or nutrient signals may regulate the assembly states and subunit compositions and investigation of tissue-specific functions of each subunit in regulating nutrient and energy metabolism in vivo."}
+{"text": "Erythrocytes regulate vascular function through the modulation of oxygen delivery and the scavenging and generation of nitric oxide (NO). First, hemoglobin inside the red blood cell binds oxygen in the lungs and delivers it to tissues throughout the body in an allosterically regulated process, modulated by oxygen, carbon dioxide and proton concentrations. The vasculature responds to low oxygen tensions through vasodilation, further recruiting blood flow and oxygen carrying erythrocytes. Research has shown multiple mechanisms are at play in this classical hypoxic vasodilatory response, with a potential role of red cell derived vasodilatory molecules, such as nitrite derived nitric oxide and red blood cell ATP, considered in the last 20 years. According to these hypotheses, red blood cells release vasodilatory molecules under low oxygen pressures. Candidate molecules released by erythrocytes and responsible for hypoxic vasodilation are nitric oxide, adenosine triphosphate and S-nitrosothiols. Our research group has characterized the biochemistry and physiological effects of the electron and proton transfer reactions from hemoglobin and other ferrous heme globins with nitrite to form NO. In addition to NO generation from nitrite during deoxygenation, hemoglobin has a high affinity for NO. Scavenging of NO by hemoglobin can cause vasoconstriction, which is greatly enhanced by cell free hemoglobin outside of the red cell. Therefore, compartmentalization of hemoglobin inside red blood cells and localization of red blood cells in the blood stream are important for healthy vascular function. Conditions where erythrocyte lysis leads to cell free hemoglobin or where erythrocytes adhere to the endothelium can result in hypertension and vaso constriction. These studies support a model where hemoglobin serves as an oxido-reductase, inhibiting NO and promoting higher vessel tone when oxygenated and reducing nitrite to form NO and vasodilate when deoxygenated. How erythrocytes modulate vascular tone has been widely studied over the last two decades. The vasodilation of the vasculature under hypoxic conditions has inspired much research ranging from the effect of oxygen partial pressure on smooth muscle cell contractility and endothelial nitric oxide synthase (eNOS) activity to nitrite reduction by hemoglobin (Hb) inside erythrocytes and subsequent production of nitric oxide Figure . Here we2 molecule. As hemoglobin binds oxygen, conformational changes occur to the protein and the binding affinity of the protein for molecular oxygen increases. Thus, binding is cooperative so that binding subsequent molecules of oxygen becomes easier after initial binding. Cooperative binding can be understood by a two-state model: The high affinity R-state and the low affinity T-state   by eNOS, which requires oxygen as a substrate along with L-arginine    extremely fast (6\u20138 \u00d7 10However, as demonstrated above in the work by Chu et al. endothelial NO does play a physiological role in vascular function (Chu et al., One can explain this paradox of NO bioavailability and Hb concentration in the blood by considering Hb encapsulation by RBCs. Experiments where RBCs are mixed with NO in suspension or in a stopped flow apparatus show that RBCs scavenge NO 1,000 times slower than cell-free Hb (Liu et al., In addition to these changes under static conditions, a cell free zone created by the fluid dynamics of blood flow further reduces NO scavenging. The velocity of blood near the vessel wall is slower than in the center of the vessel due to friction. This creates a pressure gradient that pushes RBCs toward the center of the vessel away from the NO producing endothelium. Bugliarello and Sevilla, Cokelet and Liao et al. experimentally showed the presence of a cell free zone and computational modeling by Butler et al. supported its ability to reduce NO scavenging (Bugliarello and Sevilla, In disease, RBC membrane abnormalities promote thrombosis Ataga, . Setty eIn addition to adhesion, polymerization of hemoglobin in sickle cell disease leads to rigid, inflexible red blood cells, which effect blood rheology. Moreover, oxygenated sickle RBC also displays changes in cell mechanics and therefore blood rheology, attributed to altered hemoglobin concentration in the cell and changes to the cell membrane (Nash et al., Work by Bor-Kucukatay et al. suggest vascular function, specifically nitric oxide production could play a role in RBC deformability and rheological alterations to RBCs during hypertension (Bor-Kucukatay et al., As reviewed above, encapsulation of Hb inside RBCs greatly reduces its ability to scavenge NO produced by the endothelium. However, in multiple diseases RBC hemolysis occurs introducing cell-free Hb into the vasculature (Reiter et al., In vitro findings suggest cell-free hemoglobin has the potential to release hemin and take part in oxidative reactions resulting in oxidative stress and inflammation (Miller et al., Cell-free hemoglobin reactions in the vasculature and surrounding tissues through extravasation may add to disease conditions (Schaer et al., In addition to releasing Hb, hemolysis also releases arginase, an enzyme that converts L-arginine to ornithine, into the blood stream. L-arginine is the substrate for nitric oxide synthesis by eNOS and therefore, the release of arginase further diminishes NO production and vascular function (Morris et al., Red blood cell breakdown not only decreases NO bioavailability through NO scavenging by cell-free Hb, but also by production of red blood cell microparticles (Donadee et al., RBC hemolysis contributes to the vascular pathology of diseases and disorders such as thalassemia, hereditary spherocytosis, Glucose-6-phosphate dehydrogenase deficiency, paroxysmal nocturnal, hemoglobinuria, and autoimmune hemolytic anemia (Johnson et al., In contrast to the role played by RBCs in diminishing NO. Research shows deoxy-RBCs promote vasodilation in the presence of nitrite (Cosby et al., 2 caused vessel dilation and an increased concentration of ATP in the effluent (Dietrich et al., ATP activates purinoceptors on endothelial cells leading to the production of NO and alteration of vascular tone (Ralevic and Burnstock, Addition of nitrite to deoxyRBCs showed an enhanced effect on vasodilation when infused (Cosby et al., in vivo SNO-Hb must form during the oxygenation/deoxygenation cycle of RBCs. This leads to the question of how SNO-Hb forms. Huang et al. and Xu et al. ruled out allosterically-controlled transfer of NO from HbNO to the beta-93 cysteine of Hb (Xu et al., The second proposed mechanism for the effect deoxyRBC and nitrite on vascular function is the formation of SNO-Hb in the presence of nitrite and subsequent release of NO from deoxygenated SNO-Hb. Research has demonstrated the hypoxic release of NO from SNO-Hb and the ability of the released NO to relax vessels (Stamler et al., In vitro studies have rejected a significant role in the reduction of nitrite by other RBC molecules such as xanthine oxidoreductase and carbonic anhydrase supporting the hypothesis that hemoglobin plays a dominant role (Liu et al., The last proposed mechanism of RBC vasodilation in the presence of nitrite is the reduction of nitrite to NO by Hb. Brooks first studied the nitrite Hb interaction in 1937 and this work was later extended by Doyle in 1981 Brooks, ,b, to fo2O3 formation (Basu et al., + for the RBC membrane, which in turn could also lead to NO escape through nitrosylation of AE1 (Salgado et al., However, once NO is formed inside a RBC, it must somehow escape rapid scavenging by the intraerythrocytic Hb. Proposed mechanisms of escape of NO bioactivity from the RBC have included S-nitrosothiol formation and the role of the RBC membrane. Research by Basu et al and Roche et al suggested S-nitrosothiol formation could occur through a metHb-nitrite mediated NOther heme-globin nitrite reducers may play a role in modulating vascular function. Deoxymyoglobin reduces nitrite faster than Hb (Shiva et al., The production of NO by deoxyRBCs in the presence of nitrite and other NO donors provide a potential therapeutic role for plasma nitrite in reducing vasoconstriction, RBC adhesion, and potentially improving RBC deformability (Space et al., Red blood cells play an important role in vascular function. Through the compartmentalization of Hb, RBCs deliver oxygen, minimize NO scavenging, sense oxygen tension, and deliver NO bioactivity in hypoxia. In healthy conditions, RBCs promote hemostasis through the well-regulated delivery of oxygen and the balance of NO scavenging and production. As data has shown, the RBC, once only viewed as a sink for NO, has the ability to produce NO bioactivity under hypoxia. The important role of the RBC in vascular function becomes more evident in diseases that alter or compromise the RBC membrane leading to conditions of oxidative stress, hypertension, thrombosis, and vaso-occlusion.CH, MG, and DK-S together conceptualized the article and its content. CH wrote the initial draft of the manuscript and further edited the manuscript. MG and DK-S heavily edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Alternatively, resigned individuals may simply be numb to the negative effects of exclusion regardless of their momentary expectations (Bernstein and Claypool, Future research should examine if and how expectations matter for chronically excluded individuals. Williams  refers tExclusion paradigms often blindside participants with exclusion (Williams and Wesselmann, whether participants will choose to respond pro- or anti-socially to exclusion, as well as the degree of their response, which is a current paradox in the literature (Wesselmann et al., get-acquainted paradigms (Wesselmann et al., life alone paradigm (Twenge et al., in vivo paradigms.Participants' expectations of inclusion also likely influence Situational factors that may influence expectations of relational evaluation could be the psychological closeness of the sources of inclusion (e.g., a romantic partner; Arriaga et al., role-based exclusion, Nezlek et al., Individual factors may also influence one's expected relational evaluation levels. For example, narcissistic individuals may expect high relational evaluation and thus respond with more aggression than non-narcissists when their expectations are violated (Bushman and Baumeister, Researchers should investigate the specific role that relational evaluation plays in the consequences of exclusion, and how situation-level and individual-level characteristics influence this construct. EW, JW, and MB each contributed to the theoretical arguments in this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Myocardial infarction afflicts close to three quarters of a million Americans annually, resulting in reduced heart function, arrhythmia, and frequently death. Cardiomyocyte death reduces the heart\u2019s pump capacity while the deposition of a non-conductive scar incurs the risk of arrhythmia. Direct cardiac reprogramming emerged as a novel technology to simultaneously reduce scar tissue and generate new cardiomyocytes to restore cardiac function. This technology converts endogenous cardiac fibroblasts directly into induced cardiomyocyte-like cells using a variety of cocktails including transcription factors, microRNAs, and small molecules. Although promising, direct cardiac reprogramming is still in its fledging phase, and numerous barriers have to be overcome prior to its clinical application. This review discusses current findings to optimize reprogramming efficiency, including reprogramming factor cocktails and stoichiometry, epigenetic barriers to cell fate reprogramming, incomplete conversion and residual fibroblast identity, requisite growth factors, and environmental cues. Finally, we address the current challenges and future directions for the field. As the leading cause of death in the United States, heart disease accounts for one out of every four mortalities \u2014that are necessary and sufficient to convert fibroblasts to induced cardiomyocyte-like cells (iCMs) both in vitro  inhibition directs cells toward a cardiac lineage fate (Karamboulas et al., Widespread epigenetic repatterning occurs during direct cardiac reprogramming. Zhao et al. performed chromatin immunoprecipitation sequencing of H3K4me2, which marks the promoters and enhancers of transcriptionally active genes, and demonstrated that one week after GHMT cocktail reprogramming 47% of the H3K4me2 peaks had shifted to align with those of primary cardiomyocytes (Zhao et al., Given that extensive repatterning of histone modifications occurs during the reprogramming process, modulation of the deposition and removal of histone modifications may promote greater reprogramming efficiency. Hirai et al. used a small molecule inhibitor of Ezh2, the catalytic component of the PRC2 complex catalyzing H3K27me2/3, to demonstrate that Ezh2 inhibition early in reprogramming increases reprogramming efficiency (Hirai and Kikyo, To identify key epigenetic barriers to the reprogramming process, we conducted a comprehensive loss-of-function screen of epigenetic modifying factors and identified Bmi1 as a critical epigenetic inhibitor of reprogramming (Zhou et al., Ebf1 is a key target of Mll1, and the reduction in Ebf1 expression caused by Mll1 inhibition mediates the observed increase in reprogramming efficiency (Liu et al., In a similar approach, Liu et al. conducted a gain-of-function screen of cardiac development epigenetic modifiers and transcription factors and identified the H3K4 methyltransferase Mll1 as a barrier to direct cardiac reprogramming (Liu et al., Direct cardiac reprogramming is accomplished through the activation of cardiac gene expression but must also be accompanied by complete silencing of the original fibroblast signature. Characterization of epigenetic repatterning during reprogramming by Liu et al. demonstrates a gradual repression of fibroblast loci (Liu et al., Maintenance of residual fibroblast gene expression presents a roadblock to the successful reprogramming of functionally mature cardiomyocytes. MicroRNAs miR-1 and miR-133 enhance direct cardiac reprogramming by suppressing fibrotic gene expression (Muraoka et al., in vitro.In another approach to erasing fibroblast identity, studies have used inhibition of pro-fibrotic signaling pathways to enhance reprogramming efficiency (Ifkovits et al., in vivo (Mohamed et al. Mohamed et al. demonstrate that repression of residual fibroblast signature using TGF\u03b2\u00a0and Wnt inhibition also enhances reprogramming and cardiac function Recent studies have examined the effect of intracellular signaling pathways on direct cardiac reprogramming. Zhou et al. modulated intracellular signaling pathways by screening a library of 192 protein kinases to assess the effect on GHMT transcription factor reprogramming (Zhou et al., Abad et al. screened seven small molecule compounds with a demonstrated role in iPSC reprogramming and found that the Notch inhibitor DAPT enhances GHMT transcription factor cocktail reprogramming (Abad et al., in vitro and in vivo (Mohamed et al., in vitro (Mohamed et al., in vivo (Mohamed et al., Mohamed et al. screened a library of 5,500 small molecule compounds in an unbiased, high throughput approach to determine cell signaling pathways that modulate reprogramming and identified the WNT and TGF\u03b2 signaling pathways as barriers to reprogramming (Mohamed et al., in vivo over in vitro (Qian et al., In vivo reprogrammed iCMs are more similar to endogenous cardiomyocytes than in vitro reprogrammed iCMs. This suggests that unidentified extrinsic factors in the in vivo microenvironment such as topographic cues, mechanical forces, growth factors, cytokines, or paracrine signaling play an important role in promoting iCM maturation.Multiple studies have noted greater conversion efficiency or more complete functional maturation of iCMs reprogrammed in vitro reprogramming generated incompletely converted, immature iCMs (Yamakawa et al., in vitro generation of functionally mature iCMs that contract spontaneously and exhibit calcium oscillations (Yamakawa et al., Lack of requisite growth factors constitutes a barrier to reprogramming. Yamakawa et al. noted that under serum-based culture conditions, in vitro substrate (Chopra et al., In addition to growth factors, environmental cues are important in developing the functional maturity of iCMs. Cultured cardiomyocytes respond differently to the stiffness of the in vitro substrate stiffness or mechanical stretch, reprogramming does respond to other topographical cues. Morez et al. demonstrated that the forward programming of cardiac progenitor cells using the cardiac lineage transcription factor cocktail Myocardin, Tbx5, and Mef2c is enhanced by topographical cues which modulate histone acetylation (Morez et al., + adult progenitor cells were reprogrammed on flat or microgrooved collagen I coated polydimethylsiloxane substrates. Reprogramming efficiency and sarcomere assembly are enhanced on microgrooved substrates compared to flat substrates (Morez et al., While direct cardiac reprogramming is unaffected by in vitro cell culture substrates directly alters reprogramming efficiency and maturity.The identity and composition of the extracellular matrix also impacts cardiomyocyte phenotype and reprogramming. Substrate adhesive ligands alter cardiomyocyte sarcomere organization and maturation through integrin signaling. Sarcomeres are well organized and polarized when cardiomyocytes are cultured on fibronectin coated polyacrylamide substrates but not on collagen I coated polyacrylamide (Chopra et al., in vivo, Li et al. cultured reprogramming iCMs in a 3D fibrin hydrogel and demonstrated that 3D culture enhances direct cardiac reprogramming (Li et al., in vivo compared to in vitro (Li et al., To more accurately mimic environmental stimuli in vivo conditions also has the potential to improve reprogramming. Promoting angiogenesis through preconditioning with VEGF increases in vivo reprogramming efficiency and improves therapeutic restoration of cardiac function (Mathison et al., Myh7 positive cardiomyocytes in the infarct zone of GMT treated hearts and increases ejection fraction by four-fold (Mathison et al., in vivo reprogramming efficiency (Qian et al., Manipulation of Additional research is required to translate direct cardiac reprogramming into a clinical therapy. Necessary steps include continued basic research, research in large animal models, improvement in human reprogramming, and bioengineering of delivery mechanisms.A better understanding is needed of the mechanism of late stage reprogramming events and iCM maturation. Research in this area is currently hindered by inefficiency in the reprogramming process. Asynchronous, heterogeneous cell populations produce low rates of fully reprogrammed cells making it difficult to acquire sufficient cell numbers to study late stage reprogramming events. Early stage studies are aided by the comparative synchrony of cells early in the reprogramming process that provides a large sample population.in vivo monitoring systems, and genetic manipulation, making the mouse a particularly productive model. However, the mouse exhibits significant cardiovascular differences compared to humans. In addition to obvious differences such as small size and short lifespan, mice differ from humans in a range of anatomical, physiological, energetic, electrophysical, and mechanical properties that include heart rate, coronary artery structure, and contraction/relaxation kinetics. Large animal models such as the dog, sheep, or pig have greater physiologic resemblance to humans with similar body size, heart size, and heart rate. In fact, physiological similarities between pigs and humans are close enough to make the pig an ideal xenotransplant donor. Recent progress in genetic manipulation of pigs will contribute to the use of the pig as a cardiovascular disease model.Research in large animal models is also required to move direct cardiac reprogramming toward clinical application. The efficiency of housing, breeding, and handling rodents has made them the most widely used animal models in biomedical research. Additionally, a wealth of tools has been developed specifically for murine research, including imaging techniques, Although significant progress has been achieved in uncovering the molecular barriers to direct reprogramming in mice, research in reprogramming human cells lags far behind. Reprogramming human fibroblasts requires the addition of extra factors but yields far lower conversion efficiency. Spontaneously beating cells are rare, indicating that more work is required to translate findings from the mouse to human and uncover undiscovered molecular barriers in human reprogramming.in vivo research uses direct injection of retroviral vectors into the infarct zone. While conceivably, direct cardiac injection could be achieved in some myocardial infarct patients during coronary bypass surgery, a non-invasive delivery method is preferable. Additionally, retroviral vectors integrate into the host cell genome, incurring the risk of gene disruption and cellular transformation. The ideal delivery vector would be non-integrating with high transfection efficiency, specificity for the target cell type, and adequate capacity to accommodate multiple reprogramming factors. Adenoviruses are promising viral vectors for the delivery of reprogramming factors. The most commonly employed vector in clinical trials, adenoviruses are non-integrating, with large capacity and high transduction efficiency. Additionally, recent research using small molecules to achieve reprogramming and developments in nanoparticle delivery systems offer potential alternatives to viral vector reprogramming factor delivery.Finally, a safe and efficient delivery system is required for the translation of direct cardiac reprogramming to clinical use. Current"}
+{"text": "The International Conference on Bioinformatics (InCoB) has been publishing peer-reviewed conference papers in BMC Bioinformatics since 2006. Of the 44 articles accepted for publication in supplement issues of BMC Bioinformatics, BMC Genomics, BMC Medical Genomics and BMC Systems Biology, 24 articles with a bioinformatics or systems biology focus are reviewed in this editorial. InCoB2017 is scheduled to be held in Shenzen, China, September 20\u201322, 2017. Abbas and Bahig  investigMycobacetrium tuberculosis could explain how azathioprine could suppress the pathogenicity of this organism in transplant patients. Le and Ou [Molecular recognition factors (MoRFs) located within longer intrinsically disordered proteins perform important cellular functions such as signalling and regulation, but are very difficult to accurately detect. Sharma et al.  have adde and Ou  have devGutierrez and Nakai  have buiCastiglione et al.  have devOne of the fundamental assumptions of structural bioinformatics is that hydrophobic residues prefer to be buried in protein structures. By analysing the standard Barton502 dataset using support vector regression on informative physicochemical properties, Liou et al.  show thaSmall organic molecules as drug lead compounds is an important area of structural bioinformatics research, where knowledge of the target\u2019s 3D structure enables rational ligand design, for therapeutic applications. Using a series of derivatives from the influenza drug zanamivir, Dholakia et al.  have genGiven the spiralling cost of drug development, a growing number of approved drug molecules are being considered for medical conditions different from their original purpose, known as repurposing or repositioning. As the number of known drug-target interactions far exceeds the potential interactions of these drugs with other potential targets, predicting the repurposing of a drug appears to be extremely challenging. Ezzat et al.  have addComputer-based morphological analysis present a rapid and efficient way to analyse biological samples. Skull analysis can be used for clinical applications as well as for species classification. Based on human orthodontic parameters used in clinical analysis, Mosleh et al.  have devIn pathology applications, cell-based microscopic analysis suffer from out-of-focus images due to depth effects. Intarapanich et al.  have devThe quality of the articles reviewed in this introduction are comparable with earlier InCoB conferences while the subject coverage has extended substantially into bioimaging. Next year's conference, InCoB2017 will be held in Shenzhen from Sept. 20\u201322, 2017 , with pa"}
+{"text": "Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase  and monacylglycerol lipase , cyclooxygenase (COX) acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1) channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain. Intravenous treatment of rats with URB937, a FAAH inhibitor with minimal penetration of the CNS decreased activity of bladder-specific afferent nerve in response to controlled filling of the bladder (Aizawa et al., AEA has been shown to be an agonist of the TRPV1 pro-nociceptive channel (Tognetto et al., Clinical trials of FAAH inhibitors failed to alleviate pain associated with osteoarthritis (Huggins et al., Although 2-AG is far more abundant than AEA, less work has been done investigating the therapeutic potential of inhibition of MAGL to ameliorate visceral pain. In a mouse chronic neurogenic pain model, MAGL inhibition alleviated neuropathic pain (Kinsey et al., A major obstacle to management of pain by inhibiting MAGL is the observation that increased systemic 2-AG actually results in enhanced response to painful stimuli due to desensitization of CB1 (Schlosburg et al., Endocannabinoids have been demonstrated to suppress inflammation in bladder (Wang et al., Mechanisms of suppression of inflammation by endocannabinoids are not completely understood, but AEA has been shown to inhibit mitogen-induced T- and B-cell lymphocyte proliferation by increasing apoptosis (Schwarz et al., in vitro damage to hippocampal slices exposed to \u03b2-amyloid by a process mediated by CB1 binding that resulted in diminished ERK 1/2 phosphorylation, decreased NF\u03baB activation, and reduced COX-2 expression (Chen et al., Binding of 2-AG to CB1 inhibits cyclooxygenase-2 in nerves resulting in suppression of MAPK/NF\u03baB signaling (Zhang and Chen, Inflammation plays a key role in release of substances that modulate nociception. Thus, it is highly likely that the analgesic effects of endocannabinoids may in part be due to their anti-inflammatory effects.Evaluation of bladder pain in rodent models can be difficult, and the presence of bladder pain is most often inferred by evaluating referred mechanical sensitivity of the hind paws or abdominal wall or activity of bladder afferent nerves (Sadler et al., in vivo with cyclophosphamide to induce inflammatory cystitis (Walczak et al., ex vivo in the presence or absence of intravesical cannabinoid agonists, and it was determined that intravesical cannabinoids suppressed afferent nerve fiber firing in inflamed bladders via CB1 activation (Walczak et al., Bladders and associated afferent nerves were isolated from mice treated Manipulation of the endocannabinoid system has emerged as an appealing alternative to opioids for management of severe bladder pain. However, the potential for undesirable side effects or lack of efficacy remain significant obstacles to advancement of this therapy. Emergence of dual inhibitors of endocannabinoid degradation and either activation of TRPV1 or COX may address many of the limitations of this approach. Information on the activity of endocannabinoids synthesized in peripheral tissues remains extremely limited. It remains unclear whether or not strategies to address organ-specific pain by manipulation of endocannabinoids is a viable option, but this is an intriguing alternative that has the potential to provide effective analgesia with minimal systemic side effects.All studies were approved by the University of Wisconsin Animal Care and Use Committee prior to performance. Procedures were consistent with guidelines provided by the Guide for the Care and Use of Laboratory Animals, 8th Edition, The National Academies Press, Washington, DC, USA.DB and ZW participated in the concept experimental design, analysis and writing. ZW was directly involved in performing experiments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "However, remyelination often fails in chronic neurological diseases, such as progressive multiple sclerosis. The lack of currently approved pro-remyelination therapies highlights the need to elucidate the cellular and molecular mechanisms underpinning this regenerative process. Whereas some T lymphocyte subsets such as Th1 and Th17 are implicated in inducing myelin injury, a recent study by Dombrowski et al. reveals a novel role for regulatory T cells (T Regeneration can occur efficiently in the central nervous system (CNS) in the form of remyelination, whereby new myelin is ensheathed around axons to reinstate trophic/ metabolic support and insulation for electrical impulse conduction. This process requires oligodendrocyte progenitor cells (OPCs) to migrate to areas of injury, proliferate, and differentiate into myelin-producing oligodendrocytes. Remyelination is limited or fails altogether in various neurological disorders, most prominently in progressive multiple sclerosis (MS), leading to axon dysfunction or loss. Although it is recognized that this failure largely reflects impaired oligodendrocyte differentiation , demonstrating that these cells directly stimulate remyelination independent of immunomodulation.While it is now recognized that the innate immune system (i.e. macrophages) supports remyelination  were detected in lesions at the time of oligodendrocyte differentiation and remyelination initiation (Dombrowski et al., regs. The effects of Treg depletion were mirrored in a distinct demyelination model (Dombrowski et al., regs in remyelination is not dependent on the mode of demyelination nor is it restricted to the spinal cord.Using a focal model of toxin-induced demyelination in the mouse spinal cord, where the temporal distinction between myelin damage and remyelination allows investigations of the regenerative process in isolation, Treg depletion in both models did not alter numbers of total oligodendrocyte lineage cells nor proliferating OPCs, suggesting effects of Tregs on the differentiation of OPCs into mature myelinating oligodendrocytes. Indeed, exposing brain explants to Tregs or their conditioned media enhanced oligodendrocyte differentiation, myelination, and remyelination, in comparison to non-polarized CD4+ T cells (Dombrowski et al., regs on OPCs was confirmed in vitro, where Treg conditioned media enhanced the differentiation of isolated OPCs and accelerated myelination in OPC-neuronal co-cultures (Dombrowski et al., reg conditioned media was carried out to identify pro-remyelination factors, and identified high expression of the growth regulator CCN3 (Dombrowski et al., reg conditioned media, as use of a blocking antibody or specific depletion from the conditioned media abolished the pro-differentiation and pro-myelination effects (Dombrowski et al., reg-derived CCN3 was sufficient to support these responses (Dombrowski et al., Tregs are direct drivers of oligodendrocyte differentiation and remyelination, thereby revealing a novel regenerative function for Tregs beyond immunomodulation. Considering this study, one must now acknowledge that the adaptive immune system is not solely involved in damage induction and modulation of inflammation, but is also a critical component of the regenerative process that follows. A recent study demonstrated that MS patient-derived CD4+ T cells injected into demyelinated mouse CNS show high variability in their ability to support remyelination (El Behi et al., regs to stimulate remyelination. Overall, these studies support that further investigations into the pro-remyelination function of Tregs and CCN3 in MS are warranted for development of novel regenerative therapies.Altogether, these data demonstrate that T"}
+{"text": "Machine learning techniques have been increasingly applied in the medical imaging field for developing computer-aided diagnosis and prognosis models. Multimodal medical imaging can provide us with separate yet complementary structure and function information of a patient study and hence has transformed the way we study living bodies. Therefore, using machine learning techniques to deal with multimodal medical images is much more challenging due to the diversity of biophysical-biochemical mechanisms. In these years, researchers mainly adapt modern machine learning and pattern recognition techniques such as supervised, unsupervised, semisupervised, and deep learning to solve multimodal medical imaging related problems.To record the ideas of talents and gather more contributions to these fields, this special issue was launched and supported by this journal. This special issue focuses on the new imaging modalities/methodologies and new machine learning algorithms/applications for the further development in the multimodal medical imaging field, which will provide opportunities for academics and industrial professionals to discuss the latest issues and progresses in the area of multimodal medical imaging. The papers contained in this special issue address the development and application of medical image segmentation, registration, fusion, classification, image restoration, image retrieval, and computer-aided diagnosis.In \u201cEstimation of Response Functions Based on Variational Bayes Algorithm in Dynamic Images Sequences,\u201d B. Shan proposes a nonparametric Bayesian model to estimate the response functions in dynamic medical imaging, in which the nonparametric Bayesian priors are designed to favor desirable properties of the functions and used to improve the estimation of response functions.In \u201cTwo-Layer Tight Frame Sparsifying Model for Compressed Sensing Magnetic Resonance Imaging,\u201d S. Wang et al. propose a two-layer tight frame sparsifying model for compressed sensing magnetic resonance imaging (MRI) by sparsifying the image with a product of a fixed tight frame and an adaptively learned tight frame, which is solved by a three-level Bregman numerical algorithm and enables accurate MRI reconstruction from highly undersampled data with efficiency.In \u201cMany is Better than One: An Integration of Multiple Simple Strategies for Accurate Lung Segmentation in CT Images,\u201d Z. Shi et al. present a novel computerized tomography (CT) lung image segmentation method by integrating multiple strategies, including the guided filter to smooth the image, the optimized threshold to get binary image, region-growing strategy to extract thorax regions, and random walk algorithm to segment lung regions and to get the state-of-the-art segmentation accuracy.In \u201cPulmonary Nodule Detection Model Based on SVM and CT Image Feature-Level Fusion with Rough Sets,\u201d T. Zhou et al. present a pulmonary nodules detection algorithm based on support vector machine (SVM) and CT image feature-level fusion with rough sets to improve the detection accuracy of pulmonary nodules in CT image. Both the unreasonable feature structure and the nontightness of feature representation are taken into consideration in this pulmonary nodules detection algorithm.In \u201cMultigrid Nonlocal Gaussian Mixture Model for Segmentation of Brain Tissues in Magnetic Resonance Images,\u201d Y. Chen et al. propose a novel segmentation method based on the regional and nonlocal information to overcome the impact of image intensity inhomogeneities and noise in human brain magnetic resonance images.In \u201cDTI Image Registration under Probabilistic Fiber Bundles Tractography Learning,\u201d Z. Guo et al. propose a diffusion tensor imaging (DTI) image registration method under probabilistic fiber bundles tractography learning, where the residual error model is modified with finite sample set and the calculated deformation field is then registered on the DTI images.In \u201cAutomated Segmentation of Coronary Arteries based on Statistical Region Growing and Heuristic Decision Method,\u201d Y. Tian et al. propose a fully automated coronary artery segmentation from cardiac data volume based on a statistics region growing together with a heuristic decision to further help cardiovascular radiologists detect and quantify stenosis.In \u201cRapid Retrieval of Lung Nodule CT Images Based on Hashing and Pruning Methods,\u201d L. Pan et al. propose a new retrieval framework based on a hashing method for lung nodule CT images, which can translate high-dimensional image features into a compact hash code to greatly reduce the retrieval time and memory space. Moreover, a pruning-based decision rule is utilized in this algorithm to improve its retrieval precision.In \u201cThe Classification of Tongue Colors with Standardized Acquisition and ICC Profile Correction in Traditional Chinese Medicine,\u201d Z. Qi et al. design a tongue color classification approach using a standardized tongue image acquisition process, color correction, and several machine learning techniques for tongue inspection-based diagnosis in traditional Chinese medicine.In \u201cDiagnostic Method of Diabetes Based on Support Vector Machine and Tongue Images,\u201d J. Zhang et al. develop a SVM-based diagnostic method for diabetes using standardized tongue images. This work shows the potential of applying digitalized tongue images, which are usually used in traditional Chinese medicine, to the diagnosis of diabetes.In \u201cA Computer-Aided Analysis Method of SPECT Brain Images for Quantitative Treatment Monitoring: Performance Evaluations and Clinical Applications,\u201d X. Zheng et al. introduce and validate a computer-aided analysis method to achieve the quantitative treatment monitoring based on single-photon emission computed tomography (SPECT) images, which can provide a convenient solution to generate a parametric image and derive the quantitative indexes from the longitudinal SPECT brain images for treatment monitoring.The papers in this special issue provide a useful message of machine learning techniques in dealing with multimodal medical images. This unique and informative collection of papers highlights the direction of related studies. This special issue illustrates the important role that machine learning techniques play in the multimodal medical imaging fields."}
+{"text": "Escherichia coli Bacteriophages Differ in Their Efficacy and Ability to Stimulate Cytokine Release In vitro,\u201d Dufour et al. suggest that the level of cytokine response generated in our paper is due to remaining bacterial debris rather than true differences between individual phages , which to our understanding is achieved through lipopolysaccharide specific binding to a phage derived protein. However, as Dufour et al. rightly point out, \u201cbacterial lysates may also contain several pathogen-associated molecular patterns (PAMPs) able to elicit a pro-inflammatory response, such as flagellin (sensed by TLR-5), unmethylated CpG Oligodeoxynucleotide DNA (TLR-9), lipoteichoic acid from Gram-positive bacteria (TLR-2) and triacyl lipopeptides (TLR-1 with TLR-2) . The additional purification step (the EndoTrap Blue system) binds endotoxins based on the conserved core of lipopolysaccharide (With hindsight and a thorough data audit, we would certainly concur that at least some component of the observed cytokine responses are due to remaining contaminants and that additional purification steps such as chromatography will further reduce possible contaminants. However, such additional steps could come at a cost, reduce overall phage concentration and potentially require additional concentration steps (Boraty\u0144ski et al., However, while it is likely that some component of the cytokine response generated is due to remaining contaminants, additional variation could also be introduced through factors which are uncontrollable, such as genetic variation in Toll receptors between different donors (Netea et al., Despite the suggestion to the contrary provided by the Dufour et al. commentary, the reduction and quantification of endotoxin in phage preparations remains an active area of research (Branston et al., MKM, YH, MN, CC, ES-E, and AN: Writing of the reply and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The author reports that Newcastle disease virus (NDV)-infected umbilical cord-derived mesenchymal stem cells (MSCs) may provide a novel effective therapeutic approach for targeting glioma stem cells (GSCs) and glioblastoma multiforme (GBM), and for sensitizing these tumors to \u03b3-radiation [I read with great interest the article by Kazimirsky et al.  entitledInternational Journal of Cancer [Stem Cell Research & Therapy.A couple of additional points can be made on this topic. The findings of Kazimirsky et al.  regardinf Cancer  and an af Cancer \u20136. In adf Cancer  stated tf Cancer . In partf Cancer . From thContinuing with this important issue, in an article with 70 references none of the previously published work is discussed or cited by Kazimirsky et al. . As we k"}
+{"text": "Traditionally, the role of \u201cemotion\u201d has received little attention in research studies of decision-making  that can be used to simulate dynamic real-life decision-making behavior as well as test the SMH  in each trial and large losses  in some trials. The selection of decks C and D results in a small gain (US$50) in each trial and small losses  in some trials. On average, selections from decks A and B over 10 trials will cause decision-makers lose US$250, and as such, these are defined as disadvantageous decks. Conversely, selections from decks C and D over 10 trials will cause decision-makers gain US$250, so these are defined as advantageous decks. The advantageous decks  provide small immediate gains in each trial, but the long-term outcome is positive; by contrast, the disadvantageous decks  provide large immediate gains in each trial, but the long-term outcome is negative . Consequently, findings related to the PDB phenomenon and gain/loss frequency have clearly echoed the main points reported in previous literature concerning behavioral decision-making  Must et al. review IGT and depression-related issues; (2) Brevers et al. review studies on IGT and gambling disorders; (3) Linnet provide a review of IGT in the context of dopamine and gambling disorders; (4) Cassotti et al. review IGT in relation to developmental studies; (5) Turnbull et al. consider IGT performance as the processing of emotion-based learning; (6) Overman and Pierce examine the effects of real plus virtual cards and additional trials; and (7) van den Bos et al. provide a global overview of rodent version of the IGT.Category II: Clinical examinations: (1) Sallum et al. discuss the IGT and attention deficit hyperactivity disorder; (2) Xiao et al. combine the IGT and functional magnetic resonance imaging (fMRI) in order to investigate adolescent smoking behavior; (3) Singh describe the connection between sleep deprivation and IGT performance; and (4) de Oliveira Cardoso et al. provide a behavior-image study that investigates the correlation between frontal and cerebellar lesions and IGT performance.Category III: Model construction: (1) Worthy et al. compare predictability between win-stay/lose-shift and Value-Plus-Preservation (VPP) models in the IGT; (2) Steingroever et al. validate the predictive power of the Prospect Valence Learning\u2013Delta model; (3) Dai et al. provide an improved cognitive model for predicting IGT choice behavior; (4) Lin et al. refine a simplified model for estimating IGT performance; and (5) Ahn et al. compare three advanced IGT-related computational models.Category IV: Theoretical integration: (1) Okdie et al. provide a statement on construal level theory for IGT-related performance; (2) Bull et al. consider sensitivity toward reward and punishment in healthy IGT participants; (3) Singh suggest a potential role for reward and punishment during the IGT; and (4) Singh consider the influence of sex-differences, handedness, and lateralization on IGT performance.Category V: Brain imaging technology: (1) He et al. combine IGT and fMRI to investigate decisions involving unhealthy food; (2) Mapelli et al. utilize the IGT and event-related potentials (ERPs) to depict the behavioral performance and brain activation of patients with Parkinson's disease; (3) Tamburin et al. combine the IGT and ERPs to detect choice behavior and brain activation in patients with chronic lower-back pain; and (4) Fernie and Tunney describe a study on the correlation between SCRs and knowledge effects in the IGT.The articles selected for inclusion in this special issue provide good coverage of neuroimaging modalities  used in previous IGT experiments. However, there might still be some room for a data-driven data analysis method  What types of brain lesions  does the IGT truly measure? (2) Can SCRs be combined with the IGT to form a critical index of somatic markers? (3) Does the IGT measure ability for implicit or explicit learning? (4) Does EV or gain/loss frequency primarily guide decision-making behavior in the IGT? (5) Is it possible to devise a more sensitive data analysis method that can allocate more specific brain responses to the precise behaviors of IGT performance, such as the events of win, loss, and the switching of card decks? We recommend that future studies of IGT consider these questions seriously and provide in-depth investigations and discussions.Y-CC, C-HL, and J-TH discussed the main structure of this article. Y-CC and C-HL drafted the preliminary title, literature review, and chapter categorization, as well as the initial draft. J-RD and C-HL provided additional viewpoints for future development in the use of brain imaging for studying the IGT. J-TH and J-RD provided final refinements to this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The term \u201cnutraceutical\u201d, derived from the words \u201cnutrition\u201d and \u201cpharmaceutical\u201d was coined in 1989 to describe substances that could be used as foods that possess health benefits. The range of nutraceutical products is widely diverse and may be divided into three main categories: (i) natural products, comprising, among others, herbs and spices; (ii) dietary supplements; and (iii) functional foods. Based on food sources, nutraceuticals can be classified as: (i) dietary fibres of plant origin; (ii) probiotics, which are live microbial feed supplements; (iii) prebiotics, dietary ingredients that selectively alter the composition or metabolism of gut microbiota; (iv) polyunsaturated fatty acids, omega-3 or omega-6 fatty-acids; (v) antioxidant vitamins, including vitamin C, vitamin E and carotenoids; (vi) biologically active phytochemicals like polyphenols; and (vii) spices, whose main components are terpenes and other constituents of essential oils.In the recent years, the field of nutraceuticals has progressed from being a mere conceptual area within biomedical research to a value-added industry with a promising future ahead. Indeed, lately, both the academic community and the general population have become increasingly interested in the health benefits and potential risks pertaining to beverages and food products beyond their basic nutritional assets. In addition, continuing scientific research has provided evidence regarding the biologically active compounds and underlying physiological mechanisms, highlighting the importance of nutraceuticals as complements to the conventional therapies and medications allowing dose reduction and decreasing the occurrence of adverse effects. Despite the undeniable progress in the field of nutraceuticals, there are still several issues that remain to be addressed. These include clinical evidence supporting in vitro claims, regulatory aspects and assurance of nutraceuticals\u2019 identity, quality and safety.International Journal of Molecular Sciences comprises one review article and 16 original research papers that provide important insights into the state of the nutraceuticals field. Nosrati et al. [Fucus spiralis in a human cell in vitro model (MCF-7 cells). Han et al. [The special issue \u201cNutraceuticals in Human Health and Disease\u201d in the i et al.  use mixei et al.  charactei et al.  investign et al.  report tFicus umbellata constituents that appears to be due to apoptosis induction through the ROS-dependent mitochondrial pathway. The work conducted by Dai et al. [Sophora flavescens, inhibits influenza A virus replication and possesses anti-inflammatory activities and that the underlying mechanism may be linked to its ability to inhibit IAV-induced activations of the TLR4, p38 MAPK, and NF-\u03baB pathways.The studies conducted by Forney et al.  provide i et al.  reveals Acanthopanax senticosus in repressing radiation-induced protein expression changes on prefrontal cortex, and suggest that this compound may be a promising alternative medicine for the treatment of radiation injury in the brain yet further testing are needed to understand whether the bioactive ingredients could be effective through the blood\u2013brain barrier. Klimaszewska-Wi\u015bniewska et al. [Studies developed by Liu and Dey  suggest a et al.  provide Collectively, these studies support a role for nutraceuticals in the prevention and amelioration of several diseases. Their innovation in the field and their successful future clinical application will be governed by evidence regarding safety, purity and efficacy. The use of these compounds in clinical practice is emerging, yet important pharmaceutical and clinical issues remain to be answered."}
+{"text": "To lessen the \u201cwear and tear\u201d of existence, cells have evolved mechanisms that continuously sense DNA lesions, repair DNA damage and restore the compromised genome back to its native form. Besides genome maintenance pathways, multicellular organisms may also employ adaptive and innate immune mechanisms to guard themselves against bacteria or viruses. Recent evidence points to reciprocal interactions between DNA repair, DNA damage responses and aspects of immunity; both self-maintenance and defense responses share a battery of common players and signaling pathways aimed at safeguarding our bodily functions over time. In the short-term, this functional interplay would allow injured cells to restore damaged DNA templates or communicate their compromised state to the microenvironment. In the long-term, however, it may result in the (premature) onset of age-related degeneration, including cancer. Here, we discuss the beneficial and unrewarding outcomes of DNA damage-driven inflammation in the context of tissue-specific pathology and disease progression. To withstand the hazards of existence, multicellular organisms need to preserve their bodily functions for long periods of time and protect themselves against pathogens. Taking the cell as a point of reference, the maintenance is directed inwards to counteract macromolecular damage. This often involves restoring injured nucleic acids back to their native form  and interleukin-8 (IL-8) , we recently showed that persistent DDR triggers a chronic auto-inflammatory response leading to severe fat depletion in mice (Karakasilioti et al., Ercc1F/\u2212 fat depots showed hallmarks of persistent DDR together with the marked up-regulation of pro-inflammatory factors, the infiltration of activated macrophages as well as the release of DAMPs known to initiate and perpetuate immune responses (Karakasilioti et al., Ercc1F/\u2212 fat depots in vivo and in adipocytes ex vivo showed that persistent DNA damage signaling triggers the induction of IL-6, IL-8, and TNF\u03b1 by promoting transcriptionally active histone marks and the dissociation of nuclear receptor co-repressor complexes from promoters; the response required ATM and it was instigated in a DNA lesion- and cell type-specific manner. In support of these findings, NF-\u03baB is stochastically activated in tissues of naturally-aged and Ercc1\u2212/\u0394 mice (unlike Ercc1\u2212/\u2212 mice, the Ercc1\u2212/\u0394 animals maintain about 10% of the wild-type ERCC1 protein levels and develop progressive, degenerative changes that markedly resemble those seen in natural aging (Tilstra et al., Ercc1\u2212/\u0394 mice. Moreover, inhibition of IKK/NF-\u03baB activity reduced cellular senescence and oxidative damage in DNA and proteins (Tilstra et al., Zmpste24\u2212/\u2212 and LmnaG609G/G609G progeroid animals. As in Ercc1\u2212/\u0394 animals, genetic and pharmacological inhibition of NF-\u03baB signaling can ameliorate the age-associated features and extend the lifespan of these animal models (Osorio et al., Atm\u2212/\u2212 animals present with infiltration of neutrophils and lymphocytes in the lungs and increased mRNA levels of pro-inflammatory e.g., IL-6, TNF cytokines (Eickmeier et al., Cellular senescence is a term used to describe cells that cease to divide in culture and has been one of the first paradigms to link DNA damage and immunity to disease (Campisi and d'Adda di Fagagna, per se but persistent DDR that triggers the repertoire of innate immune responses (Fumagalli and d'Adda di Fagagna, ssDNA intermediates generated during e.g., transcription or DNA replication may also activate DDR and trigger a pro-inflammatory response (Abe et al., DNA damage-driven inflammation can be both beneficial and detrimental for organismal survival Figure . To undeFuture strategies aimed at identifying new players or delineate key pathways may shed light on the biochemical crosstalk DNA repair and immune factors allowing us to gain insights onto how both systems contribute to disease origin and progression at old age. In this regard, the use of e.g., tissue-specific or tagged knockin animals and high-throughput proteomics and genomics approaches will likely prove valuable toward the development of rationalized interventions (Tilstra et al., AI and EG researched the literature, prepared a schematic first draft, and Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Coffee is the most consumed beverage worldwide. Epidemiological studies with prospective cohorts showed that coffee intake is associated with reduced cardiovascular and all-cause mortality independently of caffeine content. Cohort and case-control studies reported an inverse association between coffee consumption and the degree of liver fibrosis as well as the development of liver cancer. Furthermore, the beneficial effects of coffee have been recently confirmed by large meta-analyses. In the last two decades, various in vitro and in vivo studies evaluated the molecular determinants for the hepatoprotective effects of coffee. In the present article, we aimed to critically review experimental evidence regarding the active components and the molecular bases underlying the beneficial role of coffee against chronic liver diseases. Almost all studies highlighted the beneficial effects of this beverage against liver fibrosis with the most solid results indicating a pivot role for both caffeine and chlorogenic acids. In particular, in experimental models of fibrosis, caffeine was shown to inhibit hepatic stellate cell activation by blocking adenosine receptors, and emerging evidence indicated that caffeine may also favorably impact angiogenesis and hepatic hemodynamics. On the other side, chlorogenic acids, potent phenolic antioxidants, suppress liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteract steatogenesis through the modulation of glucose and lipid homeostasis in the liver. Overall, these molecular insights may have translational significance and suggest that coffee components need clinical evaluation. Coffea, a member of the Rubiaceae family, which includes hundreds of different species. Commercial production mainly exploits the seeds of Coffea arabica (arabica coffees), which represent about 70% of the world market, while Coffea canephora (commonly known as robusta coffees), which has a more bitter taste than arabica, is used principally for instant and espresso coffees (www.ico.org).Coffee is the most consumed beverage worldwide with an impressive impact on the economy of producing countries. Coffee is prepared from the seeds of the coffee plant, genus The association between coffee consumption and all-cause and cause-specific mortality, especially cardiovascular mortality, has been investigated in independent studies evaluating prospective cohorts, with most solid studies finding an inverse association with all-cause and cardiovascular mortality for both caffeinated and decaffeinated blends ,2. RecenIn this review, we aimed to summarize experimental evidence regarding molecular mechanisms underlying the hepatoprotective effects of coffee by reviewing in vitro and in vivo studies. A search of the electronic databases Medline and Embase was performed to retrieve relevant articles published up to May 2016. A combination of the keywords \u201ccoffee\u201d, \u201ccaffeine\u201d, \u201ccoffee polyphenols\u201c, \u201cchlorogenic acid\u201d, \u201ccafestol\u201d, \u201ckahweol\u201d, \u201cmelanoidins\u201d, \u201cliver steatosis\u201d, \u201cliver damage\u201d, \u201cliver injury\u201d, \u201cliver inflammation\u201d, \u201cliver fibrosis\u201d, \u201cliver cirrhosis\u201d, \u201cliver cancer\u201d was searched. All published studies in the English language were considered. Additional papers were retrieved by references of epidemiological studies on coffee and liver diseases. After careful evaluation, the following studies were excluded from the review: (i) studies reporting in vivo effects on acute models of liver damage or failure ; (ii) studies reporting in vitro effects on metabolic processes without assessing effects on cell steatosis or apoptosis (pure metabolic studies).Convincing results from a meta-analysis of 28 prospective studies have indicated that both caffeinated and decaffeinated coffee consumption is associated with lower risk of diabetes in a dose-response manner . ConsistPpar\u03b3), cluster of differentiation (Cd36), fatty acid binding protein 4 (Fabp4) and Mgat1 genes; more interestingly, CGA treatment also attenuated inflammation in the liver and white adipose tissue accompanied by a decrease in the mRNA levels of macrophage marker genes including EGF-like module-containing mucin-like hormone receptor-like 1 (F4/80), cluster of differentiation (Cd68), integrin Cd11b, integrin Cd11c and tumor necrosis factor alpha (Tnf\u03b1), monocyte chemotactic protein 1 (Mcp-1) and C-c chemokine receptor type 2(Ccr2) encoding inflammatory proteins.To our best knowledge, the first experimental study showing a protective effect of a coffee component against liver steatosis was from Rodriguez de Sotillo and Hadley , who shoDue to the tight connection of NAFLD with cardiovascular mortality, it is important to highlight the results from Panchal et al. , who evaRecently, further studies suggested the impact of coffee components not only on metabolic pathways in the liver but also on endoplasmic reticulum stress and autophagy, which are pivot processes in NAFLD . Our groThe association of coffee consumption with fibrosis and cirrhosis development has been investigated in several studies . In a pr4) or thioacetamide and attributed this effect to its nonselective adenosine receptor antagonist activity [Coffee has been consumed for several centuries worldwide for its flavor and taste but also because of the psychoactive effects of caffeine, an alkaloid which is contained in different quantities according to coffee species, techniques of roasting and brewing ,23. To tactivity  Table 24 or thioactivity  showed tactivity  and to ractivity .Arauz et al. and Furtado et al. ,36 indepThe anti-fibrotic effects of caffeine have been also evaluated in in vitro cultures of human and rodent hepatic stellate cells. Shim et al. assessed the effect of caffeine on human hepatic stellate cells (HSC) proliferation and migration and found that caffeine attenuates the progression of liver fibrosis by inhibiting HSC adhesion and activation . Wang etBeside morphological evidence for the anti-fibrotic activity of caffeine coming from the mentioned studies, recently it was elegantly shown by Hsu et al. that caffeine may also favorably impact hemodynamic changes in a rat model of portal hypertension . In this4-induced cirrhosis; the authors found that CGA reduces liver fibrosis and the expression of collagen I and collagen III. Consistently, rats treated with CGA displayed reduced levels of VEGF, TGF-beta and alpha-smooth muscle actin, thus indicating that CGA is able to counteract liver fibrogenesis in rats [Although the anti-fibrotic effects of caffeine are well characterized, few experimental studies have been conducted so far to investigate the effects of polyphenols, such as CGA, in in vitro and in vivo models of liver fibrosis. Shi et al. first explored the effect of the oral administration of CGA in rats with CCl in rats . Success in rats . These f in rats .The epidemiological association between coffee intake and liver cancer prevalence or incidence has been extensively studied throughout the two last decades  Table 3Table 3. At the experimental level, different studies have been conducted so far to identify the molecular determinants of such effects. To our best knowledge, the first experiment that showed the beneficial effects of a coffee component on liver carcinogenesis was conducted by Mori H et al. , who rep4. One week after DEN injection, the groups started receiving coffee or 0.1% caffeine ad libitum for 24 weeks. The groups receiving coffee or caffeine alone not only had a reduction in collagen content but also displayed a significant reduction in the size and area of pre-neoplastic lesions and in the mean number of neoplastic lesions [Katayama et al. assessed the effects of coffee in a liver cancer\u2013prone Long Evans Cinnamon rat and showed that coffee administration for 25 weeks delayed the occurrence of hepatitis, significantly improved survival, reduced the expression of inflammatory cytokines, and reduced the incidence of small pre-neoplastic liver foci in Long-Evans Cinnamon (LEC) rats . Similar lesions .As concerns the molecular targets involved in the chemopreventive effects of coffee, evidence points out the importance of Nrf-2. Cavin et al.  showed aSeveral epidemiological studies have associated the consumption of coffee with a decreased risk of developing chronic liver diseases. Consistently, experimental data suggest that specific coffee components, in particular caffeine and CCA, favorably impact liver steatogenesis, fibrogenesis and carcinogenesis by acting on different molecular and cellular targets . Therefo"}
+{"text": "When facing various extrinsic or intrinsic stimuli, BBB is damaged which is an early event in pathogenesis of a variety of neurological diseases in old patients including acute and chronic cerebral ischemia, Alzheimer\u2019s disease and etc. Treatments that could maintain the integrity of BBB may prevent neurological diseases following various stimuli. Old people often face a common stress of sepsis, during which lipopolysaccharide (LPS) is released into circulation and the integrity of BBB is damaged. Of note, there is a significant decrease of melatonin level in old people and animal. Melatonin has been shown to preserves BBB integrity and permeability via a variety of pathways: inhibition of matrix metalloproteinase-9 (MMP-9), inhibition of NADPH oxidase-2, and impact on silent information regulator 1 (SIRT1) and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. More important, a recent study showed that melatonin supplementation alleviates LPS-induced BBB damage in old mice through activating AMP-activated protein kinase (AMPK) and inhibiting gp91 The blood brain barrier (BBB) is a regulated interface between the peripheral circulation and the central nervous system , composed of occludin, claudin and zo-1, are key components of the BBB  could produce neuroinflammation Shi, , promotiper se but also on the incidence or severity of age-related diseases /NF-\u03baB signaling pathway in neonatal rats (Hu et al., in vitro cell model (Zhao et al., in vivo mice model (Zhou X. et al., phox up-regulation in brain capillary endothelial cells (Figure AMPK activation has been shown to play important role in maintaining the integrity of BBB (Liu et al., s Figure . AMPK acMMP-9 has been shown to play important role in BBB damage (Jin et al., SIRT1 was reported to be beneficial in sepsis. Using EX527, a SIRT1 inhibitor, the authors figured out that melatonin alleviated BBB damage in mice which subjected to cecal ligation and puncture via SIRT1 to inhibit inflammation, apoptosis and oxidative stress (Zhao et al., Aging and sepsis triggered NLRP3 inflammasome activation (Volt et al., Although acute toxicity of melatonin is extremely low in both animal and human studies, melatonin may still cause minor adverse effects, such as headache, insomnia and nightmares (Malhotra et al., In conclusion, decreased melatonin levels may account for the BBB damage in old people who often face the common stress of sepsis and neuroinflammation. Melation supplementation treatment significantly inhibits such events. Therefore, continuous daily melatonin supplementation may help prevent sepsis and neuroinflammation-related neurological diseases through maintaining the integrity of BBB in old people. Since melatonin has low toxicity profile and high efficacy in many pathophysiological states, it should be more commonly tested/used in the medical and veterinary arenas. Further studies are needed to verify the important significance of daily melatonin supplementation in old people.W-CL, XW, XZ, XC and XJ wrote the manuscript and XC, XJ obtained the funding. XW drew the figures. All authors have approved the final version of this review article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recently, a genome-wide study about gene copy number gains and corresponding expression levels has been analyzed in a cohort of 190 non-small cell lung cancer (NSCLC) patients . The auSince decades, much effort has been invested to better understand the relationship between gene expression and prognosis of tumors (Hellwig et al., 2016; Stock e"}
+{"text": "During 2014\u20132016, we conducted mosquito-based Zika virus surveillance in Rio de Janeiro, Brazil. Results suggest that Zika virus was probably introduced into the area during May\u2013November 2013 via multiple in-country sources. Furthermore, our results strengthen the hypothesis that Zika virus in the Americas originated in Brazil during October 2012\u2013May 2013. Aedes aegypti mosquito is considered the main vector of Zika virus in urban and suburban areas throughout the world, including Brazil, where the mosquito has been confirmed, together with Ae. albopictus mosquitoes, as a vector for the virus , which we pooled (n = 178) and subjected to Zika virus detection using real-time RT-PCR  clustered within the same strongly supported lineage, which included strains detected in Rio de Janeiro and other parts of Brazil in late 2015 and in 2016  Figure. Ae. aegypti mosquitoes that were collected during a mosquitoborne virus surveillance program in Rio de Janeiro. Information regarding Zika virus infection rates is lacking for female and male mosquitoes trapped in the field. However, experiments performed in the laboratory demonstrated transovarial transmission of Zika virus among Ae. aegypti mosquitoes and revealed a minimal filial infection rate of 1:290 (In this study, we detected Zika virus RNA in 2 pools of engorged Ae. aegypti mosquitoes trapped in Rio de Janeiro before the first case of autochthonous Zika virus disease was diagnosed in the city (In conclusion, we showed the presence of Zika virus in engorged Bayesian maximum clade credibility tree representing the time-scale phylogeny of the Zika virus outbreaks in the Americas."}
+{"text": "A characteristic of post-surgery patients, particularly the more elderly, can be a persistent self-propagating cerebral inflammatory syndrome referred to as post-operative cognitive dysfunction (POCD). Changes can be analogous to those seen in Alzheimer's disease , a synthetic sedative with analgesic and anxiolytic properties, is widely used in surgery. It is a selective \u03b1Physical trauma, including that caused by surgery, induces an innate immune response that includes release of pro-inflammatory cytokines such as TNF and interleukins (Arvin et al., Since systemic TNF has long been known to cross the blood-brain barrier (Gutierrez et al., ++ homeostasis, and thus the ionic signaling cascades on which normal function of these cells depends (Park et al., Dexmedetomidine has an extensive history of improving neurological function, for example when given preemptively in animal models tibial fracture (Zhu et al., 2-adrenoceptor agonist appears implicated, in that yohimbine, an \u03b12-adrenoceptor antagonist, enhanced TNF levels when the two were compared in a lipopolysaccharide-induced liver damage model (Chen et al., Various pathways of TNF inhibition by dexmedetomidine have been explored. Its action as a \u03b1Using the same mouse tibial fracture model as did others with dexmedetomidine six years later (Zhu et al., Given the pleiotropic nature of TNF, reducing its excess production with dexmedetomidine may also cast light on the mechanisms of other useful outcomes of therapy with this agent that are presently little understood. For instance dexmedetomidine is an acknowledged analgesic, particularly in surgical settings (Vaughns et al., Escherichia coli protecting them completely from harm (Tracey et al., The background information required to rationalize the contrasting outcomes reported in the two trials (Su et al., Thus it seems logical that, in the context of post-surgical delirium (Su et al., A useful step in understanding its mechanism further would be to experimentally compare preemptive use of dexmedetomidine and one of the specific anti-TNF biologicals reported to minimize POCD delirium, pain and anxiety, and to induce morphine tolerance. Because of their molecular size, these biologicals would require administering intracerebroventricularly or perispinally (Tobinick, IC proposed the scope of the review. Both authors were involved in planning and editing the manuscript, blending their complementary expertises. Both authors read, altered and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Serial crystallography was developed for the use at free-electron lasers but the approach has recently also been adapted to synchrotron sources. Here we discuss how the synergy between the two X-ray sources will facilitate a wide application of the technique in microcrystallography, room-temperature structure determination and time-resolved studies. For time-resolved studies, the small crystal size allows for rapid diffusive saturation in mix-and-inject analysis of biochemical reactions, and full optical saturation of the sample by a pump laser in studies of light-driven proteins. The ability to outrun most radiation damage avoids the need for sample cooling and its artifacts, allowing studies of molecular machines at work in their correct room-temperature thermal bath or a controlled chemical environment.Recently we have seen rapid progress in the serial crystallography (SC) method at X-ray free-electron lasers (XFELs). Injection of thousands of protein microcrystals into the \u223c10Despite these achievements, the XFEL community remains relatively small, due to the limited availability of XFEL beamtime which, at present, allows only two simultaneous data collections worldwide (in Japan and USA). In addition, serial femtosecond crystallography (SFX) at XFELs is experimentally demanding and complex, currently requiring sizable interdisciplinary teams of collaborating scientists and engineers. The transfer of the SC approach to next-generation synchrotrons upgraded for higher flux density and with beamlines using sophisticated focusing optics, submicron beam diameters and fast low-noise photon-counting detectors offers a way out of this dilemma. In applications such as room-temperature data collection or phasing from radiation-sensitive microcrystals, serial millisecond crystallography (SMX) at synchrotrons has developed into a viable alternative. In the near future, it may even be possible to extend the method to time-resolved studies. Already it frees beamtime at XFELs to exploit their unique capabilities, such as outrunning damage in structure analysis from nanocrystals or ultrafast time-resolved crystallography.et al., 2008et al., 2011et al.  shows many papers on SC, with some of the most cited examples devoted to the interplay between synchrotrons and XFELs.The experimental origins of fast SC can be traced to an early proposal to fire bioparticles in a continuous single-file stream across a beam for diffraction analysis using a Rayleigh jet (Spence & Doak, 2004 al. 1998. Rossmanet al., 2013The term \u2018serial\u2019 in synchrotron studies has recently become popular in a wider sense, and may also refer to taking a series of diffraction patterns along a few larger crystals, or the scanning of fixed target devices. Such serial approaches share the idea of distributing the radiation dose, to get the maximum signal from all of the available crystal volume. Short millisecond exposures may outrun slower secondary radiation damage from diffusing radicals or relaxation of individual damaged molecules (Warkentin et al., 2015et al., 2016cis\u2013trans reaction. Yet both proteins are available in large amounts and can be grown into big crystals suitable for time-resolved Laue diffraction experiments at a synchrotron. A recent study of the light-driven proton pump bacteriorhodopsin, for which only a few micrometre thick crystals were available, resulted in a series of 13 snapshots at logarithmically spaced time points after activation (Nango et al., 2016An important application where injector-based SC has proven advantageous is fast time-resolved pump\u2013probe crystallography. Myoglobin (Barends et al., 2014et al., 2015et al., 2015et al., 2016The work was only feasible using sample-efficient high-viscosity injectors (Weierstall"}
+{"text": "Reactive oxygen and nitrogen species are generated during normal cellular metabolic activities but can also play an etiopathogenetic role in a variety of conditions, including cardiovascular diseases, neurodegenerative diseases, and cancer.Although the role of oxidative stress in human physiology and pathology has been intensely studied for several decades, it is still far from being understood. Certainly, the roles of free radicals and antioxidants have been significantly redefined. Some \u201cnegative\u201d actions of free radicals in human biology and pathology are now known to be \u201cpositive,\u201d and the hypothesis that \u201cclassical antioxidants\u201d  could be always beneficial for the human health was not confirmed by several epidemiological and clinical studies. The possible reasons of the failures of the current antioxidant therapies, including methodological pitfalls in the drug development and delivery and the lack of good biological markers to select the patients, have been reviewed elsewhere , 2.We currently believe that instead of \u201cantioxidants,\u201d it is more appropriate to develop \u201cmodulators of oxidative stress\u201d because, depending on the condition, it could be more beneficial to reduce or increase the oxidative stress.\u03b2-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?\u201d by J. B. Vicente et al., \u201cProtective Mechanisms of the Mitochondrial-Derived Peptide Humanin in Oxidative and Endoplasmic Reticulum Stress in RPE Cells\u201d by L. Minasyan et al., \u201cEffect of Emodin on Preventing Postoperative Intra-Abdominal Adhesion Formation\u201d by G. Wei et al., and \u201cOpuntia spp.: Characterization and Benefits in Chronic Diseases\u201d by M. del Socorro Santos D\u00edaz et al.), some cardiovascular effects of modulators of oxidative stress , some neurological effects of modulators of oxidative stress , and some effects of modulators of oxidative stress related to cell growth and cancer development  Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver\u201d by A. Butanda-Ochoa et al., \u201cPreclinical Antileukemia Activity Of Tramesan: A Newly Identified Bioactive Fungal Metabolite\u201d by M. R. Ricciardi et al., and \u201cMarkers of Oxidative Stress and Inflammation in Ascites and Plasma in Patients with Platinum-Sensitive, Platinum-Resistant, and Platinum-Refractory Epithelial Ovarian Cancer\u201d by J. C. Cant\u00f3n-Romero et al.).In this special issue, several aspects of the modulation of oxidative stress were examined including the role of polyphenols  and other natural substances  Opuntia spp., stressing that all Opuntia components  used as nutritional and pharmaceutical agents exhibit beneficial properties mainly resulting from their high content in antioxidants, while several other phytochemical components , which have been characterized, also contribute to the medicinal properties of Opuntia spp. that might have a great economic potential because these plants grow in arid and desert regions.In particular, this special issue contains two interesting contributions coming from INSERM Toulouse. The first one is an original research paper prepared in collaboration with CNRS and Palau Sabatier University in which C. Camare et al. investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxidized LDL, contributes to its proangiogenic properties. Using the immunofluorescence analysis of human atherosclerotic lesions, they found colocalization of HNE adducts with CD31 (marker of the endothelium), indicating a close relationship between 4-HNE and neovascularization. Moreover, they revealed that physiological concentrations of 4-HNE also enhance the formation of tubes by human microvascular endothelial cells (HMEC-1), through mechanisms involving reactive oxygen species (ROS) and activation of the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1) pathway. Eventually, they found that carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited such proangiogenic effects of 4-HNE. In their second paper  prepared jointly with partners from Mexico and from INRA in Toulouse, they described in detail features of the well-known plants of In the original research paper prepared by partners from Riga and from Zagreb, we found novel information about growth-modulating effects of the dihydropyridine derivatives (DHPs) with potential antioxidant capacities. Thus, I. Bruvere et al. revealed that cell-type-specific differences in the growth-modifying effects of the DHPs in vitro can be attributed only to the novel types of the DHPs, which differentiate these substances from their well-known predecessor diludine. Since the growth-modifying effects of the novel DHPs indicate possible differential effects on cancer and on nonmalignant cells, which might be also different from their antioxidant effects, these substances deserve particular attention and further studies.The original research paper prepared by three teams from Karlsruhe, Germany, reveals the possible beneficial effects of pentaerythritol tetranitrate (PETN), which were not described before. Namely, pulmonary arterial hypertension was induced by the ranging dosage of the i.v. applied monocrotaline, which induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration, thus causing an increase in pulmonary arterial pressure, followed by the increase in heart/body and lung/body weight ratios. However, in this study, S. Steven et al. found also that PETN therapy could act beneficially upon these pathophysiological processes, most likely by upregulation of heme oxygenase-1 (HO-1)."}
+{"text": "There is a natural decline in cognitive function as we age, particularly in processing speed and working memory. A range of modifiable factors can increase the risk of accelerated cognitive decline including hypertension, chronic inflammation, atherosclerosis, diabetes, atrial fibrillation, stroke, and impaired central nervous system glucose regulation. Given the lack of adequate interventions for cognitive decline and dementia, it is essential that treatments with the potential to reduce the risk of cognitive impairment are thoroughly explored.Nutraceutical and lifestyle medicines, including vitamins, herbs, supplements, physical activity, and diet, have been shown to possess anti-inflammatory, antihyperglycaemic, and antihypertensive properties, suggesting their utility in targeting the pathophysiology associated with risk for cognitive decline. The purpose of this special issue was to explore the role of such complementary medicines in the modification of risk factors for cognitive decline.Clinical trials involving nutraceutical and herbal medicine interventions for people with mild cognitive impairment and dementia are reviewed in G. Z. Steiner et al. The manuscript titled \u201cA Systematic Review of Intervention Studies Examining Nutritional and Herbal Therapies for Mild Cognitive Impairment and Dementia Using Neuroimaging Methods: Study Characteristics and Intervention Efficacy\u201d focuses on papers that feature neuroimaging outcome measures.D. Chang et al. provide a detailed review of the literature on herbal medicine for vascular dementia in their paper titled \u201cHerbal Medicine for the Treatment of Vascular Dementia: An Overview of Scientific Evidence.\u201dVascular disease, such as cerebrovascular disease and atherosclerosis are risk factors for cognitive impairment. X. Zhou et al. review the evidence on this link and promising Traditional Chinese Medicines in their paper titled \u201cVascular Contributions to Cognitive Impairment and Treatments with Traditional Chinese Medicine.\u201dThe fourth review featured in this special issue summarises the evidence on the efficacy of physical activity in reducing depression. D. C. Mathersul and S. Rosenbaum's paper is titled \u201cThe Roles of Exercise and Yoga in Ameliorating Depression as a Risk Factor for Cognitive Decline.\u201dH. Macpherson et al. outline the findings of a clinical trial on older adults in their paper titled \u201cThe Effects of Four-Week Multivitamin Supplementation on Mood in Healthy Older Women: A Randomized Controlled Trial.\u201d\u03b21\u201342.\u201dThe first preclinical paper in this special issue explores the effectiveness of Huannao Yicong extract, a Traditional Chinese Medicine, in reducing tau hyperphosphorylation in Alzheimer's disease model rats. Y. Cao et al.'s paper is titled \u201cTraditional Chinese Medicine Huannao Yicong Decoction Extract Decreases Tau Hyperphosphorylation in the Brain of Alzheimer's Disease Model Rats Induced by A\u03b2 and LRP1 in Hippocampus.\u201dX. Wang et al. report their findings from an electroacupuncture treatment on Alzheimer's disease model mice in their paper titled \u201cImprovement of Electroacupuncture on APP/PS1 Transgenic Mice in Spatial Learning and Memory probably due to Expression of AThe second electroacupuncture paper in this special issue explores the effects of this treatment on cerebral hypoperfusion model rats. C.-X. Zheng et al.'s paper is titled \u201cElectroacupuncture Ameliorates Learning and Memory and Improves Synaptic Plasticity via Activation of the PKA/CREB Signaling Pathway in Cerebral Hypoperfusion.\u201dIn the paper titled \u201cPreservation of Cognitive Function by Lepidium meyenii (Maca) Is Associated with Improvement of Mitochondrial Activity and Upregulation of Autophagy-Related Proteins in Middle-Aged Mouse Cortex\u201d by S.-S. Guo et al., maca  was found to improve cognition and behavior, and mitochondrial dysfunction in middle-aged mice.\u03b2-induced neurotoxicity on SH-SY5Y cells are modulated by a the Traditional Chinese Medicine, Yi-Zhi-Fang-Dai formula. The paper is titled \u201cYi-Zhi-Fang-Dai Formula Protects against A\u03b21\u201342 Oligomer Induced Cell Damage via Increasing Hsp70 and Grp78 Expression in SH-SY5Y Cells.\u201dIn an in vitro study by L. Liu et al., the effects of AThe final paper in this special issue by M. A. Akhtar et a. titled \u201cMedicinal Plants of the Australian Aboriginal Dharawal People Exhibiting Anti-Inflammatory Activity\u201d explores the medicinal effects of a range of Eucalyptus plants used in traditional Australian Aboriginal medicine by the Dharawal people.Authors contributed with a range of papers including original research and review articles spanning in vitro, in vivo, and human studies that improve the understanding of the pathology involved in cognitive impairment in older age and the development of evidence-based complementary treatment strategies for cognitive decline. This collection of works provides a snapshot (that is by no means exhaustive) of current research and some of the emerging trends in this field. This special issue features 11 papers including 4 reviews and 7 original research articles. The complementary therapies explored include nutritional supplements (2 papers), herbal and traditional medicines (6 papers), physical activity (1 paper), and electroacupuncture (2 papers). A brief description of these 11 works is detailed below."}
+{"text": "In 1920, German neuropathologist Alfons Maria Jakob  describeEtymologia series is dedicated to the memory of Richard T. Johnson, MD (1931\u20132015), the leading prion disease authority in the United States for many years and great friend of CDC\u2019s infectious disease programs, so many of which involve central nervous system disorders.This issue of Emerging Infectious Diseases\u2019 long-running"}
+{"text": "Neuroinflammation is an important component of many neuroinflammatory and neurodegenerative diseases. Microglia and astrocytes play a key role in neuroinflammation. Activated glial cells under neuroinflammatory condition produce proinflammatory cytokines, chemokines, nitric oxide (NO), and other neurotoxic mediators. Thus, it has been conventionally thought that the inhibition of such glial activation might be an effective neuroprotective strategy under inflammatory or degenerative disease conditions in the central nervous system (CNS). However, recent studies indicated that activated glia could adopt either neuroprotective or neurotoxic phenotype depending on instigating stimuli present in the given microenvironment . LipopolIn a recent study by Song et al. , a phenoIn summary, based on a high-throughput screen of an approximately 3,500-member in-house library, Song et al. identified a novel small-molecule compound that has an anti-neuroinflammatory effect via the phenotypic switch towards the M2-like anti-inflammatory state in glia. The GPM is a specific PPAR-\u03b3 agonist that can be used to fine-tune glial phenotypes and functions. The GPM-mediated anti-inflammatory state of brain glia may lead to beneficial neuroprotective effects and has therapeutic potential in neuroinflammatory and neurodegenerative diseases. Recent studies suggested that functional phenotypes of macrophages and glia are closely associated with their glucose metabolism. A more recent study by Van den Bossche et al. ["}
+{"text": "Coxiella burnetii, Brucella abortus, Salmonella enterica serovar Typhimurium, Legionella pneumophila, Chlamydia trachomatis, and Orientia tsutsugamushi manipulate the endocytic and secretory pathways. Understanding how bacterial effector proteins manipulate host processes not only gives us keen insight into bacterial pathogenesis, but also enhances our understanding of how eukaryotic membrane trafficking is regulated.Intracellular bacteria have developed numerous strategies to hijack host vesicular trafficking pathways to form their unique replicative niches. To promote intracellular replication, the bacteria must interact with host organelles and modulate host signaling pathways to acquire nutrients and membrane for the growing parasitophorous vacuole all while suppressing activation of the immune response. To facilitate host cell subversion, bacterial pathogens use specialized secretion systems to deliver bacterial virulence factors, termed effectors, into the host cell that mimic, agonize, and/or antagonize the function of host proteins. In this review we will discuss how bacterial effector proteins from  Obligate and facultative intracellular bacteria have developed numerous methods to hijack host membranes to promote uptake, survival, and intracellular replication. Following uptake, intracellular pathogens must engage host organelles and subvert host defense mechanisms to establish their unique intracellular niches. To facilitate interactions with the host, many pathogenic bacteria deliver bacterial virulence proteins, termed effectors, into the host cell using specialized secretion systems. These proteins traffic to distinct subcellular locations within the host cell  Rabex-5  are synthesized in the rough endoplasmic reticulum (ER), delivered to the ER-Golgi intermediate compartment (ERGIC), modified as they move through the Golgi, and are ultimately packaged into transport vesicles for delivery to their final destination  associates with early and late endosomal compartments , encoded on two Salmonella pathogenicity islands  that matures by trafficking through the endocytic pathway and interacts with the secretory pathway  in the SCV, altering the membrane surface charge  that project from the SCV  2 and 3 play an integral role in maintaining SCV positioning and depletion of SCAMP2 or 3 results in dispersion of the SCV within the host cell  GTPases  or de-PCylation, respectively . Interestingly, ubiquitination of these proteins does not require host E1 or E2 enzymes, representing a method of ubiquitination that is unique to trans-Golgi network and is recruited to target membranes by GTP-bound Rab7 P and potentially modulates the activity of the retromer complex. Mutation of ridL results in decreased L. pneumophila replication in macrophages, LAMP1 accumulation on the LCV, as well as recruitment of retrograde cargo receptors (Vps10 and CIMPR) and SNX1 and 2 , ectopic pregnancy, and infertility ; IncA (CT119), InaC (CT813), and IPAM (CT223)  where it undergoes extensive interactions with the Golgi (Grieshaber et al., C. trachomatis causes relocalization of SNXs from endosomes to the inclusion membrane and induces inclusion tubulation (Aeberhard et al., L. pneumophila, knockdown of retromer components enhances C. trachomatis replication, suggesting the retromer complex controls infection (Mirrashidi et al., trans-Golgi network (Mirrashidi et al., In a study to map the host-Inc interactome, an interaction between the inclusion membrane protein IncE and SNX5/6, a component of the retromer complex, was identified (Mirrashidi et al., C. trachomatis hijacks non-vesicular ER-TGN transport to acquire ceramide, a sphingomyelin precursor. Host lipids including sphingomyelin, cholesterol, phosphatidylcholine, and phosphatidylinositol are incorporated into the bacterial cell (Hackstadt et al., In addition to acquiring nutrients by exploiting host vesicular trafficking pathways, C. trachomatis T3SS substrates localize to the inclusion membrane, an additional subset of T3SS proteins are predicted to be secreted into the host cell cytosol (Subtil et al., While a large number of Orientia tsutsugamushi is an obligate intracellular bacterium that is the causative agent of scrub typhus, a potentially fatal disease that is endemic to the Asia-Pacific region. O. tsutsugamushi is transmitted to humans via the bite of an infected trombiculid mite (Valbuena and Walker, O. tsutsugamushi is internalized by clathrin-dependent endocytosis and associates with early and late endosomes as evident by co-localization with EEA1 and LAMP2, respectively (Chu et al., O. tsutsugamushi is released into the cytoplasm where it moves along microtubules to the MTOC (Kim et al., O. tsutsugamushi escapes the phagosome is unknown, however it encodes a hemolysin, tlyC and a phospholipase D (Ge and Rikihisa, C. burnetii (Pan et al., L. pneumophila (Pan et al., Anaplasma phagocytophilum (Caturegli et al., O. tsutsugamushi Ikeda possesses 47 Ank open reading frames (ORFs; Nakayama et al., Orientia infection, the ER is distended and the Golgi is perturbed. While the exact mechanism of how this occurs and the benefit to Orientia is unknown, it is possible that at least part of this is dependent on Ank9.The ankyrin repeat domain is a 33-residue eukaryotic motif involved in mediating protein-protein interactions for numerous host cell processes including transcription, cell cycle regulation, signal transduction, and cytoskeletal rearrangements (Voth et al., Obligate and facultative intracellular bacteria have developed sophisticated strategies to modulate host endocytic and secretory trafficking to promote formation of their unique replicative niches. The adaption of genetic tools for manipulation of obligate and facultative intracellular pathogens has substantially enhanced our understanding of host-pathogen interactions and effector function. While great strides have been made toward understanding how effector proteins manipulate host processes to redirect membrane and nutrients to the parasitophorous vacuoles, the function of most effector proteins still remains ill-defined and genetic manipulation of some of these organism presents specific challenges. Large-scale screens to identify putative binding partners of ectopically produced type III secreted effectors (Mirrashidi et al., All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "X-ray free-electron lasers (XFELs) provide ultra-bright femtosecond X-ray pulses that are intense enough to enable data collection of small weakly scattering objects and short enough to outrun most radiation damage effects. These beam features allow not only to study highly radiation-sensitive systems such as metalloproteins and tiny crystals but also to capture fleeting reaction intermediates in time-resolved studies. They therefore expand the structural biologist\u2019s toolbox by a great deal . Second, there is the serial femtosecond crystallography (SFX) data collection scheme that only once probes randomly oriented microcrystals intersecting the XFEL beam and gives a still image. Thus, it had long been doubted that the resulting integrated Bragg intensities are accurate enough for de novo phasing to be successful. A number of XFEL-specific phasing approaches have been suggested  using in vivo grown nanocrystals diffracting to better than 2.5\u2005\u00c5 resolution  becomes meaningful and fewer images (and thus less sample and beam time) are needed to obtain accurate Bragg intensities.Knowing whether one can solve a structure by SAD phasing and when to stop collecting more data because the anomalous signal in SAD phasing is high enough is still an active area of research [see, for example, Terwilliger  al. 2016 and refe al. 2017 in this de\u00a0novo phasing required 60000 indexed patterns for fully automatic model building (Barends et al., 2014et al., 2016et al. (2015et al., 2017In fact, data processing programs have improved significantly in recent years. This is reflected in the finding that fewer and fewer diffraction patterns of a given dataset are needed for phasing. For example, the very first demonstration of  al. 2015 could no"}
+{"text": "Clinical observations that hyperlipidemia and diabetes are both reversed in mice and in patients taking Gleevec support the drugs' primary metabolic targets by biguanides and statins. This is evident by structural data demonstrating that Gleevec shows pyridine- and phenyl-guanidine homology with Phenformin and identical phenylcarbamoyl structural and ligand binding homology with Lipitor. The misunderstood mechanism of action of Gleevec is emblematic of the pervasive flawed reasoning that genomic analysis will lead to targeted, personalized diagnosis and therapy. The alternative perspective for Gleevec's mode of action may turn oncotargets towards metabolic channel reaction architectures in leukemia and melanoma, as well as in other cancers.Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs' significant pharmacokinetics, pharmacodynamics and structural homologies, which are reviewed herein. Gleevec's success in turning a fatal leukemia into a manageable chronic disease has been trumpeted in medical, economic, political and social circles because it is considered the first successful targeted therapy. Investments have been immense in omics analyses and while in some cases they greatly helped the management of patients, in others targeted therapies failed to achieve clinically stable recurrence-free disease course or to substantially extend survival. Nevertheless protein kinase controlling approaches have persisted despite early warnings that the targeted genomics narrative is overblown. Experimental and clinical observations with Phenformin suggest an alternative explanation for Gleevec's mode of action. Using  Gleevec's  demonstrated anti-proliferative action in chronic myeloid leukemia ushered in the era of targeted therapies with claims that the drug blocks the constitutively active BCR-ABL tyrosine kinase thereby inhibiting phosphorylation of multiple downstream proteins of the mitogenic signaling pathways . Partly et al. [in vitro studies have thrown into similar question whether the single-target kinase signal blocking mechanism is indeed the primary mechanism for STI-571's mode of action [13C-guided precise flux measurements, in a comparative multiple cell line study. Targeted 13C-glucose tracer fate association studies demonstrated the drugs' downstream impact on submolecular fatty acid processing and deuterium depleting metabolic events that occurred independent of Gleevec's molecular target. Clinical observations that hyperlipidemia and diabetes are both reversed in mice and in patients taking Phenformin and Gleevec support the drugs' primary metabolic targets [In their excellent paper Petrachi et al.  reiteratf action  using 13 targets \u201310.et al.'s work in melanoma [The structural homology between Phenformin and Gleevec certainly links Petrachi melanoma  to Gleevmelanoma , the guamelanoma  and Gleemelanoma , which hmelanoma , 14 detemelanoma . Strikinmelanoma  so that et al.'s work [via six hydrogen bond interactions [via distinct amino acid residues that are also known to bind Lipitor, Metformin and Phenformin in their own protein targets. These low affinity and high capacity drug binding architectures are evidently shared by Lipitor, Phenformin and Gleevec, which include histidine, leucine, iso-leucine, as well as serine, as specific amino acid ligands in two dimensional visual structures [13C-glucose guided metabolomics studies [It is worth knowing that all analogues designed to treat Gleevec resistance share guanide structural similarities and target the same ATP pocket for binding, all of which result in remissions in chronic myeloid leukemia. Petrachi .'s work  may exteractions . Such hyractions . Figure ructures . Gleevec studies , 12. The studies  to Metfo studies , a struc studies \u201324. Thes studies , 23. MorIn summary, the excellent paper by Petrachi et al. [et al. [i et al.  that demi et al.  as well i et al. \u201329. The  [et al.  opens di [et al. , 14, bas [et al. ."}
+{"text": "Control of cell-cell coordination and communication is regulated by several factors, including paracrine and autocrine release of biomolecules, and direct exchange of soluble factors between cells through gap junction channels. Additionally, hemichannels also participate in cell-cell coordination through the release of signaling molecules, such as ATP and glutamate. A family of transmembrane proteins named connexins forms both gap junction channels and hemichannels. Because of their importance in cell and tissue coordination, connexins are controlled both by post-translational and post-transcriptional modifications. In recent years, non-coding RNAs have garnered research interest due to their ability to exert post-transcriptional regulation of gene expression. One of the most recent, well-documented control mechanisms of protein synthesis is found through the action of small, single-stranded RNA, called micro RNAs (miRNAs or miRs). Put simply, miRNAs are negative regulators of the expression of a myriad proteins involved in many physiological and pathological processes. This mini review will briefly summarize what is currently known about the action of miRNAs over Cxs expression/function in different organs under some relevant physiological and pathological conditions. Cell-cell communication and signaling is regulated by exchange of soluble factors between cells through gap junction channels (GJC) , the level of miR-1 is downregulated with a concomitant upregulation of Cx43 within the endoneurium of the sciatic nerve  the presence of Cx43 GJCs. However, after fusion, Cx43 is downregulated by both miR-206 and miR-1 in myocytes in vitro (Anderson et al., In the cell line C2C12, which is a mouse myoblast cell line, it has been shown that miR-206 promotes muscle differentiation (Kim et al., As in skeletal muscle cells, miR-1 also controls Cx43 levels in smooth muscle cells. Thus, in overactive bladder, it was shown that MYOCD downregulates Cx43 expression by controlling miR-1 levels, showing that reduction of Cx43 could be a key factor in this pathology (Imamura et al., in vivo\u2014was observed (Inose et al., Cx43 is the main Cx expressed in osteocytes, and its presence is fundamental for their differentiation (Civitelli, GJs play a key function in propagating action potentials, and the heart is no exception to this principle. Both Cx40 and Cx43 localize along the axis of atrioventricular conduction, including atrioventricular node, atrioventricular bundle and Purkinje fibers suggesting an important role in conducting the impulse (Gourdie et al., As mentioned, miR-1 is involved in downregulation of Cx43 in skeletal muscle development (Anderson et al., miR-1 is not the sole master switch, controlling Cx43 levels in the heart. On one hand, it has been shown that miR-19 a/b decrease Cx43 levels, and that this change is associated with cardiac arrhythmia observed in a mouse constitutively overexpressing the miR-17-92 cluster in smooth muscle and cardiomyocytes (Danielson et al., in vivo and in vitro, and inhibits tumor growth in vivo (Li et al., Significant changes in gene expression patterns that promote rapid cell division are the unifying hallmark of tumorigenesis. Each different type of cancer has a distinctive signature of \u201cdriver\u201d mutations, which are recurrent across patients and affect genes that encode key components of the cell cycle machinery (Vogelstein et al., In nasopharyngeal carcinoma associated with the Epstein-Barr virus, downregulation of miR-218 has been consistently observed (Alajez et al., In breast cancer cell line MDA-MB-231, transfection of hsa-miR-206 decrease Cx43 levels, which was correlated with a decrease of proliferation rate and cell migration (Fu et al., An interesting potential avenue of research is to better understand whether changes in expression levels of Cxs in different types of cancer are partially or fully mediated by miRNAs. Therefore, biologically accurate models are required in order to dissect the mechanism that underlies promotion of invasiveness and worsens the clinical course of different forms of cancer.This review revisits insurmountable evidence of the relevant role of Cxs in health and disease. In addition to this, we have discussed the most recent findings in microRNA-mediated regulation of Cxs for several muscle and skeletal disorders as well as rhythm-associated and structural heart defects, and several types of cancer. Table JFC and MAR wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers, and demonstrated SNCA is a modifier of pathology in motor neuron disease.The term \u201cmotor neuron disease\u201d encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an  The term \u201cmotor neuron disease\u201d refers to a group of disorders, causing progressive paralysis of affected patients due to the degeneration of motor neurons cells which control voluntary movements. Importantly, not all motor neurons appear to be affected in the same way, with those that control the face being affected less that those that control the abdomen. The reason why some motor neurons are more vulnerable is unknown; however, understanding this may provide new targets for therapeutics to slow motor neuron degeneration either as stand-alone therapeutics or in combination with SMN-inducing compounds. In this study, we analysed gene expression in different groups of motor neurons and compared this to previously published expression data to identify commonalities. One of the common transcripts was alpha-synuclein (SNCA), which was consistently expressed at lower levels in vulnerable motor neurons. Importantly, when SNCA levels were increased in a mouse model of motor neuron disease, the disease phenotype was significantly reduced, including an extension in survival and reduction in motor neuron pathology. Collectively, these results demonstrate that this approach can identify disease modifiers that can reduce disease severity in models of motor neuron disease and potentially identify new therapeutic targets. SMN1 gene and visualised with Cy3-conjugated secondary antibodies . Muscles were then whole-mounted in Dako Fluorescent mounting media. Confocal microscopy was performed using a Nikon A1RThe percentage of fully occupied endplates was determined by classifying each endplate in a given field of view either fully occupied  completely overlies endplate (BTX)), partially occupied ), or vacant (no pre-synaptic label overlies endplate). At least 4 fields of view were analysed per muscle totalling >100 endplates per muscle.All data was assembled and analysed using Microsoft Excel and GraphPad Prism.S1 TableTable shows the ensembl ID , the official gene symbol (gene), the chromosomal location (locus), the average normalised read count from an N of 2 samples for resistant (BS-WT) or vulnerable (SC_WT) samples, the log2 fold change, and the relevant statistics .(XLSX)Click here for additional data file.S2 TableTable includes the mouse official gene symbol and the log2 fold change identified in Brockington et al., Kaplan et al., Murray et al., and Hedlund et al.(XLSX)Click here for additional data file.S3 TableTable includes the mouse official gene symbol and the log2 fold change identified in Brockington et al., Kaplan et al., Murray et al., and Hedlund et al.(XLSX)Click here for additional data file."}
+{"text": "I am concerned by an article \u201cDetecting Key Genes Regulated by miRNAs in Dysfunctional Crosstalk Pathway of Myasthenia Gravis\u201d by Cao et al., 2015 [In this study, the authors used data from public databases to compare microarray data from the thymus and miRNome data from peripheral blood mononuclear cells (PBMCs). They analyzed the regulation of mRNAs from the thymus by miRNAs from peripheral blood mononuclear cells: two different \u201ctissues.\u201d Of course, they ended up with results but one can really wonder about the meaning of these results.Moreover, in their manuscript, Cao et al. compiled thymic microarray data altogether while data are from different categories of patients (seropositive (for anti-AChR antibodies) and seronegative patients)  ["}
+{"text": "Tenascins represent key constituents of the extracellular matrix (ECM) with major impact on central nervous system (CNS) development. In this regard, several studies indicate that they play a crucial role in axonal growth and guidance, synaptogenesis and boundary formation. These functions are not only important during development, but also for regeneration under several pathological conditions. Additionally, tenascin-C (Tnc) represents a key modulator of the immune system and inflammatory processes. In the present review article, we focus on the function of Tnc and tenascin-R (Tnr) in the diseased CNS, specifically after retinal and optic nerve damage and degeneration. We summarize the current view on both tenascins in diseases such as glaucoma, retinal ischemia, age-related macular degeneration (AMD) or diabetic retinopathy. In this context, we discuss their expression profile, possible functional relevance, remodeling of the interacting matrisome and tenascin receptors, especially under pathological conditions. Numerous studies demonstrate that retina and optic nerve degeneration is highly associated with remodeling of various extracellular matrix (ECM) components. Glycoproteins and proteoglycans that surround retinal cells and optic nerve fibers represent major constituents of the ECM meshwork, known as the matrisome , Tnc exhibits high expression during early development. With ongoing maturation, it is progressively downregulated, but re-expressed under pathological conditions , diabetic retinopathy, glaucoma and retinal vascular occlusion (Mizener et al., Several studies reported on a dysregulation of Tnc following cerebral, hepatic as well as myocardial ischemia (Lu et al., In the CNS, tenascins represent main structural and functional constituents of synaptic sites (Dityatev et al., AMD is defined by a deterioration of the macula and represents a major cause of vision impairment worldwide (Jager et al., The tenascin family member Tnx was identified in AMD patients in a genome-wide association study (Cipriani et al., Additionally, high levels of Tnc were observed in choroidal neovascular membranes from AMD patients (Nicol\u00f2 et al., Diabetic retinopathy is also highly associated with retinal vascular dysfunction. Tnc was found in intravitreal membranes of patients with traumatic and idiopathic proliferative vitreoretinopathy as well as in diabetic retinopathy (Hagedorn et al., RGC nerve fibers exhibit a poor regeneration capacity after injury, which often leads to irreversible vision loss. Therefore, multiple studies focused on the improvement of RGC survival as well as axonal regrowth, guidance and pathfinding (Fischer and Leibinger, After optic nerve damage, Wallerian degeneration, demyelination, immune activation and glial scar formation can be observed. In this context, it has become evident that next to the intrinsic cellular repertoire, an inhibitory environment prevents regrowth of optic nerve fibers Fischer, . ECM proin vivo. Tnr was also described as a repulsive guidance molecule of newly growing as well as regenerating optic nerve fibers in the zebrafish (Becker and Becker, in vitro. In contrast to the reduced Tnr expression levels observed in the optic nerve of the salamander (Becker et al., in vivo. In addition, Tnr and axon growth-promoting molecules were found upregulated in the regenerating visual pathway of the lizard Gallotia galloti (Lang et al., Compared to mammals, the CNS of the zebrafish displays a robust axonal regeneration capacity and allows visualization of axonal regeneration and re-myelination Since Tnr is highly associated with myelinated optic nerve fibers and nodes of Ranvier, it was proposed that it might have a functional relevance in myelination processes. Recordings of action potentials from Tnr knock-out mice revealed reduced axonal conduction velocities compared to control mice. In contrast, no significant differences in the number of myelinated optic nerve fibers or in the myelin ultrastructure were observed in Tnr knock-out compared to wild-type mice (Weber et al., A potential role of Tnc in neural repair of the injured rat optic nerve was initially reported by Ajemian et al. . Here, aA huge diversity of interacting molecules can be observed for the tenascin proteins. For Tnc this includes the cell adhesion molecules contactin-1 (Rigato et al., The signaling of integrins in RGC-glia interactions is crucial for RGC survival and process extension (Vecino et al., in vitro. Furthermore, Tnc knock-out mice show an impaired de-differentiation capacity (Besser et al., As mentioned above, CSPGs are major interaction partners of Tnc. In the CNS, CSPGs are widely recognized as major inhibitory constituents of the glial scar (Silver and Silver, in vitro (Tom et al., Likewise, Tnc displays a complex interactome with other ECM glycoproteins. For instance, its interaction with fibronectin and Tnr was reported (Chiquet-Ehrismann et al., The adhesion molecule contactin-1 was identified as an important neuronal receptor for Tnr. Interaction of these two molecules was reported to mediate the repulsion and defasciculation of neurites (Pesheva et al., In the CNS, tenascin glycoproteins are important constituents of a highly regulated and dynamic matrisome. In sum, the current literature supports the notion that Tnc and Tnr are implicated in various pathological processes following retinal and optic nerve degeneration as well as various eye diseases Table . Under pJR wrote the manuscript. LR designed the figures. LR and AF revised the manuscript. All authors have approved the final article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Inflammatory response, oxidative stress, and endoplasmic reticulum (ER) stress are important pathophysiological bases of the occurrence and development of diabetes mellitus (DM) and macroangiopathy complications. Selenoprotein S (SELENOS) is involved in the regulation of these mechanisms; therefore, its association with DM and macroangiopathy has gradually received attention from scholars worldwide. SELENOS has different biological functions in different tissues and organs: it exerts antioxidant protection and has anti-ER stress effects in the pancreas and blood vessels, while it promotes the occurrence and development of insulin resistance in the liver, adipose tissue, and skeletal muscle. In addition, studies have confirmed that some SELENOS gene polymorphisms can influence the inflammatory response and are closely associated with the risk for developing DM and macroangiopathy. Therefore, comprehensive understanding of the association between SELENOS and inflammation, oxidative stress, and ER stress may better elucidate and supplement the pathogenic mechanisms of DM and macroangiopathy complications. Furthermore, in-depth investigation of the association of SELENOS function in different tissues and organs with DM and macroangiopathy may facilitate the development of new strategies for the prevention and treatment of DM and macrovascular complications. Here, we summarize the consensus and controversy regarding functions of SELENOS on currently available evidence. In 2016, the World Health Organization (WHO) declared that diabetes mellitus (DM) had become the eighth most prevalent cause of disease-related mortality. Its onset is no longer mainly observed in economically developed areas; in recent decades, the number of patients has increased significantly in middle- and low-income countries. Therefore, DM has been confirmed to be a \u201cglobal\u201d public health issue [Selenium (Se), a trace element, is a key component of selenoproteins involved in a wide range of functions, including redox homeostasis, inflammatory regulation, thyroid hormone metabolism, immunity, myocardial and tumoral diseases, and reproduction \u20136. MoreoPsammomys obesus (P. obesus) by Walder et al. [Selenoprotein S (SELENOS), as a member of the selenoprotein family, was first discovered in the liver of r et al.  and was r et al. , 14\u201316. r et al. \u201321. The r et al. \u201325. Ther188UGA codon in SELENOS variant 2 CDS can be normally encoded as Sec to produce the protein SELENOS isoform 2, with 189 amino acid residues. Because the SECIS in SELENOS variant 1 is spliced, the 188UGA in the mRNA CDS cannot be encoded as Sec and is recognized as the translation termination signal. Therefore, a short protein, SELENOS isoform 1, with 187 amino acid residues, is produced [The human SELENOS gene (GenBank: NG_013322.1) is located on 15q26.3. Its primary transcript produces two types of transcription variants after selective splicing: SELENOS variant 1 (GenBank: NM_203472.2) and SELENOS variant 2 (GenBank: NM_018445.5). The main difference between these two transcripts is that the selenocysteine insertion sequence (SECIS) in the 3\u2032untranslated region (3\u2032UTR) of SELENOS variant 1 is spliced \u201330. Therproduced , suggest174Cys and 188Sec that has reductase activity [SELENOS is a single-pass transmembrane protein with an ER region (1st\u201325th amino acid residues), a transmembrane region (26th\u201351st amino acid residues), and a cytoplasmic region (52nd\u2013189th amino acid residues). The cytoplasmic region contains the valosin-containing protein (VCP)-interacting motif  composed of the 78th\u201388th amino acid residues, and there is a selenosulfide bond between In addition to localizing in the ER membrane , 18, SELWhen Walder et al.  first diZhang et al.  found thFurthermore, studies in recent years on the association between SELENOS gene polymorphisms and inflammation have also become a hot research topic. Previously, Curran et al.  showed t188Sec and was maintained through the restoration of the selenosulfide bond between 174Cys and 188Sec. In other words, in the reduction process, 188Sec of SELENOS and substrates formed a mixed selenosulfide bond to cause substrate reduction. Next, through the restoration of the selenosulfide bond between 174Cys and 188Sec, SELENOS broke the mixed selenosulfide bond between SELENOS and substrates to maintain the activity of the SELENOS reductase. Liu et al. [174Cys and 188Sec depended on the function of thioredoxin (Trx), indicating that SELENOS was a Trx-dependent reductase. In addition, they also showed that SELENOS had peroxidase activity and could break down its substrate, hydrogen peroxide (H2O2), into H2O [2O2 could up-regulate SELENOS expression in HEK293 human embryonic kidney cells, while inhibition of SELENOS expression could further aggravate the LPS-induced increase of reactive oxygen species levels in HepG2 human liver cancer cells, down-regulation of GPx expression, and inhibition of cell viability. These results suggested that SELENOS may have the function of protecting tissues and cells from oxidative stress-induced damage. Previously, Gao et al. [2O2 damage and enhance cell viability. Our study group induced SELENOS overexpression in human umbilical vein endothelial cells (HUVECs) and showed that SELENOS overexpression could significantly increase HUVEC viability after H2O2 stimulation, enhance the activity of superoxide dismutase (SOD), and reduce the production of methane dicarboxylic aldehyde (MDA) [2O2, which was accompanied by the further increase of ROS and MDA levels and further reduction of the GPx activity. They also confirmed that the antioxidant protection function of SELENOS was associated with mitogen-activated protein kinase (MAPK) and c-JUN N-terminal kinase (JNK).Christensen et al.  showed tu et al.  showed tinto H2O . The abointo H2O  and Zenginto H2O . They foo et al.  showed tde (MDA) . Gan et de (MDA)  showed tde (MDA)  indicateAs an ER membrane protein, SELENOS plays an important role in the maintenance of the morphology and distribution of ER in cells . In addiIn addition to investigating the relationship between SELENOS and inflammation, Fradejas et al.  also anaMart\u00ednez et al.  comparedP. obesus. In addition, the inhibition of SELENOS expression by glucose in a concentration-dependent manner was also confirmed in in vitro cultured HepG2 liver cancer cells. Moreover, Gao et al. [Walder et al.  showed to et al.  confirmeo et al.  induced The expression of SELENOS in 3T3-L1 adipocytes was inhibited by glucose or insulin in a concentration-dependent manner . KarlssoThe contradiction of the association of adipose tissue SELENOS with glucose metabolism in the aforementioned studies was also present in related studies on the association of skeletal muscle SELENOS with glucose metabolism. Walder et al.  confirmeSAA can interact with SELENOS, which was confirmed by both a yeast-two hybrid experiment and surface plasmon resonance analysis , and the2O2 damage and enhance cell viability, suggesting that SELENOS was a protective factor in pancreatic islet and could protect pancreatic islet \u03b2 cells from oxidative stress damage. The study by Christensen et al. [174Cys and 188Sec in the molecular structure of SELENOS rendered SELENOS with reductase activity; in addition, the study by Liu et al. [The progressive apoptosis of pancreatic islet \u03b2 cells is an important feature of the occurrence and development of DM, and oxidative stress damage induced by high glucose is one of the reasons for pancreatic islet \u03b2 cell apoptosis. The study of Gao et al.  showed tn et al.  showed tu et al.  confirmeIn addition to the localization of SELENOS in the plasma membrane, secreted SELENOS was also detected in the culture medium of HepG2 liver cells and human serum samples. However, secreted SELENOS was not detected in the culture medium of 3T3-L1 adipocytes, L6 skeletal muscle cells, Min6 pancreatic islet \u03b2 cells, HEK293 human embryonic kidney cells, HUVECs, or human aortic vascular smooth muscle cells (HA/VSMCs), suggesting that serum SELENOS was mainly secreted by hepatocytes , 33. In Therefore, SELENOS in different tissues and organs has different functions. The results are summarized in Fig.\u00a0Hyrenbach et al.  used the2O2; the changes after inhibition of SELENOS expression had the opposite results [Vascular endothelial cells play an important role in the maintenance of cardiovascular homeostasis, while endothelial dysfunction is the initiating step in the development of atherosclerosis \u201378. Our  results . These r2O2 or TM and increase VSMC apoptosis. Therefore, it was speculated that SELENOS could increase the resistance of VSMCs to oxidative stress and ER stress [VSMCs are important components of the tunica media of vascular walls. Their abnormal proliferation is involved in the formation of early atherosclerosis plagues, and the apoptosis of VSMCs in advanced atherosclerosis plaques will induce the reduction of collagen production to cause fibrous cap thinning and reduce plague stability , which iR stress .2O2. When SELENOS expression was inhibited, Cav-1 and protein kinase C\u03b1 (PKC\u03b1) expression levels increased [2O2, indicating that SELENOS increased the resistance of VSMCs to oxidative stress damage through the MAPK/JNK pathway. In addition, the antioxidant function of SELENOS in blood vessels may also be associated with the aforementioned 188Sec in its molecular structure. Furthermore, the study of Liu et al. [2O2 into H2O, which could partially explain the study results of our group [Our study group further showed that high SELENOS expression could inhibit the increase of caveolin-1 (Cav-1) induced by Hncreased , suggestncreased  confirmeu et al.  also shour group  and thosur group . These rShibata et al.  confirmeIt has been confirmed that various SELENOS SNPs are associated with the risk of the development of autoimmune inflammatory diseases. Marinou et al.  showed tSELENOS is closely associated with inflammation, oxidative stress, and ER stress. In-depth and comprehensive understanding of its association with the above reactions may not only elucidate or supplement pathogenic mechanisms of relevant diseases but also provide new evidence for clinical physicians to develop new strategies for disease prevention and treatment. However, the current understanding of this aspect is limited; there are still some scientific questions that need to be further confirmed or studied in-depth, such as whether SELENOS can inhibit the expression of other inflammatory factors and whether the regulation of ER stress by SELENOS is different in different cell types. Furthermore, whether the human SELENOS gene promoter region has negative regulatory elements that can regulate SELENOS gene expression and whether there are transcription factors that can interact with these elements should also be further explored. These studies will help to provide new targets for drug intervention and to discover more effective disease treatment methods.The functions of SELENOS in inflammatory reactions, oxidative stress, and ER stress point to its great potential in DM and macroangiopathy. It has been shown that SELENOS expressed in different tissues and organs has different effects on the occurrence and development of DM and its macroangiopathy. The high expression of SELENOS in pancreatic islets and blood vessels can exert an antioxidant protection function and can increase the defense capacity of VSMCs to ER stress, while SELENOS expressed in liver, adipose tissue, and skeletal muscle can promote the occurrence and development of DM and insulin resistance. Based on the above functional characteristics of SELENOS, the method by which tissues and organs specifically regulate its expression to fully utilize the advantages of SELENOS and weaken its adverse effects still require further in-depth studies. SELENOS gene polymorphism is associated with DM, macroangiopathy, tumors, and autoimmune inflammatory diseases; therefore, it is expected to become one of the indicators for the prediction of the risk of the above diseases and one of the theoretical bases for the adoption of primary preventive measures for the population carrying relevant SNPs. However, SELENOS SNPs that have been discovered to be associated with disease development must still be confirmed in different populations using larger sample sizes."}
+{"text": "Scientific Reports6: Article number: 3482410.1038/srep34824; published online: 10062016; updated: 12092016The Acknowledgments section in this Article is incomplete:\u201cWe are grateful to Gerrit Ansmann and Christian Geier for interesting discussions and for critical comments on earlier versions of the manuscript and by the Verein zur Foerderung der Epilepsieforschung e.V. (Bonn)\u201d.should read:\u201cWe are grateful to Gerrit Ansmann and Christian Geier for interesting discussions and for critical comments on earlier versions of the manuscript. This study was supported by the Deutsche Forschungsgemeinschaft DFG (Grant No.: LE 660/5-2) and by the Verein zur Foerderung der Epilepsieforschung e.V. (Bonn)\u201d."}
+{"text": "The majority of the reported adverse events seen in these studies are mild or moderate in severity and tend to affect the gastrointestinal or nervous systems. These adverse events, which are common in both adults and children, are also typical of symptoms of malaria or concomitant infections present in these patients. The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. This finding is especially relevant for children from regions with high malaria transmission rates who often receive many courses of anti-malarial medications during their lifetime. Data are also available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations. In addition, post-marketing experience, based on the delivery of 250 million treatments as of July 2009, has not identified any new safety concerns for artemether/lumefantrine apart from hypersensitivity and allergies, known class effects of artemisinin derivatives.This article reviews the comprehensive data on the safety and tolerability from over 6,300 patients who have taken artemether/lumefantrine (Coartem Plasmodium falciparum resistance to monotherapy , G\u00fcrkov et al [et al [et al [et al [et al [et al [There have been case reports of neurological problems  occurring after administration of herbal artemisinin  or artesov et al , and Adjl [et al , as showet al 1, G\u00fcrkov l [et al , and Mayl [et al , as showl [et al  or Makanl [et al , which aLumefantrine is chemically related to halofantrine, an anti-malarial known to be associated with significant prolongation of QTc interval. Indeed, QTc prolongation is a known class effect of many anti-malarial drugs. As such, cardiac safety has been thoroughly investigated during the preclinical and clinical development of AL.+ channels have been investigated in stably transfected human embryonic kidney cells (HEK293) using a whole cell patch-clamp technique [in vitro hERG channel assay showed that lumefantrine and desbutyl-lumefantrine have higher IC50 values (approximately 200-fold) than halofantrine  have been delivered to malaria-endemic countries. Post-marketing experience has not identified any new specific safety concerns apart from hypersensitivity and skin reactions , a recognized class effect for artemisinin derivatives [\u00ae) from published Novartis-sponsored and independently-sponsored clinical trials. Data are available to support the use of a six-dose regimen of AL as a safe and well-tolerated treatment for P. falciparum malaria or malaria due to mixed infection including P. falciparum in adults, adolescents, children and infants. Indeed, the safety profile of this drug is similar in both adults and children, and many of the reported adverse events are typical of symptoms of malaria or concomitant infections that are commonly seen in these patient populations. Reported adverse events are mainly of mild or moderate severity, with very few serious adverse events reported and even fewer serious adverse events considered related to treatment. In addition, no notable neurological adverse events or cardiac safety concerns were identified in the many studies that examined the safety of AL. As patients  often take repeated courses of treatment for malaria, it is reassuring to note that data are available that show repeated administration of AL is not associated with an increased risk of adverse drug reactions, in particular with regard to neurological adverse events. In addition, a thorough review of the clinical data for AL does not identify any potential cardiac safety issues. Data are also available to show that there were no clinically relevant differences in perinatal mortality, neonatal mortality, still birth, pre-term delivery, low birth weight and spontaneous abortion in women exposed to AL compared with SP during pregnancy.This review summarizes some of the safety and tolerability data on AL  treatments have been delivered and post-marketing experience confirms the favourable safety and tolerability profile for this drug. In addition, this wealth of safety evidence has not identified any safety concerns for AL apart from rare type 1 hypersensitivity reactions, a recognized class effect of artemisinin derivatives [In conclusion, AL is a safe and well-tolerated treatment for 50: Inhibitory concentration 50 (the concentration that gives 50% inhibition); ICH: International Conference on Harmonization; IKr: Rectifying K+ current; MAS: Mefloquine plus artesunate; MedDRA: Medical Dictionary for Regulatory Activities; SAE: Serious adverse event; SP: Sulphadoxine-pyrimethamine; vs.: Versus; WHO: World Health Organization.ACT: Artemisinin-based combination therapy; AE: Adverse event; AL: Artemether/lumefantrine; AQ: Amodiaquine; AQSP: Amodiaquine plus sulphadoxine-pyrimethamine; AS: Artesunate: ASAQ: Artesunate plus amodiaquine; ASTMH: American Society of Tropical Medicine and Hygiene; CQ: Chloroquine; CQSP: Chloroquine plus sulphadoxine-pyrimethamine; DNP: Dihydroartemisinin plus napthoquine plus trimethoprim; DP: Dihydroartemisinin-piperaquine; ECG: Electrocardiogram ; hERG: Human ether-a-go-go related gene; ICThe authors would like to acknowledge that Novartis Pharma AG sponsored this supplement. However, none of the authors works for, or represents in any way, Novartis Pharma AG.All authors met International Committee of Medical Journal Editors criteria for authorship."}
+{"text": "The author conducted a review of studies that compared the efficacy, tolerability and indication for the use of clozapine in current perspectives for the treatment of resistant schizophrenia/ partial responders. In the early 1960s, German psychiatrists working with G. Stille at Wander Pharmaceuticals in Bern, Switzerland, worked to refute the concept that EPS and antipsychotic efficacy were linked.3 ClinicaHowever, enthusiasm for the drug was maintained by a small cadre of clinical investigators including G. Honigfeld at Sandoz, who observed that clozapine, was remarkably effective in treatment-resistant patients. This led to a landmark double-blind study of clozapine in a well-defined group of treatment-resistant patients whose blood cell counts were closely monitored during treatment and ulti1The mechanisms of action which account for the effectiveness of clozapine as a pharmacotherapy for the treatment of neuroleptic non-responders and neuroleptic intolerant schizophrenic subjects remain elusive. It is characterized by generally lower affinities for D2 receptors and relatively greater affinities for serotonin (5-hydroxytryptamine) 5-HT2A receptors in particular, but also for noradrenergic receptors (\u03b11 and \u03b12), muscarinic acetylcholine receptors, histamine and other dopamine (DA) subtype receptors.et al,[11C] SCH23390 and [11C]raclopride to investigate D1 and D2 receptor occupancy in vivo in 25 schizophrenic patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine or risperidone. They concluded that among the atypical antipsychotics, clozapine appeared to have a simultaneous and equivalent occupancy of dopamine D1 and D2 receptors. Whether its effect on D1 receptors represents agonism or antagonism is not yet clear. This issue is still unresolved in the preclinical arena. The distinctive effect on D1/D2 receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.Tauscher et al, used PosMeta analysis of controlled trials involving patients who had treatment resistant schizophrenia\u201312 and aet al.,[In an open trial by Agarwal et al., drug-resMoncrieff comparedSeveral authors have questioned whether clozapine should be indicated as a first-line treatment for early psychosis.\u201317 The ret al., reported the interesting observation that clozapine, in comparison with fluphenazine, was similarly efficacious for new-onset patients with schizophrenia or schizoaffective disorder.[2 receptors in their brains. Typical antipsychotics may cause the upregulation because they dissociate slowly from the D2 receptor[Woerner disorder. It is frdisorder. that pat receptor and the  receptor may allo receptor Because  receptoret al.,[Pragmatic trials, supposed to provide more complete information for physician in clinical practice, support et al., in a phaet al., studied et al., Patientset al,[In another pragmatic trial Lewis et al, studied a second generation antipsychotic, Tuunainen et al,[In a Meta analysis comparing clozapine with en et al, found a et al., found that the magnitude of improvement in mean BPRS and CGI scores from baseline to end of the study was significantly greater in the clozapine group than in the risperidone group. Statistically significant differences in favor of clozapine were also seen for most of the secondary efficacy measures . The adverse event profile was similar for both treatment groups, with a lower risk of extrapyramidal symptoms in the clozapine group.In a Double-Blind Comparative Study, includinClozapine has shown consistent clinical benefit in schizophrenic patient with persistent aggressive and violent behavior.30 Whetheet al.,[McGurk et al., investiget al.,[Bilder et al., examinedet al.,[Purdon et al., examinedIt is estimated that approximately 30% of patients treated with clozapine do not respond adequately, remaining with persistent psychotic symptoms despite taking adequate treatment for sufficient period. Such patients are called \u201cpartial responders to clozapine,\u201d \u201cclozapine resistant,\u201d or even \u201csuper refractory\u201d. Despite 353745In a study conducted at psychiatry center, S.M.S. medical college, Jaipur, by Dr. R.K. Solanki and Dr. Paramjeet Singh, 100 diagnosed cases of schizophrenia on clozapine maintenance (not showing adequate response) were augmented with risperidone (2-4 mg/d). Patients showed significant improvement after 4 week on CGI, BPRS and PANSS scales.et al.,[Lieberman et al., reviewedIn international suicide prevention trial includinet al.,[Turetz et al., treated et al.,[et al.[Green et al., examined.,[et al.It is als.,[et al.Clozapine is least likely to worsen the neurological disorder so it isA number of authors have investigated the factors associated with response to clozapine but findings are contradictory. Reviewing the evidence Chung and Remington suggesteP<0.001), in 12 (60%) it lasted longer (P=0.0368) and in 17 (85%) it occurred more quickly on rechallenge (P<0.001).they concluded that after risks and benefits have been considered, rechallenge may well be justified in some patients.Apart from common side effects like sedation, dizziness, syncope, tachycardia, hypotension, ECG changes, nausea and vomiting, fatigue, weight gain, constipation, anticholinergic effects and subjective muscle weakness, several rare side effects has been described during clozapine treatment. One most important is neutropenia which may lead to fatal agranulocytosis, occurs in about 1% patient. Its mechanism is unclear but may be the result of direct toxicity or an immune response. Annan LJIn a review Wetterling suggested that Average weight gain with clozapine is 1.72 kg /month, occurring most frequently during first 6 to 12 month of treatment. There haet al.,[2. Thirty patients (36.6%) were diagnosed with diabetes during the 5-year follow-up. Weight gain, use of Valproate and total daily dose of clozapine were not significant risk factors for developing diabetes mellitus. Patients experienced significant weight gain that continued until approximately month 46 from initiation of clozapine. There was a nonsignificant increase in total serum cholesterol and a significant increase in serum triglycerides level.In a 5 year naturalistic study Henderson et al., examinedet al.,[Howes et al.,examined et al., Similarlet al.,et al.,[Akathisia occurs even occasionally with clozapine. Very raret al., reviewedet al.,et al.,[Cohen et al., conducteet al.,69 Myocaret al., There iset al.,Clozapine is known to increase seizure frequency. In a review seizure 74Clozapine specifically has two important risks of intestinal dysfunction: potentially severe ileus and sialDe novo emergence or exacerbation of obsessive-compulsive (OC) symptoms during treatment with clozapine has been described in the literature. Lykouras et al.,[s et al., revieweds et al.,Toxic delirium can occur in about 3% of patient.ClozapineData regarding the potential teratogenacity of clozapine are not unanimous. There are some reports of congenital malformations and other complications during pregnancy. But there is report of succeThe ten years of clinical experience of clozapine use in the dose range 100-400 mg/day as monotherapy or augmentation has been significantly safe and acceptable at large by patient subgroups. The side effect profile remained comparable to other SGA's, as evident from the unpublished data of the ongoing study at psychiatry center, SMS medical college, jaipur.The result of the different studies indicated that clozapine exhibit superiority over typical antipsychotics in terms of both efficacy  and safety. However the magnitude of its effect is not consistent. Efficacy data for other SGA's in the treatment of refractory schizophrenics were inconclusive.So there is growing need to consider different treatment strategies. Whether monotherapy or adjuvant therapy for non responsive or partially responsive schizophrenics."}
+{"text": "Sir,et al for their interest in my letter published in 2003 on traditional behavioural practices and exchange of saliva among sub-Saharan African populations. The comments by M Coluzzi et al on my letter highlight a potentially important behavioural practice associated with human herpesvirus 8 (HHV-8) transmission; the use of saliva to soothe blood-sucking arthropod bites. As mentioned in my letter, I found some evidence of this practice in reviewing ethnographic material from the Human Relations Area Files (HRAF). However, neither the extent nor frequency of saliva-associated behavioural practices, including those highlighted by Coluzzi et al, has been investigated among sub-Saharan African populations. The HRAF files present only descriptive, ethnographic data. Scientifically oriented epidemio-logical studies need to be developed to better characterise the frequency and distribution of saliva-associated behavioural practices and evaluate the potential association between these practices and risk of infection with HHV-8.I thank M Coluzzi et al discuss ecological data from a previous study The \u2018promoter arthropod\u2019 hypothesis raised by"}
+{"text": "An outbreak of acute hemorrhagic conjunctivitis occurred in Delhi, India, during August and September 1996. The etiologic agent was confirmed as enterovirus type 70 by a modified centrifugation-enhanced culture method followed by immunofluorescence and neutralization tests. After nearly a decade, this virus is reemerging as a cause of acute hemorrhagic conjunctivitis in India."}
+{"text": "Newer techniques of Laser Trabeculoplasty have revived the procedure and gained widespread acceptance by the ophthalmic community. This review was undertaken to address the evolution of different laser trabeculoplaty techniques, proposed mechanisms of action as well as review current studies of the therapeutic effects of these interventions. Laser trabeculoplasty (LT), first described in 1974 by Worthen and Whickham,Several other lasers including krypton (647.1 or 568.2 nm) diode (810 nm), DLT and continuous wave, frequency-doubled Nd: YAG 532 nm), the work by Latina and colleagues (1998)2 nm, the4Most glaucoma specialists regard LT as an adjunct to maximum tolerated medical therapy. Alternatively, it can be used as an initial glaucoma therapy. LT provides successful results in POAG, pseudo exfoliation and pigmentary glaucoma and in eyes with combined mechanism glaucoma. It does not appear to be effective in glaucoma secondary to uveitis, congenital glaucoma, juvenile open angle glaucoma, iridocorneal endothelial syndrome, iridocorneal mesodennal dysgenesis, steroid induced glaucoma, and glaucoma secondary to elevated episcleral venous pressure.SLT results in selective absorption of energy by trabecular pigmented cells sparing adjacent cells and tissues from thermal damage. It delivers a 400 um diameter treatment spot in three nanoseconds, by using short bursts at low power settings . SLT delivers energy fluence levels to the TM cells that are several thousand times lower than with ALT. One consequence of this energy reduction is that SLT seems to produce less thermal tissue damage to TM than ALT.5MLTMLT utilizes an 810-nm diode laser emitting a train of repetitive short pulses to allow the surgeon to control and spatially confine the laser-induced thermal elevation to produce the intended sub lethal photo thermal effects to elicit a thermal stress response in the TM cells. It is typically performed to deliver 60 to 65 (or 120-130) confluent 300-um diameter invisible laser applications covering the whole height of the TM over 180- (or 360-) angle. Due to the combination of (a) low absorption of the 810-nm laser wavelength by the TM and (b) low irradiance of 2W over the relatively large 300 um spot, MLT seems to interact and thermally affect all superficial and deep TM-pigmented cells without producing visible photo thermal changes, tissue blanching, or bubble formation. The treatment is invisible to the surgeon and uneventful for the patient with no pain and no dazzling laser flashes (810 nm is invisible).Many prospective and retrospective studies compare SLT with ALT indicating that a similar short- and long-term efficacy of ALT and SLT can be expected in patients with OAG with a similar and a mild risk profile.The GLT results demonstrate that ALT could be considered a primary therapy for OAG. Several other studies have also demonstrated that ALT is effective at lowering IOP.18Studies investigating the use of SLT as initial therapy using a 180-treatment report a mean reduction of 7.7 plus 3.5 mmHg (30%)19et al.et al.et al.McIlraith et al.et al.et al.Other variables such as age, sex, type of OAG and degree of trabecular meshwork pigmentation are not associated with improved outcomes in the group of participants receiving SLT.et al.et al.et al.et al.Repeat ALT effectiveness was assessed in a few studies. Feldman et al.et alet al.8Since SLT does not induce trabecular meshwork scarring, Latina et al.et al.Repeat SLT was assessed by Shah The findings are encouraging and suggest that 360-degree SLT may be repeated after an initially successful 360-degree SLT fails and with IOP reduction that suggests only slightly diminishing returns. Findings also suggest that these results may be achieved as early as six months after the first treatment.In a randomized pilot study conducted in the University of Missouri Kansas city,Along with medications, LT effectively and safely lowers elevated IOP. SLT and MLT can be performed with minimum iatrogenic damage to the TM- lowest intraoperative and postoperative complications and side-effects. This will eventually gain widespread acceptance by the ophthalmic community. Newer techniques may assume an increasingly important role of LT in our management of glaucoma."}
+{"text": "To the Editor: We thank Su and Chee (The range of dengue-related ophthalmic complication is still being investigated, and we agree with Su and Chee that other ophthalmic manifestations may occur in patients with dengue fever. In a retrospective observational case series involving 22 eyes of 13 patients with visual impairment from dengue infection, carried out in our hospital, Chan et al. ("}
+{"text": "Environmental Health Perspectives, La Pensee et al. (2009) postulated that bisphenol A (BPA), at nanomolecular doses, confers chemo resistance in estrogen receptor (ER)-\u03b1\u2013positive and \u2013negative breast cancer cells. Certainly, drug resistance is well-known to be an important complication in a variety of cancer chemotherapy options. Several molecular mechanisms have been suggested to explain the onset of drug resistance. Determining the exact mechanism in a particular case is challenging both at the clinical and preclinical research levels because the genome-wide and proteomic approaches to mechanistic studies are still at a developing stage , suggesting that direct or rapid response to E2 is widespread at the mRNA levels in these genes. 2 and environmental endocrine-disrupting chemicals in the uterus of women. Involvement of these gene transcripts, which are present in breast, uterine, and ovarian tissues, in the environment\u2013endocrine inter action suggests the possibility of a utero-ovarian feedback control of breast cancer chemo sensitivity effected by npcRNAs.Recent reports from other laboratories have tended to support a role of npcRNAs in BPA-mediated mechanisms involved in breast cancer and a possible physiochemical interaction of BPA with estrogen and non-estrogen-mediated chemosensitivity-inducing pathway elements. For example, These observations suggest that there may be a utero-ovarian feedback control mediated by ERs on the uterus that cross-talk with vasoneural pathways; the feedback control may mediate estrogen involved in chemoresponsive pathways of breast cancer. Furthermore, these pathways may be regulated by noncoding npcRNAs whose functions may be physiochemically modified by environmental toxicants such as BPA and other related chemials.in Vitro and Laboratory Animal Studies for Assessing Risks to Human Health\u201d in Chapel Hill, North Carolina, on 28\u201330 November 2006 (Since the forum titled \u201cBisphenol A: An Expert Panel Examination of the Relevance of Ecological, ber 2006 , there h"}
+{"text": "Time-resolved structural studies of proteins have undergone several significant developments during the last decade. Recent developments using time-resolved X-ray methods, such as time-resolved Laue diffraction, low-temperature intermediate trapping, time-resolved wide-angle X-ray scattering and time-resolved X-ray absorption spectroscopy, are reviewed. Proteins undergo conformational changes during their biological function. As such, a high-resolution structure of a protein\u2019s resting conformation provides a starting point for elucidating its reaction mechanism, but provides no direct information concerning the protein\u2019s conformational dynamics. Several X-ray methods have been developed to elucidate those conformational changes that occur during a protein\u2019s reaction, including time-resolved Laue diffraction and intermediate trapping studies on three-dimensional protein crystals, and time-resolved wide-angle X-ray scattering and X-ray absorption studies on proteins in the solution phase. This review emphasizes the scope and limitations of these complementary experimental approaches when seeking to understand protein conformational dynamics. These methods are illustrated using a limited set of examples including myoglobin and haemoglobin in complex with carbon monoxide, the simple light-driven proton pump bacteriorhodopsin, and the superoxide scavenger superoxide reductase. In conclusion, likely future developments of these methods at synchrotron X-ray sources and the potential impact of emerging X-ray free-electron laser facilities are speculated upon. Currently approximately 20 new structures are deposited daily within the Protein Data Bank, adding to an accumulated total of more than 60\u2005000 structural entries. This mass of structural knowledge has provided detailed biological insight into protein structure and function relationships and uncountable details into the specific biochemistry of cellular reactions. Despite this impressive history of success, understanding the details of protein conformational changes presents a major challenge for structural biology. This is because X-ray diffraction, by far the most successful technique for elucidating new protein structures at high resolution, intrinsically relies upon the presence of well ordered arrangements of identical copies of the same protein. Flexible regions of a protein are frequently not visible within a crystal structure and proteins known to display large levels of flexibility, such as membrane protein transporters and receptors : the first is that the maximum available X-ray flux from the synchrotron insertion device may be utilized; the second is that the broad spectrum of the X-ray beam enables a large number of full X-ray diffraction reflections to be collected  without the need to rotate the crystal, which is essential when one wishes to record snapshots on sub-millisecond timescales. Nevertheless, this approach encompasses a large number of technical challenges which have been widely discussed  at a given time delay following reaction triggering within three-dimensional crystals. An alternative approach to real-time room-temperature studies is to control the kinetics of the reaction by using temperature or the chemical environment, and thereby find conditions for which a large population of a desired intermediate becomes trapped within three-dimensional crystals. Once conditions have been identified under which the population of a specific intermediate builds up, standard monochromatic X-ray diffraction data can be collected. While conceptually less elegant than time-resolved Laue diffraction, intermediate trapping methods have proven very popular in the search to understand the structural pathways of protein-mediated reactions F            obs \u2212 F            calc electron density map) is visible close to the iron atom, indicating a reactive hydrogen peroxide species within the active site, but the resolution of the electron density map does not allow an atomic model to be built without additional chemical restraints. To address this issue, off-resonance Raman spectra were recorded from both crystals and solutions of superoxide reductase treated with hydrogen peroxide   show very good agreement between the low-temperature structure -induced conformational changes in bacterio\u00adrhodopsin [see Hirai & Subramaniam 2009 and Ande al. 2009 for over4.a).Although time-resolved Laue diffraction and intermediate trapping studies have provided several detailed insights into protein-mediated reactions, these methods necessarily probe protein conformational dynamics within the crystalline state. Structural probes applicable to liquid phases would explicitly side-step this fundamental limitation of time-resolved crystallographic studies of proteins. Time-resolved wide-angle X-ray scattering is an emerging technique that addresses this shortcoming, whereby X-ray scattering data are recorded as a function of time from an ensemble of samples in a liquid environment. Thus the breakage and formation of chemical bonds within small molecules, or the rearrangement of secondary structural elements within proteins, can be visualized since the internal distances between the atoms of the sample change with time. On the other hand, all structural information accessible using wide-angle X-ray scattering is averaged over all orientations of a randomly ordered ensemble of molecules within the sample. As such, the level of structural detail that can be envisioned, even in principle, is significantly less than what can be gleaned using X-ray diffraction. The experimental set-up at the ESRF is shown in Fig. 4et al., 2001et al., 2004et al., 2005 et al., 2005et al., 2006et al., 2006et al., 2004et al., 2005et al., 2005et al., 2009et al., 2006et al., 2008et al., 2008Time-resolved wide-angle X-ray scattering was first successfully applied to probe the structural dynamics of a number of photosensitive small molecules in solution et al., 1998Time-resolved wide-angle X-ray scattering has also recently been extended to probe the conformational dynamics of proteins (Cammarata b)et al. (2008b            b            c)Difference time-resolved wide-angle X-ray scattering data recorded from solubilized haemoglobin are reproduced in Fig. 4t, following photoactivation. These data were fitted to three basis spectra and their characteristic time constants determined. Structural refinement against the intermediate and late state basis spectra  records the modulation of an X-ray absorption spectrum in the energy region from 50\u2005eV to approximately 1000\u2005eV above the absorption edge, whereas X-ray absorption near-edge structure (XANES) focuses upon the smaller energy region up to approximately 50\u2005eV above the edge et al., 2005Myoglobin in complex with carbon monoxide again provided a convenient system for proof-of-principle X-ray spectroscopy studies of protein conformational dynamics about a metal centre. It is more than two decades since the first time-resolved X-ray absorption near-edge spectra of the photodissociation of carbon monoxide from the haem iron of myoglobin were described  and Japan (http://www-xfel.spring8.or.jp/) and the first American XFEL facility has recently reported lasing at 8\u2005keV (http://lcls.slac.stanford.edu/). These fourth-generation X-ray sources promise extremely intense hard X-ray bursts of approximately 100\u2005fs in duration, and will thereby create new opportunities for imaging of biological molecules from extremely small samples  are currently under construction in Europe (et al., 2005et al., 2008et al., 2007Within the realm of time-resolved pump\u2013probe structural studies, the most obvious benefit of these emerging sources will be their remarkable capability to probe the structural dynamics of light-driven reactions with a temporal resolution of 100\u2005fs. Several landmark measurements have already been reported on this timescale at linear-accelerator-based X-ray sources, including key technical innovations for synchronizing the femtosecond laser and X-ray pulses (Cavalieri et al., 2003et al., 2003et al., 2004et al., 2005et al., 2005et al., 2004et al., 2000et al., 2000While taking a very optimistic viewpoint of these emerging opportunities, it seems likely that several technical challenges will be encountered along this path. For example, when using pump\u2013probe methods to study protein reaction dynamics in the crystalline phase, it may well prove advantageous to use the full width of the background undulator spectrum of the XFEL to perform \u2018pink\u2019 time-resolved Laue-diffraction (Bourgeois et al., 2008et al., 2009et al., 2005et al., 2006et al., 2006Time-resolved wide-angle X-ray scattering (Cammarata In closing, the last decade has witnessed several significant technical improvements to existing methods, as well as the development of novel approaches, for elucidating the structural details of protein catalyzed biochemical reactions as a function of time. Even a conservative extrapolation of these recent developments can foresee intermediate trapping and time-resolved wide-angle X-ray scattering studies becoming increasingly widely applied approaches within structural biology. We also foresee that that domain of applications of time-resolved Laue diffraction and X-ray absorption spectroscopy will grow, albeit more slowly. Finally, the imminent application of ultra-fast extremely intense XFEL-generated X-ray pulses to probe the reaction pathways of light-sensitive proteins will offer unique opportunities, delivering many surprises as it opens new structural windows upon fundamental photochemical events on the timescale at which they\u00a0occur."}
+{"text": "Indirect immunofluorescence with serum is used in the diagnosis of pemphigus. We report a case in whom blister fluid was used as the specimen for indirect immunofluorecscence. Immunofluorescence is one of the diagnostic tests done in cases of pemphigus. In 1941, Coons et al. developed the technique of immunofluorescence. In 1964, Beutner and Jordon used the indirect immunofluorescence (IIF) technique to demonstrate antibodies in the sera of pemphigus patients.[Pemphigus vulgaris is an autoimmune blistering disease characterized histologically by suprabasal blister and immunopathologically by A 30-year-old female a known case of pemphigus was biopsied for histopathology and direct immunofluorescence (DIF). Blister fluid along with serum was taken for indirect immunofluorescence (IIF). DIF showed strongly positive IgG deposits. Serial dilutions of blister fluid using phosphate buffered saline (PBS) were incubated with cryostat sections of normal skin (substrate). Subsequently sections were incubated with FITC-labeled anti-human IgG for 30 min at 37\u00b0C. Slides were washed with PBS and mounted in buffered glycerol. Fluorescent microscopy revealed moderately strong ICS deposits of IgG  and focal weak ICS deposits of C3  Figures . IIF witet al.[et al.[et al.[Immunofluorescence is nowadays commonly used in the diagnosis of vesicobullous disorders. Direct immunofluorescence requires perilesional skin, whereas serum is used for indirect immunofluorescence. Blisters are formed as a result of a breakdown of tissue integrity and fluid accumulation in a specific compartment of the skin. In pemphigus, simple binding of the antibody to the ectodomain of the antigen (desmoglein 3) triggers blister formation, perhaps by impairing the function of the molecule. Blister l.[et al. comparedl.[et al. had desc"}
+{"text": "The resulting cascade of reactions greatly magnifies melatonin's efficacy in reducing oxidative stress and apoptosis even in the presence of mitochondrial electron transport inhibitors. The actions of melatonin at the mitochondrial level are a consequence of melatonin and/or any of its metabolites. Thus, the molecular terrorism meted out by reactive oxygen and nitrogen species is held in check by melatonin and its derivatives.The intracellular environmental is a hostile one. Free radicals and related oxygen and nitrogen-based oxidizing agents persistently pulverize and damage molecules in the vicinity of where they are formed. The mitochondria especially are subjected to frequent and abundant oxidative abuse. The carnage that is left in the wake of these oxygen and nitrogen-related reactants is referred to as oxidative damage or oxidative stress. When mitochondrial electron transport complex inhibitors are used, e.g., rotenone, 1-methyl-1-phenyl-1,2,3,6-tetrahydropyridine, 3-nitropropionic acid or cyanide, pandemonium breaks loose within mitochondria as electron leakage leads to the generation of massive amounts of free radicals and related toxicants. The resulting oxidative stress initiates a series of events that leads to cellular apoptosis. To alleviate mitochondrial destruction and the associated cellular implosion, the cell has at its disposal a variety of free radical scavengers and antioxidants. Among these are melatonin and its metabolites. While melatonin stimulates several antioxidative enzymes it, as well as its metabolites (cyclic 3-hydroxymelatonin, N N-acetyl-5-methoxytryptamine) is an endogenously-produced molecule found throughout the animal kingdom from unicells to humans  which is coupled to oxidative phosphorylation provides cells with their major means of generation of its energy requirements  inhaled and eventually taken up by cells is processed in the mitochondrial ETC where it is converted to water following its four electron reduction. However, during this reductive process, partially reduced species of O2 are also produced including reactants that are reduced by one, two or three electrons, i.e., the superoxide anion (O2\u00b7\u2013) and hydroxyl radical (\u00b7OH) and one non-radical product, hydrogen peroxide (H2O2). Collectively, these agents are referred to as reactive oxygen species (ROS).The majority of molecular oxygen , respectively. Since H2O2 is the immediate precursor of the highly damaging \u00b7OH, it is imperative that H2O2 be removed from the intramitochondrial environment as quickly as possible. The major enzyme that accomplishes this is glutathione peroxidase (GPx), which metabolizes H2O2 to water and O2; in this process GPx also converts reduced glutathione (GSH) to its oxidized metabolite (GSSG). Given the major importance of GSH in mitochondrial physiology, it is essential that GSSG be reduced back to GSH; this is accomplished by glutathione reductase (GRd) . O2O2 from the mitochondrial environment is never complete and, via the Fenton reaction, some damaging \u00b7OH are always formed. Cellular organelles have no enzymatic means to remove \u00b7OH so it must either be neutralized by a free radical scavenger or it mutilates a bystander molecule. This carnage occurs in the immediate vicinity of where the \u00b7OH is formed because of its extremely rapid reaction rate; the damage is referred to as being site specific.The removal of H\u2013). Mitochondrial NO functions as a reversible antagonist of complex IV of the ETC by competing with O2 for its binding site. Usually tissue concentrations of NO and O2 are, respectively, in the ranges of 100\u2013500 nM and 10\u201330 \u00b5M. In these concentration ranges, NO causes roughly half maximal inhibition of mitochondrial respiration. Thus, NO is a physiological regulator of respiration and also of the rate of ATP synthesis ; two of these are nitric oxide (NO) and the peroxynitrite anion  has been proposed to exist in mitochondria (mtNOS) . This latter product was identified by mass spectral analysis and carbon and proton-nuclear magnetic resonance (Tan 1-acetyl-N2-formyl-5-methoxykynuramine (AFMK)   , GPx and GRd. The SOD isoforms dismutate Oet al., et al., et al., et al., It has been known for more than a decade that the activities of the antioxidative enzymes mentioned above are heightened in the presence of exogenously administered, pharmacological doses of melatonin , in the production of this tripeptide antioxidant. Often, under elevated oxidative stress conditions, melatonin preserves intracellular GSH levels. This is not necessarily related to the ability of melatonin to stimulate \u03b3-GCS since the indoleamine could preferentially scavenger free radicals and thereby preserve basal intracellular GSH concentrations. The stimulation of \u03b3-GCS, as originally described by Urata  et al., .One final aspect should be considered when melatonin's ability to attenuate molecular impairment due to ROS/RNS is discussed. It is what Hardeland  refers tThis section briefly summarizes the multiple processes by which melatonin may restrict the destruction of molecules and organelles normally inflicted by ROS/RNS. Whereas these processes have all been documented in vivo, the significance of each in forestalling oxidative damage may be cell specific.Several drugs have been identified which are classified as mitochondrial poisons, i.e., they interfere with the transfer of electrons through the ETC. These drugs greatly exaggerate the escape of electrons into the mitochondrial intramembraneous space leading to a reduction of molecular oxygen and formation of radicals. Additionally, reduced oxidative phosphorylation precipitates a depletion of ATP Beal, . These cet al., et al., Rotenone, a specific inhibitor of complex I of the mitochondrial ETC, causes the generation of an excessive number of free radicals. The damage inflicted by this drug is believed to be a consequence of the \u00b7OH , strongly potentiated rotenone-mediated death of pheochromocytoma (PC12) cells, a response attenuated by melatonin. Furthermore, in the presence of melatonin, free radicals were not detected to be released from PC12 cells co-exposed to rotenone plus the Ca2+ ionophore. Since melatonin did not change the concentration of Ca2+ nor did it prevent the inhibitory effect of rotenone on mitochondrial complex I, the authors concluded that the beneficial effects of melatonin on the mitochondria were primarily related to the antioxidative and free radical scavenging capacity of the indoleamine . It was immediately suspected that the drug caused damage to the dopaminergic cells of the substantia nigra which are the major neurons lost in individuals with idiopathic PD. When these individuals died and the brain was examined there was, in fact, a selective destruction of the mesencephalic dopamine-containing neurons. As tragic as these instances were, the identification of this destructive drug provided experimentalists with an agent that causes parkinson-like signs in animals. Use of MPTP has now become a model of examine the processes of PD as well as to investigate drugs that may modify the course of the disease.+). The latter molecule is then released from the glial cells and is taken into dopaminergic nerves via the dopamine transporter. MPP+ interferes with complex I of the mitochondrial ETC; this leads to cellular energy depletion and eventually to the death of dopaminergic cells.When administered to animals, MPTP is taken up by astrocytes surrounding dopaminergic neurons and terminals where it is metabolized to 1-methyl-4-phenylpyridinium  was increased by melatonin treatment. The reduction in cyanide-mediated neural toxicity by melatonin was assumed to be related to the free radical scavenging activity of the indoleamine.Yamamoto and Tang  performeWhen cultured rat cortical neurons were exposed to potassium cyanide over a range of concentrations (0.01\u20131.0 mM) lactate dehydrogenase efflux, indicative of cellular damage, into the culture medium was observed. Melatonin significantly reduced escape of the enzyme from the neurons and preserved their morphology  opening, cytochrome c release, positive YOPRO-1 staining of the early apoptotic nuclei and DNA laddering. Besides inhibiting the apoptotic events initiated in astrocytes by H2O2, melatonin also reduced free radical formation and other degenerative cellular processes that resulted from the exposure of cells to either tert-butyl hydroperoxide or cumene hydroperoxide. Additionally, the protective effect of melatonin against these damaging agents was better than that provided by vitamin E (Jou et al., In a second, more complete study, this group examined in detail many aspects of apoptosis and showed that melatonin also prevented death of cells caused by the oxidizing agent, Het al., et al., et al., The greater efficacy of melatonin in reducing observable free radical generation and apoptotic processes than vitamin E is a common observation. A number of studies have compared melatonin with classic antioxidants, e.g., glutathione, mannitol, vitamin C, vitamin E, etc., and invariably melatonin performs in a superior manner (Sofic et al., According to Jou and colleagues  the openet al. (Besides reducing free radical-mediated, mitochondrial-dependent apoptosis, a process that does not require an interaction of melatonin with a receptor, melatonin may also have a receptor-mediated means of reducing the likelihood of apoptosis. Kilic et al.  examinedet al.  concludeet al., et al., et al., et al., et al. (L and the reduction in cytochrome c release from mitochondria by melatonin in the damaged newborn rat brain.A follow-up study by the same group that melatonin acts to preserve the function of the PI-3 K/Akt pathway (Kilic , et al.  who repoMitochondria are the site of a large percentage of free radicals and related toxicants that are generated in cells. These reactive products cause damage to essential mitochondrial molecules which result in opening of the mitochondrial transition pore, release of cytochrome c and activation of the down stream events that culminate in free radical-mediated, mitochondrial-dependent apoptosis.Since melatonin was discovered to be an indirect antioxidant and direct efficient free radical scavenger, its ability to reduce oxidative stress and to curtail cellular apoptosis has been repeatedly documented. It has also been shown that part of melatonin's ability to quell the oxidation of key molecules stems from its conversion to metabolites, i.e., cyclic 3-OHMEL, AFMK and AMK when it incapacitates free radicals and their related products.The ability of melatonin to protect against oxygen- and nitrogen-based reactants is obvious in situations where toxins that inhibit the mitochondrial electron transport complexes are used. The mitochondrial poisons cause electron leakage with the resultant formation of large numbers of free radicals and consequentially molecular damage. This mutilation is inhibited by melatonin and its metabolites.et al., et al., et al., et al., et al., et al., et al., et al., et al., While melatonin readily resists mitochondrial oxidative damage and cellular apoptosis, there are many unanswered questions remaining. Some of the most noteworthy relate to the intramitochondrial concentrations of melatonin, the precise location of the indoleamine in relation to the complexes of the ETC, is it melatonin or a melatonin derivative that is the active agent in mitochondria and a definitive explanation for its high efficacy in preventing mitochondrial and cellular free radical-mediated destruction. Melatonin's very low toxicity combined with its high efficacy, however, portends its use in clinical medicine to treat conditions that are associated with elevated free radical damage, e.g., septic shock (Gitto"}
+{"text": "Human Mutation by Gottlieb et al. [BAK1 genotype among abdominal aortic anerurysm (AAA) patients and some controls. In particular, sequencing revealed a statistically significant number of instances in which single nucleotide polymorphisms (SNPs) present in tissue samples from patient abdominal aorta (AA) were absent from matching blood samples. The authors proposed a novel hypothesis \u201cpostulating that multiple variants of genes may preexist in \u2018minority\u2019 forms within specific non-diseased tissues and be selected for, when intra- and/or extra-cellular conditions change\u201d [Gottlieb et al., An article published in b et al.  receivedThe implications of this unusual finding are of potential significance as regards the role somatic mutation and intraorganismal selection might play in genetic disease, not to mention the suitability of using blood-derived genomic DNA to evaluate patient mutational status of genetic diseases that affect various tissues. The work was challenged in a Letter to the Editors by Hatchwell , who argIn the current issue, K\u00fcry et al.  discuss Human Mutation, we feel that discussion of the original article by Gottlieb et al. [These four letters were all carefully peer reviewed and evaluated editorially, but within the limitations of the rather constrained \u201cLetter to the Editors\u201d format. As the Managing Editor and Co-Editors of b et al.  and its"}
+{"text": "Phantom breast syndrome is a type of condition in which patients have a sensation of residual breast tissue and can include both non-painful sensations as well as phantom breast pain. The incidence varies in different studies, ranging from approximately 30% to as high as 80% of patients after mastectomy. It seriously affects quality of life through the combined impact of physical disability and emotional distress. The breast cancer incidence rate in India as well as Western countries has risen in recent years while survival rates have improved; this has effectively increased the number of women for whom post-treatment quality of life is important. In this context, chronic pain following treatment for breast cancer surgery is a significantly under-recognized and under-treated problem. Various types of chronic neuropathic pain may arise following breast cancer surgery due to surgical trauma. The cause of these syndromes is damage to various nerves during surgery. There are a number of assumed factors causing or perpetuating persistent neuropathic pain after breast cancer surgery. Most well-established risk factors for developing phantom breast pain and other related neuropathic pain syndromes are severe acute postoperative pain and greater postoperative use of analgesics. Based upon current evidence, the goals of prophylactic strategies could first target optimal peri-operative pain control and minimizing damage to nerves during surgery. There is some evidence that chronic pain and sensory abnormalities do decrease over time. The main group of oral medications studied includes anti-depressants, anticonvulsants, opioids, N-methyl-D-asparate receptor antagonists, mexilitine, topical lidocaine, cannabinoids, topical capsaicin and glysine antagonists. Neuromodulation techniques such as motor cortex stimulation, spinal cord stimulation, and intrathecal drug therapies have been used to treat various neuropathic pain syndromes. One in eight women will develop breast cancer of which approximately 60% are treated surgically for axillary node staging and primary breast tumor resection. It is estimated that over 50% of women suffer chronic pain following treatment for breast cancer surgery. \u201cPhantom Breast Syndrome\u201d (PBS) is a type of condition in which patients have a sensation of residual breast tissue and can include both non-painful sensations as well as phantom breast pain. Patient may have pain and discomfort, itching, pins and needles sensations, tingling, pressure, burning, and throbbing. The syndrome can start even after more than one year of surgery. The incidence varies across different studies, ranging from approximately 30% to as high as 80% of patients after mastectomy. PBS can et al.,[et al.,[et al.,[et al.,[et al.'s review, there were 21 studies with follow-up periods from 1-96 months (one study of 210 months), which revealed the following widely varying ranges of prevalence estimates: Phantom breast pain 3-44%, intercostobrachial neuralgia (ICN) 16-39% for all breast cancer surgery, ICN in breast-conserving surgery 14-61% and neuroma pain 23-49%.[et al.,[et al.,[In a recent review, Jung et al., found th,[et al., suggeste,[et al., distingu,[et al., revealed,[et al.,6 Inciden,[et al., Neuroma ,[et al., Other ne,[et al., found thThere are a number of assumed factors causing or perpetuating persistent neuropathic pain after breast cancer surgery. There is, however, a lack of large-scale multiple risk factor studies identifying the variables as independent risk factors or evaluating their relationships with other variables, which are known to affect the development of chronic pain. From the literature currently available, the most well-established risk factors for developing phantom breast pain and other related neuropathic pain syndromes are severe acute postoperative pain and greater postoperative use of analgesics.9 These aUnderlying each of the four classifications of pain after breast cancer surgery is damage to various nerves during surgery. Nerve preservation approaches have shown reduced incidence of sensory deficits (53% vs 84% of women) but nerve-sparing is only successful in 65% of the cases where it was attempted. EvidencePhantom breast pain and other pain syndromes severely affect the quality of life of patients. The negative impact on a patient's physical and psychosocial functioning is consistent with many chronic and cancer pain syndromes. It has been reported that up to half of patients report negative impact of pain on their activities and up to one-quarter report moderate to high impact on their daily activities at home and work. Not surprisingly, studies have also found that breast cancer surgery patients with chronic pain have a greater psychological stress and psychiatric morbidity than the general population.12Based upon current incomplete evidence, the goals of prophylactic strategies could first target optimal perioperative pain control and minimizing damage to nerves during surgery. Peri-operative Pain Control: Medications traditionally used for persistent neuropathic pain such as topical EMLA, gabapent16et al.,[There is some evidence that chronic pain and sensory abnormalities do decrease over time. Unfortunet al., found thet al.,[Well-established PBS needs treatment. In 2005, Finnerup et al., reviewedFor persistent post-breast cancer surgery neuropathic pain, there exist very few randomized, double-blind, placebo-controlled trials. The use of topical capsaicin23 or amiHowever, many unanswered questions remain about the optimal doses, timing and coordination of therapy with ongoing adjuvant treatment for breast cancer. There are also a number of medications and multidisciplinary approaches showing benefit for other types of neuropathic pain that have yet to be trialed. In women with early-onset or established post-breast cancer surgery neuropathic pain, neuromodulation techniques such as motor cortex stimulation,26 spinalThe small scale of existing studies in persistent pain after breast cancer surgery creates considerable uncertainty regarding the generalizability of their findings, and also regarding the identification of potentially modifiable risk factors. Recent improvements in neuropathic pain screening tools now make early identification and syndrome classification of neuropathic pain more achievable. Many imp"}
+{"text": "Recent evidences prove that, release of potent lysosomal enzymes e.g. \u03b2-Glucuronidase by degranulation of polymorponuclear leukocytes in host gingiva may contribute significantly to tissue destruction and the pathogenesis of periodontal disease. The purpose of the present study was to compare and correlate GCF \u03b2-Glucuronidase with periodontal status among diabetic and non-diabetic patients with chronic periodontitis. A total number of 75 patients were equally divided into Group I (control group), Group II (non diabetic with chronic periodontitis) and Group III (diabetic with chronic periodontitis). Clinical parameters like Plaque index, Gingival index, Probing Pocket Depth and RBS were recorded. The \u03b2-Glucuronidase level in GCF of all three groups was determined by spectrophotometric analysis. It was observed that the periodontitis patients irrespective of their diabetic status, showed increased periodontal destruction with elevated level of \u03b2-Glucuronidase than the controls. Also, the diabetic patients showed increased severity of periodontal destruction and the elevated level of \u03b2-Glucuronidase, thus indicating diabetics at a higher risk for progressive periodontal destruction. Much effort has been made in recent years to identify risk factors responsible for initiation and progression of periodontal diseases. Mounting evidences indicate that, gingivitis and periodontitis are caused by various host responses which are associated with the continuous presence of microorganisms in the gingival crevice. They mayGingival Crevicular Fluid (GCF) provides a non invasive means of studying the host response factor by change of constituents in the fluid. The inflammatory exudates from gingival microcirculation crosses inflamed periodontal tissue and en route collects molecules of potential interest from the local inflammatory reaction. Therefore, the fluid offers a great potential source of factors like enzymes that may be associated with tissue destruction.\u03b2-Glucuronidase is a neutrophil derived lysosomal acid hydrolase enzyme which is stored in the neutrophil primary (azurophil) granules and is released in response to inflammation during periodontal destruction. This enzyme is active in degradation of proteoglycans and the ground substance and is an indicator of neutrophil (PMN) influx into the crevicular environment. Lamster in a recPeriodontal disease has been shown to be more severe in diabetics as compared to non-diabetics. SignificAlthough, a positive relationship of \u03b2-Glucuronidase level and traditional clinical parameters for diagnosis of periodontal disease has been widely studied, but there are inadequate number of studies for comparing \u03b2-Glucuronidase level as a potential marker for disease activity in diabetic and non diabetic patients suffering form chronic periodontitis. Hence, the present study was conducted with the following aims and objectives:To compare GCF \u03b2-glucuronidase activity with periodontal status among diabetic and non-diabetic patients.To correlate GCF \u03b2-glucuronidase activity with periodontal status among diabetic and non-diabetic patients.The patients for this study were selected from the Department of Periodontology and Implantology, Bapuji Dental College and Hospital, Davangere, Karnataka State.Patients with good oral hygiene and clinically healthy periodontium (Group I).Non-diabetic patients having probing pocket depth of 5-9 mm with a radiographic evidence of bone loss on at least 2 teeth, in minimum of two quadrants (Group II).Diabetic patients having probing pocket depth of 5-9 mm with a radiographic evidence of bone loss (Group III) on at least 2 teeth, in minimum of two quadrants.Patients with history of intake of any antibiotics and regular use of anti-inflammatory medication or the use of other drugs known to affect the periodontium, in past 6 months.Patients who had professional teeth cleaning or any other periodontal treatment within last 6 months.Patients who were unable to perform routine oral hygiene procedures.A total number of 75 patients,  in the age group of 30-60 years were selected for this study. The selected patients were divided into three groups as follows:Group I: (Control Group) consists of 25 patients with clinically healthy periodontium and good gingival status .Group II: Consists of 25 non-diabetic patients with chronic periodontitis having 5-9 mm probing pocket depth and radiographic evidence of bone loss.Group III: Consists of 25 diabetic patients with chronic periodontitis having 5-9 mm probing pocket depth and radiographic evidence of bone loss.The following clinical parameters were recorded after the selection of test sites.Plaque Index (PI) (Silness and Loe 1964)Gingival Index (GI) (Loe and Silness 1963)Probing Pocket Depth (PD) was measured by using William's graduated periodontal probe, held parallel to the long axis of tooth from free gingival margin to base of pocket.Random blood sugar (RBS) level was recorded for Group II and Group III patients.The rate of hydrolysis of phenolphthalein glucuronidase serves to assay the activity of \u03b2-Glucuronidase.The phenolphthalein liberated is estimated by the red colour which it gives, at alkaline pH. Phenolphthalein glucuronide has hardly any absorption at the same pH.A single test site was selected from each patient of Group I, II and III. After light supragingival scaling, a standard volume of 0.5 \u00b5l GCF was collected extrasulcularly from isolated test site . Collectet al.[The \u03b2-Glucuronidase level in GCF was estimated by using the reagent kit supplied by Sigma Diagnostics  and specet al.Between the study groups, a significant increase in PI, GI, PD, RBS and \u03b2-Glucuronidase level was observed . On compPeriodontal disease process is site specific and has multifactorial origin where periodontal pathogens, host response, genetic, systemic and behavioral risk factors interplay to develop the disease process. Hence, various measures have been taken to include microbial, immunologic, systemic, genetic and behavioral factors, in addition to traditional clinical and radiographic parameters, for assessing patient's periodontal status.The activity of \u03b2-Glucuronidase is associated with severity of inflammation and also with the presence of putative pathogenic flora. This enzyme has been detected in GCF of patients with active site of periodontal disease, thus making \u03b2-Glucuronidase as an important biochemical marker for disease activity and for predicting future attachment loss.Diabetes mellitus encompasses a heterogenous group of disorders with common characteristics of altered glucose tolerance and impaired lipid and carbohydrate metabolism. Diabetes develops from either deficiency in insulin production or an impaired utilization of insulin.Diabetes is linked to severe periodontal destruction. Uncontrolled diabetic frequently show a combination of inflammatory and degenerative changes ranging from a mild gingivitis to advanced chronic periodontitis with a widened periodontal ligament, exudation from periodontal pockets, and/or multiple lateral periodontal abscesses. Although it may be more severe in nature, the periodontal disease of the diabetic seems to be clinically similar to that found in non-diabetic individuals. This suggests that the diabetic state serves as a predisposing factor which can accelerate periodontal destruction originated by microbial agents.In the present study, we have attempted to test the hypothesis that \u2018diabetics with chronic periodontitis have higher levels of disease activity markers in GCF as compared to non-diabetics with chronic periodontitis\u2019. The probing pocket depth in chronic periodontitis patients with or without diabetes was standardized, so that these parameters did not have any bearing on the level of activity of GCF \u03b2-glucuronidase, thus allowing comparisons to be made between \u03b2-glucuronidase activity of diabetic and non-diabetic patients. Also, this study was aimed to determine \u03b2-glucuronidase activity in host tissues and not from the bacterial origin hence acidic pH was used to detect activity of enzyme.et al.[In this study, plaque index, gingival index and probing pocket depth values were significantly lower in Group I, as compared to Group II and Group III patients. Though there was statistically non-significant difference in plaque index and gingival index in between Group II and Group III patients, the average probing pocket depth was significantly higher in Group III as compared to Group II. These findings are consistent with that of Oliver and Tervonen and Lamset al.The relationship between oral hygiene to periodontal disease has long been well established in the dental literature. In this study, with respect to oral hygiene (Plaque Index) and gingival status , the values in diabetic and non-diabetic patients with chronic periodontitis (Group III and II) were statistically not significant. However, when compared with Group I patients, these values were significantly higher.et al.[In Group I , low levels of \u03b2-glucuronidase activity could be demonstrated, similar to the findings of Lamster et al. In theirP < 0.001), as compared to healthy individuals, showing highly significant correlation between GCF \u03b2-glucuronidase level and probing pocket depth. These results are consistent with the findings of Bang et al.[et al.[This study demonstrates that there is an increase in GCF \u03b2-glucuronidase level in Group II patients i.e. non diabetic with chronic periodontitis . This finding is in accordance with study by Bacic et al.,[The present study also demonstrates that there is higher level of GCF \u03b2-glucuronidase activity in patients of diabetes with chronic periodontitis as compared to non-diabetic with chronic periodontitis (t=2.09, c et al., who showc et al., demonstret al,[et al,[Shlossman et al, stated tl,[et al, claimed et al,[et al,[It is also observed that there was a significant positive correlation between GCF \u03b2-Glucuronidase and RBS levels, in diabetics with chronic periodontitis. This observation is comparable to the findings of Oliver et al, who demol,[et al, did not Another important observation made in the present study was that even with difference in clinical parameters between study groups, periodontitis patients irrespective of their diabetic status, showed an increased periodontal destruction with elevated \u03b2-Glucurondiase level than control. This suggests that \u03b2-Glucuronidase level can be used as a biochemical marker for chairside diagnostic kit, which can diagnose early phases of disease with reasonable confidence.Following conclusions were drawn from the present study:Periodontitis patients irrespective of their diabetic status, showed increased periodontal destruction with elevated levels of \u03b2-Glucuronidase, than in the control group.Diabetic patients had highest level of \u03b2-Glucuronidase level and increased severity of periodontal destruction. This confirms the fact that diabetes is a risk factor for periodontal disease.The presence of \u03b2-Glucuronidase level in GCF can be used as a biochemical marker for diagnosing the chronic periodontitis cases."}
+{"text": "Sir,et al based upon our recent report  as the fourth-line therapy. After 8 weeks, a 24% reduction in tumour size per RECIST criteria was observed. The pre-treatment (A) and post-treatment (B) computed tomography images are shown in accompanying figure. The subsequent treatment course was complicated by cholangitis and radiographic progression occurred after 20 weeks.In the commentary by Santini et al that further prospective studies are needed to determine the role of anti-EGFR therapy in SBA. In an attempt to build upon our previous work with the combination of capecitabine and oxaliplatin, CAPOX (We agree with Santini"}
+{"text": "In striated muscle, the actin cytoskeleton is differentiated into myofibrils. Actin and myosin filaments are organized in sarcomeres and specialized for producing contractile forces. Regular arrangement of actin filaments with uniform length and polarity is critical for the contractile function. However, the mechanisms of assembly and maintenance of sarcomeric actin filaments in striated muscle are not completely understood. Live imaging of actin in striated muscle has revealed that actin subunits within sarcomeric actin filaments are dynamically exchanged without altering overall sarcomeric structures. A number of regulators for actin dynamics have been identified, and malfunction of these regulators often result in disorganization of myofibril structures or muscle diseases. Therefore, proper regulation of actin dynamics in striated muscle is critical for assembly and maintenance of functional myofibrils. Recent studies have suggested that both enhancers of actin dynamics and stabilizers of actin filaments are important for sarcomeric actin organization. Further investigation of the regulatory mechanism of actin dynamics in striated muscle should be a key to understanding how myofibrils develop and operate. \u00a9 2010 Wiley-Liss, Inc. Actin is one of the major cytoskeletal proteins in eukaryotic cells and plays essential roles in a number of cellular processes including cell migration, cytokinesis, vesicle transport, and contractile force generation . However, the function of CAS-1 is currently unknown.Proteins that bind to G-actin influence actin dynamics by altering polymerization/depolymerization kinetics and exchange rates of actin-bound ATP or ADP [Paavilainen et al., C. elegans striated muscle, tropomyosin functions antagonistically to ADF/cofilin and AIP1 to stabilize sarcomeric actin organization [Ono and Ono, TPM1 cause hypertrophic and dilated cardiomyopathies [Thierfelder et al., TPM2 cause nemaline myopathy [Donner et al., TPM3 cause nemaline myopathy [Laing et al., TPM3 causes nemaline myopathy and reduces affinity of tropomyosin with tropomodulin, a pointed-end capping protein, thereby potentially influencing the actin dynamics at the pointed ends [Akkari et al., Proteins that bind to the side of actin filaments are integral components of sarcomeric thin filaments and commonly stabilize actin filaments. Tropomyosin is perhaps the best characterized side-binding protein that regulates muscle contraction as well as actin filament stability [Gunning et al., NEB) cause nemaline myopathy [Pelin et al., Nebulin is a large protein (600\u2013800 kDa) that has been proposed to be a ruler that determines lengths of sarcomeric thin filaments [McElhinny et al., MYOT) cause myotilinopathy that includes three known types of skeletal muscle diseases: limb girdle muscular dystrophy type 1A, myofibrillar myopathy, and spheroid body myopathy. Myotilinopathy patients commonly exhibit progressive disorganization of sarcomeres with disarrayed Z-bands [Olive et al., Several actin-binding proteins with multiple immunoglobulin-like (Ig) repeats are expressed in striated muscle and associated with myofibrillar actin filaments. The palladin/myopalladin/myotilin family of Ig-repeat proteins localize to the Z-band and play important roles in sarcomeric organization [Otey et al., Drosophila and C. elegans. Kettin is associated with actin filaments during early myofibrillogenesis in Drosophila muscle [Ayme-Southgate et al., sallimus (sls) gene that also encodes zormin and connectin/titin by complex alternative splicing [Machado and Andrew, sls mutant phenotypes is complicated due to defects in multiple sarcomeric proteins. By contrast, C. elegans kettin is encoded by ketn-1 that is a separate gene from other connectin/titin-related genes in C. elegans [Ono et al., C. elegans kettin by RNAi causes disorganization of sarcomeric actin filaments when muscle is subjected to chemically induced hypercontraction, suggesting that kettin is important for stability of sarcomeric actin during contraction. C. elegans kettin cooperates functionally with \u03b1-actinin and ALP-enigma [Ono et al., Kettin is a large protein of 500\u2013700 kDa with 30-35 Ig-repeats that is specifically present in invertebrate striated muscle. Kettin directly binds to actin filaments and localizes to the I-band and Z-band [Lakey et al., Xin is a muscle-specific protein in vertebrates that stabilizes actin filaments. Xin contains 15\u201328 repeats of 16-amino-acid sequence, called Xin repeats. Xin repeats directly bind to actin filaments in vitro and stabilize actin filaments in stress fibers when Xin repeats are expressed in cultured smooth muscle cells [Pacholsky et al., C. elegans cause disorganization of sarcomeric actin filaments in body wall muscle, but this phenotype is suppressed when muscle contraction is reduced, suggesting that UNC-87 stabilizes actin filaments during actomyosin contraction [Goetinck and Waterston, C. elegans does not have nebulin or Xin, UNC-87 might be a functional homologue of these actin stabilizing proteins in striated muscle.UNC-87 is a calponin-like protein that stabilizes actin filaments and is found only in nematode muscle [Goetinck and Waterston, Both pointed and barbed ends of sarcomeric actin filaments are capped by capping proteins. However, as described above, sarcomeric actin filaments are capable of exchanging actin monomers at both ends, indicating that the filaments have dynamic caps rather than permanent caps. The barbed ends of sarcomeric actin filaments are capped by CapZ  and aligned in register at the Z-band [Casella et al., Drosophila [Bai et al., C. elegans [Stevenson et al., Tmod1 null cardiac myocytes develop fewer and thinner myofibrils than wild-type cells but with sarcomeric organization of uniformly aligned actin filaments [Ono et al., The pointed ends of sarcomeric actin filaments are capped by tropomodulin (Tmod) [Fowler et al., TPM3 causes nemaline myopathy and reduces the affinity of tropomyosin for Tmod [Akkari et al., C. elegans muscle, TMD-1 (C. elegans Tmod) appears to cooperate with ADF/cofilin and AIP1 in sarcomeric organization of actin filaments [Yamashiro et al., Drosophila sarcomere length short (SALS) functions to enhance elongation of thin filaments by antagonizing the activity of Tmod [Bai et al., Drosophila striated muscle, knockdown of SALS shortens the length of thin filaments, while overexpression of SALS elongates thin filaments from their pointed ends. The sals gene encodes two SALS isoforms that have one or two WASP homology 2 (WH2) domains. However, in vitro, a SALS fragment containing two WH2 domains binds to the actin pointed ends and inhibits elongation rather than promoting elongation as expected from the in vivo observations. Therefore, the precise mechanism of SALS-mediated thin filament elongation remains unclear. An ortholog of SALS appears to be absent in vertebrates and nematodes, and it remains to be determined whether a functional homolog of SALS exists in other organisms.Tmod cooperates with other actin-regulatory proteins and regulates length or stability of thin filaments. Tropomyosin binds to Tmod and enhances its capping activity [Fischer and Fowler, Drosophila SALS.Leiomodin (Lmod) is a Tmod-related protein with a unique C-terminal extension containing a poly-proline sequence and a WH2 domain [Conley et al., C. elegans, FHOD-1 is the only formin of the FHOD subfamily, and it is predominantly expressed in several types of muscle cells. FHOD-1-null mutant worms exhibit some thinner striated muscle cells than wild-type worms but show no major abnormalities in sarcomeric actin organization [Pruyne et al., As mentioned above, an actin nucleator for initial assembly of thin filaments in muscle cells has not been identified. The Arp2/3 complex nucleates branched actin networks [Goley and Welch, Drosophila embryonic muscle, nonmuscle myosin II (zipper) is required for formation of striated sarcomeres [Bloor and Kiehart, Myosin II is the force-generating enzyme in sarcomeres. It is also an important regulator of myofibril assembly. Pharmacological perturbation of myosin motor activity disrupts organized assembly of sarcomeric actin filaments [Soeno et al., Studies in live muscle cells have demonstrated that actin in sarcomeres is dynamic during assembly and even in mature myofibrils. A number of regulators of sarcomeric actin dynamics have been identified, and functional studies have revealed their important roles in myofibril assembly, sarcomere organization, and maintenance of myofibrils . Regulat"}
+{"text": "Sir,et al. on the usage of silicone gel for the treatment of hypertrophic scars.[et al. mentioned that \u201cThe results of the self-drying silicone gel have been satisfactory.[et al. reported that \u201csilicone gel is able to reduce the formation of keloid and hypertrophic scars and the signs/symptoms associated with the healing process (paraesthesia, pulling sensation, alterations in colour.[et al. recently performed a comparative study among silicone gel, silicone gel sheeting and topical onion extract, including heparin and allantoin, for the treatment of postburn hypertrophic scars and concluded that \u201cSilicone products, either in gel or sheet, are superior to Contractubex in the treatment of the hypertrophic scar.[et al. also mentioned that \u201cThe therapist should select the most appropriate agent according to the patient\u2019s need and guidelines of these signs.[I read with great interest the report by Puri ic scars. Puri et sfactory.\u201d Indeed,n colour.\u201d Howeverhic scar.\u201d Karagozse signs.\u201d Further"}
+{"text": "A century after Robert Koch linkedindividual cultured microbes to specific diseases (Koch's postulates), it hasbecome increasingly apparent that the complex community of microorganisms associated with the human body plays a key role in health and disease. The NationalInstitutes of Health recently announced the Human Microbiome Project as part ofthe NIH Roadmap for medical research, with a primary goal of advancing ourunderstanding of the relationships among host-associated microbial communities,health, and disease. Many physicians and researchers, however, have onlypassing familiarity with the concepts involved in the study and therapeuticmanipulation of complex microbial communities.This special issue was conceived toaccomplish several goals. We wanted to provide readily accessible overviews ofthe concepts and methods used in the study of complex microbial communities,and demonstrate how changes in indigenous microbial communities can play a rolein diseases such as antibiotic-associated diarrhea and bacterial vaginosis. Wealso set out to find examples of how probiotics can be used for the therapeuticmanipulation of the indigenous microbiota.Clostridium difficile infection through the lens of microbial ecology,\u201d by S. Walk and V. Young, discusses the role of thegut microbiota in antibiotic-associated diarrhea and Clostridium difficile infection while Y. Sanz et al., in the seventh article \u201cInsightsinto the roles of gut microbes in obesity,\u201d review the evidence for therole of gut microbes in obesity. In the eighth article \u201cThe human vaginal bacterial biota and bacterialvaginosis,\u201d by S. Srinivasan and D. Fredericks review the human vaginalbacterial microbiota and theninth article \u201cTemporal shifts in microbial communities in non-pregnantafrican-american women with and without bacterial vaginosis,\u201d by J. Wertzet al., examines this microbial community in the setting of bacterialvaginosis. The tenth article \u201cVaginal microbiota and the use of probiotics,\u201d by S. Cribby et al. discusses the use of probiotics toalter the vaginal microbiota. Finally, the eleventh article \u201cProbiotics and gastrointestinalinfections,\u201d by R. Britton and J. Versalovic, and the twelveth article\u201cProbiotic bacteria influence the composition and function of the intestinal microbiota,\u201d byP. O\u2019Toole and J. Cooney, summarize the potential role of probiotics toinfluence gastrointestinal health.We were fortunate to receive a strong collection of reviewarticles and primary research manuscripts to meet the goals of this specialissue. In the firstarticle \u201cConceptualizing the human microbiota: from multicelled organ toecological community,\u201d B. Foxman et al. present a novelconceptualization of the human microbiome that blends perspectives of epidemiologists,classical ecologists and infectious diseases physicians. The second article \u201cApplication ofecological network theory to the human microbiome,\u201d by J. Foster et al.,outlines how ecological network theory can be applied to studies of the humanmicrobiome, while the third article \u201cInteractions of the intestinal epithelium with the pathogen andthe indigenous microbiota: a three way crosstalk,\u201d by C. V. Srikanth and B. McCormick, review the interactions between epithelial pathogens and theindigenous microbiota in the mammalian gut. In the fourth article \u201cApplication of sequence-dependentelectrophoresis fingerprinting in exploring biodiversity and populationdynamics of human intestinal microbiota: what can be revealed?\u201d G. Huyset al. review the use of sequence-dependent fingerprinting methods for studyingthe structure and dynamics of complex microbial systems using the humanintestinal microbiota as an example. The fifth article \u201cEcological characterization of thecolonic microbiota of normal and diarrheic dogs,\u201d by J. Bell, employssuch a fingerprinting method to study the canine colonic microbiota. The sixth article \u201cEmerginginsights into antibiotic-associated diarrhea and"}
+{"text": "Helicobacter pylori (HP)-independent growing tumors. However a few cases of regression of high-grade gastric lymphomas after the cure of Helicobacter pylori infection had been described.Treatment of primary gastric diffuse large B-cell lymphoma is still controversial. The treatment of localized disease was based on surgery alone, or followed by chemotherapy and/or radiotherapy. High-grade gastric lymphomas are generally believed to be We report here a case with primary diffuse large B-cell lymphoma that showed a complete pathologic remission after HP eradication and we reviewed the literature. A computerized literature reach through Medline, Cancerlit and Embase were performed, applying the words: high grade gastric lymphoma, or diffuse large B cell, MALT gastric lymphoma, DLBCLL (MALT) lymphoma and Helicobacter. Articles and abstracts were also identified by back-referencing from original and relevant papers. Selected for the present review were papers published in English before January 2007.Helicobacter pylori as first line therapy in high grade gastric lymphoma: 22 of a total of 38 enrolled patients obtained complete remission. Depth of gastric wall infiltration and clinical stage were important factors to predict the response to antibiotic therapy. Our case and the review of the literature show that high-grade transformation is not necessarily associated with the loss HP dependence. In early stage, for high-grade B-cell HP-positive gastric lymphomas, given the limited toxicity of anti-HP therapy, this treatment may be considered as one of the first line treatment options.Forty two cases of primary high grade gastric lymphoma that regressed with anti HP treatment were found. There were anedoctal cases reported and patients belonging to prospective studies; four trials studied the effect of eradication of  Helicobacter pylori (HP) infection plays an important role in the development and growth of gastric mucosa-associated lymphoid tissue (MALT) lymphomas [ymphomas ,2. Eradiymphomas .in vitro study by Hussell et al [It has been demonstrated by laboratory and clinical studies that primary gastric large B cell MALT lymphomas are transformed, antigen independent, autonomously growing tumors that are unlikely to respond to eradication therapy of the HP infection. An ll et al  showed tll et al ,6.et al [However anedoctal cases of primary gastric large B-cell lymphoma that responded to antibiotic therapy had been described and, more recently, Chen et al  reportedWe report here a patient with diffuse large B cell lymphoma of the stomach, that achieved a complete pathologic remission after anti HP therapy and a detailed review of literature is also presented.In May 2003, a 43-year-old man was admitted for epigastric pain of two months duration and weight loss (more than 10% of the body weight). Clinical examination was unremarkable and laboratory data were within normal values; only a mild hypochromic anemia was disclosed (Hb 12.4 g/dl).Helicobacter pylori was identified in the mucosa. The previously reported diagnostic criteria for gastric diffuse large B-cell lymphoma were used [A gastroscopy was performed and revealed an ulcerative lesion in the gastric antrum ranging 3 cm in diameter. Biopsies established the diagnosis of diffuse large B cell lymphoma (DLBCL) of the stomach and ere used ,8  showed a hemicircumferencial thickness of the anterior gastric wall, which was infiltrated until to the serosa. Staging was completed with neck, chest and abdominal computed tomography and with bone marrow biopsy. There were not other lymphoma-deposits outside the stomach, and a clinical stage E IThe patient refused chemotherapy and a surgical treatment was then planned. Waiting this treatment, the patient underwent an HP eradication therapy. He received a triple therapy with omeprazole (20 mg twice a day), amoxicillin (1 g twice a day) and clarithromycin (500 mg twice a day) for seven days, and after that omeprazole (20 mg every day) for other 21 days.Prior to surgery, the patient underwent repeat gastroscopy (a month later) that showed a clear improvement of the ulcerative lesion of the gastric antrum and biopsies showed a complete disappearance of the lymphoma Figure .The patient was informed of the good results from anti HP therapy but he preferred to undergo to subtotal gastric resection. The histological examination revealed complete remission of the lymphoma and absence of Helicobacter pylori. He did not receive additional treatment and is in continuous complete remission after 42 months.We selected all cases reported with primary gastric large B-cell lymphoma treated with anti HP treatment and all cases of primary gastric large B-cell lymphoma treated in prospective studies with anti HP-therapy. According to the WHO classification, low grade MALT lymphoma with focal high grade component constituted by \"solid or sheet-like proliferations of transformed cells\" were included as diffuse large B-cell lymphoma .Tumors were staged clinically according to the modified by Musshoff  and  Schmidt-Vollmer, Ann Arbor Classification  for extrHelicobacter pylori as first line therapy in gastric high grade gastric lymphoma: 22 of a total of 38 (57.9%) enrolled patients obtained complete remission. Data of the 42 responsive patients are reported in Table A total of 61 patients, including the present case, with primary gastric large B-cell lymphoma were treated with anti HP treatment ,10-25 anHelicobacter pylori in one patient) with remaining nodal disease. In one patient, large B cells disappeared, but areas of MALT lymphoma and nodal disease persisted. The patient with Burkitt-like lymphoma, obtained a complete remission.Different schedules of eradication treatment were used and were based on a proton pump inhibitor  together with a combination of antibiotics . Forty-two of 61 patients obtained a complete remission of the lymphoma. In two patients there was gastric complete remission  in the majority of patients; only in one patient, there was a progression of disease after an initial partial response .Four patients including present case underwent subtotal or total gastrectomy, after endoscopic confirmation that Helicobacter pylori infection was cured and lymphoma regressed ,22.Other patients in complete remission didn't undergo further treatment, except one patient with AIDS who relapsed after 6 months and needed chemotherapy. This is the only one relapse described. Two patients, in partial remission after eradication treatment, gained complete regression of lymphoma after chemotherapy ,22. Becaet al., [The median period of follow-up was 22 months. The longer period of follow-up was reported in the series of Chen et al., : all theInformation about genetics of large B cells didn't express bcl-6 and p53; in the patient with Burkitt-like lymphoma, malignant cells expressed bcl-6 and p53; in the with Burkitt-like lymphoma, malignant cells expressed bcl-6 and not bcl-2; in two patients there were not alterations of p53 and k-ras genes and microsatellite instability .et al., [et al., [et al., [et al., [In 20 patients, tumor response was unexpected, but in 22 cases it was obtained in prospective trials. Chen et al.,  reported[et al.,  5 cases,[et al.,  2 cases In the present case, eradication of HP infection obtained with a short course of antibiotic therapy resulted in a complete pathologic remission of a diffuse large B cell lymphoma of the stomach. This complete regression of the disease was confirmed not only by gastroscopy and biopsies but also by gastrectomy.Helicobacter pylori stimulation. This assertion was supported by in vitro and in vivo results.This finding confirms one more time that large B cell HP-positive gastric lymphomas are not necessarily associated with loss of HP dependence. Until few years ago, large B cell gastric lymphoma was considered independent of et al., [in vitro in response to Helicobacter pylori, as MALT lymphoma cells did.A study by Hussell et al.,  showed tIn vivo confirmation came from the fact that a number of cases of antibiotic-resistant MALT lymphoma contained large B cells in deep layers of the stomach and these cells were thought responsible for absent response of these tumors [et al., [Helicobacter pylori eradication could play a part in optimum treatment of an accompanying low grade component.e tumors ,6. Boot [et al.,  concludeet al., [et al., [Helicobacter pylori associated chronic active gastritis; she refused chemotherapy and received only eradication treatment with an unexpected tumor remission. These two cases were the first published cases of regression of large B cell lymphoma after eradication therapy. Afterwards analogous surprising situations were reported.In 1997, Rudolph et al.,  describe[et al.,  reportedet al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [Morgner et al., , collect[et al., , in 50% [et al.,  and in 5[et al., . Alpen e[et al.,  started [et al.,  and Hiya[et al.,  are a we[et al., . Alpen e[et al.,  in theiret al., [et al., [et al., [These authors paid attention to different prognostic factors. Hiyama et al.,  focused [et al., ; for Nak[et al., , 93% of In this review of the literature, age, sex, location of tumor and the presence or absence of areas of MALT lymphoma don't seem to influence the response of anti Helicobacter therapy. Clinical stage and depth of tumor invasion are the most important predictive factors of complete remission . HoweverHelicobacter pylori infection, to MALT lymphoma and large B cell lymphoma. There is consistent evidence for the clonal link between the small cell tumor and the large cell tumor [de novo [de novo. The absence of the low grade component could be due to sampling bias or to overgrowth by large cells [Helicobacter pylori eradication have a common genetic pattern and if cases without areas of MALT lymphoma are transformed lymphomas or de novo lymphomas.Very little is reported about genetics of these tumors ,29. Accoll tumor . This evll tumor . t disease was based on surgery alone, or followed by chemotherapy and/or radiotherapy, however recent studies showed that clinical outcome of localized gastric lymphoma treated by systemic chemotherapy alone was similar to that treated by surgery followed by chemotherapy in terms of tumor response, disease-free survival and overall survival suggesting that surgery be reserved for those with residual lymphoma after chemotherapy -38.According to this review, among patients with complete remission obtained after eradication therapy, only one patient, who was affected by HIV infection, relapsed. These data suggest that after a complete remission, no other treatment including gastrectomy might be necessary, even if full thickness of gastric wall is infiltrated at presentation.Helicobacter pylori eradication, but a late response of up to 45 months has been described [et al., [et al., [In most cases of gastric MALT lymphoma remission is achieved within 12 months after escribed . Among tescribed ,10,22. A[et al.,  extendedIn all cases that responded to eradication therapy, initial or complete regression of lymphoma was evident at the first endoscopic and histologic examination. Only in one case, there was a disease progression, after an initial response, at the second examination .Our case reported here and the review of the literature allow us to conclude that:1. Complete remission was obtained after HP eradication treatment in 42 of 61 patients with primary gastric HP related DLBCL.2. There is no marker that can predict if the tumor will regress after antimicrobial therapy. However, depth of gastric wall infiltration and clinical stage can strongly predict the probability of a complete remission, it must be emphasized that complete remission was reached in anecdotal cases independently of these factors after anti HP eradication.Helicobacter pylori infection a complete staging with endoscopic ultrasonography, computed tomographic imaging and bone marrow biopsy should be carried out and the patients should first be treated by anti HP treatment. An endoscopic revaluation 4\u20136 weeks after the eradication treatment should be performed. These evolutions of lymphoma can happen:From a practical point of view we suggest that all patients with primary gastric DLBCL associated with - No response or progression: patient must undergo to surgery or other conventional treatment.- Partial remission: lymphoma is probably responsive and could obtain a complete remission; patient must be strictly monitored to detect signs of progression or a complete remission.- Complete remission: patient must be strictly monitored but may not require further treatments.The author(s) declare that they have no competing interests.LC diagnosed and treated the patient, revised and finally approved the manuscript for been published, RP performed bibliographic research and participated in manuscript revision process, PS performed bibliographic research and participated in manuscript revision process, AZ and CP performed pathological diagnosis and histological pictures. All authors read and approved the final manuscript."}
+{"text": "Recent advances in understanding the characteristics of renal cell carcinoma (RCC) have brought to our attention many prognostic markers that affect and predict the survival outcome of patients with the disease. For the moment, however, patients with RCC have not received any benefit from such markers. If a patient is diagnosed as \u201chigh risk\u201d by using such prognostic markers, there is no promising systemic therapy available. In this review we mainly focus on biomarkers of RCC that can be applied for therapeutic use reported in recent publications. Several issues and limitations in the reported studies are also highlighted and discussed. Developing biomarkers from the viewpoint of therapeutic application will lead to improvement of the prognosis of RCC patients. Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. It accounts for 3% of all adult malignancies and for approximately 95,000 deaths per year worldwide. More tha2Somatic and epigenetic mutations of the von Hippel-Lindau (VHL) disease tumor suppressor gene are observed in 42-57% and 5-19% of sporadic clear cell RCCs, respectively. Under hyet al.,[et al.,[Lidgren et al., demonstret al., Therefor,[et al., who demoet al.,[et al., showed that CAIX expression was a significant predictor in univariate and multivariate analyses and proposed accurate systems for predicting survival for patients with localized or metastatic RCC.[et al.,[et al.,[Carbonic anhydrase IX is one of the most validated prognostic biomarkers of RCC. Bui et al., performeatic RCC.13 They c.[et al., reported,[et al., detected,[et al., Carbonicet al.,[et al.,[et al.,[+ target cells and production of IFN-\u03b3 on stimulation with such cells in all patients. However, liver enzyme disturbances reached National Cancer Institute Common Toxicity Criteria Grades 2 to 4 in all three patients. They performed liver biopsy, which suggested that the liver toxicity was caused by a specific attack of the scFv(G250)+ T-cells against CAIX+ bile duct epithelial cells. Therefore, CAIX may not be an appropriate target for specific therapy.Recently CAIX-targeted therapies were reported in several studies. Uemura et al., discusse,[et al., investig,[et al., transducUpregulation of VEGF, the most potent growth factor for tumor vasculature, is significantly associated with upregulation of HIF-\u03b1. Renal cec in the cytoplasm.[c, released by tBID (truncated BH3-interacting-domain death agonist) from the mitochondria, binds and activates apoptotic protease activating factor-1 (Apaf-1). It forms a multiprotein caspase-activating complex (apoptosome) and leads to activation of caspase-9, undergoing autoactivation to promote recruitment and cleavage of caspase 3. Caspase 3 cleaves its target substrates to affect the changes associated with apoptosis.[Apoptosis is essential to sculpt the developing organism by removing outdated or unneeded structures and also central to the homeostasis of adult tissues by maintaining the balance between cell production and cell elimination. Since caytoplasm. Cytochropoptosis.c release by inhibiting the terminal effector caspase-3 and caspase-7 and interfering with caspase-9 activity and processing. It has also been reported to affect cell division, cell cycle progression, signal transduction pathways and protein degradation.[Inhibitor of apoptosis protein can inhibit apoptosis by binding to prevent a common step downstream of mitochondrial cytochrome radation. Eight huin vitro.[et al.,[et al.,[Although the expression of c-IAP1 and c-IAP2 is not tumor-specific, their overexpression can suppress chemotherapy-induced apoptosis in vitro. Kempkens.[et al., performe,[et al., reportedet al.,[et al.,[Survivin is overexpressed in various human malignancies and its expression is associated with features of biologically aggressive disease, resistance to therapy and poor clinical outcome in patients with various malignancies. Parker et al., demonstr,[et al., evaluate,[et al., However,et al.,[Smac (second mitochondria-derived activator of caspase)/DIABLO (direct inhibitor of apoptosis-binding protein with low PI) is a proapoptotic protein that in healthy cells resides in the intermembrane space in the mitochondria, but is released into the cytosol during apoptosis, where it interacts with IAPs and disrupts their ability to bind caspases . The balet al., evaluateIt is well known that RCC frequently harbors numerous tumor-infiltrating lymphocytes (TILs), suggesting that a host antitumoral immune response is stimulated by the malignant transformation of cells. However, there is a paradoxical relation between increased levels of TILs and diminished cancer-specific survival. Tumor-inet al.,[+ cells. Moreover, significantly fewer NK cells in peripheral blood, a lower proportion of CCR5/CXCR3/CD4+ cells and a higher proportion of CCR4/CD4+ cells were observed in patients with metastatic RCC in the study. These results indicate a change in helper T responses during the progression of RCCs. Donskov and von der Maase[+ cells  were significant prognostic factors of poor survival both in univariate and multivariate analyses, whereas intratumoral macrophages, CD4+, CD8+, CD20+ and CD56+ cells were not significant ones. However, it is not yet clear why \u201clow\u201d CD57+ NK cells can be a prognostic factor for IL-2-based immunotherapy. Furthermore, there seems to be a discrepancy between the results of the two studies. Thus, the question remains: \u201cIs infiltration of NK cells into tumors a positive prognostic factor or a negative one?\u201dC\u00f3zar et al., evaluateder Maase analyzedNatural killer cells mainly kill tumor cells that have reduced major histocompatibility complex (MHC) Class I expression and can escape killing by cytotoxic T lymphocytes (CTLs). If the tumor cells have acquired escape mechanisms from CTLs, NK cell-infiltration can be a positive finding for suppressing the tumor. Therefore, it is important to evaluate the expression of MHC Class I molecules on RCC cells. We recently demonstrated that MHC Class I was down-regulated in 38% of conventional RCCs and the down-regulation was an independent prognostic factor. Unfortun+ T cells that coexpress CD25, the IL-2 receptor \u03b1-chain. In search of more specific markers for Treg, the transcription factor forkhead box P3 (FOXP3) has been identified. Forkhead box P3 is not only a key intracellular marker but also a crucial developmental and functional factor for Tregs. Siddiqui et al.,[+ CD25+ FOXP3\u2212 (but not CD4+ CD25+ FOXP3+) T cells was significantly associated with higher TNM stage, larger tumor size, the presence of coagulative tumor necrosis and poorer cancer-specific survival. Interestingly, they also showed that CD4+ CD25+ FOXP3\u2212 TILs expressed more IL-10 (cytokine synthesis inhibitory factor) than CD4+ CD25+ FOXP3+ cells, suggesting that FOXP3\u2212 Tregs have a powerful inhibitory function. Moreover, Dannuli et al.,[389 IL-2, acting like a CD25-specific antibody, reduced the number of Tregs present in the peripheral blood of metastatic RCC patients without severe side-effects and abrogated Treg-mediated immunosuppressive activity in vivo. They also demonstrated that the antitumor effects of DAB389 IL-2 followed by vaccination with RNA-transfected DCs significantly improved the tumor-specific T cell responses. Thus, depletion of Tregs is one of the strategies to suppress the progression of RCCs.Another topic of TIL is the regulatory T cell (Treg) that regulates the activation of other T cells and may be necessary to maintain peripheral tolerance to self antigens. One mechanism by which cancers evade immune destruction is by recruiting regulatory cells into the tumor microenvironment. Treg is i et al., demonstri et al., demonstret al.,[et al.,[The B7 family of molecules on antigen-presenting cells (APCs) is one of the best-defined costimulators for T cells. These molecules bind to the CD28 molecule on T cells and provide signals required for the activation of naive T cells. B7-H1, a member of the B7 family, can be induced on T lymphocytes, but aberrant expression on tumor cells has been described in various human malignancies. The expression of B7-H1 on tumor cells is considered to enhance apoptosis of activated tumor-specific T cells. Thompson et al., demonstret al., Furtherm,[et al., indicateet al.,[Here we will introduce two papers with high impacts on biomarker studies. Jiang et al., assessedet al.,[During the past decade, a large number of markers have been studied for their prognostic value in RCC. For example, molecular tumor proliferation markers, including Ki-67 (MIB-1), proliferation cell nuclear antigen (PCNA), topoisomerases and p100, have been investigated in many studies, but their value as prognostic markers is still controversial. Furthermore, urologists cannot apply most such results to improve the survival of RCC patients. Therefore, it is important to identify novel RCC-specific antigens. Recently, bioinformatical approaches have been used to search for such antigens. Yao et al., examinedDuring the past decade, a large number of proteins that are putatively important in carcinogenesis and cancer biology have been studied for their prognostic value in RCC, but their clinical use remains controversial. Recently, however, novel biomarkers have been identified by various methods and some of them have been verified as clinical predictors of prognosis of RCC patients . It is i"}
+{"text": "Dear Editor,et al.,[I read the article by Dhingra et al., which deAutofluorescence in Inflammatory CNVMMany reports showed the utility of AF as a marker for early disease and in predicting the outcome of treatment in CNVM due to age-related macular degeneration. There are very few reports on AF findings in inflammatory CNVM.Inflammatory CNVM, which is usually of the classic type (type 2), is seen on AF photography as a precise hyper-autofluorescent area due to the hyperplastic retinal pigment epithelium (RPE). Following treatment, CNVM may contract and leave a zone of absent RPE causing a hypo-autofluorescence.Secondary choroidal neovascularization in multifocal choroiditis and panuveitis (MCP) is readily visible as a hyper-autofluorescencent area originating from a hypo-autofluorescent spot (scar). With increasing follow-up time, the hyper-autofluorescence associated with CNV decreases. AF imaging provides a method to image the appearance of new or enlarging spots that appear, which is more sensitive than using ophthalmoscopically visible signs.More studies are required to understand the role of AF in inflammatory diseases. AF imaging could be an important noninvasive tool to reduce the need for angiography and to help in early diagnosis, as also in the follow-up of inflammatory CNVM patients.Use of Anti Vegf0 in Inflammatory CNVMThere are potential disadvantages of treating inflammatory CNV with photodynamic therapy (PDT). PDT can cause localized inflammation and increase VEGF production. Local release of VEGF, after PDT, may be associated with a higher incidence of recurrent choroidal neovascularization (CNV).et al, studied 10 patients with CNV, who were refractory to previous immunosuppression and PDT or intravitreal triamcinolone (IVTA). They reported that intravitreal bevacizumab improved the best corrected visual acuity (BCVA) and reduced the central macular thickness in the eyes with 2.5 injections (mean), and this was seen at 7.5 months of follow up. In this study they included a patient who recurred three months after pegaptanib injection and responded well.[et al reported successful treatment of inflammatory CNVM with ranibizumab in a patient with multifocal choroiditis and pan uveitis (MCP), who did not responded to bevacizumab or the PDT and IVTA therapy.[Tran ded well. Fine et  therapy.et al reported significant improvement of 2.2 lines in BCVA at 24 months, with a significant decrease in foveal thickness (265 microns), with only 1.3 injections (mean). This study confers the long-term benefits of intravitreal bevacizumab.[The recent and largest case series by Monsour ckness 26 microns,Serious side effects and chances of recurrence make PDT an obsolete treatment option. Recent promising results favor intravitreal bevacizumab as a primary / mono therapy in inflammatory CNVM."}
+{"text": "The conference venue included two locations: the Lindy Boggs Conference facility at the University of New Orleans (UNO); and Dinner/Speaker venues in the French Quarter \u2013 Broussard's of New Orleans and The House of Blues. The conference featured three days of technical presentations, with the third day partly devoted to a satellite Conference on Nanopore Cheminformatics with an on-site demo presentation of a nanopore detector (from the Research Institute for Children and UNO Nanopore Cheminformatics/Biophysics Labs). The theme of this year's conference was \"Computational Frontiers in Biomedicine\".The Fourth Annual MidSouth Computational Biology and Bioinformatics Society (MCBIOS-IV) conference was held in New Orleans, Louisiana on February 1st place went to 1st: Mutlu Mete of UALR, 2nd place to William Sanders of MSU and 3rd place to Stephanie Byrum of the UALR. In Poster Session II, 1st place went to Matthew Landry of UNO, 2nd place to Terra Colvin, Jr. of UALR, and 3rd place to Iftekhar Amin of UNO.  1st place for outstanding oral presentation went to Vijayaraj Nagarajan of USM.At MCBIOS 2007, awards for outstanding poster presentations were given to the following students: In Poster Session I, 1This year, 24 out of 31 submitted papers were accepted for inclusion in the proceedings (77%), similar to the number published in last year's Proceedings . Each ofet al [One of the most important challenges of current miRNA research is to decipher the \"code\" of miRNA regulation \u2013 to find the connection between miRNA expression and phenotypic changes. Gusev et al  report tet al study is that there is a large body of microarray data that is becoming available for analysis. As such, methods to begin inferring regulatory networks from this data are important. In another paper, Peng Li et al compare probabilistic Boolean Network (PBNs) and Dynamic Bayesian Network (DBNs) approaches to correctly inferring regulatory networks [One of the things evident from the Gusev networks . They fiet al [Enterococcus bacteria. A complex response was mapped out involving cytoskeletal rearrangement, immune response, modulation of growth and cellular metabolism, and Wnt signaling, as well as responses heretofore unrecognized because they involve poorly annotated genes.While microarray technology is steadily improving, it still suffers from noise; hence experiments are repeated several times to reduce error. To reduce the amount of replication necessary, Dozmorov et al  used F-tet al [Biological analysis spans several different areas from the genome/proteome to the metabolome, collectively referred to as \"omics\" for the study of different biological bodies. In one study, Schnackenberg et al  study agS. aureus. Their combination of methods suggests that Msa is membrane-bound with sites for phosphorylation and protein-binding, suggesting it plays a role in signal transduction, which is consistent with its known activity as a modulator of the protein SarA.Nagarajan and Elasri  use bioiet al. [Not all peptide fragments are represented equally in mass spectrometry (MS) experiments. To help predict which peptides might be lost or underrepresented, Sanders et al.  use artiBridges et al  develop DNA-protein binding interactions: (1) TBP \u2013 TATA receptor binding, and (2) HIV Integrase \u2013 HIV DNA Terminus binding. The method is also effective at detecting DNA-DNA binding interactions that occur with annealing of DNA single-strand overhangs [protein-protein binding interactions for the medically important case of antibody-antigen interactions [Four papers explore a new transduction-based nanopore detector mechanism. The first  introducverhangs  as well ractions .clustering (unsupervised learning) \u2013 a marked departure from the standard supervised-learning approach to SVMs. The author's objective was to have a powerful, non-parametric, method for phase tracking on nanopore transduction signals, a key requirement for extracting binding kinetics from channel current signals. They also describe a new form of Hidden Markov Model (HMM) that has the strengths of the much more complex HMM-with-Duration (HMMwD) models, but at a computational cost approximating the simpler HMM [Pattern recognition is a critical part of making sense of the high-throughput data gathered in modern biomedical experiments. Four papers explore the development of machine learning based pattern recognition methods and their application to resolving complex nanopore-transduction detector signals. The first  describepler HMM . The goapler HMM , examinepler HMM , exploreet al [Rather than focus on refinement of methods, several authors report the effectiveness and utility of existing bioinformatics approaches to better understand a biological system. For example, Nan Mei et al  studied et al. [Guo et al.  used micCircadian rhythms are generally associated with the sleep/wake cycle, but also regulate many activities and affect the expression pattern of practically all genes. Time-course microarrays can potentially detect this baseline oscillation, which Ptitsyn and Gimble  use in aIdentification of DNA binding sites for transcription factors (motifs) is important for a complete understanding of co-regulation of gene expression, but has proven to be quite challenging. Das and Dai  review pet al [Loganantharaj et al  have proet al [Eisenia fetida, which is often used in toxicology studies. They describe the sequencing and analysis of 3,144 new ESTs.Pirooznia et al  report tet al [The insertion of new or altered genes into genomes is a key step in many functional analysis studies, and it is important to determine how many copies of each of these transgenes are present. Yuan et al  report tet al [k-median, but which uses statistical spatial depth to identify the \"center\" of a cluster. A new subcluster selection rule, Relative Average Depth, is also introduced. In data sets that are noisy or have high dimension and low sample size, which is common in gene expression data sets, the bisecting k-spatial median algorithm does well compared to the component-wise bisecting k-median algorithm.Ding et al  propose et al [Cancer diagnosis usually begins with histopathological examinations of tissue biopsies. These evaluations are usually somewhat subjective and the growing number of such images has provides an opportunity to test automated approaches to tissue sample categorization. Mete et al  report ard and 24th, 2008. Our web site, , contains further information on the society and future meetings. MCBIOS is a regional affiliate of the International Society for Computational Biology .The fifth annual MCBIOS Conference will be held in Oklahoma City, Oklahoma in the Cox Convention Center in downtown Oklahoma City on February 23The authors declare that they have no competing interests.All authors served as co-editors for these proceedings, with JDW serving as Senior Editor. All authors helped write this editorial."}
+{"text": "In May 1998, three large outbreaks of salmonellosis, affecting 91 persons, were identified in the Republic of Georgia. Eighteen Salmonella Typhimurium strains were characterized by arbitrary primed polymerase chain reaction and pulsed-field gel electrophoresis; the results suggested that all cases were part of a single outbreak caused by a distinct clonal strain."}
+{"text": "Molecular Neurodegeneration and Institute for Biomedical Research, Xiamen University co-organized the 2009 International Conference on Molecular Neurodegeneration in Xiamen, China on May 18-20, 2009. The objectives of this meeting were to (1) promote cutting-edge neurodegeneration research in China and in neighboring Asian countries; (2) facilitate the exchange of information relevant to neurodegenerative research; (3) provide education opportunity for students, postdocs and physicians; and (4) provide a platform for investigators at different career levels to interact and network, and to foster collaborations at the international levels. About 100 investigators presented their recent discoveries with a wide range of scopes of neurodegeneration research, including new genes, molecular pathways, animal models, and potential therapeutics.Age-related neurodegenerative diseases are great challenges as the aging population grows. To promote neurodegeneration research and to share recent progress in understanding molecular mechanisms underlying these devastating diseases, the journal  As life expectancy continues to increase and a growing number of people enter the aged population, neurodegenerative diseases have increasingly become a major problem for which treatments are critically needed. Although much progress has been made in the past 20 years on understanding the mechanisms of neurodegenerative diseases and on developing novel therapeutic strategies, most of these achievements are from the United Stated and European countries. Neurodegeneration research in Asian countries, most of which are very populated and also suffered severely with the spread of neurodegenerative diseases, is lagged far behind. The 2009 International Conference on Molecular Neurodegeneration is designed to bridge this gap. The major aim of this meeting is to provide a unique platform for Asian researchers and scientists from Western countries to exchange information and ideas, to share their most recent research advances, and to establish future collaborations in neurodegeneration studies.Molecular Neurodegeneration , an open access, peer-reviewed online journal that publishes all aspects of neurodegeneration research, and Institute for Biomedical Research, Xiamen University , which is dedicated to revealing the fundamental molecular causes of diseases and devising the innovative therapies of tomorrow. Finacial supports of this meeting come from both foundations and pharmaceutical companies including Alzheimer's Association, Ellison Medical Foundation, National Natural Science Foundation of China, Science and Technology Bureau of Xiamen City, Raptor Pharmaceutical, GlaxoSmithKline, Beckman Coulter, Zeiss, Perkin Elmer, Millipore, Applied Biosystems, and Genetimes Techonolgoy, Inc. Drs. Guojun Bu from Washington University School of Medicine and Huaxi Xu from Burnham Institute for Medical Research, Editors-in-Chief of Molecular Neurodegeneration, are co-chairs of this conference.This conference is jointly sponsored by More than 20 world-renowned scientists, including Dr. Aaron Ciechanover, a 2004 Nobel Laureate in Chemistry for his discovery of the ubiquitin system, and Dr. Steven Heinemann, a member of the US National Academy of Sciences, presented their research progress in the meeting. In addition, researchers from Asian countries, including China , Japan, and South Korea, also presented their work in short talk and poster sessions.See figure \u2022 Keynote Speaker: Aaron Ciechanover : \"The ubiquitin proteolytic system: from basic mechansisms through human diseases and onto drug targeting\"Session I: ApoE and apoE receptors in AD\u2022 Guojun Bu (Washington University School of Medicine): \"ApoE receptors in apoE and A\u03b2 metabolism\"\u2022 Mary Jo LaDu (University of Illinois at Chicago): \"A\u03b242 and apoE structure/function interactions: implications for Alzheimer's disease\"Session II: APP processing: \u03b2- and \u03b3-secretases\u2022 Robert Vassar (Northwestern University): \"Regulation of BACE1 in Alzheimer's disease\"\u2022 Takeshi Iwatsubo (University of Tokyo): \"Alzheimer's disease: unraveling the structure-function relationship of gamma-secretase\"\u2022 Gopal Thinakaran (University of Chicago): \"Function and dysfunction of presenilins\"Session III: Presenilin and amyloid beta\u2022 Sam Sisodia (University of Chicago): \"Presenilin function in adult neurogenesis\"Short Talk Session I\u2022 Taisuke Tomita (The University of Tokyo): \"Identification and analysis of a substrate-specific genetic modulator for the \u03b3-secretase activity\"\u2022 Yingying Le : \"Activation of \u03b2-adrenergic receptor on microglia promotes uptake and clearance of Alzheimer's disease-associated amyloid \u03b2 peptide\"\u2022 Wandong Zhang : \"ABCG2 is up-regulated in Alzheimer's brain with cerebral amyloid angiopathy and acts as a gatekeeper at the blood-brain barrier for A\u03b2 peptides\"Keynote Address- Steve Heinemann : \"New approaches to understanding Alzheimer's disease\"Session IV: Functions of APP and its processing products\u2022 Hui Zheng (Baylor College of Medicine): \"APP function in neurons and synapses\"\u2022 Frederic Checler : \"Regulatory functions of APP intracellular domain\"Session V: Parkinson and trinucleotide repeat disorders\u2022 Jie Shen : \"Impaired neurotransmitter release in Alzheimer's and Parkinson's diseases\"\u2022 Xiaojiang Li (Emory University): \"Synaptic toxicity of mutant huntingtin\"Short Talk Session II\u2022 Hongyu Hu : \"Mechanism of \u03b1-synulcein aggregation associated with Parkinson's disease\"\u2022 Hua Gao (Key Laboratory for Neurodegenerative Disease of the Ministry of Education): \"DJ-1 decrease rotenone-mediated dopaminergic cell death via ERK signaling\"\u2022 Cristine Alves da Costa (Institut de Pharmacologie Moleculaire et Cellulaire): \"DJ-1-mediated cell death control by p53 is regulated by caspase proteolysis\"\u2022 Lingqiang Zhu : \"Activation of glycogen synthase kinase-3 inhibits long term potentiation with synapse-associated impariments\"Session VI: BDNF and novel genes in neurodegeneration\u2022 Eric Tzeng (Beckman Coulter): \"The latest total solution characterizes neurodisorder diseases\"Yunwu Zhang (Xiamen University): \"A novel gene that inhibits Alzheimer's \u03b2-amyloid generation and tau phosphorylation\"Short Talk Session III\u2022 Jin Tae Hong : \"Mutant presenilin 2 (N141I) increases beta-secretase activity through increase of ERK pathway dependent hydrogen peroxide generation\"\u2022 Ling Li (University of Alabama at Birmingham):\"Simvastatin prevents cognitive and hippocampal synaptic deficits in APP/PS1 double transgenic mice\"\u2022 Wangxia Wang (University of Kentucky): \"MicroRNA miR-107 targets genes related to neurodegenerative disease\"\u2022 Qingyan Liu : \"A novel transmembrane protein down regulated in Alzheimer's brains and interacts with a DnaJ-like heat shock protein (DNAJB4)\"\u2022 Xiuqi Bao : \"Establishment of gonadectomy-accelerated brain aging model in mice\"Session VII: Metal, cell cycle and signaling in neurodegeneration\u2022 Ashley Bush (University of Melbourne): \"The metal theory of Alzheimer's disease: from bench to clinic\"\u2022 Karl Herrup (Rutgers University): \"Cell cycle events as risks for neurodegeneration: a look into mechanism\"\u2022 Yong Shen : \"Tumor necrosis factor and Alzheimer's disease\"Session VIII: AD genetics and therapy\u2022 George Martin (University of Washington): \"Classes of gene action with the potential to modulate the times of onset and the rates of progression of neurodegenerative disorders\"\u2022 Edward Koo : \"Gamma secretase modulators, nonsteroidal anti-inflammatory drugs, and Alzheimer's disease\"\u2022 Colin Masters : \"A\u03b2 oligomers as tractable targets for Alzheimer's disease: diagnostics and therapeutics\"The authors declare that they have no competing interests.GB supervised plans for the meeting and made final decisions regarding meeting and planning.YZ helped prepare and set up for the meeting and wrote this article and cover letter.LO helped prepare program and agenda for meeting, cooresponded with all involved and served as administrative contact."}
+{"text": "To the Editor: Gupta et al. raise important issues regarding molecular profiling as an epidemiologic tool (Gupta et al. interpret their experience as indicating that, with geographically dispersed isolates, a higher degree of genomic similarity than is reliably provided by single-enzyme PFGE is necessary to improve specificity, thereby avoiding fruitless investigative efforts ("}
+{"text": "Sir,et al for their interest in our recent study and for their remarks concerning the safety of using involved-field irradiation in treating limited-stage small-cell lung cancer (SCLC). We have updated our analysis of failure patterns in patients with limited-stage SCLC who were treated in our phase II study of involved-field irradiation during the second and third cycles of carboplatin, paclitaxel and etoposide (We thank Dr Chun-Ru Chien Recently, A phase III trial of concurrent chemoradiotherapy without elective nodal irradiation in limited-stage SCLC, where patients will be randomised to either once daily irradiation to a dose of 66\u2009Gy or twice daily irradiation to a dose of 45\u2009Gy will shortly commence . Such a"}
+{"text": "Sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell. Therefore melatonin shows beneficial effects against acute SM toxicity in a variety of manner. It scavenges most of the oxygen- and nitrogen-based reactants, inhibits inducible nitric oxide synthase, repairs DNA damage and restores cellular energy depletion. The delayed toxicity of SM however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to genetic mutations, epimutations can also involve in the pathogenesis of a variety of human diseases. Several actions of melatonin are now delineated by epigenetic actions including modulation of histone acetylation and DNA methylation. Future studies are warranted to clarify whether epigenetic mechanisms are involved in pathogenesis of delayed sulfur mustard toxicity and melatonin alleviates delayed toxicity of this warfare agent. Among the available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been a widely used chemical weapon. Because of its devastating toxicity, its use during the World War I earned it the sobriquet \u201cking of the battle gases\u201d. Other compounds such as nitrogen mustard (HN2) were developed during World War II, but found to be unsuitable as a munition. Soon after discovering HN2, it became the first non-hormonal agent used in cancer chemotherapy. A number of HN2 derivatives including cyclophosphamide (CP), ifosfamide, mechlorethamine, melphalan and chlorambucil are valuable cytotoxic and radiomimetic agents for the treatment of cancer    and triggers the expression of selectins and cellular adhesion molecules, via enhancing nuclear factor (NF)-\u03baB and activator protein (AP)-1 activation, thereby promoting pro-inflammatory responses including most importantly tumor necrosis factor (TNF)-\u03b1 and interleukin (IL)-1\u03b2.ONOO\u2013 also induces apoptosis and necrosis in cells depending on the exposure concentration. In case of higher concentration, a DNA repair enzyme poly (ADP ribose) polymerase-1 (PARP-1), mediates ONOO\u2013-induced necrosis  to various nuclear proteins. In case of severe DNA injury, overactivation of PARP-1 depletes the cellular stores of NAD+, an essential cofactor in the glycolytic pathway, the tricarboxylic acid cycle, and the mitochondrial electron transport chain. As a result, the loss of NAD+ leads to a marked reduction in the cellular pools of ATP, resulting in cellular dysfunction and cell death via the necrotic pathway. Experimental evidence has established that the PARP-1 pathway of cell death plays a pivotal role in tissue injury and organ dysfunction in mustard-induced acute toxicity , histone acetyl transferases (HATs) and DNA methyltransferases (DNMTs)  is glucocorticoid resistance. Although inhaled glucocorticoids are highly effective in asthma, they provide relatively little therapeutic benefit in COPD, despite the fact that active airway and lung inflammation is present. This may reflect that the inflammation in COPD is not suppressed by glucocorticoids, with no reduction in inflammatory cells, cytokines or proteases in induced sputum even with high doses of inhaled and oral glucocorticoids  that have been activated during the chronic inflammatory process. The increased expression of most of these inflammatory proteins is regulated at the level of gene transcription through the activation of pro-inflammatory transcription factors, such as nuclear NF-\u03baB and AP-1. The molecular pathways involved in regulating inflammatory gene expression are now being delineated and it is now clear that chromatin remodeling and a variety of epigenetic mechanisms play a critical role in the transcriptional control of genes. Stimuli that switch on inflammatory genes do so by changing the chromatin structure of the inflammatory gene, whereas glucocorticoids reverse this process.et al., et al., et al., Glucocorticoids produce their effect on responsive cells by activating the glucocorticoid receptor (GR) to directly or indirectly regulate the transcription of target genes. Most of the anti-inflammatory actions of glucocorticoids are due to suppression of the actions of AP-1 and NF-\u03baB Barnes, . The actet al., et al., et al., et al., et al., \u2013  are similar to those that have been observed previously in patients with asthma and chronic bronchitis from other common causes (Emad and Rezaian, \u2013 scavenging agent in both in vivo and in vitro (Sourdeval et al., et al., et al., et al., et al., et al., et al., et al., et al., Melatonin shows beneficial effects against SM-induced acute toxicity as a multifunctional antioxidant and ONOOet al., Despite 75 years of research, there is still no antidote for mustard. This fact is especially crucial when we consider that probably at least a dozen countries have mustard in their arsenals today. Melatonin has been administered in both physiological and pharmacological amounts to humans and animals, and there is widespread agreement that it is a non-toxic molecule. In pregnant rats, maternal lowest no observed effect level has been found to be 200mg/kg/day and developmental no observed adverse effect level is \u2265 200 mg/kg/day (Jahnke"}
+{"text": "Frequent ventricular premature complexes  (VPC) can result in left ventricular dysfunction. Several case reports have found this association and reversal with radiofrequency ablation -4. OtherThe relation between the burden of ventricular ectopy and left ventricular function was evaluated by Baman TS et al . VPC burImprovement in left ventricular end systolic and end diastolic dimensions as well as ejection fraction has been documented after VPC ablation . In spitDarrieux FC, et al  noted anLelakowski J et al  reportedTwo articles in this issue of the journal focus on the ablation of VPCs. While Sheldon SH et al  discusse"}
+{"text": "GABAergic inhibitory neurotransmission contributes to diverse aspects of brain development and adult plasticity, including the expression of complex cognitive processes. This is afforded for in part by the dynamic adaptations occurring at inhibitory synapses, which show great heterogeneity both in terms of upstream signaling and downstream effector mechanisms. Single-particle tracking and live imaging have revealed that complex receptor-scaffold interactions critically determine adaptations at GABAergic synapses. Super-resolution imaging studies have shown that protein interactions at synaptic sites contribute to nano-scale scaffold re-arrangements through post-translational modifications (PTMs), facilitating receptor and scaffold recruitment to synaptic sites. Additionally, plasticity mechanisms may be affected by the protein composition at individual synapses and the type of pre-synaptic input. This mini-review article examines recent discoveries of plasticity mechanisms that are operational within GABAergic synapses and discusses their contribution towards functional heterogeneity in inhibitory neurotransmission. The plasticity of individual synapses occurs downstream of activity or neuro-modulatory signaling and must be reconciled with homeostatic mechanisms to maintain overall network function  receptors. These CB1 receptors are pre-synaptically enriched at CCK+ synapses and participate in the depolarization-induced suppression of inhibition , post-synaptic scaffolding and signaling proteins, and trans-synaptic adhesion molecules which facilitate effective communication between the pre- and post-synapse for efficient neurotransmission. GABAARs are composed of pentamers from a family of subunits encoded by 19 distinct genes . Although it has been recently shown that many receptor subunits can access the synaptic space (Hannan et al., ARs composed of the combination of \u03b11\u20133 subunits along with \u03b21\u20133 and \u03b32 subunits, whereas those containing the subunits \u03b14\u20136 and \u03b4 tend to be extra-synaptic (Fritschy and Panzanelli, ARs are trafficked to the plasma membrane from cytoplasmic pools, or diffuse laterally within the membrane in and out of synapses to alter the local concentration of receptors and therefore synaptic strength (Flores and M\u00e9ndez, ARs is an important mechanism by which inhibitory plasticity is achieved (Petrini and Barberis, ARs scales with the size of gephyrin clusters (Specht et al., via decreased confinement of GABAARs (Jacob, AR clustering. For example, activity induction in hippocampal slices leads to inhibitory potentiation that is correlated to increases in gephyrin cluster size concordant with mIPSC amplitude (Flores et al., AR synaptic organization can be used to understand mechanistic bases for synapse alterations.The GABAergic post-synapse contains GABAs Jacob, . SimilarAR synaptic accumulation through CaMKII signaling (Flores et al., ARs at synapses, large increases in calcium leads to reduced retention of GABAARs (Petrini and Barberis, While plasticity occurs at all synapses, basal synapse characteristics such as size, strength, and composition are variable, and therefore the extent of induced synaptic plasticity is also variable. For example, spinal cord synapses contain over four times as many gephyrin molecules per synapse and at a higher density than cortical synapses (Specht et al., ARs, the interaction between GABAARs and post-synaptic scaffolds, or the dynamics of the post-synaptic scaffolds themselves could all contribute to modulating synaptic receptor retention and therefore the function of inhibitory synapses (Choquet and Triller, via altered receptor-scaffold interactions. Of these, modification of GABAARs (Comenencia-Ortiz et al., ARs and gephyrin result in enhanced surface localization (Matt et al., ARs controls both surface trafficking and removal (Comenencia-Ortiz et al., via gephyrin-dependent (Mukherjee et al., Direct modification of GABAARs as well as those of pre-synaptic vesicle release sites clearly demonstrating that synaptic gephyrin nano-domains represent functional organizational units (Crosby et al., ARs has been shown by perturbing gephyrin clustering via overexpression of dominant-negative gephyrin, which causes a reduction in the number and size of GABAAR nano-domains (Crosby et al., ARs at synaptic sites (Battaglia et al., Recent efforts towards describing post-synaptic dynamics have employed live-imaging and super-resolution microscopy to determine real-time and nano-scale re-organization of the post-synapse (Specht et al., AR retention at synapses. A recent study has found that phosphorylation of gephyrin at serine 268 (regulated by ERK1/2; Tyagarajan et al., AR synaptic dwell time (Battaglia et al., AR dynamics outside of synaptic sites, suggesting that gephyrin is involved in extra-synaptic receptor scaffolding regulated by phosphorylation of distinct serine residues (Battaglia et al., via receptor-scaffold interactions. Phospho-proteomic analyses of synaptic proteins indicate that more than just gephyrin and GABAARs are dynamically phosphorylated, and that altered brain states such as sleep deprivation (Wang et al., ARs and gephyrin (\u0160mid\u00e1k et al., PTMs have now been shown to control gephyrin nano-domain structure and GABAARs dynamics and inhibitory synapse function have been identified (Fritschy et al., Models for receptor-scaffold interactions propose that modifying the number of scaffolds or the affinity of receptor-scaffold binding will define the equilibrium governing immobilization of receptors at the synapse (Choquet and Triller, ARs and adaptor proteins (Cajigas et al., AR subunit is disrupted in a loss-of-function mouse model null for the RNA binding protein NONO, leading to a reduction in synaptic GABAARs and gephyrin clustering (Mircsof et al., Recent data suggests that local translation of mRNA coding for synaptic proteins could offer a way to acutely modify synaptic composition in a synapse-specific manner (Rangaraju et al., The findings highlighted in this mini-review article (summarized in BC and ST contributed to the organization and writing of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease with variable clinical intensity. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib). We searched the most recent English literature (1997-2017) regarding any article with the key word of \u201cglycogen storage disease type I\u201d in PubMed, Science Direct, Scopus, EMBASE, and Google Scholar. We will present all of the published articles about the molecular genetic characteristics and old-to-new diagnostic methods used to identify GSD I in regard of methodology, advantages and disadvantages. Diagnosis of GSD type I and its variants is challenging because it is a genetically heterogeneous disorder. Many molecular methods have been used to diagnose GSD I most of which have been based on mutation detection. Therefore, we discuss complete aspects of all of the molecular diagnostic tests, which have been used in GSD type I so far. With the advent of high throughput advanced molecular tests, molecular diagnosis is going to be an important platform for the diagnosis of storage and metabolic diseases such as GSD type I. Next-generation sequencing, in combination with the biochemical tests and clinical signs and symptoms create an accurate, reliable and feasible method. It can overcome the difficulties by the diagnosis of diseases with broad clinical and genetic heterogeneity. Glycogen storage diseases (GSDs) are a group of metabolic disorders determined by the accumulation of glycogen in different tissues. GSDs are caused by the enzyme deficiencies effect on glycogen synthesis, glycogen breakdown or glycolysis (glucose breakdown), typically within muscles and/or liver cells. The disorders were numbered as they were discovered which classified chronologically by GSD type I (von Gierke disease) to GSD type XI . MajoriGSD (Glycogen storage disease) type I or von Gierke disease is the second most common type of GSDs. GSD type I typically presents in early childhood. Von Gierke disease is an autosomal recessive disorder. There is no report regarding ethnic difference in the incidence of GSD type I, however there are different types of mutations in Caucasian, Hispanic, Asian and Jewish populations . The ovHistorically, in 1929, Edgar von Gierke was the first to describe a glycogen storage disease (GSD), which initially was named in his honor  regarding any article with the key word of \u201cglycogen storage disease type I\u201d in PubMed, Science Direct, Scopus, EMBASE, and Google Scholar.GSD I is characterized by accumulation of glycogen and fat in the liver and kidneys, leading to hepatomegaly and renomegaly. The clinical manifestations of von Gierke disease include growth retardation, hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, osteoporosis and hyperlipidemia . The paThe clinical presentations of GSD Ib is quite similar to that of GSD Ia, however the symptoms of the patients with GSD Ia, such as hepatomegaly, a characteristic ''doll-like'' face, short stature, and chronic fatigue are more severe. Unlike patients with GSD-Ia, most patients with GSD-Ib also suffer from neutrophil dysfunction and neutropenia, lead to frequent bacterial infections. Clinical differential diagnosis of GSD-Ia from Ib is difficult because neutropenia is sometimes periodic or never develops in GSD-Ib  was codified the enzyme translocase and mutations within this gene in GSD Ib patients were described  to translocate glucose-6-phosphate (G6P) from the cytosol to the lumen of the endoplasmic reticulum (ER) and two other transport systems to transport the reaction products phosphate (Pi) and glucose (G6PT2 and G6PT3 respectively) to the cytosol , which al., 1997). G6PT1 al., 2002). It hasal., 2002). G6PC and most patients with GSD Ic and Id have mutations in the G6PT1 gene SLC37A4, therefore GSD I is now divided into two general subtypes GSD Ia and GSD I non-a, respectively  and GSD-Ib, a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) . But wial., 1995; Veiga-Dal., 1995). Howeveal., 1995; Kishnanal., 1995; Janeckeal., 1995). Among al., 2001).The final and conclusive diagnosis of GSD needed pathologic diagnosis in combination with biochemical and clinical findings; however, liver biopsy is an invasive procedure . PractiPrompt and accurate diagnosis is the most important point for the proper treatment of metabolic diseases. Diagnosis of GSD I is sometimes complicated because there are common features between GSD I and III, including hepatomegaly, hypoglycemia, and hyperlipidemia. Validated and clinically useful tools with a positive predictive value > 90 % are necessary for the diagnosis of GSD I. The diagnosis of GSD I currently relies on clinical features, pathologic diagnosis of liver biopsy, biochemical, and molecular genetic tests  and pathologic findings of the liver biopsy in favor of GSD .G6PC or G6PT1 gene unique to Caucasian, Hispanic, Chinese/Japanese/ Korean, and Jewish GSD I patients have been described, suggesting separate ethnic founder effects for some mutations . Transfal. (1999) has conal. (1999) analyzeal. (1999) showed al., 2000; Nakamural., 2000).Eventually, even a single base alteration can be detected by the altered mobility of the single-stranded DNA molecule in SSCP. In 2004, in one study the frequency of two prevalent mutations of GSD Ia patient in Caucasian (the Q347X and R83C mutation) was reported to screen the Ashkenazi Jewish population by SSCP method as an accurate and easy technique which leads to a predicted prevalence  five times higher than in the general Caucasian population .According to the above literature, disadvantages of SSCP method include the requirement of highly standardized electrophoretic conditions in order to get constant results. Furthermore, some mutations may remain undetected, and accordingly definite absence of mutation cannot be proven. In HD method single-base substitutions are less stable and excessively sensitive to environmental changes. This fact reduces the sensitivity of this method for this type of mutations, which is frequently found in GSD I , two deletions (540del5 and 158delC) and one nonsense mutation (Q347X). Three of them have not been described previously and the R83C was the most common mutation among the Czech and Slovak patients  has been applied for screening of unknown point mutations. Identification of mutations in the al., 2000). This tal., 2000).G6PC (GSD Ia) and SLC37A4 (GSD Ib) full genes can be used for confirming the diagnosis of these diseases precisely  have launched that are referred to as massively parallel or next-generation sequencing (NGS). Direct sequencing has proven extremely successful because of its accuracy and affordability, but it is inappropriate for large-scale screening projects because it has been developed to sequence only one amplified DNA molecule at one time  in a given sample on both strands . Moreoval., 2014; Janeckeal., 2014). Directal., 2014; Gerin eal., 2014). Directal., 2017). Since al., 2017; Lam et al., 2017; Ihara eal., 2017; Triocheal., 2017; Chiang al., 2017; Koz\u00e1k eal., 2017; Reis etal., 2017; Yuen etal., 2017; Qiu et al., 2017; Ki et aal., 2017; Miltenbal., 2017; Qiu et al., 2017; Tamhankal., 2017; Liang eal., 2017; Gu et aal., 2017; Lu et aal., 2017; Mahmoudal., 2017, Choi etal., 2017), Koreanal., 2017), Brazilal., 2017), Chinesal., 2017; Chiang al., 2017; Qiu et al., 2017; Gu et aal., 2017; Lu et aal., 2017), Indianal., 2017; Karthi al., 2017), Japaneal., 2017), Czech al., 2017), Hungaral., 2017) and Freal., 2017) patiental., 2017), Chinesal., 2017; Qiu et al., 2017; Liang eal., 2017) Japanesal., 2017) populatiga, 2018). Converiga, 2018; Wang etiga, 2018). Briefliga, 2018). SuccesWang et al. (2013) have deSeveral approaches have been used for detection of known mutations. These methods usually started with the polymerase chain reaction (PCR) and additional assay steps are performed based on the type of mutation such as RFLP-PCR . Ihara non-A patients which is advantageous for a primary molecular genetic diagnostic approach. They concluded that the principal advantages of DHPLC are its semi-automated nature, with rapid results (a few minutes per sample), and the feasibility to collect eluted DNA for next analyses, but DHPLC alone cannot provide the details about the nature of mutations. Also, the sensitivity of the method is dependent on the temperature of analysis, the selection of which is dependent on operator experience  technique after PCR . Thoughal., 2000). Lam etal., 2000) have real., 2000).G6PC gene because it is a major cause of GSD-Ia among Japanese patients. The high reproducibility and sensitivity of this technique indicates that the method may be safely applied to clinical diagnosis. Afterward, Kojima et al.  combined with a TaqMan fluorogenic probe (TaqMan-ASA)  used a al. (2004) performal. .Lately, high resolution melting analysis (HRMA), a simple real-time PCR-based method for detecting sequence variations for GSD Ia was developed. The basis of this method is that changes in amplicons of HRM are dependent on their DNA melting curves in the presence of saturating DNA binding dyes . TherefIn the last decade, the use of DNA microarray technique for diagnosis of genetic diseases has been reported , the cost, speed and accuracy of detection increase. The authors declare that they have no conflicts of interest."}
+{"text": "The prevalence and social cost of clinical depression are rapidly increasing, and the field continues to attract considerable research interest  and a major downstream target of the ERK signaling pathway, is upregulated both in depressive suicides and in animal models of depression induced by unpredictable chronic mild stress (UCMS) and social defeat  is associated with the diverse signs and symptoms of depression (see for example, Dwivedi et al., However, the authors did not mention other ways of regulating ELK-1 activity, which have been demonstrated in previous studies. For example, ELK-1 can be degraded by FBXO25, a ubiquitin ligase (Teixeira et al., There are also other issues to be resolved around ELK-1 regulation. SIRT6, a histone deacetylase, interacts with ELK-1 to suppress ELK-1-dependent transcription (Cea et al., Furthermore, ELK-1 has isoforms and splice variants (Rao and Reddy, Besides the issues raised above, the work presented by Apazoglou et al. provides clear evidence that ELK-1 is a promising drug target for clinical depression. Interestingly, ELK-1 has been implicated in diseases comorbid with depression (Mayeux et al., Although the signaling pathways and molecules involved in depression have been studied extensively over the decades (Duman and Voleti, The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HS and handling editor declared their shared affiliation at time of review."}
+{"text": "The spatiotemporal control of DSB formation occurs within a specialized chromosomal structure characterized by sister chromatids organized into linear arrays of chromatin loops that are anchored to a proteinaceous axis. Although SPO11 and its partner proteins required for DSB formation are bound to the axis, DSBs occur preferentially within the chromatin loops, which supports the \u201ctethered-loop/axis model\u201d for meiotic recombination. In this mini review, we discuss insights gained from recent efforts to define and profile DSB hotspots at high resolution in eukaryotic genomes. These advances are deepening our understanding of how meiotic recombination shapes genetic diversity and genome evolution in diverse species.Homologous chromosomes must pair and recombine to ensure faithful chromosome segregation during meiosis, a specialized type of cell division that occurs in sexually reproducing eukaryotes. Meiotic recombination initiates by programmed induction of DNA double-strand breaks (DSBs) by the conserved type II topoisomerase-like enzyme SPO11. A subset of meiotic DSBs are resolved as crossovers, whereby reciprocal exchange of DNA occurs between homologous chromosomes. Importantly, DSBs are non-randomly distributed along eukaryotic chromosomes, forming preferentially in permissive regions known as hotspots. In many species, including plants, DSB hotspots are located within nucleosome-depleted regions. DSB localization is governed by interconnected factors, including  Meiosis is a specialized cell division program that is essential for sexual reproduction in eukaryotes. During this program, replication of chromosomal DNA to form sister chromatids is followed by two rounds of cell division. Maternal and paternal chromosomes (homologs) segregate at the first division and sister chromatids segregate at the second division. Chromosome number is thereby halved and, in diploid organisms, meiosis culminates in the production of haploid progeny cells (gametes). Chromosome segregation during meiosis is imperative for the continuation of the species, as it enables the formation of a zygote that inherits the full chromosome complement in the next generation by fusion of a male and a female gamete  and mouse, DSB hotspots have been defined as loci meeting or exceeding given thresholds for Spo11-oligo density and physical size  -based peak-calling approach  in gene promoters   than in wild-type budding yeast cells, indicative of a negative feedback loop in which homolog engagement following DSB formation suppresses Spo11 activity and prevents further breaks  group participate in the assembly of the synaptonemal complex and promote crossing over    targeted to meiotic hotspots suppresses crossover recombination , Copia LTR and LINE-1 classes less than expected (Choi et al., Arabidopsis and mouse, however, fewer-than-expected maize DSB hotspots occur in Copia LTR and LINE retrotransposons (He et al., Despite SPO11-1-oligo depletion in Arabidopsis, significant overlap occurs between comparable classes of DNA elements and DSB hotspots, many of which are located within functionally conserved sequences (Choi et al., Arabidopsis hotspots may be more evolutionarily stable. Nonetheless, comparisons between eukaryotes indicate that repeated sequences may influence meiotic recombination initiation landscapes in related ways.Citing the hotspot paradox hypothesis, Yamada et al.  speculatATM in budding yeast, suppresses the formation of clustered DSBs in cis over distances of ~70\u2013100 kb (Garcia et al., ATM activity allows DSBs to form independently of one another over \u00b120\u2013100-kb distances, giving rise to DSB formation in neighboring regions at frequencies comparable to those expected by chance. Over distances of \u00b1 ~7.5 kb, by contrast, Tel1ATM inactivation permits the formation of adjacent DSBs significantly more frequently than expected, generating localized regions of \u201cnegative DSB interference\u201d (Garcia et al., cis-interference suggests that hotspots within the same loop domain are \u201cprimed\u201d for cleavage. Cooper et al. (ATM-dependent cis-interference, which restricts DSB formation to only one of the primed intra-loop hotspots. Spatial regulation of meiotic DSB formation also occurs in trans via a mechanism involving Tel1ATM and Mec1ATR, another DDR signal transduction kinase (Zhang et al., trans-interference inhibits DSB formation at the corresponding locus on its sister, its homolog or frequently both. This mechanism is thought to ensure that an intact template is available for DSB repair, and to prevent DSB formation at allelic loci on both homologs (Zhang et al., Meiotic DSB hotspots are identified by mapping the DSB landscape in a population of cells. This landscape reveals a continuum of variation within which loci with high probabilities of DSB formation may be detected (Pan et al., r et al.  speculatGenome-wide DSB mapping in different eukaryotes has revealed diversity with regard to the hierarchical combinations of factors that shape meiotic recombination landscapes and hotspots. These distinctions highlight the importance of studying DSB landscapes in diverse eukaryotes and beyond model organisms. Efforts to elucidate the mechanisms that determine DSB hotspot designation may inform genetic or epigenetic manipulations intended to reshape naturally constrained meiotic recombination landscapes. For example, the presence of hotspots in conserved genomic elements, such as nucleosome-depleted promoters, has relevance for targeting crossover recombination to specific loci in plants (Sarno et al., AT and IH wrote and edited the manuscript. AT created Table The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "DNA methylation is an epigenetic marker that has been shown to vary significantly across different tissues. Taking advantage of the methylation differences between placenta-derived cell-free DNA and maternal blood, several groups employed different approaches for the discovery of fetal-specific biomarkers. The aim of this study was to analyse whole-genome fetal and maternal methylomes in order to identify and confirm the presence of differentially methylated regions (DMRs). We have initially utilized methylated DNA immunoprecipitation (MeDIP) and next-generation sequencing (NGS) to identify genome-wide DMRs between chorionic villus sampling (CVS) and female non-pregnant plasma (PL) and peripheral blood (WBF) samples. Next, using specific criteria, 331 fetal-specific DMRs were selected and confirmed in eight CVS, eight WBF and eight PL samples by combining MeDIP and in-solution targeted enrichment followed by NGS. Results showed higher enrichment in CVS samples as compared to both WBF and PL samples, confirming the distinct methylation levels between fetal and maternal DNA for the selected DMRs. We have successfully implemented a novel approach for the discovery and confirmation of a significant number of fetal-specific DMRs by combining for the first time MeDIP and in-solution targeted enrichment followed by NGS. The implementation of this double-enrichment approach is highly efficient and enables the detailed analysis of multiple DMRs by targeted NGS. Also, this is, to our knowledge, the first reported application of MeDIP on plasma samples, which leverages the implementation of our enrichment methodology in the detection of fetal abnormalities in maternal plasma. Using a novel doubleenrichment approach (MeDIP in combination with insolution hybridization enrichment followed by NGS), we have confirmed the presence of a set of 331 DMRs in multiple CVS, WBF and PL samples. The results of this study demonstrate that there is a clear distinction between the methylation levels of fetal and maternal DNA for the selected DMRs. The utilization of a novel doubleenrichment approach in this study provides a significant expansion in the number of fetalspecific biomarkers. This increase in fetal biomarkers sets the foreground for the implementation of our approach in the detection of the most common fetal aneuploidies.2.2.1.In total, 11 WBF, 10 PL and 11 firsttrimester CVS (11\u201314 weeks of gestation) were used in this study . The stuet al., Peripheral blood was collected from women donors into two 8-mL EDTAcontaining tubes. An average of 8 mL of plasma was isolated using a doublecentrifugation protocol as previously described  and the QIAamp DNA Mini kit (Qiagen), respectively, according to the manufacturer's instructions. DNA from PL samples was extracted using the QIAsymphony DSP Virus/Pathogen Mini Kit (Qiagen).2.2.DMR identification was initially performed on three WBF, three CVS and two PL samples using wholegenome MeDIPNGS. Based on specific criteria (see Section 3.2) we selected 331 DMRs that were found to be hypermethylated in the fetal tissues and hypomethylated in maternal whole blood and plasma. Confirmation of the methylation status of the 331 DMRs was performed on eight CVS, eight WBF and eight PL samples using MeDIP followed by targeted insolution enrichment and NGS.2.3.\u03b2globin loci, as described previously , according to the manufacturer's protocol. The remaining MeDIP experiments  were performed using mouse anti5\u2032methylcytosine monoclonal antibody , as described previously using 18\u201330\u00a0ng of genomic DNA  were used in order to confirm primer specificity. PCR reactions were performed using MyTaq HS DNA Polymerase , as described elsewhere , 10\u00d7 blocking agent (Agilent), blocking oligonucleotides  the regions selected exhibited consistent DNA hypermethylation profiles in all CVS and hypomethylation in all the female nonpregnant tissues; (b) selected regions had preferentially more than two CpG dinucleotides in the DNA sequence; (c) potential DMRs that were in copy number variable regions or in repetitive element regions were excluded; (d) selected DMRs should be located 200\u00a0bp away from repetitive elements; and (e) the adjusted (Bonferroni correction) et al., P value <0\u00b71 were considered for subsequent analysis. These bins were merged into consecutive regions (DMRs) after specific criteria selection and filtering.Pairwise genomewide methylation comparisons between CVS, WBF and PL were performed using the MEDIPS package . The response variable in this model is the read depth, which in our experiments acts as a proxy for the methylation level of each region, while the categorical variable is the sample type and consists of three levels . The additional random effect allows for different methylation variability between the different DMRs. Subsequent od Holm, .3.3.1.Three WBF, three CVS and two PL samples were subjected to wholegenome MeDIPNGS analysis to enable genomewide identification of fetalspecific DMRs. The resulting alignment files were used as input for the R package MEDIPS, where the differential coverage between two groups of samples (i.e. CVS vs. WBF and CVS vs. PL) was calculated. Using MEDIPS criteria (see Section 2.7.1), 3574 DMRs were identified in the CVS vs. WBF comparisons, of which 1888 regions showed hypermethylation in CVS and hypomethylation in WBF samples, while 1686 regions showed hypomethylation in CVS and hypermethylation in WBF samples . Similar3.1.1.P\u00a0<\u00a02\u00a0\u00d7\u00a010\u221216 for all three pairwise posthoc tests (The overlap of the DMRs obtained from the two comparisons (WBF vs. CVS and PL vs. CVS) provided 1453 common fetalspecific DMRs that showed hypermethylation in CVS and hypomethylation in maternal samples. Those ranged from 100 to 2300\u00a0bp in length. Comparison of the overall methylation status of the aforementioned DMRs showed a clear distinction of the methylation status between CVS and maternal tissues (WBF and PL), with adjusted oc tests a). Overa3.2.To further ascertain and characterize the identified biomarkers, a subset of 331 potential fetalspecific DMRs  was selected based on specific criteria (see Section 2.7.1). In addition, selection was focused on autosomal chromosomes and on regions located in significant regulatory regions such as potential promoters, CpG islands (CGIs) and exonic (coding) regions. Specifically, 294, 64 and 73 DMRs were located within coding regions (67\u00b77% in gene bodies and 32\u00b73% in exons), potential promoters and CGIs, respectively . Resulet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The methylation status of the selected DMRs was also compared with previous studies that utilized methylation differences between fetal and maternal tissue for the identification of fetalspecific biomarkers. Common DMRs were found between our approach and DMRs identified using bisulphite conversion, methylationsensitive restriction digestion and microarrays (Old 4.In this study, we undertook the genomewide biomarker discovery of DMRs between fetal and maternal DNA and confirmed the presence of a subset of these DMRs by combining for the first time MeDIP with insolution targeted enrichment and NGS.et al., Also, this is, to our knowledge, the first reported application of MeDIP in plasma samples. Previous studies have employed MeDIP in order to characterize the methylation status of different tissues using large amounts of input DNA. We were able to overcome this limitation and successfully enrich and characterize the methylome of multiple plasma samples using modifications of an existing MeDIP protocol (Borgel et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Previous studies have employed different methods for the discovery of fetalspecific biomarkers using methylation differences between fetal and maternal DNA, including sodium bisulphite conversion, methylationsensitive restriction digestion or affinitybased techniques (Gitan et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Comparison of the selected DMRs with previous reports showed that the methylation patterns of several DMRs that were confirmed in our study are consistent with other methylationbased approaches (Old Based on the characteristics of the validated DMRs and due to the great potential of this approach to be utilized in the clinical setting for the detection of the most common aneuploidies, future work will focus on the identification and characterization of additional DMRs on chromosomes 13, 18 and 21. In addition, the discovery of DMRs across all autosomes using our approach opens the way for identifying and validating markers associated with subchromosomal copy number changes, such us clinically relevant microdeletions and microduplications."}
+{"text": "Sci., 2018, 9, 4071\u20134082.Correction for \u2018Thermoreversible crystallization-driven aggregation of diblock copolymer nanoparticles in mineral oil\u2019 by Matthew J. Derry  The authors regret that in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The FruM proteins have a 101 amino acids (a.a.)-long extension at the N-terminus which is absent from FruCOM. We suggest that this N-terminal extension might confer male-specific roles on FruM interaction partner proteins such as Lola, which otherwise operates as a transcription factor common to both sexes. FruM-expressing neurons are known to connect with other neurons to form a sexually dimorphic circuit for male mating behavior. We propose that FruM proteins expressed in two synaptic partners specify, at the transcriptional level, signaling pathways through which select pre- and post-synaptic partners communicate, and thereby pleiotropic ligand-receptor pairs for cell-cell interactions acquire the high specificity for mutual connections between two FruM-positive cells. We further discuss the possibility that synaptic connections made by FruM-positive neurons are regulated by neural activities, which in turn upregulate Fru expression in active cells, resulting in feedforward enhancement of courtship activities of the male fly.The  The genfru gene spans over 150 kb of the genome, and harbors at least four promoters, P1\u2013P4  in females  of the number of X-chromosomes over the number of autosome pairs  is 1.0  or larger, the cell adopts the female fate, whereas, when the X/A value is 0.5  or smaller, the cell adopts the male fate. Counting of the relative numbers of X-chromosomes is performed by a transcriptional two-directional switch at the Sex-lethal (Sxl) gene, which is transcribed only when X/A exceeds 1.0. Thus the Sxl gene typically produces the Sxl protein only in XX individuals. The female-specific Sxl protein functions as a splicing regulator that induces female-specific splicing of its target, the transformer (tra) gene primary transcript. Only a transcript spliced in the female pattern can encode a functional Tra protein, which in turn induces female-specific splicing distinct from a default splicing that occurs in males in its targets, e.g., the primary transcript from the P1 promoter of the fru gene (fru-P1). Upon binding to the Tra target motif in the fru-P1 primary transcript  in neurons and neuron-restricted FruM (P1 products) expression do not necessarily mean that FruCOM is \u201cnon-neural.\u201d Lee et al. (P1-dependent fru-positive neurons (hereinafter fru[+]-neurons) that are sexually dimorphic derive from multiple neuroblasts rather than a few dedicated neuroblasts: in fact, all type II neuroblast lineages bring about sexually dimorphic fru[+]-neurons  leads to an increase in the proportion of female-typical neurons at the expense of the male-type neurons in the mAL cluster  acts on Or47b olfactory neurons in mature adult males to boost their ligand sensitivity, making these elder males more successful in copulation than younger males (Lin et al., fru[+] neurons called P1 neurons (Chen et al., IR52a-expressing fru[+]-chemosensory neurons on the wing margin mediate input to stimulate male-male courtship (He et al., fru expression in the IR52a-sensory neurons as positive regulators for male-male courtship is also modulated by neural activities during the adult stage.The nervous system of holometabolous insects such as  Jallon, . Notably Jallon, . These uon Hall, . Recent fru gene produces two major protein groups: FruM and FruCOM. The FruM proteins have an N-terminal extension that FruCOM proteins lack, but we do not know how important this structural difference is in terms of the protein functions. The expressions of the FruM and FruCOM proteins are mutually exclusive both spatially and temporally (e.g., neuroblasts vs. neurons in the postembryonic nervous system; Sato et al., The robo1 gene, a direct target of FruM (Ito et al., robo1 in males, whereas truncated Lola inhibits full-length Lola\u2019s action to repress robo1, with the result that the ipsilateral neurite forms in males but not females (Sato et al., fru mutations that lost FruCOM while retaining FruM proteins (Song et al., fru mutants (Song et al., Molecular studies on the actions of FruBM protein have revealed that this protein forms a transcriptional complex with an isoform of Lola, a pleiotropic transcription factor, to transcriptionally repress the robo1 gene is the sole established target of FruM (more specifically, FruBM; Ito et al., The The loss of FruM expression by the olfactory receptor mutations observed in adult pheromone neurons (Hueston et al., fru gene became potentiated to achieve a specialist role\u2014i.e., a neural masculinizer role\u2014by creating structurally distinct FruM proteins in addition to FruCOM proteins. We assume that FruM proteins specify coherent signaling pathways in the pre- and postsynaptic neuron pair to form a Fru-labeled neural circuit. This circuit is probably consolidated by the fly\u2019s experience via use-dependent synaptic enhancement. However, this model describing how the actions of fru could induce adaptive changes in the nervous system of a fly during its individual lifetime remains to be tested in future experiments.These considerations prompt us to speculate that the DY: conceptualization, review and editing. KS and DY: funding acquisition and writing the original draft. JG: experimental work. KS: result analysis and visualization.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The electrophysiology of the paralimbic network (\u201cdefault mode\u201d) for self-awareness has drawn much attention in the past couple of decades. In contrast, knowledge of the molecular organization of conscious experience has only lately come into focus. We here review newer data on dopaminergic control of awareness in humans, particularly in self-awareness. These results implicate mainly dopaminergic neurotransmission and the control of GABAergic function directly in the paralimbic network. The findings are important for understanding addiction, developmental disorders, and dysfunctional consciousness. Self-awareness is a conscious experience with the self as an object. It is an essential part of conscious experience of the world, and is a tool for conscious self-monitoring and for controlling behavior. Its default may have grave consequences. The \u201cneural correlates\u201d of self-awareness have been studied by several investigators, including Devue and Br\u00e9dart  and D\u2019Aractive during self-awareness , we have realized that a paralimbic network is indeed instrumental in self-awareness: the network is not only 1 and D2 receptor agonist pergolide is effective in increasing confidence in seeing words and in improving performance in a forced-choice word recognition task. This demonstrates neurotransmitter regulation of subjective conscious experience of perception and provides the first direct evidence that dopamine is instrumental in conscious experience (Lou et al., Functional brain imaging has indicated that abnormal conscious experiences in schizophrenia, like hallucinations and delusions, are associated with abnormal dopaminergic neurotransmission (Changeux and Lou, The site of dopamine-GABA interaction for self-awareness in the human brain was unknown until recently. To clarify this issue, we have used a PET ligand for GABA receptor binding. With this ligand, we were able to detect changes in dopamine-induced GABA binding under different physiological conditions at well-defined brain sites (Lou et al., The GABA receptors are constructed as ligand ion channels. According to Stephens et al. , they arIn premature infants, functional MR imaging together with diffusion tensor imaging-based tractography has been used to study the relationship between performance on the Bayley Scales of Infant Development and early myelination (Cui et al., Newborn infants already show a form of \u201cbasic consciousness\u201d by establishing rudimentary eye contact with their mother (Lagercrantz and Changeux, A recent review showed that the default mode network follows an inverse U-shape, where it is weaker in children and elderly and stronger in adults. Cognitive function is positively correlated with default mode network functional connectivity (Mak et al., In later childhood and adulthood, disturbance of the paralimbic network is linked to severe pathology. Thus, deficient GABA neurotransmission is prominent in disorders with poor self-awareness and self-monitoring such as addiction (Lingford-Hughes et al., To determine if deficient GABA neurotransmission in pathology could be a primary event or secondary to toxic or pathological effects in more complex disorders, we examined if deficient dopamine-GABA neurotransmission was present in a relatively mono-symptomatic disorder such as gambling disorder (M\u00f8ller et al., dopamine. It is also a prominent site of cholinergic activity. Interaction between the cholinergic and dopaminergic system via GABA receptors has been well described (Changeux and Lou, The basal forebrain part of the system is not only regulated by The widespread dysfunction of self-awareness in disease is likely to be a consequence of the exceedingly high oxygen demand of the paralimbic network. The high oxygen requirement is considered to be the result of dense concentrations of parvalbumin GABAergic interneurons in the richly connected hubs of the paralimbic network. In particular, the fast gamma oscillations are susceptible to metabolic disruptions because of their high energy-demand (Kann et al., via GABA receptors in the paralimbic network. This finding has already resulted in a large and promising study of disabled persons with faltering self-awareness and consciousness (Sanz et al., Until recently, conscious experience and self-awareness were considered off-limits for the natural sciences. Neurobiological research shunned the \u201chard question\u201d of how conscious experience and self-awareness arise from a physical basis. Hence, it has been fashionable to limit neuroscience to try to identify neural \u201ccorrelates\u201d of conscious experience and self-awareness. The risk is evident for arriving at two parallel worlds: a mental and a physical, without understanding how they interact. This limitation has impeded our understanding of the biological function of self-awareness, and how it may account for disease. We have here reported data showing that self-awareness and conscious experience can be disturbed by electrophysiological manipulation of the paralimbic network (Lou et al., HL conceptualized the review and wrote the initial draft. KR and J-PC participated in writing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We assessed whether the risk of various psychotic disorders and non-psychotic bipolar disorder (including mania) varied by migrant status, a region of origin, or age-at-migration, hypothesizing that risk would only be elevated for psychotic disorders.We established a prospective cohort of 1 796 257 Swedish residents born between 1982 and 1996, followed from their 15th birthday, or immigration to Sweden after age 15, until diagnosis, emigration, death, or end of 2011. Cox proportional hazards models were used to model hazard ratios by migration-related factors, adjusted for covariates.migrants: 2.20, 95% CI 1.96\u20132.47; aHRchildren : 2.00, 95% CI 1.79\u20132.25), affective psychotic disorders , and other non-affective psychotic disorders . For all psychotic disorders, risks were generally highest in migrants from Africa  and elevated at most ages-of-migration. By contrast, risk of non-psychotic bipolar disorders was lower for migrants  overall, and across all ages-of-migration except infancy , while risk for their children was similar to the Swedish-born population .All psychotic disorders were elevated among migrants and their children compared with Swedish-born individuals, including schizophrenia and schizoaffective disorder (adjusted hazard ratio [aHR]Increased risk of psychiatric disorders associated with migration and minority status may be specific to psychotic disorders, with exact risk dependent on the region of origin. The Cause of Death register was used to obtain the date of death and the Migration Register was used to record date of migration. Individuals who died emigrated for the final time, or who were diagnosed with a psychiatric outcome before age 15 were excluded.et al., We linked participants to the National Patient Register to determine a psychiatric diagnosis in either inpatient or outpatient settings according to the International Classification of Diseases, 10th revision [ICD-10]. We studied four psychiatric outcomes: schizophrenia or schizoaffective disorder ; affective psychotic disorders , other non-affective psychotic disorders  and; bipolar disorder or manic symptoms without confirmed psychotic symptoms . For individuals who received diagnoses on multiple visits to in- or outpatient services, we adopted a hierarchal classification system, informed by clinical expertise  and consistent with earlier research  children of migrants if they were born in Sweden with one or both parents born outside of Sweden, and; (iii) Swedish-born if they were born in Sweden to two Swedish-born parents. The region of origin was defined by Statistics Sweden as Sweden, Finland, other Nordic countries, other European countries, Asia and Oceania, the Middle East, Africa, North America, South America, and unknown, based on country of birth. For migrants, we categorized age-at-first-migration into five groups: infancy (0\u20132 years), early childhood (3\u20136 years), middle childhood (7\u201312 years), adolescence (13\u201318 years) and early adulthood (19\u201329 years). We considered sex, current age, and follow-up period (see below) as a priori confounders. We also controlled for income in supplemental analyses, obtained from the Longitudinal Integration Database for Health Insurance and Labour Market Studies [LISA]. Since 1990, LISA has estimated total disposable family income from all sources each year , weighted for family size. As age 16 is the earliest an individual is included in the LISA, for most participants, we utilized information on their family income at age 15 via linkage to their parents, including adoptive parents where relevant. For migrants arriving in Sweden after age 15, we included their family income as first recorded in the LISA database. Where no income could be estimated, participants were excluded from these analyses (see below). We calculated income quintiles in each year for the entire population and assigned this value to participants in the year of their cohort entry. This method implicitly takes income inflation into account.We defined migrant status according to information in the Total Population and Multi-Generational registers. Participants were classified as (i) et al., et al., We first generated descriptive characteristics of the sample. Next, for each outcome, we investigated whether incidence varied by migrant status, region of origin, and age-at-migration using Cox proportional hazard regression. We estimated unadjusted and adjusted hazard ratios [aHR] and 95% confidence intervals [95% CI] for each exposure. To account for possible period effects , we split the data into 5-year bands of calendar time , modelled as a time-varying covariate. We also modelled age as a time-varying covariate , given risk of psychiatric disorders varies substantially by age , being highest amongst the Swedish-born population (59.2%) and lowest amongst migrants (45.0%). As expected, migrants with psychiatric diagnoses were more likely to be in the lowest income quintile (30.2%) compared to 5.3% of Swedish-born, and 8.6% of children of migrants . Additional cohort characteristics are presented in We identified 1\u00a0796\u00a0257 individuals who contributed over 12.79 million person-years of follow-up . Of thesRisk of all psychotic disorders was elevated among migrants and their children compared with Swedish-born individuals, after adjustment for confounding. For example, risk of schizophrenia and schizoaffective disorder was approximately doubled in migrants  and their children , with similar results obtained for other non-affective psychotic disorders . Risk ofThe excess risk of psychotic disorders in migrants persisted for participants from all regions of origin . Thus, fadolescence: 2.38, 95% CI 1.79\u20133.16; aHRearly adulthood: 2.77, 95% CI 1.64\u20134.69). For other non-affective psychotic disorders risk was elevated at all ages-of-migration, except early adulthood . Risk of affective psychosis was elevated among those who migrated in infancy , adolescence  and early adulthood , but not childhood. In contrast, bipolar disorder without psychosis was associated with lower risks at all ages-of-migration, except during infancy .Risks of all psychotic disorders were elevated across most ages-of-migration compared with the Swedish-born population . For schThese associations were partially attenuated following adjustment for income, but this did not substantially alter our findings (online Supplementary Tables S1\u2013S3). A sensitivity analysis excluding possible prevalent cases in migrants  did not change the pattern of our results (online Supplementary Tables S4\u2013S6). Schoenfeld tests and examination of log-log residual plots revealed no evidence of departure from proportionality across our main exposures for schizophrenia or affective psychosis (online Supplementary Table S7). These tests did suggest a departure from proportionality for our other two outcomes, but log-log residual plots revealed these effects were small and the departure from a zero-slope was negligible .This is the first longitudinal study to investigate how migrant status, region of origin, and age-at-migration affect the risk of schizophrenia, schizoaffective disorder, affective psychotic disorders, other non-affective psychotic disorders, and non-psychotic bipolar disorder. We discovered distinct signatures of risk, which varied according to the presence or absence of psychosis. Thus, migration-related exposures substantially increased the risk of psychotic disorders, albeit with more attenuated effect sizes for affective psychoses. In contrast, non-psychotic bipolar disorder showed a markedly different pattern, with generally lower risks across our three migration-related exposures compared with the Swedish-born population. Our results were impervious to adjustment for income and were unlikely to be explained by prevalent cases amongst migrants, or by age, sex, or period effects.et al., et al., We used to register data from a nationwide cohort of nearly 1.8 million people, with nearly complete coverage, and virtually no loss-to-follow-up. Clinical recording of schizophrenia spectrum disorders is known to be highly complete in the registers with good validity , which may have introduced bias vis-\u00e0-vis residual confounding; from the available data, however, any confounding effect appeared modest, and income may lie on the causal pathway between migration and mental health, making adjustment inappropriate.et al., et al., et al., et al., et al., Further sensitivity analyses suggested our results were unlikely to be attributable to prevalent cases amongst migrants, arguing against selective migration, consistent with previous observations (Selten et al., et al., et al., et al., et al., et al., et al., et al., Our results are consistent with previous research demonstrating an increased risk of schizophrenia-spectrum disorders among migrants and their children (Lloyd et al., et al., et al., Comparisons with previous findings with respect to age-at-migration and psychotic disorders require careful attention. In one study (Veling et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The different signatures of risk we observed between psychotic and non-psychotic disorders with respect to migration suggest that exposure to adversities related to migration and minority status could act specifically on psychotic rather than affective pathways. Emerging research supports the hypothesis that psychotic and non-psychotic bipolar disorder may have distinct neurodevelopmental origins (Murray et al., et al., et al., Repeated exposure to factors associated with migration \u2013 including social disadvantage, trauma or discrimination experienced prior to, during, or following migration \u2013 may also prime individuals to expect a greater level of threat from the environment (Reininghaus et al., et al., et al., et al., et al., We should also give credence to another possible explanation of our results: misdiagnosis. It has been suggested that higher rates of psychotic disorders in some ethnic minority groups are due to diagnostic bias, with people from the majority group less likely to receive a stigmatizing diagnosis such as schizophrenia compared with bipolar disorder (Schwartz and Blankenship, The shared patterns of risk across three categories of psychotic disorders with respect to various migration-related exposures suggest that migration may act specifically on psychotic rather than affective pathways to disorder. This provides potentially important clues to the aetiology of serious mental illnesses and should galvanise efforts to identify the exact social, environmental, and biological determinants of this preventable, gross inequality experienced by migrant and minority populations (Kirkbride,"}
+{"text": "Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural and functional elements in axons, supporting neurite differentiation and growth, as well as transporting motor proteins along the axons, which use MTs as support tracks. Tau is a stabilizing MT associated protein, whose functions are mainly regulated by phosphorylation. A disruption of the MT network, which might be caused by Tau loss of function, is observed in a group of related diseases called tauopathies, which includes Alzheimer\u2019s disease (AD). Tau is found hyperphosphorylated in AD, which might account for its loss of MT stabilizing capacity. Since destabilization of MTs after dissociation of Tau could contribute to toxicity in neurodegenerative diseases, a molecular understanding of this interaction and its regulation is essential. Tau is a microtubule-associated protein  assembled head-to-tail, which form a pseudo helical lattice , 269\u2013284 (in R2), and 300\u2013313 (in R3) is proposed, based on the attenuation of Tau NMR signal upon addition of paclitaxel-stabilized MTs  was used to compare Tau binding mode to Taxol-stabilized MTs and to tubulin when Tau is used as the sole inducer of the polymerization  of RB3 . Change in the isoform ratio has an indirect impact on MT assembly and the dynamics of the MT networks because the 3R Tau is known to have a lower capacity of MT stabilization and tubulin polymerization than the 4R Tau (Scott et al., in vitro assays. Surprisingly, R406W Tau is reported to be the most affected, despite the fact that the mutation is not near the MTBR (Hong et al., in vitro assays. However, there is no agreement on the extent of the specific effect of each of these mutations (Barghorn et al., Tau protein is encoded by the in vivo using Paclitaxel treatment in AD mouse models (Cash et al., One of the proposed strategies in seeking AD treatment consists of compensating the loss of the MT-stabilizing Tau function (Cash et al., Drosophila model of tauopathy (Quraishe et al., MT stabilizing peptides are another option chosen to restore MT stability (Quraishe et al., Drosophila, HDAC6 null mutation rescues MT defects through increased tubulin acetylation (Xiong et al., Finally, MTs could be stabilized not by mimicking MAP function, but by modulating MT PTMs, which have a crucial role in MT dynamics. Levels of total \u03b1-tubulin are reduced by approximately 65% in AD-patient brains compared to age-matched control brains but the relative ratio of acetylated tubulin is increased by approximately 31% compared to the controls (Zhang F. et al., Overall, Tau implication in neurodegenerative diseases, and other diseases where MTs play an important role, clearly shows the interest of the Tau/MTs interaction as a potential target for intervention (Pachima et al., The content of the manuscript was drafted and edited by all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "N- and O-sulfation and N-acetylation patterns. Its low concentration in crude extracts, containing other heterogeneous GAGs, leads to a purification process that is very complex, and which is well-guarded by manufacturing companies. Van der Meer et al. [The seven reviews and the eleven articles in this special issue provide an updated survey of recent research and developments in the ever-growing field of heparin, along with low molecular weight heparins (LMWHs) and glycosaminoglycans (GAGs). The complex biosynthetic process, and the variability of tissues and animal species, has led to heparin chains heterogeneous in size and both r et al. , throughAs a consequence of the \u201cheparin crisis\u201d in late 2007, an updating of heparin pharmacopeia monographies in the USA and the EU with new NMR and HPLC tests increased the quality control capabilities for crude and API porcine heparins, with some limitations in detecting the addition of non-porcine crude heparins or other GAG-like contaminants. An improvement to this process  [Lima M. et al.  reviewedTwo Italian teams   review tThe interactions and binding sites of heparin/HS with BMPs and cytokines of the TGF-\u03b2 superfamily are reviewed by Rider C. and Mulloy B. . The actIn a collaborative study of 6 laboratories in the USA, Europe and India  [An article   reports 2 cells.Three Italian groups   exploredA collaborative study by an Israeli and Italian team   led to tThe review by authors from the Departments of Neurosurgery at two US Universities   suggestsA Belgian team (Minet V.)  reviewedCompositional analysis of both LMWH Dalteparin   and Danacis-Pt, have been studied \u201cin vitro\u201d and in xenograft models  [cis-Pt resistance in a cancer-resistant cell line. In vitro preliminary studies show that Tinzaparin has no effect on cis-Pt accumulation in cis-Pt-resistant xenografts but strongly increases the Pt content in non-cis-Pt-resistant ones.The interactions of Tinzaparin, a LMWH used as antithrombotic prophylaxis in clinical oncology with  et al.) . In vitrComponent fractionation of Semuloparin, an ultra LMWH obtained by a depolymerization process preserving the AT binding region, has allowed a team at Sanofi   to isola\u00ae, have also been defined on the basis of a determination of single-crystal X-ray conformation. Quantitative NMR were also used, confirming that this method shows intrinsic robustness for content determination  [An extended physico-chemical characterization of Fondaparinux, the synthetic \u03b1-methyl glycoside of the AT binding pentasaccharide, and the active ingredient of the anticoagulant drug Arixtra et al.) .A team from Heidelberg University   has syntAuthors from the Trondheim University (Norway) (Arlov \u00d8. and Skj\u00e5k-Br\u00e6k G.)  review t"}
+{"text": "Plants are the primary source of human food and animal feed and also form the basis of numerous industrial and pharmaceutical products. This special issue reflects the diversity of modern research in the field of plant molecular genetics. It covers a wide range of modern technologies and scientific approaches that aim to achieve a better understanding of the various aspects of molecular mechanisms underpinning the key traits in major crops and other commercially important plant species. Phytophthora capsici in Chili Pepper\u201d reported on 11 novel molecular markers targeting resistance to the soil-borne pathogen Phytophthora capsici in chili pepper. The markers developed through high-resolution melting analysis, represent an excellent tool for marker-assisted selection. Another type of molecular markers, SSR, was used for the study of genetic diversity in cultivated and wild melon . The authors found enormous genetic variability within the collection, and deployment of the well-known SSR markers enabled the generation of a phylogenetic tree showing the relationships between melon accessions. An investigation presented by R. Ben Ayed and A. Rebai  revealed a significant link between the five SNP markers analysed and the biochemical composition and quality of olive fruits.Three papers in this issue deal with the development, study, and application of molecular markers in plant breeding. N. Kim et al. in \u201cDevelopment of Clustered Resistance Gene Analogs-Based Markers of Resistance toLinum usitatissimum L.)\u201d presented by G. S. Krasnov et al. reported valuable results from RNAseq analysis and candidate gene identification for flax genotypes tolerant or sensitive to a high concentration of Al. The authors' conclusions on glutathione metabolism, oxidoreductase, and transmembrane transporters can be further applied both in academic study and in practical breeding. Very few investigations have been conducted on plant growth in the absence of gravity during space-shuttle orbit around our planet. The paper presented by O. Yu. Yurkevich et al. (\u201cMolecular Cytogenetics of Pisum sativum L. Grown under Spaceflight-Related Stress\u201d) describes a chromosome analysis of pea progenies derived from plants grown in space using a novel FISH approach. Minor chromosome rearrangements were observed in response to \u201cspaceflight-related stress,\u201d which could lead to better guidelines for biological experiments with plants during future space-shuttle missions.Several of the presented reports are related to the genetic control of plant response to abiotic stresses. Drought is one of the major challenges being faced in agriculture. The paper presented by N. M. Kamal et al. (\u201cStay-Green QTLs Response in Adaptation to Post-Flowering Drought Depends on the Drought Severity\u201d) provides important findings on QTLs identified in sorghum grown in Sudan (Africa) under drought conditions. The presented data, generated in cooperation with the International Atomic Energy Agency (IAEA), Austria, can be used for the improvement of grain yield in drought-prone environments using a \u201cstay-green\u201d approach through the application of QTL analysis. Tolerance to aluminum toxicity represents an entirely different type of abiotic stress, but this too is an important agricultural problem, especially in acidic soils. The paper \u201cAluminum Responsive Genes in Flax .\u201d This is an extremely intricate cytogenetic study of the centromeric nucleosomes in dividing cells. The authors presented some critical results from CENH3 gene analysis, a central player in this very complex cytological trait, offering promising potential outcomes.IAEA also supported a study on the generation of mutant bread wheat with improved micronutrient content in the grain. S. Kenzhebayeva et al. presented their paper \u201cMutant Lines of Spring Wheat with Increased Iron, Zinc, and Micronutrients in Grains and Enhanced Bioavailability for Human Health,\u201d where stable breeding lines of wheat were produced from the M Phaseolus beans using diverse characteristics derived from the seed morphology of these species. L. Sinkovi\u010d et al. presented their paper \u201cMorphological Seed Characterization of Common (Phaseolus vulgaris L.) and Runner (Phaseolus coccineus L.) Bean Germplasm: A Slovenian Gene Bank Example,\u201d which contained an interesting comparison of seeds, accompanied by color images. The presented findings are essential for a better understanding of the wide diversity of bean species, which can be directly used for genetics and breeding of these nutritionally important crop varieties. In contrast, another paper \u201cIn Silico Genome-Wide Analysis of the ATP-Binding Cassette Transporter Gene Family in Soybean (Glycine max L.) and Their Expression Profiling,\u201d presented by A. K. Mishra et al., reported on computer analyses of available databases concerning the important gene family of the ATP-binding cassette transporter, in soybean. The authors provided a very accurate and detailed analysis of all identified genes and protein isoforms, arranging these new findings within the context of other pertinent information and comparisons.A remarkable level of genetic polymorphism was found in a germplasm collection ofP. Soundararajan et al. presented a detailed review entitled \u201cInsight on Rosaceae Family with Genome Sequencing and Functional Genomics Perspective.\u201d The Rosaceae family is one of the most significant plant families, and the fruits, berries, flowers, and many other important parts of these plants are familiar to each of us from early childhood. The authors have provided a comprehensive overview on the modern level of genetic knowledge and technology employed in comparative genomics and functional genome analysis for many Rosaceae species. Whole genome sequences in this plant family are so important for genetics, breeding, and agriculture that the presented review will surely be of broad general interest to future investigations in this area.In conclusion, the review presented by N. Borisjuk et al., entitled \u201cGenetic Modification for Wheat Improvement: From Transgenesis to Genome Editing,\u201d summarizes the attempts and results of wheat improvement using various genetic engineering approaches. The authors reflect the progress achieved since the dawn of genetic transformation up until the recent emergence of precise modern genome editing using CRISPR/Cas9 and related systems in wheat. This comprehensive review can provide a strong stimulus for both current and future researchers to pursue work on wheat improvement, and deploy all available modern technologies to secure a sustainable supply of quality agricultural produce for our growing global population.Yuri ShavrukovNikolai BorisjukNarendra K. Gupta"}
+{"text": "Several physiological processes such as fertilization, apoptosis, muscle contraction, neuronal activity, and sensory perception are based on the spatial and temporal variation in intracellular Ca2+ and rely on a class of proteins that specifically respond to these highly dynamic stimuli. Neuronal calcium sensor (NCS) proteins are exclusively expressed or enriched in neurons, and their structural and biochemical diversity reflects the multiplicity of their biological roles, which include control of gene transcription, neuronal growth and survival, channel and receptor regulation, neurotransmitter release, synaptic plasticity, and regulation of enzymatic activity. Neurological disorders and neurodegenerative diseases are increasingly associated with altered functions of specific NCS proteins. This Research Topic includes original articles and reviews that provide an interdisciplinary collection of up-to-date biochemical and biophysical research on NCS proteins and their established and novel biological roles in normal and altered  conditions.The precise detection and regulation of free intracellular CaRatai et al. show that NCS-1 plays an important role in adipocyte function and its deficiency gives rise to obesity and diabetes type 2 in adult mice, thus suggesting a potential genetic link between psychiatric disorders and the risk of being obese. The progressive degeneration of dopaminergic neurons within the Substantia nigra is the hallmark of Parkinson's disease and causes its motor symptoms. The link between dopamine release and NCS-1 and its possible implications in Parkinson's disease has been reviewed by Catoni et al., who summarize the role of the interplay between Ca2+ and dopamine signaling in neuronal activity and cell death. Simons et al. provide novel data at the transcript level that link NCS-1 deficiency to impaired ATP-production and elevated metabolic stress in Substantia nigra dopaminergic neurons in mice. An overview of other novel roles of NCS-1 is provided by the review of Nakamura et al., which focuses on both the neuronal system and the heart, presenting NCS-1 as a regulator of voltage-gated Ca2+ channels, ionotropic dopamine receptors, and inositol 1,4,5-trisphosphate receptors. A complex interplay between Mg2+, Ca2+ and Zn2+ binding to NCS-1 leads to the appearance of multiple protein conformations and modulate its functional status as suggested by Tsvetkov et al., who demonstrate that NCS-1 binds Zn2+ with differential affinities favoring either the interaction with targets or protein aggregation. Choudhary et al., who focus on optical tweezers investigations to reveal a complex folding mechanism underlaid by a rugged and multidimensional energy landscape, provide insight into the structural and mechanistic details of the folding and misfolding processes of NCS-1 at the single molecule level.Neuronal calcium sensor-1 (NCS-1) is highly conserved from yeast to human, and it has been implicated in a number of psychiatric conditions including autism, bipolar disorder, schizophrenia, and X-linked mental retardation. At odds with other members of the NCS family, NCS-1 interacts with several cellular targets, which is reflected by a variety of roles. 2+-binding motifs and amino acids involved in target recognition has been investigated by Marino and Dell'Orco, who suggest for NCS-1, recoverin and GCAP1 an evolution-driven correlation between the amino acids mediating many persistent interactions and their conservation. An inter-domain interaction triggered by Mg2+-binding is essential for the ubiquitous Ca2+ sensor CIB2 to reach a fully functional conformation, as shown by Vallone et al., who found that the apparently conservative E64D mutation associated with Usher Syndrome 1J and non-syndromic hearing loss prevents this long-range allosteric mechanism. Mutations in calmodulin, another ubiquitous Ca2+ sensor, were long thought to be incompatible with life due to the completely conserved amino acid sequence across all vertebrates. The review by Jensen et al. provides an overview of the human missense mutations found in patients with severe cardiac arrhythmias.The importance of allosteric interactions between Ca2+ dependent. The review by Ames summarizes the results of recent studies on GCAPs, VILIP1 and recoverin dimerization. A paradigmatic example of the myristoyl-switch protein, recoverin is involved in the regulation of the phototransduction cascade in rods and cones as reviewed by Zang and Neuhauss. Four different recoverin isoforms exist in zebrafish photoreceptors. Their specific Ca2+-sensing properties and conformational changes have been investigated by Elbers et al., who found that binding of Ca2+ leads to less pronounced structural rearrangements compared to the bovine ortholog indicating either a modified Ca2+-myristoyl switch or no switch at all. Novel roles for recoverin in health and disease-associated conditions have been found by Zernii et al. who provide in vitro and in vivo evidence that illumination of the mammalian retina leads to the accumulation of disulfide dimers of recoverin, which are thought to favor light-induced oxidative stress and photoreceptor apoptosis.Many NCS proteins form dimers, a process that is often Ca2+. Rehkamp et al. present a chemical cross-link/mass spectrometry investigation on the interaction between GCAP2 and GC-E, while Wimberg et al. investigate five recently identified GC-E mutants associated with Leber Congenital Amaurosis, a cone-rod dystrophy, finding severe alteration of the cGMP synthesis. Another prototypical guanylate cyclase, the atrial natriuretic factor receptor guanylate cyclase is found to be regulated by the Ca2+ sensor neurocalcin \u03b4 and hormone ANF via two distinct and non-overlapping transduction modes, as elucidated by Duda et al.The complex between GCAPs and the retinal guanlylate cyclases is a crucial component of the vertebrate phototranduction machinery as it regulates the interplay between the second messengers cGMP and Ca2+-binding proteins have been found to be involved in the complex etiology of psychiatric disorders. By combining a stereology-based approach and molecular analyses Lauber et al. investigated the involvement of parvalbumin in autism spectrum disorder, finding a dysregulation of its expression in Cntnap2 knockout mouse. The review by Mundhenk et al. presents a detailed structural and biophysical characterization of the Ca2+-sensor proteins caldendrin and calneuron-1 and\u22122, focusing also on their cellular function and their role in neuropsychiatric disorders.Ca2-domain protein otoferlin in modulating the Ca2+-triggered exocytosis at the ribbon synapse in mouse inner hair cells is proposed by Takago et al. by a combination of electrophysiology and biochemical analyses. The importance of Ca2+-binding proteins in regulating the fundamental process of exocytosis and synaptic coupling is emphasized in the review by Maj et al., focusing on secretagogin and its novel roles in developing and adult neuronal cells and Bornschein and Schmidt, focused on synaptotagmin 1 and 2 and their role in presynaptic voltage-gated Ca2+ channel regulation.A role for the multi CPeraza et al. identifies by biochemical and biophysical investigations a novel ligand of DREAM that modulates Kv4 potassium channels currents, with consequences that are relevant for physiology and disease. The role of DREAM/KChIP3 in pain transmission and its possible involvement in emotional processing was studied by Guo et al., who assess the pain sensitivity and negative emotional behaviors of Kcnip3\u2212/\u2212 rats and find a possible role for the protein in central nociceptive processing. Novel tools to regulate the role of DREAM in the endoproteolysis of endogenous presenilin-2 in mouse brain are presented by Naranjo et al., who suggest that the interaction between the two proteins may have a therapeutic potential in Alzheimer's disease. Finally, the review by N\u00e9ant et al. summarizes the current knowledge regarding Ca2+ signaling in quiescent glioblastoma stem-like cells and discussed how Ca2+ via KCNIP proteins may affect gene expression in glioblastoma.Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3 exerts multiple functions, including the regulation of A-type outward potassium currents. The contribution by Taken together, this Research Topic delivers new visions to our knowledge on NCS proteins and will stimulate future research. We wish to thank all the authors for having submitted papers of high quality and all the reviewers that contributed with constructive and fruitful suggestions.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mops condylurus) trapped in the city of N\u2019Zerekore and in a nearby village.In 2018, a previously unknown Ebola virus, Bombali virus, was discovered in Sierra Leone. We describe detection of Bombali virus in Guinea. We found viral RNA in internal organs of 3 Angolan free-tailed bats ( Ebolavirus (family Filoviridae), Bombali virus (BOMV), was discovered in Sierra Leone (Chaerephon pumilus (little free-tailed bat) and Mops condylurus (Angolan free-tailed bat). Both bat species are widespread in Africa, and their ranges include countries where human Ebola virus disease (EVD) outbreaks have occurred. Forbes et al.  and in a pool of liver and spleen tissues (Ct 28.2) of an M. condylurus bat from a school in the city of N\u2019Zerekore in March 2019  in China, and another study showed that 3 distinct groups of unclassified filoviruses are circulating in Eonycteris spelaea and Rousettus spp. fruit bats in China (Mar\u00ed Sa\u00e9z et al. (EBOV IgG was detected in the human population of Sierra Leone in 2006, 8 years before the EVD outbreak began in that country (M. condylurus bats provides additional confirmation that BOMV could amplify in these bats and that this species is a reservoir host of this virus.Although BOMV had been detected in the northern part of Sierra Leone (Mops condylurus bats, Guinea.Additional information on Bombali virus in"}
+{"text": "Dear Editor,in vitro techniques of liver . In recal., 2013; Grinberal., 2013; Leist eal., 2013; Ghallabal., 2013), kidneyal., 2013; Jiang eal., 2013; Su et aal., 2013; Valenteal., 2013; Lee et al., 2013), neuronal., 2013; Yang etal., 2013; Colaianal., 2013; Sisnaisal., 2013) and deval., 2013, 2016[22al., 2013; Waldmanal., 2013). Stem cIndices have been developed to identify a possible hazard of developmental toxicity based on genome-wide expression data. A precondition is the definition of so-called developmental genes of a test system. Developmental genes are up- or down-regulated during the differentiation process in the absence of test compounds. Developmental potency describes the fraction of all developmental genes, whose expression is altered by test compounds (Shinde et al., 2017; WaldmanMuch progress has been achieved in analyzing disturbed developmental processes. However, it still remains challenging to differentiate stem cells to adult cell types that closely resemble the corresponding mature cell type in vivo (Godoy et al., 2015; Cameronin vitro, but there is still a long way to go until the techniques are ready for routine use and to replace animal studies in pharmacology and toxicology. Stem cell-based alternative test methods offer powerful tools to analyze developmental toxicity The author declares no conflict of interest."}
+{"text": "Candida albicans and Staphylococcus aureus interactions, one from the Candida perspective  [Staphylococcus perspective (Todd and Peters) [Aspergillus fumigatus and Pseudomonas aeruginosa  [Candida albicans and Pseudomonas aeruginosa (Fourie and Pohl) [Cryptococcus neoformans (Mayer and Kronstad) [Candida albicans and the oral bacterial microbiome that contribute to the pathogenesis of oral candidiasis (Bertolini and Dongari-Bagtzoglou) [We would like to thank all the contributors to the Special Issue on Fungal\u2013Bacterial Interactions\u2014Current Knowledge and Future Perspectives. In total, seven 7) reviews/perspective papers were published in the issue. A wide range of various fungal\u2013bacterial interactions were covered. Two papers covered  et al.) , and the Peters) . Another et al.) . Other snd Pohl) , bacterironstad) , and dystzoglou) . Lastly, reviews/"}
+{"text": "Gracilibacteria (formerly GN02) and Saccharibacteria (formerly TM7) of the recently described Candidate Phyla Radiation  and not to Gracilibacteria as reported by Espinoza et al. (Saccharibacteria genomes showed a 7-fold increase in the number of single-copy core genes (To briefly demonstrate their composite nature, we refined some of the key Espinoza et al. MAGs through a previously described approach  and the a et al. . A pangere genes . These fre genes . Composire genes  recruiteCo-assembly of a large number of metagenomes that contain very closely related populations often hinders confident assignments of shared contigs into individual bins. Nevertheless, even when proper refinement is not possible, reporting composite MAGs as single genomes should be avoided. As of today, highly composite Espinoza et al. MAGs (The rapidly increasing number of MAGs in public databases already competes with the total number of microbial isolate genomes , and inc7\u2013"}
+{"text": "Ad-HBV is a product T101) aiming to treat chronic HBV firstly developed by Transgene S.A., France then by Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., Tianjin, China in China. So, in the originally published article [01 aimingAdditionally, in the \u201cAcknowledgements\u201d section in the originally published article, \u201cThe Ad-HBV were a kind gift from Xia Meng (Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., Tianjin, China). We want to thank Zhiming Wang and Xiaomin Wang (Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., Tianjin, China) for teaching neutralization activity detection of anti-Ad antibodies\u201d should be replaced by \u201cWe want to thank Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., to provide us the opportunity to participate in the non-clinical safety assessment of T101, and most of the research work appeared in this paper came from the non-clinical safety assessment of T101\u201d."}
+{"text": "Protein kinases represent a large and diverse multi-gene family of enzymes, which catalyze the transfer of the \u03b3-phosphate group from its natural co-substrate adenosine triphosphate (ATP) to a free hydroxyl group of an amino acid side chain. They are involved in numerous cell signaling pathways. Diseases might arise when deregulation or mutation of a kinase takes place. Therefore, kinases are promising drug targets for the treatment of several disorders ranging from cancer, autoimmune pathologies, inflammation, or neurodegenerative diseases. After the approval of imatinib in 2001, 38 kinase inhibitors were introduced to the market by the beginning of 2018. Numerous kinase inhibitors are currently in clinical trials.Structural data\u2014e.g., from the structural genomics consortium (SGC)\u2014as well as the high-quality kinase probe programs from the Chemical Probe Portal and the SGC kept pushing forward both the identification of new kinase targets and the design of novel kinase inhibitors within the last years. The numbers of reported type I\u00bd, type III, and type V kinase inhibitors as well as covalent kinase inhibitors have continuously increased in the last few years.This Special Issue deals with the design and development of novel inhibitors addressing different kinases as well as with strategies to inhibit kinases. The Special Issue consists of eight original research articles and four reviews, as briefed below.Brenner et al. described the efficacy of six inhibitors of CDC25, dual-specificity phosphatases that activate cyclin-dependent kinases, on acute myeloid leukemia cells isolated from patients . The resIn their study, Halekotte et al. designed and synthesized optimized 4,5-diarylimidazoles as ATP-competitive inhibitors of CK1\u03b4 and discussed their structural relation to the p38\u03b1 mitogen-activated protein (MAP) kinase . The resb]pyrazine-based FGFR inhibitors starting from a c-Met inhibitor [Zhang et al. described the ligand-based design of pyrrolo2,3--bpyrazinAn analysis of kinase inhibitors and their specificity with respect to their scaffold diversity is described by Dimova and Bajorath . Yang et al. reported the synthesis of novel pyrrolidone-fused methylpyrrole derivatives and their biological evaluation as potential multi-target tyrosine kinase receptor inhibitors . An exteIn their study, Tegethoff et al. showed that 1-methylisoindigo is a Stat3-related inhibitor of various tyrosine kinases . The autThe metabolic stability of two potent pyridinylimidazole-based p38\u03b1 mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 was improved by Heider et al. . The novThe number of both approved kinase inhibitors and kinase inhibitors in clinical trials increases continuously. In their research article, Carles et al. presented an extensive analysis of their monthly-updated Protein Kinase Inhibitor Database (PKID) . The PKIIn their review, Lee at al. summarized recent advances in the targeting of the p38\u03b1 MAP kinase as a potential strategy for the treatment of Alzheimer\u2019s disease . InhibitLee et al. discuss the pro- and anti-tumorigenesis functions of senescence as well as the roles of kinase modulators in these processes . An overIn their comprehensive review, Cheng et al. summarized the recent progress of MEK inhibitors and focused on marketed MEK inhibitors and inhibitors in clinical trials . ClinicaSchmidt et al. presented a timely review on the two members of the WEE kinase family, WEE1 and PKMYT1 . Both ki"}
+{"text": "This research describes how Department of Veterans Affairs (VA) and non-VA home-based long-term care (LTC) environments prepared for and secured the safety and wellbeing of elderly and disabled persons in the wake of Hurricane Maria, which struck Puerto Rico on September 20, 2017. In-person interviews, home visits, and field observations were conducted in Puerto Rico from January-March 2019. Staff from three of the VA\u2019s Caribbean Healthcare System\u2019s home-based LTC programs were interviewed, as well as caregivers in non-VA LTC environments. Veterans, family members of Veterans, family members of VA caregivers, and community members with expertise in disaster recovery were also interviewed for a total of N = 58 interviews and N = 12 home visits. Preliminary results of qualitative content analysis show VA and non-VA LTC environments prepared residents and caregivers for Hurricane Maria through providing education and recommendations in advance, including having enough medications and food on hand. Participants described Hurricane Maria not simply as a disaster but a \u201ccrisis\u201d and a storm unlike any they had ever experienced. The interconnected nature of the VA seemed to provide a stronger support network compared to non-VA environments that were often independently run. Health of Veterans and non-Veterans was reported to be mostly stable during recovery. Perspectives from VA and non-VA entities allowed for a fuller picture to emerge around how Hurricane Maria impacted home-based LTC environments in Puerto Rico. This research can inform policies and procedures for such environments caring for elderly and disabled populations in areas prone to disasters."}
+{"text": "The tumor microenvironment (TME) constitutes an important component of any cancer. The histology of TME consists of a series of normal resident cells and a variety of recruited cells, which are involved in complex and dynamic interactions with cancer cells . These iSachs et al., describe a novel method for overcoming this problem by demonstrating, in different cancer models, the ability of new small molecules to reverse chemotherapy resistance. Munoz et al., address the problem of chemoresistance of glioblastoma multiforme (GBM), a fatal malignancy of the central nervous system. They show that MiR-93 and\u2212193 are specifically expressed in temozolomide (TMZ) resistant glioblastoma cells (GBM), including resistant neurospheres from a patient with TMZ resistance. Part of the resistance occurs by miR-93 and\u2212193 decreasing Cyclin D1 to reduce GBM cycling. This may open up avenues for new therapeutic approaches to reverse such chemoresistance . Besides chemoresistance in GBM, expansion of residual glioma cells is also a challenge in the context of chemotherapy. Work by Tsidulko et al., indicates that conventional anti-glioblastoma therapy such as TMZ affects proteoglycan structure and composition of normal brain tissue. Proteoglycan alteration may be involved in brain extracellular matrix (ECM) deterioration and the development of residual glioma cells .In this Research Topic, diverse facets of the TME are addressed, including different tumor types and tissue specificity of TME . RecentlLadomersky et al., demonstrate a significant association between advanced age of patients and immunosuppression in the circulation and central nervous system. Based on their findings, the authors propose that normal human aging suppresses immune surveillance and immunotherapeutic efficacy against glioma, and thus, contributes to GBM initiation and progression .Although immune checkpoint blockade therapy has afforded new hope for the durable treatment of many cancers, it has not provided yet substantial benefit to patients with glioblastoma. Utilizing a series of epidemiological, genome expression, and immunome databases, Yang et al., focus their study on bronchoalveolar lavage fluid-derived exosomes, released in the TME and demonstrate their role in fueling inflammation and tumor invasiveness via mast cells/neutrophils activation and cytokines release in TME. In a gastric cancer study, Zhao et al., analyze the role of NEDD9 in cancer cell migration under hypoxia. They demonstrate that NEDD9 regulates MICAL1, which facilitates hypoxia-induced gastric cancer cell migration in a Rac1-dependent manner .Using a lung cancer model, Tuo et al., address the role of the cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1) in the progression of hepatocellular carcinoma (HCC). PCK1 is a rate-limiting enzyme in gluconeogenesis which occurs mainly in the liver. The authors find that the expression of PCK1 is down regulated in HCC and associated with poor outcome. In hepatoma cells, the authors demonstrate that reactive oxygen species (ROS) production and nuclear translocation of Nrf2 and thioredoxin reductase 1 (TXNRD1) are suppressed during PCK1 overexpression. Furthermore, the authors show that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro .Hu et al., investigate the effect of berberine (BBR) in gastric cancer (GC). BBR is a natural isoquinoline alkaloid, presumably involved in lipid metabolism and glucose homeostasis by regulating the expression of HNF4\u03b1. The authors show that BBR inhibits the proliferation, invasion, and migration of GC cell lines, and thus reduces GC tumor growth in vivo. The antitumor effect of BBR shown appears to involve the AMPK-HNF4\u03b1-WNT5A signaling pathway . Using scutellarin, an active flavone extracted from Erigeron breviscapus Hand-Mazz (EBHM), Sun et al., investigate cisplatin resistance in non-small cell lung cancer (NSCLC). The authors find that scutellarin sensitizes tumor cells to cisplatin by enhancing apoptosis and autophagy via downregulation of p-AKT and c-Met in autophagy and caspase-3-dependent apoptosis. They suggest that the combination of cisplatin and scutellarin may be a novel therapeutic strategy for patients with NSCLC .The role of natural products in the modulation of the TME is likewise addressed in this Research Topic. Tirado-Hurtado et al., highlight the role of DNA Damage Inducible Transcript 4 (DDIT4) in cancer. The DDIT4 gene is expressed under stress situations, turning off the metabolic activity triggered by the mammalian target of rapamycin (mTOR). The authors propose targeting DDIT4 for the development of novel drugs that could be more specific and efficient than current mTOR inhibitors .The impact of DNA damage on TME is also investigated. Chulpanova et al., address the use of MCSs for drug delivery in oncology. The authors focus on MSC and tumor interactions, which are crucial for cancer control. They also describe novel therapeutic strategies using MSCs and MSC-derived membrane microvesicles for cancer therapy .Mesenchymal stem cells (MCSs) play important role in the TME . ChulpanIn conclusion, investigation of TME continues to be a vital focus toward the elaboration of novel strategies that produce more effective treatments for localized cancers and metastases. Findings presented in this Research Topic have the potential to make a major impact on this field and to inspire further discoveries.AL drafted the manuscript. AL, MB, KC-S, and AZ critically reviewed the manuscript for important intellectual content and approved it for publication.AL and KC-S are Founders and Shareholders of Lambda Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To identify which patient-related effect modifiers influence the outcomes of integrated care programs for type 2 diabetes in primary care.Integrated care is a widespread management strategy for the treatment of type 2 diabetes. However, most integrated care programs are not tailored to patients\u2019 needs, preferences and abilities. There is increasing consensus that such a patient-centered approach could improve the management of type 2 diabetes. Thus far, it remains unclear which patient-related effect modifiers should guide such an approach.PubMed, CINAHL and EMBASE were searched for empirical studies published after 1998. A systematic literature review was conducted according to the PRISMA guidelines.In total, 23 out of 1015 studies were included. A total of 21 studies measured the effects of integrated diabetes care programs on hemoglobin A1c (HbA1c) and three on low-density lipoprotein cholesterol, systolic blood pressure and health-care utilization. In total, 49 patient characteristics were assessed as potential effect modifiers with HbA1c as an outcome, of which 46 were person or health-related and only three were context-related. Younger age, insulin therapy and longer disease duration were associated with higher HbA1c levels in cross-sectional and longitudinal studies. Higher baseline HbA1c was associated with higher HbA1c at follow-up in longitudinal studies. Information on context- and person-related characteristics was limited, but is necessary to help identify the care needs of individual patients and implement an effective integrated type 2 diabetes tailored care program. More than 90% agreement was reached. Therefore, the remainder of the titles and abstracts were screened by 1 reviewer (D.H.). Second, the first 20 full texts were screened independently by two reviewers (D.H. and A.E.). Again, more than 90% agreement was reached and therefore, each reviewer independently screened half of the full texts. Third, the reference lists of the included studies were screened to obtain additional studies. Steps 1 and 2 of the study selection process were then repeated.Descriptive data on studies were extracted by 1 reviewer (D.H.) between August and October 2015. Studies were coded for author names, year of publication, country, study design, length of follow-up, population size, age, percentage of males and CCM components. In case of uncertainties, a group discussion was held with two other authors (A.E. and M.B.).et al., The Effective Public Health Practice Project Quality Assessment Tool (EPHPP) was used to assess the quality of the included studies (Armijo-Olivo Two reviewers (D.H. and M.B.) independently performed the quality assessment for each study. Disagreements were resolved via discussion conform EPHPP guidelines.The included studies were categorized according to: (1) the reported outcome(s) of interest ; and (2) the type of patient characteristic(s) investigated in subgroup analyses. Characteristics were classified as person-related (predisposing), context-related (enabling) or health-related (illness level) characteristics according to Andersen and Newman\u2019s  Behaviorn=453), and/or type of care was not integrated (n=257). After the title, abstract and full text screening, 27 studies were included , blinding (n=9) and selection bias (n=9). Almost all studies (n=25) scored high on the domain data collection. The overall study quality was strong for four studies, moderate for 11 studies and low for 12 studies. Most studies with low quality had a cross-sectional study design and did not report on or adjust for possible confounders.The methodological quality of the included studies can be found in Supplementary Table 1. The domains with the most \u2018weak\u2019 ratings were confounders (n=20) was 15 months (range 6\u2013112). The median sample size consisted of 376 individuals (range 80\u2013105 056) with an average age of 60.0 years (range 50.5\u201370.9); the percentage of male subjects ranged from 31.3 to 68.0.Of the included studies, nine (33.3%) were retrospective cohort studies, seven (25.9%) cross-sectional studies, seven (25.9%) (randomized) controlled studies and four (14.8%) prospective cohort studies. n=25), followed by self-management support (n=20). Of the studies that included the components delivery system design, most introduced a care team (n=13), followed by regular follow-up visits (n=8). Self-management support was mostly realized through individual educational sessions on diabetes, health and nutrition (n=14).In total, 18 uncontrolled studies \u2013 including prospective, retrospective and cross-sectional cohort designs \u2013 measured the effects of integrated care programs on HbA1c. In addition, seven studies compared the influence of patient characteristics on the effectiveness of integrated diabetes care programs between intervention and control groups. In total, 51 patient characteristics were assessed as potential effect modifiers of the relationship between integrated care and HbA1c. The results will be presented according to study design. For RCTs all characteristics assessed by this study design will be discussed. Due to the high number of characteristics assessed by the cross-sectional, retrospective and prospective cohort studies, only characteristics assessed by three or more studies will be presented.(Randomized) controlled trials: Five RCTs and two controlled trials (CTs) compared the influence of patient characteristics on the effectiveness of integrated diabetes care programs on the HbA1c level between intervention and control groups . In totaet al., et al., et al., et al., et al., Sex and age were the person-related characteristics evaluated as potential effect modifiers. Three studies assessed sex as a potential modifier, of which two found that women in the intervention group had statistically significant lower HbA1c values at follow-up compared to women in the control group , depression and diabetes mellitus (DM) duration. Each characteristic was assessed by one study. Patients with high FBG (>10 mmol/L) at baseline receiving integrated diabetes care had significantly lower HbA1c levels at follow-up compared to patients receiving usual care  and sex (n=9). In seven studies the effect of integrated diabetes care programs on HbA1c differed significantly across ranges of age: younger patients had higher HbA1c levels at follow-up compared to older patients (n=5) and experienced greater change from baseline in HbA1c (n=2) , baseline HbA1c (n=7) and duration of type 2 diabetes (n=6). The effect of integrated diabetes care programs on HbA1c was different for people on insulin therapy. These patients had higher HbA1c levels at follow-up compared with patients on diet and/or oral therapy in five studies   , body mass index (BMI) (n=6) and sex (n=5). Four studies of integrated care programs found non-significant associations between age and HbA1c  and medication use (n=4). The effect of integrated care programs on HbA1c differed significantly across ranges of diabetes duration in four studies (De Alba Garcia et al., et al., et al., et al., et al., et al., et al., et al., Most examined health-related characteristics were duration of type 2 diabetes (No context-related characteristics were assessed by three or more studies.Three prospective and retrospective cohort studies measured the effect of integrated diabetes care programs on LDL-c. The RCTs and cross-sectional studies included in this review did not measure this effect. In total, 11 patient characteristics were assessed by the studies. Only those results that were assessed by at least two studies will be discussed.et al., et al., Prospective and retrospective cohort studies: The person-related characteristic age was examined by three studies (Sperl-Hillen and O\u2019Connor, et al., The modifying effect of baseline LDL-c on the relationship between integrated diabetes care programs and changes in LDL-c over baseline was assessed by two studies (Sperl-Hillen and O\u2019Connor, No context-related characteristics were assessed by the included studies.Four retrospective and prospective cohort studies measured the effect of integrated diabetes care programs on SBP. In total, nine patient characteristics were assessed by the studies. Only those results that were assessed by at least two studies will be discussed.et al., et al., et al., et al., et al., et al., et al., et al., Retrospective cohort and prospective cohort studies: Age was measured by three studies (Mold et al., et al., et al., et al., et al., et al. (et al., et al. found that the effect of integrated diabetes care programs on health-care utilization was different between males and females (Liu et al., Health-care utilization was assessed by three studies: one RCT (Nielsen , et al.  found th et al., . For malThis paper presents a literature review on relevant patient characteristics for guiding tailored integrated type 2 diabetes care in primary care. HbA1c was considered an outcome in 93% of the 27 studies identified. Many different patient characteristics were investigated by these studies. Findings indicate that the effect of integrated primary care programs on HbA1c differs significantly according to a number of person and health-related characteristics. Younger age, longer disease duration, higher baseline HbA1c and insulin therapy were associated with higher HbA1c levels. Health insurance status, living situation and income were the only context-related characteristics in the included studies and were not frequently assessed.Compared to HbA1c, LDL-c, SBP and health-care utilization were included far less. It was found that higher baseline LDL-c lead to greater LDL-c improvement. Patients with higher age had higher SBP levels at follow-up as well as greater improvements in SBP compared to younger patients. The relationship between integrated care and health-care utilization seemed to be modified by sex: women had more consultations per year compared to men.et al., et al., \u03b2 cell function and pancreatic insulin secretion, resulting in the need for a more complex and intensive drug therapy (Al Omari et al., et al., et al., et al., et al., et al., et al., Several factors might explain the elevated HbA1c levels in a subset of patients with type 2 diabetes. Younger patients tend be more non-adherent to oral medication therapy and experience less profound diabetes-related health problems than older patients (Pyatak et al., \u03b2-cell dysfunction (Heianza et al., et al., et al., High HbA1c at baseline also seemed to be predictive of later HbA1c. First, type 2 diabetes is a heterogeneous disease in both pathogenesis and clinical manifestation (Inzucchi et al., et al., et al., Several factors could explain the differences in levels of LDL-c, SBP and health-care utilization between levels of patient characteristics. Prescription of statins usually follows when LDL-c level is 2.5 mmol/L or higher, possibly leading to greater improvements in LDL-c for those patients with high baseline LDL-c levels (The Dutch college of general practitioners, et al., et al., et al., et al., Overall, our results indicate the need to implement integrated diabetes care programs specifically tailored to the needs, values and preferences of younger patients and to those on insulin therapy, with longer disease duration and/or higher HbA1c levels and older patients with high SBP levels. These effect modifiers can help to provide the right care to the right person at the right time. At this moment, not every patient with these characteristics receives such care. Current practice might therefore not be suitable for all patients. Lack of motivation, family support and feeling burned-out from managing diabetes are reported barriers to optimal self-management (Browne et al., et al., et al., et al., This review has several limitations that should be taken into account. First, given the scarceness of studies assessing the differences in the effect of integrated diabetes care programs on diabetes control measures by levels of patient characteristics, it was decided to include RCTs, prospective and retrospective cohort studies. However, this introduced significant heterogeneity and made it impossible to conduct a meta-analysis. Second, quality of the studies was weak for most studies. This was mainly due to the cross-sectional study design of more than one-third of the studies and the use of less robust statistical methods. Fortunately, it is unlikely that these studies altered the results, as their findings were similar to those of the other, more robust studies. Third, very few context- and person-related characteristics were analyzed. Studies performed in a non-integrated diabetes care setting, found that context-related characteristics, such as socio-economic status and social network, are associated with measures of diabetes control and are likely to be strong predictors of diabetes control (Jotkowitz et al., The current review provides a good understanding of which characteristics can help to identify patients with different health-care needs and preferences. However, to implement an effective integrated type 2 diabetes tailored care program, it is necessary to know which context- and person-related characteristics are important to identify patients. Furthermore, implementation of an effective tailored diabetes care program is only possible by taking into account the care preferences of patients and caregivers. In the next phase of the PROFILe project (Elissen"}
+{"text": "Dear Editor,n\u2009=\u200943) or omnivorous diet (n\u2009=\u200946). The research compared biochemical parameters  and erythrocyte parameters, as well as estimated energy and nutrient intakes, between the two groups. The vegetarian children had a two-fold decrease in serum hepcidin level accompanied by decreased ferritin level and slight but statistically significant increase in concentration of soluble transferrin receptor (sTfR), but no differences in concentration of hemoglobin, mean corpuscular volume, iron, and transferrin compared to the omnivorous group. Moreover, vegetarian children had comparable total iron intake but consumed more (approx. by 30%) ascorbic acid in food [We read with great interest the paper by Ambroszkiewicz et al.  entitled in food . The papOwing to the increasing popularity of vegetarian diets, their clinical consequences are becoming clearer and include such potential health benefits as decreased all-cause mortality and decreased risks of obesity, type 2 diabetes, and coronary heart disease . HoweverMost data on the health effects of vegetarian diets were collected from adults, so the study by Ambroszkiewicz et al. , despiteThe study by Ambroszkiewicz et al.  reportedp\u2009<\u20090.01) and decreased hepcidin level  in lacto-ovo-vegetarian children. Based on these findings, the authors suggest that the vegetarian children may suffer from subclinical iron deficiency. Their view is supported by two references in which similar trends in hepcidin and sTfR levels were found in children diagnosed with iron deficiency [Ambroszkiewicz et al.  noted thficiency , 15. Howficiency . Using tficiency , only foWe would like to suggest that instead of diagnosing a potential disease condition in the lacto-ovo-vegetarian children, the biochemical changes could be considered a form of adaptation wherein a slight increase in sTfR and two-fold decrease in hepcidin as observed by Ambroszkiewicz et al.  are evidFinally, simple measures can be taken to enhance the availability of dietary iron in children or adults who do develop clinical iron deficiency on vegetarian diets. The consumption of diets containing ferritin-rich seeds  provides iron in a more bioavailable form than other vegetables . In someIn summary, there is no evidence that the adaptive changes described by Ambroszkiewicz et al.  in veget"}
+{"text": "Obesity and metabolic syndrome are considered major public health problems, and their negative impact on cardiovascular disease (CVD) and diabetes mellitus type 2 (DM2) is profound. Targeting modifiable risk factors such as dietary habits is therefore of great importance. Many of today\u2019s health challenges with overweight and obesity may have behavioral roots, and traditional methods such as regulations and campaigns are often insufficient to improve dietary choices. Nudging or choice architecture might be a viable tool to influence people\u2019s everyday choices and behaviors to better outcomes. This paper reviews the current state of the rapidly expanding number of experimental field studies that investigate the effects/associations of nudging on healthy food choices. A systematic literature search was conducted in PubMed, where 142 citations were identified. Based on selection criteria, six randomized controlled trials and 15 non-randomized controlled trials were ultimately included. The results of this systematic review show that many of the studies included traffic-light labeling, which may be a promising strategy. The reviewed findings, however, also highlight the challenges that confront experimental studies examining the impact of nudging on diet.  Metabolic syndrome (MetS) affects public health, and has been associated with a doubling of cardiovascular disease (CVD) risk as well as a five-fold increased risk of diabetes mellitus type 2 (DM2) . To be dThroughout the past decades research in behavioral sciences has revealed that human behavior and decision-making is boundedly rational, and as a result, people make suboptimal, often self-destructive decisions . TherefoTo improve health outcomes nudging or choice architecture (a related term)  might beSeveral systematic reviews have suggested that nudging may be effective in increasing the consumption of healthy food and decreasing the consumption of unhealthy food: Broers et al., 2017   choice architecture and food, and (3) nudging and healthy food. In order to identify published studies examining nudging and/or the related term choice architecture , versus According to Hollands et al., 2013 . The lasThe majority of studies regarding nudging and/or choice architecture consist of multiple nudges and/or interventions. This makes it a challenge to map the different nudges and to evaluate their effects. However, Hollands et al., 2013 [nudge and food choice), 79 in the second search (choice architecture and food), and 32 in the third search . After screening 74 studies , 62 full-text articles were retrieved and assessed for eligibility. After removing duplicates and those not making it through quality assessment, 21 studies were included in this review. The included studies comprise of six RCTs and 15 non RCTs. A matrix was designed to get an overview over all the included articles. The articles were structured according to reference, participants/site, and results. The study characteristics are provided in The literature search identified 142 citations, of which 31 were found in the first search . The participants were blinded to group assignment. The intervention group received placemats featuring two healthy \u201cKids\u2019 Meals of the Day\u201d upon the restaurant entry, to nudge children toward healthy options. Forty-eight families had looked at the placemat before ordering . After the families finished dining, researchers recorded children\u2019s orders and collected leftovers for quantifying dietary intake via weighed plate waste. Families who were exposed to the study placemats ordered more healthy food compared to controls. However, there were no significant differences in dietary intake when comparing the intervention versus control groups overall. Nevertheless, children who ordered one of the promoted healthy entr\u00e9es consumed less saturated fat across the total meal compared to those who did not (p = 0.04).Anzman-Frasca et al., 2018  investign = 4) or control (n = 10) for five months. Then, the chef schools were further randomized to chef (n = 2) or chef + smart caf\u00e9 (n = 2), and the control schools were further randomized to smart cafe (n = 4) or control (n = 6). In the smart caf\u00e9, vegetables were offered at the beginning of the lunch line. Fruits were placed in attractive containers, or next to the cash registers. Signage and images promoting fruits and vegetables were prominently displayed. White milk selection was placed in front of sugar-sweetened milk . All the modifications were simultaneously present and applied daily by existing food service staff. School food selection was recorded, and food consumption was measured using plate waste methods. The study revealed no association between the smart caf\u00e9 intervention alone and food consumption. Fruit selection increased in the chef , smart caf\u00e9 , and chef plus smart caf\u00e9  schools compared with the control schools. Vegetable selection increased in the chef , smart caf\u00e9 , and chef plus smart caf\u00e9 schools  compared with the control schools.Cohen et al., 2015  investign = 4), vegetable (n = 3) or control group (n = 3). However, the paper only focuses on the fruit intervention and control groups. The fruit intervention group made changes to the convenience, visibility, and attractiveness of fruit in their lunchrooms for a period of 6 weeks. The control group made no changes. The selection and plate waste data were assessed. Fruit selection increased overall by 36% (p < 0.001), and fruit consumption increased overall by 23% (p < 0.017) in the fruit intervention group, compared to controls.Greene et al., 2017  conducteHollands et al., 2018  examinedp = 0.044) in energy purchased in the day following the introduction of calorie labeling was found in one site. However, the effect diminished over time. No changes in energy purchased were revealed in the remaining five sites.Vasiljevic et al., 2018  investigVelema et al., 2018  examinedCole et al., 2018  investign = 43, 11\u201322 years) with intellectual and developmental disabilities were included. The intervention included: (i) prompting by \u2018celebrity servers\u2019, (ii) the creation of fruit and vegetable-inspired artwork for the dining hall, (iii) classroom-based taste-testing activities, and (iv) logo naming and branding activities. Selection and plate waste of foods at lunch were assessed. Smarter lunchroom increased selection (whole grains) and consumption  of healthy food, and decreased selection and consumption of unhealthy food (refined grains).Hubbard et al., 2015  investigKroese et al., 2016  investign = 4642) of a large hospital in Boston, MA, US, and regular cafeteria patrons. In the first phase, a traffic-light labeling system was introduced to encourage the patrons to purchase healthy items (labeled green) and avoid unhealthy items (labeled red). In the second phase, certain cafeteria items were rearranged, making green-labeled items more accessible and the red-labeled items less accessible. The main outcome measures were proportion of green or red labeled items purchased. Labeling decreased the red item purchases and increased green purchases. The intervention effects were similar across all race/ethnicity and job types.In a 9 months longitudinal study, Levy et al., 2012  investign = 96, BMI = 29.7 \u00b1 6.0 kg/m2) who regularly ate lunch at their workplace cafeteria, were randomly assigned into one of two intervention groups: (1) Environmental change (low-energy-dens foods and food content labeling) or (2) Environmental change, education and pricing incentives. Food intake and energy intake was assessed with scan card technology coupled with computerized cafeteria cash registers. No difference in total energy intake were revealed between the groups over the study period. However, significant changes in energy intake were observed across the groups from baseline to the intervention period, with an increase in the percentage of energy from carbohydrates and a decrease of energy from fat. Lowe et al., 2010  investigNikolaou et al., 2014  investigp < 0.01).Olstad et al., 2014  investigSeward et al., 2016  investigThorndike et al., 2014  investigThorndike et al., 2012  investign = 291) examined the strength of combinations of toppings and bread type, and the main study consisting of a two (bread type) by two (topping type) between-subjects design. The included participants (n = 226) were given a free sandwich at a university stand with an unhealthy deep-fried snack (croquette) or a healthy topping. About half of the participants were offered a whole wheat bun unless they asked for white bun, and the other half were offered a white bun unless they asked for a whole wheat bun. Regardless of the topping, the whole wheat bun was the default option in 94% of the participants. When the default of bread offered was white, 80% of the participants chose the default option. The study revealed a strong default effect of bread type.Van Kleef et al., 2018  investigVan Kleef et al., 2015  investign = 1113) responded to a survey including questions about the breakfast. Results showed that consumption of fun-shaped whole wheat bread rolls almost doubled consumption of whole wheat bread (p = 0.001). However, consumption of white bread rolls did not differ according to shape.Van Kleef et al., 2014  investigVan Kleef et al., 2012  investign = 24, 86%) of french fries consumers noticed the reduction in portion size during the intervention.Vermote et al., 2018  investigAl-Khudairy et al., 2019  have modNudging or choice architecture interventions aim to improve dietary choices, but empirical evidence to support the effectiveness has been scarce. An important criterion for an intervention to qualify as a nudge is that the targeted audience/participants/customers retain their freedom to make a choice . In thisLabeling is the most frequent used nudge in this review and nineteen of the studies include labeling. Previous studies have shown mixed results and labeling has been debated . DespiteAvailability refers to how accessible an object or stimuli are, and rearranging the positions of food is a common nudge, for instance, in food stores. Seven studies used an availability nudge. Placing healthy food near the cash register increase the sale of these food because people are prone to pick up something in the \u201clast-minute\u201d as done in the study by Van Kleef et al., 2012 . HoweverPriming is, according to Marteau et al. (2012) , a promiThe results of this systematic review show that the majority of the studies include traffic-light labeling, and that may be a promising strategy. The results suggest that the majority of the interventions were effective. Thirteen studies measured effects on purchasing healthier food, and nine of them, plus one site in the study of Vasiljevic et al., 2018 , showed In most of the field experiments, the participants were not aware that they were part of an experiment. This limited social influence regarding desirable behavior and observer reactivity . The fieDespite the tremendous interest and studies on nudging and choice architecture regarding public health, it is still a relatively new and under-explored field. Many of the studies reviewed during this systematic review lacked definitional and conceptual clarity that might lead to poor methodology and unclear effects. A benefit of nudging is that it does not requires any additional actions for the individual or the targeted audience. Furthermore, the interventions are usually no cost or low cost, and that makes it easier to implement. Another important issue is that our environment, whether we like it or not, influences our behavior. Then it makes sense to alter the environment in a way that we make better choices that will be beneficial in the long run . Many ofThis systematic review was executed independently by both authors to minimize errors and bias. When there was discrepancy regarding a study, the study was thoroughly discussed based on the inclusion criteria and the quality check list. We prepared a checklist for measuring study quality based on the Downs and Black validated checklist from 1998 , but resNudging and/or choice architecture alone will not solve the worldwide health challenges caused by poor health choices. Although behavioral economics can provide great benefits if appropriately used, it is still necessary with an underlying political fundament . In otheMoving forward, nudging and choice architecture would benefit from a better conceptual clarity and a more systematic approach. There are no \u201cquick fix\u201d or \u201cmagic bullets\u201d when it comes to changing people\u2019s behavior. Additionally, even though it might be challenging, nudging interventions should be compared to more traditional interventions such as information campaigns and educational strategies. Future research should have longer study durations such as Thorndike et al., 2014 , and incThe results of this systematic review show that the effect sizes are very diverse and also low. Many of the studies included traffic-light labeling that might be a promising strategy. Moreover, this study also highlights the challenges that must be addressed when experimental studies concerning nudging are conducted. According to Marteau et al. (2012) , we live"}
+{"text": "From their discovery in biological systems, reactive oxygen species (ROS) have been considered key players in tissue injury for their capacity to oxidize biological macromolecules. Aerobic organisms possess a system of biochemical defenses to neutralize the oxidative effects of ROS, but the balance between ROS generation and the antioxidant system is slightly in favor of the ROS so that a continuous low level of oxidative damage exists . When thThe papers reported in this Special Issue deal with different aspects of reactive oxygen species (ROS) actions in living organisms. Some papers consider the role of ROS in inducing cellular dysfunction.2O2 to obtain a cell model of oxidative stress to study the role of sphingomyelin synthase 2 (SMS2) in endothelial disease (ED). They found that SMS2 induces the stress of the endoplasmic reticulum (ER) that leads to ED both activating the Wnt/\u03b2-catenin pathway and promoting intracellular cholesterol accumulation, both of which contribute to the induction of ER stress and finally lead to ED.Thus, Hua et al.  treated 2O2 or doxorubicin to verify if trimethylamine N-oxide (TMAO), an organic compound derived from dietary choline and L-carnitine, is a factor involved in the progression of atherosclerosis and other cardiovascular diseases. They show that TMAO does not affect the treatment\u2019s effect on cell viability, sarcomere length, intracellular ROS, and mitochondrial membrane potential. Therefore, they conclude that TMAO cannot be considered a direct cause or an exacerbating risk factor of cardiac damage at the cellular level in acute conditions.Querio et al.  used aduAnother work evaluates the role of ROS as agents able to induce cellular protection. Lin et al.  demonstrROS can also be involved in the therapeutic action of some antitumoral drugs. Soltan et al.  evaluate2O2). Artemisinin prevents cell death at clinically relevant doses in a concentration-dependent manner. Artemisinin restored the nuclear morphology, prevented the increased intracellular ROS, and attenuated apoptosis. These data suggested that artemisinin protected neuronal cells. Similar results were obtained in primary cultured hippocampal neurons. Cumulatively, these results indicated that artemisinin protected neuronal cells from oxidative damage, at least in part through the activation of AMPK. These findings support the role of artemisinin as a potential therapeutic agent for neurodegenerative diseases.The antioxidant capacity to protect against oxidative stress-linked disease has been evaluated by Zhao et al. , who stuMoreover, some reviews are presented in this Special Issue. L\u00e9vy et al.  reviewedDamiano et al.  examinedXiao and Meierhofer  reviewedSiauciunaite et al.  summarizThe review of Di Meo et al.  analyzedIsmail et al.  collecteIt is our opinion that the articles included in this Special Issue, despite dealing with such different topics, represent an important contribution to the knowledge of the physiological and pathological role of ROS, and give some information on the benefits and limitations of antioxidant treatment."}
+{"text": "Growing evidence suggests that the mechanical interaction between the cells and their microenvironment is of critical importance to their behaviors under both normal and diseased conditions, such as migration, differentiation, and proliferation. The study of tissue mechanics in the past two decades, including the assessment of both mechanical properties and mechanical stresses of the extracellular microenvironment, has greatly enriched our knowledge about how cells interact with their mechanical environment. Tissue mechanical properties are often heterogeneous and sometimes anisotropic, which makes them difficult to obtain from macroscale bulk measurements. Mechanical stresses were first measured for cells cultured on two-dimensional (2D) surfaces with well-defined mechanical properties. While 2D measurements are relatively straightforward and efficient, and they have provided us with valuable knowledge on cell-ECM interactions, that knowledge may not be directly applicable to in vivo systems. Hence, the measurement of tissue stresses in a more physiologically relevant three-dimensional (3D) environment is required. In this mini review, we will summarize and discuss recent developments in using optical, magnetic, genetic, and mechanical approaches to interrogate 3D tissue stresses and mechanical properties at the microscale.Cells  Tissues are composed of a large collection of ECM macromolecules (Frantz et al., Tissues and native ECMs are heterogeneous, anisotropic (Jones et al., The microscale tissue or cellular mechanical properties and constitutive relationships can be probed by active microrheology (Wilson and Poon, ex-vivo tissues (Iwashita et al., By laser tracking the deflection of the probing cantilever tip during indentation and retraction , AFM indin vitro and in vivo.Optical tweezer has been used to probe the viscoelasticity of living cells and tissues (Staunton et al., Micro-injected cell-sized ferrofluid microdroplets  can be uECM or tissue deformations provide useful information on the stress states of cells and tissues (Nam and Chaudhuri, TFM is one of the most widely adopted approaches using matrix deformations to compute cell generated traction forces (Dembo and Wang, In principal, TFM can be adapted to 3D (Hall et al., 3D TFM relies mostly on randomly distributed fluorescent beads to compute matrix deformations, which is generally infeasible for tissue deformations. This obstacle can be overcome by monitoring tissue deformations directly after releasing the stored solid stresses (Stylianopoulos et al., in vitro or in vivo (Camp\u00e0s et al., To overcome the complexities associated with the development of 3D TFM, the dependence of the stress calculation on the local tissue mechanical properties must be eliminated. Hence, several recent studies introduced microbead/droplet-based stress sensors of well-controlled mechanical properties to 3D systems. These types of stress sensors can be introduced to virtually any system, in vitro cell aggregates or living embryonic tissues (Camp\u00e0s et al., Cell-sized fluorescent oil microdroplets, with defined mechanical properties and coated with adhesion ligands, can be introduced to in vivo (Mohagheghian et al., In addition to the wide application as a compliant substrate in 2D TFM, elastic polyacrylamide hydrogels have also been used to quantify 3D stresses by creating microbeads that are embedded into tissues to act as cell-like pressure sensors (Dolega et al., Unlike the incompressible microdroplet method which measures anisotropic stresses, the elastic microbead method measures the isotropic stresses using volume strain. With more information about bead deformations, either through surface tracking (Lee et al., Stress sensors can also be engineered to be of the molecular size to detect sub-cellular forces with piconewton sensitivity. Unlike the cell-sized sensor described above, the force-induced displacement in the molecular sensor is readily converted to a shift in emitted fluorescence, such as that observed in FRET . Howeverin vivo applications (Cai et al., Cells can be engineered to directly express FRET-based sensors (Cost et al., Molecular tension sensors can also be functionalized to the substrate to detect cell-matrix forces (Liu et al., Tensions within the plasma membrane can be measured by the tether-pulling method, where controlled forces are applied through functionalized AFM cantilevers or optical/magnetic tweezer beads that are tethered to the membrane (Lieber et al., Unlike the stress probing methods discussed earlier, which are based on either the stress-strain constitutive relationship or the displacement-fluorescence relationship, the last collection of approaches discussed here do not rely directly on strain/displacement information.Fluctuation of a freely diffusing Brownian particle has long been used in passive rheology to measure the particle diffusion coefficient and fluid viscosity (Wilson and Poon, in vitro to in vivo (Scarcelli et al., Mechanical properties and states can also directly affect a material's optical properties, which can therefore be used to probe tissue mechanics. One of such approaches with increasing application in mapping tissue mechanical properties is Brillouin light scattering microscopy based on acousto-optic interaction (Scarcelli et al., With the growing interest in exploring the roles of tissue mechanics in physiology and pathology, there are significant recent advancements in developing tools that can map 3D tissue mechanical properties and stresses at the microscale. Future work may be directed at increasing the throughput and/or accuracy of the 3D mapping of tissue mechanics using existing methods such as active microrheology and stress sensors. Opto-mechanical approaches will provide new insights into tissue mechanics due to their non-invasive, label-free and high-throughput nature. Furthermore, simultaneous mapping of local mechanical properties and measurement of 3D deformations will enable accurate 3D TFM. With our developing knowledge of cellular mechanotransduction, it will be possible to utilize and/or engineer some of the cell's intrinsic behaviors as a type of new mechanical probe, as evidenced by the fluctuation-based approaches. However, caution should also be paid to the discrepancies when interrogating tissue mechanics using different approaches (Wu et al., JZ contributed to the conception of the work and wrote the article. NC wrote the article. CR-K supervised the work and wrote the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the original article, there was an error. We mistakenly stated that 5-MeO-DMT is part of the ayashuasca brew.Introduction, paragraph one:A correction has been made to the 2A >5-HT2C >5-HT1A receptors (Szabo et al., Ayahuasca, a millenarian decoction used as a sacrament by south American indigenous tribes, known to induce powerful hallucinogenic states when administered with monoamine oxidase inhibitors (MAOI; Ara\u00fajo et al., Ayahuasca is used by many syncretic churches ritualistically, as a way to heal many physical and mental illnesses with or without scientific knowledge about the effects (Frecska et al., Ayahuasca can potentially treat recurrent depression (Os\u00f3rio Fde et al., \u201cPsychoactive tryptamines are a class of molecules that act as a neurotransmitter in the vertebrate brain (Jacob and Presti, Discussion, paragraph three:Additionally, a correction has been made to the Ayahuasca acute administration to depression diagnosed patients (dos Santos et al., Ayahuasca tea, are composed of several psychoactive substances including DMT analogs and MAOi (Frecska et al., Ayahuasca tea the DMT is administrated with MAOi, in order to avoid tryptamines degradation. Using oral or intraperitoneal administration without MAOi may reduce the availability of 5-MeO-DMT to the central nervous system, since the monoamine oxidase will readily destroy any tryptamine, in the bloodstream, guts and also in the brain (Halberstadt et al., per se can increase neurogenesis, at least in vitro cultured hippocampal cells (Morales-Garc\u00eda et al., \u201cThe choice of a single dose treatment, was made to address the gap between the molecular mechanisms, subjective and hormonal effects underlying The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Dear Mr Editor,Herpesviridae reactivation in patients under veno-venous extracorporeal membrane oxygenation (VV ECMO) for severe acute respiratory distress syndrome (ARDS) and raised some important questions. Data available do not allow to conclude once for all, however, we might provide some pieces of answers.Huang et al. recently commented on our publication concerning Herpesviridae reactivation is so common in ARDS patients under ECMO who often combine sepsis and prolonged mechanical ventilation (MV). It would be of high interest to perform a matched controlled study in order to determine if ECMO occurring during ARDS enhances the frequency of Herpesviridae reactivation.First, the \u201cwho?\u201d. In a general population of ARDS patients (without ECMO), Ong et al.  showed tHerpesviridae reactivation or active infection in ICU patients is rather touchy. The positivity of biological samples signs the evidence of viral transition from latency to replication, but end-organ disease symptoms  can be difficult to identify in such complex patients. One key question would be the comparison of performance diagnosis of blood and airway CMV PCR with antigenemia, which is considered as the reference test in end-organ disease diagnosis. Concerning the timing of HSV and CMV reactivation, Heininger et al. [Second, the \u201chow?\u201d. The precise definition of r et al. , compariHerpesviridae reactivation during ARDS [Herpesviridae reactivation with specific markers such as monocytes HLA-DR expression [Finally, the \u201cwhy?\u201d. Several hypotheses have been stated to explain the poor outcomes of patients exhibiting ing ARDS . Viral ppression .Herpesviridae in ARDS patients, and even more in those under ECMO.To summarize, despite several decades of research, much remains to be done to lighten the role of"}
+{"text": "Camellia senenisis plant, is the second most consumed beverage worldwide after water, and is consumed by more than two-thirds of the world population  inhibits neuroblastoma cell growth and neurosphere formation in vitro ; the autZhao et al., reported that Fuzhuan brick-tea protects against UVB irradiation-induced photo-aging via MAPKs/Nrf2-mediated down-regulation of MMP-1, and suggested that this tea could be used as not only a functional food but also a good candidate in the development of cosmetic products and medicines for the remedy of UVB-induced skin photo-aging .Annunziata et al., evaluated colon bioaccessibility and antioxidant activity of tea polyphenolic extract by using an in vitro simulated gastrointestinal digestion assay . They foPan et al., report that polyphenols in Liubao tea prevent carbon tetrachloride-induced hepatic damage in mice through their antioxidant function . MoleculShen et al., examined the association between tea consumption and risk of hospitalized fracture in 453,625 Chinese adults. Their study concluded that habitual tea consumption was associated with moderately decreased risk of any fracture hospitalizations, and the participants with decades of tea consumption and those who preferred green tea were also associated with lower risk of hip fracture .Unno et al., determined the stress-reducing function of matcha green tea  in both animal experiments and clinical trials . They foRode et al., determined, in a cross-sectional observational study among a population of 273 hypercalciuric stone-formers, whether daily green tea drinkers experienced increased stone risk factors  compared to non-drinkers, and found no evidence for increased stone risk factors or oxalate-dependent stones in daily green tea drinkers .Furthermore, Khan and Mukhtar extensively reviewed the health-promoting effects of tea polyphenols , by summIlex, including the large-leaved Kudingcha (Ilex latifolia Thunb and Ilex kudingcha C.J. Tseng), Yerba Mate (Ilex paraguariensis A. St.-Hil), Yaupon Holly (Ilex vomitoria), and Guayusa (Ilex guayusa Loes), and suggested their potential applications in the pharmaceutical or nutraceutical industries [In another review article, Gan et al., summarized the distribution, composition, and health benefits of several caffeinated beverages from the genus dustries .Tea consumption is also considered a natural complementary therapy for neurodegenerative diseases such as Alzheimer\u2019s disease that affects an increasing patient population among the elderly. Polito et al., reviewed epidemiological studies on the association between tea consumption and the reduced risk of Alzheimer\u2019s disease, along with the anti-amyloid effects and the role of tea in preventing this neurodegenerative disease .While beneficial effects by tea consumption have been documented in various human disease models as mentioned above, there are major challenges in developing some tea components (such as green tea polyphenols) as therapeutic agents, including how to improve their bioavailabilities, stability, efficacies, and specificity . FurtherI would like to thank all the authors for their exceptional contributions."}
+{"text": "Decades ago, Oriental Medicine doctors could use just traditional tools including acupuncture, moxibustion, and herbal medicine despite its long history. However, technology improves and modern medical devices are invented to assist the Oriental Medicine doctors in performing diagnosis and treatment. Now, they can use exclusive medical devices such as pulse meter, tongue diagnosis, and face system with their own sensors and diagnostic skills to get information of body and disease from patients. They also can use modern therapeutic tools including electroacupuncture, pharmacopuncture, and electric-moxibustion as well as traditional ones. Experimental and translational studies on these new tools are underway.For this special issue, we invited manuscripts with the following topics: improvement of tools in oriental medicine, pharmacopuncture (Chinese medicine injection), electroacupuncture and electric-moxibustion, validation of treatment efficacy, development of pulse meter and tongue diagnosis system, and experimental and translational studies on modern device of Oriental Traditional Medicine. We received 105 manuscripts from various labs for six months and 22 manuscripts were accepted for publication. Here we highlight some of the key ongoing challenges published in this special issue.The efficacy of medical devices using radiofrequency is demonstrated in the papers \u201cMoxibustion-Simulating Bipolar Radiofrequency Suppresses Weight Gain and Induces Adipose Tissue Browning via Activation of UCP1 and FGF21 in a Mouse Model of Diet-Induced Obesity\u201d and \u201cShort-Term Efficacy of Pulsed Radiofrequency Thermal Stimulation on Acupoints for Chronic Low Back Pain: A Preliminary Study of a Randomized, Single-Blinded, Placebo-Controlled Trial\u201d.Granule, one of modern forms of herbal medicine, is used in the studies \u201cStudy of the Treatment Effects of Compound Tufuling Granules in Hyperuricemic Rats Using Serum Metabolomics\u201d and \u201cRandomized, Double-Blind, Placebo-Controlled Study of Modified Erzhi Granules in the Treatment of Menopause-Related Vulvovaginal Atrophy\u201d.The article \u201cCinobufacini Injection Improves the Efficacy of Chemotherapy on Advanced Stage Gastric Cancer: A Systemic Review and Meta-Analysis\u201d reviews the literature on the efficacy comparison between Cinobufacini injection (one of Chinese medicine injections) combined with chemotherapy and chemotherapy solely used in advanced gastric cancer treatment.The protective effect of patches on acupoints against electromagnetic fields is shown in \u201cEvaluation of the Effectiveness of Protective Patches on Acupoints to Preserve the Bioenergetic Status against Magnetic Fields\u201d.The clinical application of the low voltage Meridian Energy Detection System is evaluated in assessing the electrodermal activity in the \u201cThe Development and Application Evaluation of Meridian Energy Detection System in Traditional Oriental Medicine: A Preliminary Study\u201d and the safety of auto manipulation device for acupuncture which can help Oriental Medicine doctors is shown in the \u201cSafety Assessment of the Auto Manipulation Device for Acupuncture in Sprague-Dawley Rats: Preclinical Evaluation of the Prototype\u201d.Different face diagnosis system is used in \u201cAn Herbal Medicine, Yukgunja-Tang is more Effective in a Type of Functional Dyspepsia Categorized by Facial Shape Diagnosis: A Placebo-Controlled, Double-Blind, Randomized Trial\u201d and \u201cDifference between Right and Left Facial Surface Electromyography in Healthy People\u201d.In this special issue, there are more valuable manuscripts besides above. We hope the readers will be interested in improvement of diagnostic and remedial tools of Oriental Medicine."}
+{"text": "Vibrio cholerae and downregulate the expression of virulence genes\u2019 by Nicolas Perez-Soto et al., Chem. Sci., 2017, 8, 5291\u20135298.Correction for \u2018Engineering microbial physiology with synthetic polymers: cationic polymers induce biofilm formation in  Vibrio cholerae strain used in this work is A1552The The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "There is a significant gap in our understanding of the molecular and cellular biology of cerebrovascular and neurodegenerative diseases to identify new therapeutic targets and develop diagnostic tools to better understand the disease progression and treatment. The cellular and molecular events linking cerebrovascular pathology and neurodegeneration are also not fully understood. The research articles and review papers published in this topic aim at a multifaceted approach to evaluating recent progress in our understanding some of the underlying molecular mechanisms of disease process and potential therapeutics targeting these diseases. Here we summarize the contributing articles to our topic conveying the aim of the pertaining research. The articles in this Research Topic highlight the challenges inspiring future research to address some of the questions and to exploit new opportunities for development of novel therapeutics for cerebrovascular and neurodegenerative diseases.Smith-Dijak et al. studied the effects of pridopidine, a drug that enhances brain derived neurotrophic factor (BDNF) signaling through stimulation of the sigma-1 receptor (S1R) and S1R agonist, in cortical neurons obtained from a mouse model of Huntington disease (HD). Several pathways implicated in synaptic functions are dysregulated in HD, including BDNF and calcium signaling. The data provide evidence for restoration of synaptic plasticity that maintain the stability of neuronal and synaptic function required for new learning and cognitive function. The results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD and may provide new avenues for neuroinflammation-related disorders treatment.Agouni et al. provided a comprehensive analysis of circulating extracellular vesicles (EVs) from vascular wall, blood, and immune cells in transient ischemic attacks (TIA) and acute ischemic stroke (AIS) patients from Southeast Asia and the Middle East. This study showed that EVs of various origins, especially those associated with endothelial cell injury and platelet activation, are increased in TIA and AIS patients. The levels of EV continue to be high for up to 30-days post-attacks indicating a sustained cellular activation, which may be associated with an increased risk of recurrence of acute events in this population.D'Angelo et al. carried out a review on antiphospholipid syndrome (APS) and multiple sclerosis (MS). APS and MS are both considered as anti-lipid autoimmune diseases with specific pathophysiological mechanisms and events. Isolated neurological APS represents a significant diagnostic challenge, as epidemiological, clinical, and neuroimaging features may overlap with those of MS. The review draws attention to the clinical relevance of diagnosing isolated neurological APS and suggests that prompt and accurate diagnosis and treatment of APS with anti-aggregant and anticoagulant could be vital to prevent or reduce APS-related morbidity and mortality.Wei et al. examined the cellular mechanisms mediating the neuroprotective effects of Homer1a, a short form of a scaffold protein, which is upregulated in rat cortical neurones following oxygen and glucose deprivation (OGD) mimicking ischemia-reperfusion (I/R) injury. The results showed that overexpression of Homer1a reduced OGD-induced lactate dehydrogenase (LDH) release, cell death, and mitochondrial dysfunctions in cultured cortical neurons. Homer1a also protects against OGD-induced injury by preserving mitochondrial function through inhibiting the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator tunicamycin (TM) suggesting that Homer1a may be a promising target of protecting neurons from cerebral injury.Yang et al. examined the effect of cyclooxygenase (COX2)/prostaglandin D2 (PGD2)-related autophagy on brain injury in diabetic rats suggesting that the COX2-PGD2 pathway is a potential therapeutic target for diabetic brain injury.Xu et al., reported that low-moderate ethanol consumption may prevent ischemic stroke and reduce brain cerebral ischemia/reperfusion injury (I/R) by suppressing inflammation, whereas heavy alcohol consumption may induce ischemic stroke and worsen brain I/R injury by aggravating inflammation.He et al. found that smilagenin, a steroidal sapogenin from traditional Chinese medicinal herbs, can have neuroprotective effect on dopaminergic neurons in a chronic mouse model of Parkinson's disease (PD) suggesting that this drug could prevent the impairment of dopaminergic neurons in PD.Zhang et al. demonstrated that Naringenin (NAR), a grapefruit flavonoid promoted microglia M1/M2 polarization, thus conferring anti-neuroinflammatory effects via the inhibition of mitogen-activated protein kinase (MAPK) signaling activation. These findings provide new alternative avenues for neuroinflammation-related disorders treatment.Hao et al. showed that heterozygous loss of activin receptor-like kinase 1 (Alk1) can lead to hereditary hemorrhagic telangiectasia, which is a vascular disease characterized by direct connections between arteries and veins leading to arteriovenous malformations (AVMs). The results of the study suggest that Alk1 induces the formation of sporadic human cerebral AVMs through affecting migration and proliferation of endothelial cells combined with vascular endothelial growth factor A.Li et al. developed a flow cytometry protocol to identify microglia and monocyte-derived macrophages from mouse intracerebral hemorrhagic (ICH) stroke model induced by collagenase or blood injection. The authors also combined magnetic-activated cell separation system that allows eight tissue samples to be assessed together. This protocol represents a very important tool for biological functions of microglial and monocyte-derived macrophage in ICH stroke and related brain diseases.Jin et al., showed that glucose-regulated protein (GRP78) a chaperone protein located in the endoplasmic reticulum (ER) is involved in the neuroglial response to neurotoxic insult in rats induced by mitochondrial toxin 3-nitropropionic acid (3-NP), which selectively damages striatal neurons. These data provide novel insights into the phenotypic and functional heterogeneity of GRP78-positive cells within the lesion core and the involvement of GRP78 in the activation/recruitment of activated microglia/macrophages and blood-brain-barrier impairment in response neurotoxic insult.Song et al. reported that the knock down of myosin light chain kinase, a key enzyme in smooth muscle cell contraction, in human brain smooth muscle cells (SMCs) caused effects similar to those observed in cultured SMCs from intracranial aneurysm patients. These results indicate that myosin light chain kinase plays an important role in maintaining smooth muscle contractility, cell survival and inflammation tolerance and is crucial to the normal function of intracranial arteries.Hoyk et al. showed elevated serum triglyceride levels, changes in functional and morphological gene expressions and blood brain barrier dysfunction in transgenic mice overexpressing the human APOB-100 protein, a mouse model of human atherosclerosis suggesting that these transgenic mice could be a useful model to study the link between cerebrovascular pathology and neurodegeneration.Yu et al. reported that injection of hydroxysafflor yellow A (HSYA), a major active chemical component of the safflower via carotid artery improves cognitive impairment and synaptic plasticity in a rat model of stroke induced by middle cerebral artery occlusion.Chen et al. showed that Gap19, a selective Connexin 43 (Cx43) -hemi -channel inhibitor, produces neuroprotective effects in cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion in mice via suppression of Cx43 and Toll-like receptor 4 (TLR4) mediated signaling pathways.Chang et al. developed a new in vitro cerebral micro-bleed model to study the interactions between brain endothelial cells and red blood cells exposed to oxidative stress. Their findings demonstrate that erythrophagocytosis mediated by the brain endothelial monolayer and the passage of iron-rich hemoglobin and RBC, may be involved in the development of cerebral microbleeds that are not dependent on disruption of the microvasculature.Faustino-Mendes et al. reviewed the current experimental models of immature ischemic brain and highlighted the need for new multifactorial experimental models to attain more efficient therapies to treat this complex vascular condition and related long-term conditions.Chen et al. showed that the compound 22a, a promising neuroprotective compound derived from tetramethylpyrazine and widely used as active ingredient of traditional Chinese medicine, effectively prevented glutamate-induced excitotoxicity in cerebellar granule cells (CGNs) via involvement of the PI3K/Akt and PGC1\u03b1/Nrf2 pathways suggesting that this compound might be useful in preventing neuronal death from ischemic stroke.Du et al. tested a hypothesis that chemokine interleukin (IL) eight released by astrocytes and C-X-C motif chemokine receptor 1 (CXCR1) in neurons are involved in neuronal apoptosis induced by methamphetamine (METH), a widely abused illicit drug, which can cause dopaminergic neuron apoptosis and astrocyte-related neuroinflammation. The results suggest that CXCR1 may be a potential target for METH-induced neurotoxicity therapy.Lu et al., aimed to explore the protective effects of rosuvastatin, a 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, against haemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rt-PA) treatment in a mouse model of experimental stroke. The beneficial effects are related to inhibition of the inflammation-related nuclear factor kappa B (NF-\u03baB) and mitogen-activated protein kinase (MAPK) pathways.Wang et al. showed that mild ER stress (\u201cpreconditioning\u201d) induced by tunicamycin (TM), can alleviate LPS-induced astrocytic activation and BBB disruption. Their findings provide a better understanding for the regulatory role of ER stress in neuroinflammation and indicate that mild ER stress might have therapeutic value for the treatment of neurodegenerative diseases.Yang et al., found that adapentpronitrile, a new adamantane-based dipeptidyl peptidase-IV (DPP-IV) inhibitor significantly ameliorated neuronal injury and decreased amyloid precursor protein (APP) and amyloid beta (A\u03b2) expression in the hippocampus and cortex of rat model of diabetes fed with high fat diet. These authors showed that adapentpronitrile protected against diabetic neuronal injury by inhibiting mitochondrial oxidative stress and the apoptotic pathway.Jang et al. reported intrastriatal injection of adeno-associated viral vector serotype DJ containing N171-82Q mutant huntingtin (HTT) gene to juvenile mice produced Huntington's disease (HD)-like symptoms including mutant HTT aggregation, neurodegeneration, and Neuroinflammation. The authors suggested that this model will a useful tool to better understand neuropathological mechanisms of HD and develop new therapeutics for this disease.Hao et al. established a stable method for the isolation of endothelial cells (ECs) from human cerebral arteriovenous malformation tissues, which play an important role in the manifestation and development of cerebral vascular malformation as well as haemorrhagic stroke and thrombogenesis. The protocol can also be adapted for other vascular diseases.He et al. demonstrated that rosuvastatin treatment significantly increased neurite outgrowth in cortical neurons after oxygen-glucose deprivation (OGD)-induced damage, reduced the generation of reactive oxygen species, protected mitochondrial function and elevated the ATP levels via Notch1 pathway. These findings highlight Notch1 signaling as important player and novel therapeutic target in promoting brain plasticity.In summary, the present Research Topic encompassed several cutting-edge techniques and models for investigating the cellular and molecular mechanisms of cerebrovascular dysfunction and neurodegeneration. Together, they provide a framework for understanding the way some of the diseases progress and potential pathways for therapeutic interventions. We acknowledged that collection of articles in a single topic cannot deal with this extremely vast subject characterized by complex conditions such as cerebrovascular dysfunction and neurodegeneration. The topics addressed, however, help developing clear ideas, not only in terms of recent studies but also the unmet needs for future research in these areas. We trust that the papers assembled in this Research Topic will prove useful in encouraging and stimulating future progress in research related to cerebrovascular and neurodegenerative diseases.SS prepared the editorial and both SK and SS edited the final version. SS and SK made substantial contributions to the review and approved the manuscripts accepted on this topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Progression from latency to active Tuberculosis (TB) disease is mediated by incompletely understood host immune factors. The definitive characteristic of progressive human immunodeficiency virus (HIV) disease is a severe loss in number and function of T lymphocytes. Among the many possible mediators of T lymphocyte loss and ineffective function is the activity of the immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO is the rate-limiting enzyme converting tryptophan to kynurenine. IDO activity was initially recognized to mediate tolerance at the foeto-maternal interface. Recently, IDO activity has also been noted to play a critical role in immune tolerance to pathogens. Studies of host immune and metabolic mediators have found IDO activity significantly elevated in HIV and TB disease. In this review, we explore the link between IDO-mediated tryptophan catabolism and the presence of active TB disease in HIV-infected patients. We draw attention to increased IDO activity as a key factor marking the progression from latent to active TB disease in HIV-infected patients. Recently, the effect of indoleamine 2,3-dioxygenase-1 (IDO) activity in various diseases, including tuberculosis (TB) and human immunodeficiency virus (HIV) disease has generated considerable interest. Tryptophan, an essential amino acid in the body, can either be converted to serotonin or oxidized to kynurenines. IDO is the rate-limiting enzyme in the conversion of tryptophan to kynurenines (Higuchi and Hayaishi, Essential micronutrients are those which cannot be produced endogenously and must be acquired through dietary sources. Humans, like other mammals, cannot synthesize tryptophan, and therefore, must obtain it from their diet and internal protein turn-over Brown, . Foods sIDO1 and IDO2 (Yamazaki et al., de novo pathway for NAD+ synthesis when niacin intake is limited in the diet (Higuchi and Hayaishi, In certain cell types, tryptophan can be converted to serotonin or melatonin by tryptophan hydroxylase (Ruddick et al., Munn and colleagues observed IDO expression and activity at the foeto-maternal interface in pregnant mice (Munn et al., Tryptophan depletion and subsequent generation of kynurenine metabolites have considerable effects on the host's immunity. The IDO pathway plays a significant role in T cell hypofunctionality, a critical concept in immune tolerance to pathogens (Mellor et al., Immune cells, in particular macrophages and dendritic cells, are sites of IDO production. IDO expression and activation creates a local immunosuppressive micro-environment, which allows pathogens to escape sterilizing immunity or containment (Nagamatsu and Schust, Downstream metabolites of the IDO pathway such as quinolinic acid, are neurotoxic and have been implicated in HIV-associated dementia (Gostner et al., in vitro (Byrne et al., in vitro studies have reported that measles, influenza, cytomegalovirus, and herpes simplex viral infections are also susceptible to tryptophan depletion (Obojes et al., Amino acids are critical micronutrients for all pathogens. Microbes either synthesize amino acids or depend on their hosts for amino acids for growing and multiplying. The ability of the host to deprive pathogens of essential micronutrients is a crucial feature of innate defense. Tryptophan, just like carbon, iron, and nitrogen are critical for microbial survival (Rohmer et al., In animal models, increased tryptophan metabolism via the IDO pathway has been associated with poor immune responses to M. TB (O'Connor et al., When co-infecting a host, HIV and M. TB influence each other, accelerating deterioration of immune function. HIV infection causes severe loss of T cells, both in number and function (Douek et al., Werner et al.  reportedin vitro (Blumenthal et al., in vivo (Gautam et al., Despite extensive work in murine and macaque models of TB, only a few studies have investigated IDO-mediated tryptophan catabolism and its metabolites in human TB . M. TB hIDO can be studied quantitatively by measuring mRNA expression or protein levels or enzymatic activity (product-to-substrate ratio; Li et al., A biomarker is defined as any characteristic that can be objectively measured as an indicator of health or disease process or as a response to a therapeutic intervention (Group et al., ex vivo M. TB challenge in cells or tissue from active or latently infected patients to understand TB pathology. Some studies have examined metabolic profiles or genes from active TB patients to identify metabolites or genes that are switched on or off, which may be implicated in the transition from latency to active disease in both HIV-infected and uninfected individuals (Weiner 3rd et al., in vitro (Zhang et al., Most TB studies have relied on animal models or It remains to be determined whether elevated IDO activity is causative of, or only associated with, progressive HIV and TB disease. Some researchers postulate that human co-existence with latent TB infection may be a human evolutionary adaptation to increase host tryptophan in times of low dietary tryptophan availability (Williams and Dunbar, Chlamydia trachomatis, an intra-macrophage pathogen, which can synthesize tryptophan, blocking IDO activity with levo-1-methyl-tryptophan led to improved susceptibility to doxycycline (Ibana et al., in vivo that M. TB induces IDO expression in the lungs of macaques and mice with active TB disease. In the macaque, inhibition of IDO activity led to a reduced M. TB burden, pathology and improved animal survival (Gautam et al., Currently, several clinical trials are exploring blocking IDO activity for therapeutic use. During infection with In summary, IDO-mediated tryptophan catabolism via the kynurenine-nicotinamide pathway represents a common axis upregulated in HIV infection and TB disease. Rather than being uniquely elevated in TB, cumulative elevation of IDO in HIV and TB may explain the extraordinarily high rate of progression to active TB in HIV-infected patients. It is unclear whether elevated IDO is causative of progression to active disease or a compensatory response to the microbe. There is much promise in using metabolites from the IDO-mediated tryptophan pathway to diagnose active TB and monitor anti-TB treatment. IDO holds promise as a TB biomarker in both HIV-positive and negative patients, but further confirmatory studies are urgently needed. Regarding new TB drug targets, it remains speculative whether IDO inhibition would be beneficial. Further exploration of this pathway is necessary to better understand TB pathogenesis and discover novel host biomarkers and potential drug targets for either TB or HIV disease.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Escherichia coli populations. Toxin\u2013antitoxin systems hold a crucial but still elusive part in bacterial response to stress. This perspective highlights how these modules can also serve as a great model system for investigating basic concepts in gene regulation. However, as the genomic background and environmental conditions substantially influence toxin activation, it is important to study (auto)regulation of toxin\u2013antitoxin systems in well-defined setups as well as in conditions that resemble the environmental niche.Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied at the transcriptional level, when a protein acts as the cognate transcriptional repressor. A recent study investigating dynamics of the bacterial toxin\u2013antitoxin MazEF system has shown how autoregulation at both the transcriptional and post-transcriptional levels affects the heterogeneity of  Escherichia coli K-12 MG1655 strain has at least 37 TA loci in total, with at least 10 toxins characterized as type II toxins with RNA-degrading activity, i.e., endoribonucleases. Type II endoribonucleases can be active independent of ribosomes or in a ribosome-dependent manner, and few of them cleave RNA sequence specifically (Masuda and Inouye Toxin\u2013antitoxin (TA) modules are highly versatile systems, generally widespread in prokaryotic genomes . Overall, the majority of the known type II TA systems are RNA-degrading enzymes, degrading RNA while bound to the ribosome, or in a ribosome-independent manner, such as the MazF toxin regulation in commonly used Measuring toxin and antitoxin levels in single cells in vivo is a challenging task. As toxin and antitoxin proteins form complexes, tagging them with fluorescent reporters would most certainly decrease stability of the complexes and prevent efficient toxin neutralization by the antitoxin. In addition, tagging toxins with fluorescent proteins could interfere with the toxin activity , or as variability in phenotypic traits of the individual cells in time  (Ackermann mazEF transcript induced pulse-like behavior and increased temporal variability in MazF levels during stress (Nikolic et al. Several previous studies indicate that the majority of chromosomally encoded type II TA systems elicit phenotypic heterogeneity in stressed bacterial populations by promoting variation in gene expression, cell size, and growth rate (Klumpp et al. mazEF autoregulation is a complex mechanism attained by several protein\u2013protein, protein\u2013mRNA and protein\u2013DNA interactions. Autoregulation of mazEF expression at the transcriptional and post-transcriptional level is responsible for fluctuations in MazF levels during ectopic stress (Nikolic et al. mazG and relA transcripts are parts of the polycistronic mRNA together with mazE and mazF (Gama-Castro et al. mazEFG transcriptional unit (Goormaghtigh et al. relA-mazEF unit (Gama-Castro et al. mazEF expression, will provide necessary details to obtain a full picture of autoregulatory processes. Stress response mechanisms might additionally regulate mazEF expression (Battesti et al. mazEF expression, and to what extent (Yamaguchi and Inouye mazEF expression during physiological induction of the toxin will further determine the importance and impact on this TA system on the behavior of bacterial cells.The"}
+{"text": "Sci., 2015, 6, 3242\u20133247.Correction for \u2018Humidity-dependent surface tension measurements of individual inorganic and organic submicrometre liquid particles\u2019 by Holly S. Morris  The corrected figure is shown below.An error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The presence of tumor cells in blood vessels, particularly extramural venous invasion (EMVI), is an independent poor prognostic factor in colorectal cancer (CRC).EMVI was present in one-quarter of EC patients after surgery alone, and in 21.6% of patients after nCRT, as confirmed by additional EVG staining.7In future, EMVI should be investigated in a larger group of EC patients undergoing nCRT followed by surgery. Our results in the nCRT group are probably influenced by case mix and less power in a relatively small group with a potential selection bias of non-responders to nCRT."}
+{"text": "Background: Space Agencies are planning human missions beyond Low Earth Orbit. Consideration of how physiological system adaptation with microgravity (\u03bcG) will be managed during these mission scenarios is required. Exercise countermeasures (CM) could be used more sparingly to decrease limited resource costs, including periods of no exercise. This study provides a complete overview of the current evidence, making recommendations on the length of time humans exposed to simulated \u03bcG might safely perform no exercise considering muscles only.Methods: Electronic databases were searched for astronaut or space simulation bed rest studies, as the most valid terrestrial simulation, from start of records to July 2017. Studies were assessed with the Quality in Prognostic Studies and bed rest analog studies assessed for transferability to astronauts using the Aerospace Medicine Systematic Review Group Tool for Assessing Bed Rest Methods. Effect sizes, based on no CM groups, were used to assess muscle outcomes over time. Outcomes included were contractile work capacity, muscle cross sectional area, muscle activity, muscle thickness, muscle volume, maximal voluntary contraction force during one repetition maximum, peak power, performance based outcomes, power, and torque/strength.Results: Seventy-five bed rest \u03bcG simulation studies were included, many with high risk of confounding factors and participation bias. Most muscle outcomes deteriorated over time with no countermeasures. Moderate effects were apparent by 7\u201315 days and large by 28\u201356 days. Moderate effects (>0.6) became apparent in the following order, power and MVC during one repetition maximum (7 days), followed by volume, cross sectional area, torques and strengths, contractile work capacity, thickness and endurance (14 days), then muscle activity (15 days). Large effects (>1.2) became apparent in the following order, volume, cross sectional area (28 days) torques and strengths, thickness (35 days) and peak power (56 days).Conclusions: Moderate effects on a range of muscle parameters may occur within 7\u201314 days of unloading, with large effects within 35 days. Combined with muscle performance requirements for mission tasks, these data, may support the design of CM programmes to maximize efficiency without compromising crew safety and mission success when incorporated with data from additional physiological systems that also need consideration. Space Agencies are planning to transition from International Space Station (ISS) missions to Lunar missions including a crewed base from which to test and develop hardware and procedures required for the longer term goal of human Mars missions Foing, . It is wBased on bed rest research and previous spaceflight experience, the ISS provides astronauts with 2.5 h per day for exercise  using a treadmill, cycle ergometer and resistance exercise device designed and adapted for \u03bcG  to search the following databases up to July 2017: Pubmed, CINAHL, Web of Science, NASA Technical Reports Server and The Cochrane Collaboration Library. No restrictions on type of bed rest or publication dates were applied, and due to the inability to use \u201cBoolean logic\u201d on the NASA Technical Reports Server, the strategy was adapted to keyword searches. The full search strategy is available in A range of relevant terms grouped by main search terms were constructed using Boolean logic (astronauthttps://rayyan.qcri.org/) , blinded to each other's decisions, using Rayyan  tool was used to assess risk of bias of all the included studies, with \u201cH,\u201d \u201cM,\u201d and \u201cL\u201d showing high, moderate and low risk, respectively, using pre-defined published definitions for each level  were calculated between pre and post-bed rest values for each outcome individually without an overall pooled effect. Hedges' g was used to bias correct for the typically small sample sizes, as only control group data from \u03bcG simulation studies were eventually included. The reported data set that was as close to immediate pre and the end of bed rest was used for the analysis. No exclusion or analysis variation was made based on the individual study analysis methods. The pooled standard deviation for Hedges' g was calculated using the root mean square of the pre and post-group standard deviations. This version does not specifically include the sample size (n), preventing any complications that could arise from inflating n when both group means are from the same sample. Results were first sub-grouped by outcome measure type and then by muscle group before being listed in order of ascending days spent in simulated \u03bcG. Individual effects sizes were calculated and plotted in figures for each outcome at every time point where data were available. To enable a brief overview of the large data set to also be provided, an unweighted mean effect at each common time point within each muscle group was used to provide a summary result. This was only done when more than one study assessed the same outcome at the same time point. These statistics were chosen due to data being from the same sample rather than a separate intervention and control group, thus making a traditional weighted effects meta-analysis pooling inappropriate. Traditional meta-analysis assumes two different sets of individuals in each group  or 1.2 (large) was highlighted as a time point when a worthwhile mechanistic change had occurred , (3) muscle activity , (4) muscle thickness , (5) muscle volume (cm3), (6) maximal voluntary contraction force during one repetition maximum  (7), peak power (W), (8) performance based outcomes  , (9) power , and (10) torques and strength . Within each subgroup data were further sub-grouped for analysis by major muscle groups. For completeness of reporting, any measures that did not fit within major muscle groupings were grouped for analysis and reported as either \u201cother lower limb,\u201d \u201cother trunk,\u201d or \u201cother upper limb\u201d outcomes, to enable every outcome measure extracted from included studies to be reported in the results. The outcomes included in the \u201cother\u201d groupings are listed in the text.Ten sub groups were created based on the measurement methods units used for each for analysis as follows : (1) contractile work capacity (J), (2) cross sectional area  generally decreased over time, however a transient increase was seen in Plantar Flexor, Dorsi Flexor and Quadriceps muscles and only at 20 days. In Plantar Flexor and Quadriceps muscles, muscle activity decreased again after 20 days, there were no data for Dorsi Flexor muscles beyond 20 days to establish a post 20 day trend. Moderate effects were apparent in upper limb muscle groups by 15 days but not until 90 days for Dorsi and Plantar Flexor muscles which were the only muscles with data at the 90 day point. The breakdown of individual activity effects per muscle is available in Maximal voluntary contraction during one repetition maximum decreased over time except for other upper limb outcomes that remained mostly unchanged as far as data were available up to 45 days. Moderate effects became apparent by 7 days and large effects by 35 days. Other lower limb outcomes that included maximal isometric force during supine squat, hip extensor force and legs total work never reached a large effect, but had no data available beyond 35 days. The breakdown of individual MVC during one repetition maximum effects per muscle is available in Power decreased over time. Moderate effects became apparent by 7 days and large effects by 20 days, although these were only seen in the Quadriceps muscle data. Hamstring, Hip Flexor, and upper limb muscles that included elbow flexors and extensors reached moderate effects by 20 days. Plantar Flexors never reached a moderate effect but data were only available at 14 days. Other trunk muscles included trunk flexors and extensors tested in combination within functional movements. The breakdown of individual power effects per muscle is available in Performance based outcomes all worsened over time, as although sit to stand, balance, and sprint time outcomes all had positive effects, this was considered a worsening effect within these measures. Endurance reached a large effect by 14 days, jumping a moderate effect at 42 days and large by 44 days, sit to stand and balance reached large effects by 60 days and sprint time by 62 days. Data for most outcomes were only available for one time point and so trends over time for individual outcomes are not able to be determined. The breakdown of individual performance based effects per outcome is available in The main finding of the review was that muscle cross-sectional area, volume, shape, size, activity, power, performance, torque, and force-based outcomes, at either regional or global level, all decline over time, based on the current evidence base. Moderate effects became apparent in the following order: power and MVC during one repetition maximum (7 days), followed by volume, cross sectional area, torques and strengths, contractile work capacity, thickness and endurance (14 days), then muscle activity (15 days). Large effects became apparent in the following order: volume, cross sectional area (28 days) torques and strengths, thickness (35 days), and peak power (56 days). No large effects were found for muscle activity. There were limited data for contractile work capacity and no large effects were apparent. In general, lower limb and trunk muscles appeared to decline more rapidly than upper limb muscles. Locomotion muscles such as Plantar Flexor and Quadriceps muscles also generally appeared to decline more rapidly than other muscles groups and with larger effect sizes.Human spaceflight missions differ in duration, so results have to be placed into the context of mission profiles and operationally important considerations. Operationally, performance-related measures such as power, MVC, torques and strengths are considered most critical. In terms of mission profiles, typical ISS missions involve approximately 180 days in \u03bcG  level of strength to achieve mission critical tasks such as donning/doffing and standing up/moving whilst wearing a space suit in low gravity, hatch opening, and pulling/dragging a fellow crew member wearing a space suit during an emergency. The absolute level is defined as the precise required strength outcome in raw units to achieve a task, as opposed to considering relative changes with effect size or percentage changes. A relative (%) reduction in strength will make all tasks with an absolute strength requirement more challenging for all individuals, but the biggest impact will be felt by those who have a lower initial level of absolute strength. For example, a strong individual might be able to lose 30% of their pre-flight strength and still comfortably achieve a mission critical task , whereas a weaker individual might already be close to their physical limit during this task without any deconditioning. Operationally, having an estimate of the most rapid possible rate of change in muscle outcomes may be useful in the case of a crew member with low pre-flight absolute strength, or an individual highly susceptible to \u03bcG adaptation. In the present study, the most extreme negative value within the confidence interval for each outcome provides an estimate of the most extreme worst likely true value that might be encountered with exposure to \u03bcG. Based on this estimation, the results of this analysis suggest that the change experienced by an individual astronaut might reach a large effect size in some muscles within a 7 day lunar transit period for volume, cross sectional area, contractive work capacity, thickness, power, and MVC. However, the confidence intervals are wide due to the small sample sizes across the current evidence base, so this estimate should be treated with caution as it may be exaggerated. Individual effects are difficult to determine in a transferable way to the true population from the data currently available or from individual case studies. Ideally, a population selected for their increased susceptible to unloading/\u03bcG-induced muscular adaptation should be studied in a long-duration \u03bcG analog to produce a representable average effect that could be transferred to the true population with more reasonable confidence. Until such data are available, estimating the maximum rate of decline in an individual in response to \u03bcG exposure of such a duration will remain difficult. In addition, consideration would also be needed should an individual be selected to perform some tasks in a mission that are not considered mission critical, but are essential to other mission goals. It may be that checking for susceptibility to outcomes that are linked more strongly to mission success is checked and made part of astronaut eligibility screening, it could also be any more susceptible mission critical individuals undergo more rigorous preflight and inflight training protocols or consider use of other more removed countermeasures beyond the scope of this review.Exercise countermeasure development may want to consider focusing on those which might best address the more susceptible outcome changes in this review, volume, cross sectional area, contractive work capacity, thickness, power, and MVC while also ensuring any proposed exercises are tailored to tasks considered critical, such as donning/doffing and standing up/moving whilst wearing a space suit in low gravity, hatch opening, and pulling/dragging a fellow crew member wearing a space suit. The impact of any chosen exercise types on future spacecraft exercise hardware would also need further consideration. Future research should consider identifying exercise countermeasures that would best address the more susceptible outcomes and be feasible with any technical constraints of new space vehicles planned for use within Moon and Mars missions.As CM are likely to be needed on the return trip from both Moon and on the journeys to and from Mars, such CM will need developing. Countermeasure devices should support lower limb and trunk muscle exercise as these decline earlier than other body regions and are essential for locomotion and for spinal function on return to G loading Bamman, . Based omuscle changes, additional holistic consideration of other physiological systems will likely be required. Finally, any CM development for exploration missions will also have to consider constraints of space vehicles that will be used, such as available physical space, limited number of devices that can be included in the space craft, consumables, generation of heat, carbon dioxide, and vibration, which are likely to be more restricted than the ISS  ISS Long Duration Mission (LDM) exercise prescriptions  (Dawson et al., Most of the studies scored four on the bed rest tool, with no studies scoring a full seven points, although 13 studies scored six. The reasons for marking studies down was mostly due it being unclear if criteria had been met rather than clearly failing a point. The most common unclear criteria was related to restricted sunlight exposure followed by ensuring a fixed daily routine. The high risk of bias results were most commonly caused by not clearly showing how confounding factors were managed and providing adequate description of participation. The participation domain considers participant eligibility criteria, source of participants, baseline descriptions, description of sampling frame and recruitment, description of period and place of recruitment, and inclusion/exclusion criteria (Hayden et al., There was some asymmetry in the funnel plot showing potential publication bias toward studies reporting a decrease in muscle outcomes. However, there were studies present on the increasing side of the plot, so the risk is not likely to be high. In addition, it is expected that many of the muscle outcomes would decrease during a period of inactivity such as bed rest, therefore, it not surprising most studies reported decreases. Therefore, while it appears a risk of reporting bias may exist, the presence of some studies reporting increases and the expected pattern of more decreases being reporting suggest this finding should be treated with caution and the potential risk is likely to be low.This review only considered muscle outcomes. Spaceflight is known to affect many more human physiological systems including bone, cardiovascular and vestibular (Pavy-Le Traon et al., The results of this review suggest that moderate effects on a range of muscle function parameters may occur within 7\u201314 days of unloading, with large effects within 35 days. Combined with identification of muscle performance requirements for future exploration mission tasks, these data, may support the design of CM programmes to optimize their efficient use without compromising crew safety and mission success. However, the data suggests CM are likely to still be needed for longer transit/orbital periods of 14\u201328+ days, such as a prolonged Lunar orbit, deep space exploration, or a Mars mission, as moderate effects occur between 7\u201314 days and large effects by 28 days for most muscle outcomes. However, if large effect sizes occur only after 28\u201335 days, to save resources, space agencies might consider short missions without exercise CM, or fixed periods of abstinence during longer \u03bcG exposures, if they could be confident that moderate changes in muscle performance could be reversed in-flight. Finally, several research gaps are highlighted for future bed rest studies in which standardized time points for measurements should be used and clear information provided on sunlight exposure control, fixed daily routine, and control of any confounding factors.1Akima et al., 2Akima et al., 3Akima et al., 4Akima et al., 5Alkner and Tesch, 6Alkner et al., 7Arbeille et al., 8Bamman et al., 9Belavy et al., 10Belavy et al., 11Belavy et al., 12Belavy et al., 13Belavy et al., 14Belavy et al., 15Belavy et al., 16Belavy et al., 17Belavy et al., 18Belavy et al., 19Berg et al., 20Berg et al., 21Berry et al., 22Buehring et al., 23Caiozzo et al., 24Cescon and Gazzoni, 25Convertino et al., 26de Boer et al., 27Dudley et al., 28Duvoisin et al., 29Ellis et al., 30English et al., 31English et al., 32Ferrando et al., 33Ferretti et al., 34Fu et al., 35Funato et al., 36Gast et al., 37Germain et al., 38Greenleaf et al., 39Greenleaf et al., 40Greenleaf et al., 41Holguin et al., 42Holt et al., 43Kawashima et al., 44Koryak, 45Koryak, 46Koryak, 47Koryak, 48Koryak, 49Koryak, 50Koryak, 51Koryak, 52Kouzaki et al., 53Krainski et al., 54LeBlanc et al., 55Lee et al., 56Macias et al., 57Miokovic et al., 58Miokovic et al., 59Miokovic et al., 60Muir et al., 61Mulder et al., 62Mulder et al., 63Mulder et al., 64Mulder et al., 65Mulder et al., 66Narici et al., 67Pisot et al., 68Portero et al., 69Reeves et al., 70Rittweger et al., 71Rittweger et al., 72Schneider et al., 73Shinohara et al., 74Trappe et al., 75Trappe et al., 1Belavy et al., 2Belavy et al., 3Belavy et al., 4Biolo et al., 5Cavanagh et al., 6Shenkman et al., 7Amorim et al., 8Rittweger and Felsenberg, 9Koriak Iu, 10Koriak Iu, 11Koriak Iu, 12Koryak, 13Bamman and Caruso, 14Bamman, 15Felsenberg et al., 16Ferretti, 17Greenleaf et al., 18Grogor'eva and Kozlovskaia, 19Guo et al., 20Hargens et al., 21Judith Hayes et al., 22Ito et al., 23Jaweed et al., 24Koryak, 25Kozlovskaia et al., 26LeBlanc et al., 27LeBlanc et al., 28Liu et al., 29Macias et al., 30Meuche et al., 31Meuche et al., 32Milesi et al., 33Miyoshi et al., 34Moriggi et al., 35Mulder et al., 36Netreba et al., 37Scott et al., AW: initial concept ideas, protocol planning and drafting, search screening, analyzing, and drafting all manuscript versions. JS: methods advice, protocol drafting, and approving final draft. NW: data extraction, analysis, and drafting final version. MV: protocol planning, search screening, data analysis, drafting text, and checking final version. NC: protocol planning, search screening, methods advice, manuscript drafting, and approving final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Fusarium mycotoxins. Further, we suggest that understanding how mycotoxin levels are regulated by microbial encounters can offer novel insights for mycotoxin control in food and feed. Microbial degradation of mycotoxins provides a wealth of chemical information that can be harnessed for large-scale mycotoxin detoxification efforts.An important goal of the mycotoxin research community is to develop comprehensive strategies for mycotoxin control and detoxification. Although significant progress has been made in devising such strategies, yet, there are barriers to overcome and gaps to fill in order to design effective mycotoxin management techniques. This is in part due to a lack of understanding of why fungi produce these toxic metabolites. Here we present cumulative evidence from the literature that indicates an important ecological role for mycotoxins, with particular focus on  Aspergillus fumigatus  with the potential to produce a myriad of secondary metabolites. One of the most powerful ways to activate BGCs is by co-cultivation or mixed fermentation of two or more microbes. Microbial interactions that have led to up-regulation of known metabolites or to discovery of novel natural products are numerous benzoic acid and citreoisocoumarinol [ in Trichoderma atroviride  and zearalenone produced by  Ch\u00e9rif, . TrichodF. oxypsorum in both plant and animal hosts (L\u00f3pez-D\u00edaz et al., F. avenaceum that lacked the ability to synthesize enniatin showed decreased virulence when infected on potato tubers (Herrmann et al., Fusarium oxysporum f. sp. melonis isolates to synthesize beauvericin or enniatin B does not contribute to virulence in melons (Moretti et al., in vitro cultures in F. graminearum and F. pseudograminearum (Mudge et al., F. culmorum, F. graminearum, and F. pseudograminearum cause fusarium head blight as well as fusarium crown rot. However, the former two pathogens are more aggressive pathogens in head blight while F. pseudograminearum shows enhanced fitness as the pathogen of crown rot. This has been attributed to the differential production of DON in the different tissues (stem base vs. wheat heads; Tunali et al., F. graminearum, DON has been demonstrated to inhibit apoptosis-like programmed cell death in Arabidospis thaliana (Diamond et al., F. graminearum (Voigt et al., F. graminearum has been proposed (Audenaert et al., Burkholderia glumae, a seed-borne bacterium and F. graminearum has been recently identified. Co-cultivation of the two microbes resulted in an increase in sporulation and DON production in F. graminearum, which is at least partially in response to a toxic bacterial metabolite. An overall increase in disease severity was observed upon co-infection of rice with the two pathogens. The two microbes were also found to be physically attached upon microscopic observations after co-cultivation (Jung et al., Fusarium spp. It is necessary to note here that microbial interactions can also reduce the virulence of Fusarium species on their plant hosts, as discussed in section Microbial Interactions in Detoxification and Degradation of Mycotoxins.Although secondary metabolites are not \u201crequired\u201d for the growth and development of fungi, they function as fitness factors. Mycotoxins have been shown to contribute to the pathogenicity, aggressiveness and/or virulence of fungi. Fusaric acid has been reported to enhance the virulence of Pseudomonas piscium, from the wheat head microbiome has shown that the bacterium secretes an antifungal agent, phenazine, against F. graminearum. Phenazine, upon entering the fungal cell, inhibits the histone acetyl transferase module of the SAGA complex which subsequently leads to an inhibition of fungal growth and pathogenicity in addition to a complete suppression of DON biosynthesis (Chen et al., Aspergillus nidulans\u2014Streptomyces rapamycinicus association where the bacterium induces histone modification mediated by the SAGA complex which results in production of orsellinic acid and its derivatives by the fungus (Nutzmann et al., Epigenetics has been steadily gaining momentum in the last few decades in the world of transcriptional regulation. There is now growing evidence that microbial communication regulates epigenetic modifiers that in turn control mycotoxin biosynthesis. The SAGA complex, conserved across eukaryotes, induces transcription of genes by mediating histone acetylation of the corresponding promoters. A study that isolated the bacterium, Fusarium mycotoxins mediated by microbes, plants and insects (The literature supports the idea that mycotoxins can be important players in shaping microbial communities and their interaction with hosts. Signaling molecules are regulated \u201ccoinage\u201d and need to be recycled\u2014through various chemical transformation processes\u2014to maintain homeostasis in the community. Thus, it is not surprising that there are several examples of degradation of  insects .Fusarium mycotoxin accumulation in grains. Preventative application of Psuedomonas fluorescens strain before inoculation with F. culmorum resulted in a significant reduction in Fusarium head blight as well as DON levels in infected wheat grains (Khan and Doohan, Paenibacillus polymyxa, isolated from wild teosinte, have been shown to produce fusaridins which contribute to the antifungal activity against F. graminearum. Co-existence of these bacteria with F. graminearum in grains during storage at room temperature resulted in a significant decrease in DON accumulation (Mousa et al., Bacteria have been shown to contribute to reduction of Aspergillus tubingenesis NJA-1, a soil isolate, has been shown to convert DON into a less-toxic product that has been speculated to be the result of hydrolysis, based on differences in the mass of the metabolites (He et al., Agrobacterium\u2013Rhizobium strain E3-39 converts DON into 3-keto DON (Shima et al., Nocardioides WSN05-2 forms the non-toxic epimer, 3-epi-DON (Ikunaga et al., Deviosa insulae forms 3-keto-DON (Wang et al., Devosia mutans 17-2-E-8 forms both 3-keto-DON and 3-epi-DON (He et al., Eggerthella spp., isolated from chicken intestine, has been reported to de-epoxify DON over a wide range of temperatures and pH (Gao et al., Tri101, encoding 3-O-acetyltransferase for 3-O-acetylation of the trichothecene ring has been characterized in F. graminearum and has been further identified in other Fusarium species (Kimura et al., Arabidopsis, it has been reported that the UDP-glycosyltransferase catalyzes transfer of glucose from UDP-glucose to the hydroxyl group at the 3-C position in DON (Poppenberger et al., Understanding the mechanisms underlying chemical transformation of mycotoxins could pave the way toward evolving novel techniques for mycotoxin decontamination in food and feed. Several mechanisms of detoxification of DON have been studied as summarized in Clonostachys rosea has been reported to produce a zearalenone-specific lactonase that catalyzes the hydrolysis of the lactone ring, which is followed by spontaneous decarboxylation (Utermark and Karlovsky, C. rosea to zearalenone. Trichosporon mycotoxinivorans has been shown to convert zearalenone into ZOM-1 which is characterized by the opening of the ring structure at the ketone group positioned at C6' (Vekiru et al., Rhizopus arrhizus catalyzes sulfation of the hydroxyl group at the C4 position resulting in the formation of zearalenone-4-O-sulfate conjugate (el-Sharkaway et al., Zearalenone mimics estrogen upon ingestion in animals and humans resulting in sexual and reproductive abnormalities. Microbes possess the ability to degrade and inactivate zearalenone, as reviewed in Ji et al. . ClonostPseudomonas (Altalhi, Bacillus (Cho et al., Rhodoccous, and Streptomyces (De Mets et al., Acinetobacter has been shown to secrete extracellular enzymes that oxidize zearalenone into smaller estrogenic products (Yu et al., Lactobacillus strains with zearalenone although the bacteria removed the mycotoxin from the cultures. The authors were able to recover zearalenone from the bacterial cultures and suggest that the bacteria bind zearalenone in a density-dependent manner (El-Nezami et al., Lysinibacillus sp. isolated from chicken intestine can remove zearalenone from cultures and the process has been shown to be significantly reduced upon heat treatment. The authors suggest a potential enzymatic process that may be involved in the interaction between the bacterium and zearalenone (Wang et al., Pseudomonas putida ZEA-1 utilizes zearalenone as a carbon source (Altalhi, Species of Altalhi, , BacilluAltalhi, .Burkholderia ambifaria, a novel bacterium isolated from barley rhizosphere has been reported to be able to utilize fusaric acid as a sole carbon source (Simonetti et al., Aspergillus tubingensis (Crutcher et al., Colletotrichum sp (Fakhouri et al., Mucor rouxii (Crutcher et al., A significant understanding of the biochemical pathways involved in detoxification processes (Carere et al., The mycotoxigenic fungal species live in complex and nutrient-deficient environments\u2014be it in soil, plant or animal hosts. The soil micro-environment often fluctuates with variations in water availability, air, light, and temperature, among other abiotic factors. Now add to this, a complex cocktail of microbes and hosts that are integral to the environment where survival of microbes heavily depends on active community participation. Mycotoxins play a significant role in the defensive strategies of mycotoxigenic fungi against the resident microbes. Interactions between microbes in such environments may involve competition or compromise where mycotoxins may serve as essential chemical language mediating communication. The host environments are usually unfriendly, thus requiring special adaptations in order for the fungi to thrive in such conditions. Several studies support a view that mycotoxins may act as signaling molecules that modulate host responses and promote successful colonization. Reports of microbes that can metabolize and detoxify mycotoxins are aplenty, highlighting the importance of examining microbial interactions to uncover strategies for mycotoxin detoxification.Fusarium spp. The evolving knowledge on molecular and genetic mechanisms that govern mycotoxin production provides us with valuable tools to study the ecological roles of mycotoxins. This is not only an achievable goal but also has the potential to be highly rewarding. Such knowledge can facilitate development of novel strategies to control infections of mycotoxigenic fungi as well as mycotoxin contamination in food and feed.In this review chapter, we have summarized existing literature that accentuate the ecological significance of mycotoxins with focus on NV along with NK conceptualized and drafted the theme of the review. NV wrote the article and NK reviewed, edited, and refined the manuscript along with NV.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mycobacterium tuberculosis (Mtb) is the bacterial pathogen that causes the majority of human tuberculosis (TB), the leading infectious disease in the world , a well-documented Mtb complex and in a related species Mycobacterium marinum, but absent from the Mycobacterium bovis Bacille Calmette\u2013Gu\u00e9rin (BCG) genome, encodes an ESX-1 type VII secretion system that has been extensively investigated as a major virulence factor  among mycobacterial species have been identified by comparative genomic studies , but their role in Mtb virulence has not been explored. Arora et al. biochemically and functionally characterized the CitE enzymatic subunits. The purified CitE1 and CitE2 proteins degraded acetyl-CoA and propionyl-CoA in vitro and the genes encoding both enzymes were up-regulated when Mtb was exposed to oxidative stress. Moreover, deletion of the citE genes from the Mtb genome reduced the resistance to oxidative stress, intracellular replication in macrophages, and growth in a guinea pig infection model. This study suggests that CitE may be a potential target for TB drug development.Bacterial citrate lyase, which is important for both metabolism and virulence, is composed of three subunits, CitD (\u03b3), CitF (\u03b1), and CitE (\u03b2)  with a global collection of Mtb genomes and identified a novel phylogenetic clade that share single-nucleotide polymorphisms (SNPs) in key virulence-associated loci, including the mce1 locus and the phoP gene. This clade includes four hypervirulent strains isolated from geographically diverse regions. The common SNPs and structural variations within the clade may be considered as potential genetic determinants of hypervirulence for future studies.Mtb is the most common cause of human TB, M. bovis can cause TB in both humans and cattle, making it a zoonotic threat to both food safety and public health  and folC (encoding FolC-dihydrofolate synthase) genes have been associated with resistance to para-aminosalicylic acid (PAS; Rengarajan et al., Howe et al. found that MetM, a putative amino acid transporter, plays a crucial role in the synthesis of folate precursors, which antagonizes PAS activity.The mutations in the Mtb. In the report done by Ilin et al., FS-1 was used in combination with standard anti-TB antibiotics on guinea pigs infected with an XDR-Mtb strain. The genetic changes in Mtb genomes following infection were analyzed and FS-1 was found to cause a counter-selection of drug-resistant variants that sped up the recovery of the infected animals from XDR-TB. While the drug resistance mutations remained intact in more sensitive isolates, reversion of drug resistance was associated with a general increase in genetic heterogeneity of the Mtb population.Drug induced reversion of antibiotic resistance has drawn recent attention as a prospective approach to combat drug resistance (Baym et al., Mtb virulence, including characterization of new roles for known virulence factors, identification of new virulence factors, and the elucidation of drug-resistance mechanisms and reversion. This Research Topic, together with many recent publications, enhances our understanding of the mechanism of Mtb virulence and pathogenesis.The articles in this Research Topic present new findings regarding the cellular and molecular mechanisms of JS, PC, and FB have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Multimorbidity is widespread, costly, and associated with a range of deleterious outcomes; it affects an estimated 67-80% of older adults. This study tests the validity of a multimorbidity resilience index developed in a Canadian sample of older adults by Wister et al., (2018), with a U.S.-based sample, using National Social Life, Health, and Aging Project (NSHAP) data, and draws upon the index to investigate the effects of resilience on outcomes over time. We mapped Wister et al.\u2019s (2018) index to NSHAP measures, and assessed cross-sectional associations with health outcomes, using logistic regression. To assess the effects of resilience on health outcomes over time, we estimated mixed models of the relationships between resilience on outcomes over a 5-year interval. Total resilience was consistently associated with improved outcomes, including pain level ; reduced utilization ; improved mental health ; self-rated physical health ; and sleep quality . Longitudinal model results indicate change in multimorbidity resilience and number of chronic diseases predict (\u03b1=.001) pain level and self-rated physical health. Effects were moderated by socio-demographic factors. Our findings validate Wister et al.\u2019s (2018) resilience index in a U.S. sample, supporting the importance of this measure to capture core components of older adults\u2019 capacity to sustain well-being in the context of living with multiple, chronic conditions. Results from the longitudinal models provide beginning insights into the effects of resilience on symptom experience and perceived health over time, highlighting potential levers for change."}
+{"text": "The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment.plus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions.This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene\u2013Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in MA bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions.Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum. Specifically, FEP individuals were recruited as part of the \u2018Functional Enviromics\u2019 work package, which consisted of an incidence and a case-sibling-control study conducted across six countries with the aim to investigate clinical, genetic, and environmental interaction in the development of psychotic disorders.Individuals suffering from their FEP were recruited between 2010 and 2015 as part of the large EUropean network of national schizophrenia networks studying Gene\u2013Environment Interactions (EU-GEI) study ; central Amsterdam, Gouda and Voorhout (the Netherlands); part of the Veneto region, Bologna municipality, city of Palermo ; 20th arrondissement of Paris, Val-de-Marne, Puy-de-D\u00f4me (France); Madrid , Barcelona, Valencia, Oviedo, Santiago, Cuenca (Spain); and Ribeir\u00e3o Preto (Brazil).et al., We screened all subjects who were referred to mental healthcare services with a suspicion of psychosis. The ascertainment period of cases ranged from 12 months in London to 48 months in Val-de-Marne and Bologna, with a median of 25 months. In each site, a psychiatrist experienced in epidemiology research oversaw the local team, which was centrally trained to minimize non-differential recruitment bias in the different healthcare systems. Written consent was obtained from the subjects who agreed to take part of the case-sibling-control study. For incidence-only cases, local research ethics committees approved the extraction of demographics and clinical information from patient records. More detailed information is available on the EU-GEI core paper on the incidence rates of schizophrenia and other psychotic disorders (Jongsma x.5).Patients were included in the current study if they met the following criteria during the recruitment period: (a) aged between 18 and 64 years; (b) presentation with a clinical diagnosis for an untreated FEP, even if longstanding ; (c) resident within the catchment area at FEP. Exclusion criteria were: (a) previous contact with psychiatric services for psychosis; (b) psychotic symptoms with any evidence of organic causation; and (c) transient psychotic symptoms resulting from acute intoxication . The OPCRIT system allows to: (1) assess the pre-morbid history and current mental state; and (2) establish the diagnosis of psychotic disorders based on algorithms for several diagnostic classification systems. It consists of a checklist which can be filled using different sources, e.g. case records or clinical interviews. Fifty-nine items relate to the mental state examination. We used diagnoses based on Research Diagnostic Criteria (RDC) , omega hierarchical (\u03c9H), and index H. Coefficient \u03c9 is an estimate of the proportion of common variance accounted by general and specific symptom dimensions. Coefficient \u03c9H is an estimate of the proportion of reliable variance accounted by the general dimension, treating variability in scores due to specific dimensions as measurement error  the general factor independently from the specific symptom dimensions, and (2) each specific symptom dimension independently from the general factor. To estimate the extent to which symptom dimensions were represented by their own set of OPCRIT items and their replicability across studies, we computed the construct reliability index H , Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC), and Sample-size Adjusted BIC (SABIC) as model fit statistics. For the model showing the best fit, we calculated reliability and strength indices, such as McDonald's omega  analysis in STATA 14  and based on clinical records for 49% (n\u00a0=\u00a01070) of the sample. The sample prevalence of psychotic symptoms is presented in Supplementary Table S1.We identified 2774 treated incidence cases of psychosis (Jongsma M\u00a0=\u00a030.1) compared with women . Age-at-first-contact differed across ethnic groups, with individuals of Black ethnicity (M\u00a0=\u00a029) being younger than individuals of White ethnicity . The most common RDC-based diagnosis was broad or narrow schizophrenia (38.6%), followed by schizoaffective disorders (35%), unspecified non-organic psychotic disorder (16.3%), bipolar disorder (5.9%), and psychotic depression (4.2%).Fifty-seven per cent of FEP were men. Subjects were mostly people of a White ethnicity. Other main ethnic groups included Black African and Black Caribbean, North African, Mixed, and Asian. Mean age-at-first-contact with psychiatric services was 32.1 years; this was lower in men  or case note review (95% CI 0.56\u20130.65), compared with a classification by chance (95% 0.32\u20130.41). Moreover, symptom dimensions showed similar diagnostic classification accuracy across countries .Findings on factor scores by gender, age-at-first-contact, and ethnicity, are shown in v. Cambridge), whereas a negative association was observed in Spain (online Supplementary Table S5).A moderate positive association was observed for more densely populated environments and the general dimension score. This is the first study on general and specific symptom dimensions in an incidence sample of psychosis. First, we found in our FEP sample that manic and delusional symptoms primarily underlie the identified general psychosis factor across diagnostic categories of non-affective and affective psychosis. Second, findings showed that specific dimensions of positive, negative, disorganized, manic and depressive symptoms are complementary to the general dimension. Third, general and specific symptom dimensions discriminated well between diagnoses of psychotic disorders. Forth, positive symptoms were more common among individuals of Black and North African ethnicity. Fifth, there was some evidence that early age-at-first-contact was associated with higher scores for several dimensions, such as of negative, disorganised and manic symptoms. Sixth, men presented with more negative and less depressive symptoms than women. Finally, higher scores for the general dimension were observed for individuals living in urban neighbourhoods.et al., et al., et al., et al., et al., et al., v. a multidimensional construct of psychosis. Hence, it was a suitable model for addressing dimensionality issues for psychosis and generating reliable phenotypes.Before interpreting our findings, we must consider potential limitations. Symptoms were rated with a semi-structured face-to-face interview or from case note review. Still, study investigators underwent a specific and centrally organized training for OPCRIT and demonstrated good inter-rater reliability for individual item ratings; moreover, OPCRIT is a tool specifically designed to allow use with different sources (McGuffin et al., et al., et al., et al., et al., In our study, the bifactor model of psychopathology best explained the observed symptoms at FEP compared with unidimensional and multidimensional models. Our findings are consistent with, and extend, previous research on psychotic symptoms in people with enduring psychotic disorders (Reininghaus et al., et al., et al., et al., et al., We found some evidence of gender differences in symptom dimension scores. Men showed less depressive symptoms and more negative symptoms compared with women. This finding is consistent with other studies in stable schizophrenia (Shtasel et al., et al., et al., et al., et al., et al., et al., We further found that symptom dimensions vary in terms of ethnicity. Consistent with a previous report (Kirkbride et al., et al., et al., et al., et al., et al., et al., We showed that high population density is positively associated with the general and specific disorganized, negative and manic dimensions. In our multinational sample, we were not able to replicate previous findings on the relationship between urbanicity and the positive dimension (Kirkbride et al., et al., et al., et al., In the context of a general effort to move away from DSM and ICD categories (Demjaha et al., From a research perspective, our findings suggest that the general dimension may reflect a phenotype for the study of general risk factors. For example, urbanicity may impact on the risk and profile of psychosis through the combination of other, more specific socio- or bio-environmental factors. In addition, we showed a substantial variation of sociodemographic determinants at the specific dimension level, which may support an integrated socio-developmental model of psychosis (Morgan et al., et al., et al., et al., We may further suggest using the general dimension as a quantitative measure of psychopathology for research into the genetic component shared across psychotic disorders. The evidence is required to establish the extent to which pathophysiology of schizophrenia, bipolar disorder, and psychotic depression is shared at the level of pathways and neuronal cell mechanisms (Forstner et al., et al., et al., et al., et al., From a clinical perspective, although each patient presents with a specific pattern of psychopathology and response to treatment at FEP, attention has been traditionally focused on the positive dimension management. Mental health professionals may integrate observations of the whole range of symptoms and signs with a consideration of neurodevelopmental and socio-environmental risk factors. Such an approach should aim to plan and optimize pharmacological and non-pharmacological treatments (Murray We may further suggest promoting mental health professionals to adopt treatment plans guided by dimensions, and increasing their confidence in dimensional classifications. Reconciling contradictory concerns of clinicians and researchers (Kendell and Jablensky,"}
+{"text": "The incidence of neurological disorders such as multiple sclerosis (MS), Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) is increasing throughout the world, but their pathogenesis remains unclear and successful treatment remains elusive. Bidirectional communications between the central nervous system and gut microbiota may play some role in the pathogenesis of the above disorders. Up to a thousand bacterial species reside in human intestine; they colonize the gut shortly after birth and remain for life. Numerous studies point to the role of microbiota composition in the development, course and treatment of MS, AD and PD. The purpose of this review is to summarize the current knowledge about the role of gut microbiota composition in the development, course, and prognosis of selected neurological diseases. Global incidence of a number of common neurological disorders is rapidly increasing Bengmark  and consThe central nervous system (CNS) and the gut microbiota interact in a bidirectional manner, e.g. the CNS modulates gut functioning in response to psychological and physical stressors affecting motility, secretion and immune reactivity Mayer , whereas11 bacteria cells can be found in 1\u00a0g of colon contents  cells target brain and spinal cord cells leading to demyelination and axonal damage  is the most common neurological disease of young adults in Europe and North America , which is the most widely used animal model of MS, showed that oral treatment with ampicillin, vancomycin, neomycin, sulfate, and metronidazole can delay the onset and reduce the severity of the disease, decrease levels of pro-inflammatory cytokines and increase levels of interleukin (IL)-10 and IL-13  before the induction of EAE resulted in its delayed onset and milder course  is a common neurodegenerative disease of the elderly accounting for 60\u201380% of all dementia cases , A\u03b2 accumulation in brain and inflammatory response , which are not synthetized by humans    were found in cerebrospinal fluid and the cerebral cortex of patients with general paresis suggesting that these bacteria might play a role in slowly progressive dementia, cortical atrophy, and local amyloidosis  , the second most common neurodegenerative disorder of elderly, is 15\u00a0years  consisting of aggregated and phosphorylated \u03b1-synuclein (Braak and Del Tredici Non-motor symptoms, including mood and cognitive impairment, sleep disorders, sensory disruption and GI dysfunction (Postuma et al. Prevotellaceae, Coprococcus, Firmicutes, Clostridium coccoides, Clostridium leptum, B. fragilis and increased representation of Lactobacillaceae, Verrucomicrobiaceae, Ruminococcaceae, Lactobacuillus, Bacteroidetes, Proteobacteria, Clostridiaceae and Akkermansia (Hasegawa et al. Lactobacillaceae could affect the ENS as these bacteria were found to increase the excitability of colonic after-hyperpolarization neurons by inhibiting calcium-dependent potassium channel opening (Kunze et al. Lactobacillus spp. quantity and serum leptin concentrations were found to be positively correlated (Queipo-Ortuno et al. Prevotellaceae and increased abundance of Lactobacillaceae have been correlated with decreased levels of gut ghrelin. The latter hormone may regulate nigrostriatal dopamine function and restrict neurodegeneration in PD (Queipo-Ortuno et al. Prevotellaceae levels are not specific for PD and were reported in other diseases such as autistic spectrum disorders (Kang et al. Prevotellaceae levels have been proposed as an excluding biomarker of PD (Scheperjans et al. Prevotellaceae below 6.5% was found to be diagnostic of PD with 86.1% sensitivity and 38.9% specificity (Dinan and Cryan Enterobacteriaceae positively correlate with the severity of postural instability and gait difficulty (Scheperjans et al. Gut microbiota abnormalities are common in PD patients and their relation to brain dysfunction is being intensively investigated (Scheperjans B. fragilis, C. perfringens, Pseudomonas spp., most strains in Enterobacteriaceae family, 12 species in Clostridium, C. coccoides group and C. leptum subgroup (Hasegawa et al. Initial studies employing per os administration of hydrogen water in rats (Fu et al. Akkermansia and Ralstonia were found to be increased in affected patients (Scheperjans Interestingly, small intestinal bacterial overgrowth was found to contribute to the pathophysiology of motor fluctuation in PD patients and eradication of bacterial overgrowth resulted in clinical improvement (Fasano et al. Some authors also found an increase in gut permeability in patients with PD when using the urinary sucralose test (Julio-Pieper et al. There was a 90% decrease of plant fiber intake between 1800 and 1970, while the consumption of calories from animal fat and refined sugar increased four times in this time period (Burkitt et al. There is ample evidence for the existence of communication between CNS, gut and intestinal microbiome (Rhee et al."}
+{"text": "Recent efforts in synthetic biology have shown the possibility of engineering distributed functions in populations of living cells, which requires the development of highly orthogonal, genetically encoded communication pathways. Cell-free transcription-translation (TXTL) reactions encapsulated in microcompartments enable prototyping of molecular communication channels and their integration into engineered genetic circuits by mimicking critical cell features, such as gene expression, cell size, and cell individuality within a community. In this review, we discuss the uses of cell-free transcription\u2013translation reactions for the development of synthetic genetic circuits, with a special focus on the use of microcompartments supporting this reaction. We highlight several studies where molecular communication between non-living microcompartments and living cells have been successfully engineered. Current Opinion in Biotechnology 2019, 58:72\u201380NanobiotechnologyThis review comes from a themed issue on Giovanni Maglia and Wesley R BrowneEdited by Issue and the EditorialFor a complete overview see the Available online 26th December 2018https://doi.org/10.1016/j.copbio.2018.10.006http://creativecommons.org/licenses/by/4.0/).0958-1669/\u00a9 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license  reactions constitute ideal model systems for deducing the rules of network composition, developing new communication pathways between cellular mimics and living cells [Simplified models of biological systems could help identify key molecular parameters and as such have the potential to uncover generalisable concepts. Proteins and other components of the transcription and translation machinery can be extracted from cells as a lysate or purified and reconstituted (PURE) in order to perform gene expression ng cells , and creng cells .In this review, we intend to first summarise the use of TXTL reactions for prototyping and implementation of novel genetic networks. We will discuss how microfluidic technologies and semipermeable microcapsules provide essential tools for cell-free synthetic biology in a context where size, composition, and individuality of the reaction are of particular importance. Finally, we will highlight important contributions of encapsulated TXTL to the development of synthetic communication paths.As the complexity of synthetic gene networks increases, more resources are shared between synthetic circuits and their host. As a result, cells experience a decrease in fitness, which limits their growth and the efficiency of synthetic circuits \u2022\u2022. Furthin vivo applications, leveraging the strong potential of riboregulation [Development of complex genetic circuits requires the use of well-characterised regulatory modules. Cell-free TXTL allows the rapid and thorough testing of new genetic parts thus enabling such characterisation .et al. proposed a method for performing TXTL reaction on a chip in which the gene template DNA was attached to a functionalised surface, first under batch conditions using wheat-germ extract [E. coli cell extract [et al. [et al. are a major technological breakthrough that will facilitate the development of numerous synthetic gene circuits in the future.In contrast with methods using free-floating DNA gene templates, Bar-Ziv  extract , and sub extract \u2022\u2022. The l [et al. \u2022\u2022  or double (water-in-oil-in-water) emulsions in order to study large number of these reactions at a cellular scale.et al., who optimised a cell-free genetic circuit based on an incoherent feedforward topology using fluorescently barcoded droplets in which lysate-based TXTL reactions can take place [Large numbers of TXTL microdroplets in oil with a controlled dispersity are easy to generate, store, and remain stable over hours, which makes them particularly interesting for screening large numbers of parameters influencing TXTL reactions c. This fke place .et al. encapsulated Xenopus egg extract in microdroplets of various size. The authors showed that the extract could undergo several mitotic oscillations, and described the influence of the size of the compartments on the period [et al. investigated the influence of surface-to-volume ratio of microcompartments on the efficiency of lysate-based TXTL, suggesting a deleterious interaction between membrane lipids and translation machinery [The reduced size of microdroplets is particularly interesting to study physical effects such as confinement. Guan e period . Sakamotachinery .et al. showed that noise in transcription reaction in systems displaying reduced diffusion resulted in gene expression bursts, which are likely to occur in cells but are not observable in bulk PURE-based TXTL reactions [Macromolecular crowding effects, which emerge in highly concentrated media such as the cytosol, can be artificially induced in TXTL mixtures using crowding additives inside microdroplets. Molecular crowding has been shown to influence the spatial segregation of biomolecules and kinetics of cell-free TXTL reactions ,48. In aeactions .et al. first implemented lysate-based TXTL reaction in a liposome permeated by haemolysin pores, which enabled the exchange of nutrients and by-products with a feeding solution, resulting in long-term gene expression [et al. tested various transcriptional cascades inside liposomes [et al. implemented a lysate-based TXTL liposome sensitive to osmotic changes via expression of the MscL calcium channel [et al. to serve as containers for the production and intratumoural delivery of a toxin protein [et al. recently described the first liposomes capable of isothermally replicating DNA using self-encoded proteins in PURE system, constituting a major step towards the construction of a true synthetic cell capable of full replication [Given that droplets are intrinsically closed systems, they cannot be utilised for long-term protein expression, nor as analogues of semi-permeable lipid bilayers for mimicking the cell membrane. Noireaux pression . Later, iposomes \u2022\u2022 , which induced the production of an enzyme disrupting an ongoing communication between an emitter bacterium (P. aeruginosa) and a receiver bacterium (engineered E. coli), a phenomenon also known as quorum quenching.Schwarz-Schilling bacteria . Each po species  (Figure Cell-free TXTL reactions are becoming an essential tool to prototype novel genetic circuits and can facilitate their integration into living hosts. In combination with microfluidic technologies and the development of novel semipermeable microcapsules, TXTL reactions constitute a unique platform for the study of gene expression and coupling to other cellular processes in a biochemically relevant microenvironment.It has been established that size and confinement have a considerable impact on TXTL reactions ,46. For Current efforts are exploring possibilities to establish communication between artificial and natural systems, working towards therapeutic applications wherein information exchange between living cells are mediated or altered. We anticipate that micro-compartmentalised TXTL\u2014by accelerating the characterisation of novel genetic circuits and orthogonal molecular communication channels\u2014will have a compelling contribution to the field of synthetic biology.Nothing declared.\u2022 of special interest\u2022\u2022 of outstanding interestPapers of particular interest, published within the period of review, have been highlighted as:"}
+{"text": "Infantile amnesia, a failure in early childhood to retain episodic memory for long periods, is a paradoxical phenomenon widely accepted as an everyday life fact, but its causes are extensively ignored. Recently, Josselyn and Frankland  proposedAfter Freud and Brill  mentioneRecently, Akers et al.  probed tThe study of McGreevy et al.  shows thLow levels of postnatal neurogenesis can also occur; maternal stress (Belnoue et al., per se. Infantile amnesia possibly allows the retention of only more critical memories, filtering those with a robust emotional component (Richardson et al., Even though higher rates of memory retention in young ages appear to be an adaptive advantage, hippocampal neurogenesis and infantile amnesia are widespread among mammals and are probably adaptive Growing evidence suggests that hippocampal neurogenesis is critical for spatiotemporal contextualization and emotional responses associated with memory processing even in humans (See references in Kempermann et al., AM-C proposed the idea. AM-C, GL-O, and PD wrote the paper. GL-O prepared the figure.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Pterosaurs are an extinct group of Mesozoic flying reptiles, whose fossil record extends from approximately 210 to 66 million years ago. They were integral components of continental and marginal marine ecosystems, yet their diets remain poorly constrained. Numerous dietary hypotheses have been proposed for different pterosaur groups, including insectivory, piscivory, carnivory, durophagy, herbivory/frugivory, filter\u2010feeding and generalism. These hypotheses, and subsequent interpretations of pterosaur diet, are supported by qualitative  and/or quantitative  evidence. Pterosaur dietary interpretations are scattered throughout the literature with little attention paid to the supporting evidence. Reaching a robustly supported consensus on pterosaur diets is important for understanding their dietary evolution, and their roles in Mesozoic ecosystems. A comprehensive examination of the pterosaur literature identified 314 dietary interpretations (dietary statement plus supporting evidence) from 126 published studies. Multiple alternative diets have been hypothesised for most principal taxonomic pterosaur groups. Some groups exhibit a high degree of consensus, supported by multiple lines of evidence, while others exhibit less consensus. Qualitative evidence supports 87.3% of dietary interpretations, with comparative anatomy most common . More speciose groups of pterosaur tend to have a greater range of hypothesised diets. Consideration of dietary interpretations within alternative phylogenetic contexts reveals high levels of consensus between equivalent monofenestratan groups, and lower levels of consensus between equivalent non\u2010monofenestratan groups. Evaluating the possible non\u2010biological controls on apparent patterns of dietary diversity reveals that numbers of dietary interpretations through time exhibit no correlation with patterns of publication (number of peer\u2010reviewed publications through time). 73.8% of dietary interpretations were published in the 21st century. Overall, consensus interpretations of pterosaur diets are better accounted for by non\u2010biological signals, such as the impact of the respective quality of the fossil record of different pterosaur groups on research levels. That many interpretations are based on qualitative, often untestable lines of evidence adds significant noise to the data. More experiment\u2010led pterosaur dietary research, with greater consideration of pterosaurs as organisms with independent evolutionary histories, will lead to more robust conclusions drawn from repeatable results. This will allow greater understanding of pterosaur dietary diversity, disparity and evolution and facilitate reconstructions of Mesozoic ecosystems. I.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Pterosaurs are an extinct clade of flying Mesozoic reptiles, with a 150\u2010million\u2010year fossil record from the Late Triassic to the latest Cretaceous  in their gut and throat (content fossils) are interpreted as direct evidence of diet  and oxygen (18O/16O) ratios from bone apatite and tooth enamel can reveal whether animals inhabited terrestrial or marine environments, allowing some limited dietary inferences to be drawn Preondactylus buffarinii and Quetzalcoatlus northropi and all its descendants  of Scotland has been considered as a basal pterosauromorph et al. i) insectivory: insects and unarmoured terrestrial invertebrates; (ii) piscivory: fish and other nektonic organisms such as cephalopods  carnivory: terrestrial vertebrates (predation and/or scavenging); (iv) durophagy: consumption of organisms with hard shells or armour  herbivory/frugivory: fruits and plant matter; (vi) filter\u2010feeding on planktonic crustacean, mollusc and/or fish larvae; (vii) generalists: where authors explicitly mention this dietary category.We used seven principal dietary categories: (i) content fossils, including coprolites; (ii) spatiotemporal associations with taxa and/or depositional environments; (iii) ichnofossils; (iv) comparative anatomy; (v) functional morphology; (vi) stable isotope analysis.We assign the evidence used to support dietary interpretations to six categories: ((3)(a)The primary data set for this study is a compilation of interpretations, each comprising a statement regarding the diet of a taxon that either is one of the recognised principal taxonomic groups, or falls within one of those groups. Each interpretation was unambiguously assigned to one dietary category and to one evidence category. Dietary statements without supporting evidence were excluded.Dietary interpretations were compiled from the literature. Publications citing previous interpretations but lacking novel data or reasoning were excluded. One hundred and twenty six publications contained at least one novel dietary interpretation. When a publication identified the same dietary and evidence categories for multiple taxa within the same principal group, this was treated as a single novel interpretation. When a publication provided a single dietary statement for a single group but supported it with more than one evidential category, this was tabulated under each evidence category.Differences in the taxonomic content of principal groups between the phylogenies led to differences in the numbers of identified interpretations. For example, a publication assessing diet for two species from the same principal group in one phylogeny was treated as one interpretation. If these two species then fell within different groups in a different phylogeny, this interpretation was counted twice, once for each group. As a result, 314 interpretations were identified for the Unwin phylogeny, 311 for the Kellner phylogeny and 301 for the Andres phylogeny.Details of interpretations for each phylogeny are included as online Supporting Information (see online Appendix S1).(b)et al. A data set of all pterosaur\u2010focused publications was compiled to estimate research effort through time, from 1784 to February 2017. The sum of all publications (1828) is likely a slight underestimate.(4)et al., P < 0.05), and therefore a Spearman's rank correlation was used when comparing dietary groups and species counts.Numbers of interpretations for each dietary and evidence category were summed for each principal group. Total percentages of each evidence category were calculated. To investigate possible biological and non\u2010biological drivers of the diversity of dietary interpretations, numbers of species from each principal group were compared to numbers of assigned dietary categories. More speciose groups are hypothesised to have greater dietary diversity because they exhibit more morphological variation  late 18th and 19th centuries (N = 3 from two publications); (ii) 1900\u20131969 (N = 17 from eight publications); (iii) 1970\u20131999 (N = 61 from 22 publications); (iv) 2000\u2013present (N = 233 from 94 publications).To assess changes in dietary consensus through time, dietary interpretations for each principal group were assigned to one of four different stages of pterosaur research history Witton, : (i) latIII.(1)Total numbers of dietary interpretations for each principal group Fig.  show lar(2)There is a large disparity in the numbers of interpretations supported by qualitative  and quantitative  approaches, with the former supporting 87.3% of all interpretations Fig. . Compara(3)N = 16, P = 0.031) .There is a moderate positive correlation between pterosaur species per principal group and dietary categories for respective principal groups when Ornithocheiridae is excluded as an outlier The phylogenetic distributions of dietary interpretations for particular groups are broadly consistent among the three phylogenies . However, \u2018basal\u2010most pterosaurs\u2019 and Rhamphorhynchidae in the Andres phylogeny contain substantially more interpretations than their equivalents in the other phylogenies.(5)P = 0.302)  Fig. A. The nu02) Fig. A. There 02) Fig. A. Publis02) Fig. A. This d02) Fig. A. The nu02) Fig. B. The ea(6)During the 19th century, 0.97% of dietary interpretations were proposed, 5.5% were proposed between 1900 and 1969, 19.7% between 1970 and 1999, and 73.8% since 2000 et al. c. 215\u2013190 Ma) of the UK and Italy   digital reconstructions from \u2018mathematical slices\u2019 of specimen illustrations do not support this hypothesis et al., Anurognathids are known from the Middle\u2013Upper Jurassic 161\u2013145 Ma) of Germany, Central Asia and China  ichnofossils Fig. . AnurognBennett, , 2007. SBennett, , 2007. ABennett, . High stBatrachognathus volans and Jeholopterus ningchengensis are known from lacustrine deposits and exhibit slightly recurved teeth c. 215\u2013176 Ma) of Central Europe and Greenland (a)et al., Rhamphorhynchines are from the Middle\u2013Upper Jurassic of Europe and China , and a rhamphotheca at the anterior end of the jaw, possibly for skim\u2010feeding on fish et al., Scaphognathines are from the Middle\u2013Upper Jurassic of Europe, Asia and Cuba  and albatrosses (Diomedeidae) et al., et al., et al., et al., Basal monofenestratans are from the Middle\u2013Upper Jurassic 165\u2013151 Ma) of China et al., Istiodactylids are from the Lower Cretaceous 130\u2013112 Ma) of the UK and China . The proportional lengths of these bones are reportedly similar to modern chameleons (Chameleonidae), and Liaoxipterus was thus reasoned to have caught insects with the aid of a projectile tongue et al., Ornithocheirids are from Lower\u2013Upper Cretaceous 140\u201395 Ma) deposits on all continents except Antarctica (a)et al., Pteranodontids are from the Lower\u2013Upper Cretaceous 100\u201380 Ma) of North America and Europe  possess similarly narrow jaws et al., Nyctosaurus gracilis exhibiting an \u2018antler\u2010like\u2019 head crest  of Mid\u2010West USA, Mexico and Brazil (a)et al., Pterodactylus species exhibit straight, thin jaws with around 50\u201370 small, conical teeth  of Germany  et al., Ctenochasmatids are from the Lower\u2013Upper Cretaceous 152\u2013100 Ma) of Argentina, Central and Western Europe, Morocco, and East Asia   Fig. . FunctioPiscivory interpretations are based on comparative anatomy Fig. . Sharp, Pterodaustro exhibit short, rounded teeth in their upper jaws, perhaps for crushing hard\u2010shelled crustaceans Lonchodectids are poorly known pterosaurs known from the Lower\u2013Upper Cretaceous 140\u201390 Ma) of China, the UK and Brazil (a)et al., Germanodactylus for example, exhibits edentulous jaw tips and low\u2010crowned teeth, supposedly for selecting and crushing bivalve and crustacean shells  of Central and Western Europe, USA and Tanzania et al., et al., et al., et al., Dsungaripterids are from the Lower Cretaceous 145\u2013100 Ma) of China, Mongolia and South America et al., et al., Tapejarids are from the Lower\u2013Upper Cretaceous 130\u201393 Ma) of Brazil, Spain and China et al., Chaoyangopterids are from the Lower Cretaceous 130\u2013112 Ma) of China and Brazil, and had 1\u20134 m wingspans and \u2018scissor\u2010like\u2019 edentulous jaws et al., et al., Thalassodromids are from the Lower Cretaceous of Brazil 125\u2013100 Ma) et al., et al., Azhdarchids are from the Upper Cretaceous (99\u201366 Ma) of North America, North Africa, Eastern Europe and Asia Overall, there is limited consensus on diets for most pterosaur groups. Most dietary interpretations are supported by qualitative evidence, most commonly from comparative anatomy. There is strong consensus on diets for some pterosaur groups, such as insectivory in Anurognathidae and piscivory in Ornithocheiridae and Pteranodontidae, supported by one or several evidential categories. For other groups there is little consensus: in both basal ctenochasmatoids and Azhdarchidae, for example, six distinct diets have been suggested. In general, pterosaur principal groups with more species exhibit a higher diversity of dietary hypotheses. Choice of phylogeny has some impact on consensus, with the largest differences observed between phylogenies for non\u2010monofenestratan groups. Numbers of dietary interpretations exhibit small increases for much of pterosaur research history, with most interpretations proposed in the 21st century. Changes in the number of dietary interpretations through time do not correlate with numbers of pterosaur publications.et al., That the majority of dietary interpretations are qualitative is unsurprising because such interpretations can be readily proposed without rigorous experiments or analyses. Comparative anatomy uses extrapolations from observational, and occasionally experimental, studies of extant organisms Aerts, . Associaet al., i) they often require specialist technology and/or equipment; (ii) they require thorough understanding of experimental design and hypothesis testing; (iii) they can require destructive sampling of specimens et al., The range of methods employed in analysis of pterosaurs has proven highly successful in generating interpretations of diet. What is less clear, however, is how well they have performed in differentiating between alternative interpretations, and this partly explains why, for most pterosaur groups, multiple interpretations have been proposed. Greater use of analytical and experiment\u2010led methodologies (Veldmeijer (a)et al., Comparative anatomy is fundamental for analysis of homology and character evolution but has limitations as a tool for analysis of function and diet. Its application in this context is based on the assumption that convergence of morphological structures between extant and extinct taxa allows us to infer similar functional roles for structures in extinct taxa, including foraging and feeding ecology et al., Despite the straightforwardness of using associations, deriving dietary interpretations from simple presence and/or absence of contemporaneous fossils amounts to little more than speculation. Likewise, solely examining depositional environments does not account for organism dispersal abilities and taphonomic biases such as carcass transportation (Veldmeijer (c)et al., in vivo data)   crania, for example, found that models which accounted for the heterogeneous nature of material properties in bone across the cranium exhibited fewest discrepancies with experimental outputs , aerial  and aquatic\u2010based (diving and wading) behaviours can provide new constraints, or corroborate existing constraints, on possible foraging strategies and food\u2010acquisition behaviours. Locomotory models, however, are heavily influenced by mass estimations Witton, . Greater(d)et al., post mortem artefacts, with items introduced via water flows et al., via alignment of photographs taken from numerous angles 15N and/or \u03b4 13C. In the context of extant animals, isotopic approaches to dietary reconstruction are not without methodological limitations . Analysis of carbon isotopes from tooth enamel is possible, but this is primarily used to infer the relative proportions of C3 and C4 plants consumed et al., et al., Only one study has examined dental wear patterns on pterosaur teeth and used this to infer aspects of diet and the material properties of food \u0150si, . Dietaryet al., et al., et al., et al., et al., A more robust approach involves quantitative analysis of the sub\u2010micron scale 3D surface textures of teeth, known as dental microwear texture analysis  A range of diets have been proposed for pterosaurs including insectivory, piscivory, carnivory, durophagy, filter\u2010feeding and generalism.(2) Most pterosaur dietary interpretations are supported by qualitative evidence including comparative anatomy, associations, content fossils and ichnofossils with a minority supported by quantitative evidence from functional morphology and isotope analyses.(3) Some pterosaur principal groups exhibit high levels of consensus regarding diet, supported by several evidential categories; others exhibit lower levels of consensus, with different interpretations inferred from conflicting evidence of the same categorical type, and typically poorly constrained analogy drawn from comparative anatomy.(4) More speciose pterosaur groups exhibit higher diversity of hypothesised diets. Whilst this may reflect biological signals such as ecological radiations or niche partitioning, non\u2010biological causes, such as historical biases in the data, quality of the fossil record and research intensity are more likely. These biases mean it is currently difficult to reliably test the hypothesis that the apparent patterns of pterosaur dietary diversity and disparity are biologically controlled.(5) Examining patterns of dietary diversity using different phylogenies reveals higher consensus among monofenestratan groups and lower consensus in non\u2010monofenestratan groups. Better resolution on the membership of pterosaur groups would assist in uncovering true diets for respective groups.(6) Numbers of pterosaur publications per year and dietary interpretations do not correlate through time. The majority of interpretations were proposed in the 21st century. The almost exponential rise in the number of publications containing dietary interpretations since the 1980s coincides with discoveries of new Lagerst\u00e4tten and other exceptionally preserved sites, as well as applications of new techniques to pterosaurs.(7) Many dietary interpretations are based on simple extrapolations and comparisons with modern biology with little scope for testing. Qualitative methods can serve as starting points for generating hypotheses, but quantitative tests provide more robust analyses and insights into dietary diversity, evolution and the ecological roles of pterosaurs. Improvements to current methods and application of novel methods to pterosaurs will provide better constraints on diets in pterosaurs with low levels of consensus, and better tests of dietary hypotheses in pterosaurs with high levels of consensus. This will allow reliable investigations into possible biological signals behind pterosaur dietary diversity and disparity, which will allow greater understanding of pterosaur dietary evolution and facilitate reconstructions of Mesozoic ecosystems.Appendix S1. Breakdowns of all pterosaur dietary interpretations, detailing dietary and evidential category assortments, for each of the Unwin, Kellner and Andres phylogenies. The Kellner and Andres pterosaur phylogenies  and dietary interpretations for each pterosaur principal group  are also included. Further information on phylogenies and the full list of 180 pterosaur species assorted into principal groups from the Unwin phylogeny is also provided.Click here for additional data file."}
+{"text": "Dear Editor,A receptor. Therefore, endothelin-1 leads to a narrowing of the liver sinusoids and an increase of portal pressure . TGR5 ial., 2019). MoreovThe prevalence of liver diseases currently increases (Jansen et al., 2017; EkhlasiThe author declares no conflict of interest."}
+{"text": "A and GABAB receptors . In immature networks and during numerous pathological conditions the strength of GABAergic synaptic inhibition is much less pronounced. In these neurons the activation of GABAAR produces paradoxical depolarizing action that favors neuronal network excitation. The depolarizing action of GABAAR is a consequence of deregulated chloride ion homeostasis. In addition to depolarizing action of GABAAR, the GABABR mediated inhibition is also less efficient. One of the key molecules regulating the GABAergic synaptic transmission is the brain derived neurotrophic factor (BDNF). BDNF and its precursor proBDNF, can be released in an activity-dependent manner. Mature BDNF operates via its cognate receptors tropomyosin related kinase B (TrkB) whereas proBDNF binds the p75 neurotrophin receptor (p75NTR). In this review article, we discuss recent finding illuminating how mBDNF-TrkB and proBDNF-p75NTR signaling pathways regulate GABA related neurotransmission under physiological conditions and during epilepsy.In the mature healthy mammalian neuronal networks, \u03b3-aminobutyric acid (GABA) mediates synaptic inhibition by acting on GABA A) receptors (GABAARs) causes membrane depolarization and Ca2+ influx in immature neurons , respectively  is ~78\u201382 mV, close to the resting membrane potential  hyperpolarization or depolarization. The activation of GABAARs during neuronal depolarization induced by the excitatory synapses allows massive Cl\u2212 entry that provides strong hyperpolarizing force and effectively compensates or diminishes the strength of the excitatory signal. The increased [Cl\u2212]i is rapidly extruded by electroneutral neuron-specific potassium-chloride cotransporter KCC2  complex which leads to a clathrin-mediated internalization  and PKC pathways , a downstream target of PI-3 kinase  signaling cascade . The surface expression of GABA transporter-1 (GAT-1), the major GABA transporter expressed by both neurons and astrocytes , attributed to the activity of KCC2  and not observed in BDNF KO mice (Fiorentino et al., BRs induce a calcium-dependent release of BDNF via the PLC-PKC signaling cascade and L-type voltage-gated calcium channels (Fiorentino et al., BRs also increased the phosphorylation levels of the \u03b1-CamKII, which play a critical role in BDNF release (Fischer et al., B-R-mediated release of BDNF. Interestingly, the regulated secretion of BDNF following GABAB receptor activation increases the number of GABAA \u00df2/3 subunits receptors at the postsynaptic membrane (Kuczewski et al., BRs activation and the subsequent BDNF secretion in developing hippocampal neurons contribute to the functional maturation of GABAergic synaptic transmission.Similarly to BDNF, a crucial factor regulating the development of inhibitory transmission is GABA itself (Ben-Ari et al., a et al.  demonstr\u2212 homeostasis are considered to play a crucial role in epileptogenesis. Initial studies regarding the contribution of BDNF to epilepsy led to conflicting conclusions, with intrahippocampal BDNF perfusion or intraventricular injection of the BDNF scavenger TrkB-IgG, both being protective in a model of dorsal hippocampal kindling (Reibel et al., NTR are markedly increased after Pilocarpine-induced seizures. The elevated amounts of proBDNF following SE are associated with reduced proBDNF cleavage machinery that results from acute decreases in tPA/plasminogen proteolytic cascade and increases in API-1, an inhibitor of proBDNF cleavage (Reibel et al., NTR response following SE selectively downregulates KCC2, which in turn promotes a chloride homeostasis dysregulation leading to an excitatory action of GABAA receptors and facilitate epileptiform discharges (Kourdougli et al., NTR during the earliest phase of epileptogenesis restores KCC2 levels and reduces seizures frequency (Kourdougli et al., NTR play a critical role in the mechanisms of epileptogenesis (see Figure A receptor endocytosis and degradation (Riffault et al., ARs \u03b11 subunit gene through the activation of JAK-STAT pathway following SE (Lund et al., NTR signaling during the first postnatal weeks causing an impaired or delayed functional maturation of GABAergic inhibition. Alternatively, an excess of BDNF production and secretion associated with reductions in proBDNF cleavage in epileptic tissues (Ernfors et al., Epilepsy is a brain disorder characterized by the appearance of spontaneous recurrent seizures due to network hyperexcitability (Fischer et al., Unveiling the mode of action of BDNF in the development and functioning of the GABAergic network is a promising quest for developing new cures of a number of neurological diseases. BDNF influences the development and functioning of the GABAergic network which in turn controls BDNF levels. As a result of this interaction, impairment of one of the two systems will most disturb the other, and since each of them is fundamental to normal CNS functioning, this will potentially lead to a host of neurological conditions. As of today, there is hope that investigation of the molecular pathways mediating the trophic action of BDNF may provide new insights into the normal development of the GABAergic network, providing new therapeutic strategies to improve the symptoms in a broad spectrum of GABA-related pathologies.The review was conceptualized, written and edited by each of the authors. CP was the supervisor.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The cerebellum plays a critical role in coordinating and learning complex movements. Although its importance has been well recognized, the mechanisms of learning remain hotly debated. According to the classical cerebellar learning theory, depression of parallel fiber synapses instructed by error signals from climbing fibers, drives cerebellar learning. The uniqueness of long-term depression (LTD) in cerebellar learning has been challenged by evidence showing multi-site synaptic plasticity. In Purkinje cells, long-term potentiation (LTP) of parallel fiber synapses is now well established and it can be achieved with or without climbing fiber signals, making the role of climbing fiber input more puzzling. The central question is how individual Purkinje cells extract global errors based on climbing fiber input. Previous data seemed to demonstrate that climbing fibers are inefficient instructors, because they were thought to carry \u201cbinary\u201d error signals to individual Purkinje cells, which significantly constrains the efficiency of cerebellar learning in several regards. In recent years, new evidence has challenged the traditional view of \u201cbinary\u201d climbing fiber responses, suggesting that climbing fibers can provide graded information to efficiently instruct individual Purkinje cells to learn. Here we review recent experimental and theoretical progress regarding modulated climbing fiber responses in Purkinje cells. Analog error signals are generated by the interaction of varying climbing fibers inputs with simultaneous other synaptic input and with firing states of targeted Purkinje cells. Accordingly, the calcium signals which trigger synaptic plasticity can be graded in both amplitude and spatial range to affect the learning rate and even learning direction. We briefly discuss how these new findings complement the learning theory and help to further our understanding of how the cerebellum works. It is widely recognized that the cerebellum is critical in coordinating muscles and learning novel movements with highly accurate and temporal precision. Even for a simple finger-to-nose task, to make different segments of hand and arm interact smoothly, humans need the cerebellum to precisely modulate the sequence and duration of elementary movements. The cerebellum has a relatively simple anatomy and the anatomic connections involved in its associated functions are also well known. In this context, the cerebellum becomes an ideal structure to explore learning rules and it also opens a window for us to begin to comprehend how the brain works.via excitatory synaptic connections. Small granule cells are electrically compact and they constitute the majority of neurons in the brain. Their axons project up into the molecular layer of the cerebellar cortex, bifurcate and form excitatory synapses onto Purkinje cell dendrites. As the sole output of the cerebellar cortex, each Purkinje cell is contacted by ~150,000 parallel fiber (bifurcations of granule cell axons) synapses. Meanwhile, parallel fibers also activate stellate cells and basket cells, which form inhibitory synapses with Purkinje cells, establishing a stereotypical feed-forward-inhibition circuit. Stellate cells tend to locate in the outer part of the molecular layer and mainly target Purkinje cell distal dendrites. In contrast, basket cells locate in the inner part of the molecular layer and mainly target Purkinje cell somas and axon initial segments (AIS).For decades, it has been of great interest to decipher cerebellar learning algorithms , adds to the confusion. In a recent experimental data-based theoretical study by Zang et al. (+ channels, and dendritic spike patterns.On one hand, a growing body of experimental evidence demonstrates the variability of climbing fiber responses, but on the other hand, it fails to provide a systematic explanation of somatic and dendritic spike initiation and variation and leads to many conflicting observations that stymie delineation of the functional role of climbing fibers in cerebellar learning. Furthermore, limited information extracted from noisy g et al. , the biog et al. . The som2+ influx can be graded by climbing fiber firing patterns, coincident background synapses, and voltage states in an analog manner. The conflicting spatial range of Ca2+ influx observed in different experiments can be accounted for by different voltage states (Miyakawa et al., 2+ channels, but also voltage-dependent K+ channels. Climbing fibers directly excite and depolarize proximal smooth dendrites (Palay and Chan-Palay, 2+ channels. When dendritic membrane potential is hyperpolarized, the large availability of K+ currents outweighs P-type Ca2+ current to \u201cbrake\u201d the initiation of dendritic spikes in distal parts. With depolarization, K+ currents inactivate and axial currents can trigger dendritic spikes in the whole dendrite. Theoretically, voltage-dependent climbing fiber responses also endow single Purkinje cells with the ability to overcome the credit assignment problem. Individual Purkinje cells can extract specific instruction information according to their firing states (equivalent to voltage states in vivo; Jelitai et al., In agreement with Ohtsuki et al.  and Otsu2+ influx is larger than spontaneous Ca2+ spikes to signal the occurrence of an unexpected sensory event. Furthermore, Ca2+-based instruction signals in Purkinje cell dendrites contain analog information that encodes the strength of instructive stimuli trial-by-trial (Najafi et al., 2+ influx in Purkinje cells. Extracellular microelectrodes are usually used to extract simple spikes and complex spikes in vivo. Nonetheless, complex spike patterns are extremely variable in spikelet numbers and durations (Warnaar et al., in vivo noise. Thus, it is easier to sort complex spikes from Purkinje cells with low firing rates compared to Purkinje cells with high firing rates, and this causes unavoidable bias in statistical analyses. Sometimes, it is even impossible to separate a complex spike with its subsequent simple spike, when the complex spike lacks a significant pause. This situation mainly occurs when there is only one dendritic spikelet that fails to hyperpolarize dendrites (see Figure 6A in Davie et al., 2+ influx (Zang et al., Although Purkinje cells and climbing fibers are capable of encoding analog signals, does this really contribute to cerebellar learning? As reported by Najafi et al. , sensoryNoticeably, theoretical studies have also started to test the role of graded climbing fiber responses in cerebellar learning. Using a cerebellar network model with necessary climbing fiber-evoked burst-pause information in Purkinje cells (different with parallel fiber-evoked burst-pause by Steuber et al., 2+ induction threshold, usually with a climbing fiber as the polarity switch (2+ influx relative to the threshold, regardless of concurrent climbing fiber signals (Parallel fiber synapses exhibit bidirectional long-term plasticity (Coesmans et al., y switch . Howevery switch , and LTDy switch . Mathy ey switch  requiredy switch . Pooling signals . In the  signals . Nonethe signals . The aut signals  demonstr signals  and ther signals . In a mo signals  demonstr2+ influx and consequently shifts plasticity from LTD to LTP.Although LTD is demonstrably critical in cerebellar learning, at least in some behavioral contexts, there is increasing awareness that it is not the sole mechanism. Accumulating evidence demonstrates that LTP of parallel fiber synapses also functions in procedural learning (Schonewille et al., 2+ influx is constrained to proximal dendrites in Purkinje cells showing decreased firing rates, as observed in vitro (Zagha et al., 2+ influx is still global in Purkinje cell dendrites, is it within the range of triggering LTP rather than LTD? In other words, does the directional change of Purkinje cell simple spike firing rates determine the polarity of parallel fiber synaptic strength changes, with LTD in \u201cbursting\u201d Purkinje cells, but LTP in \u201cpause\u201d Purkinje cells?In cerebellum-related behaviors such as saccadic eye movement (Herzfeld et al., 2+ threshold-dependent plasticity rule (Coesmans et al., A recent study proposed synaptic plasticity rules that strikingly contradict the current consensus of plasticity induction to solve the credit assignment problem (Bouvier et al., 2+ influx determines the computational unit of climbing fiber responses and constrains the learning capacity of individual Purkinje cells. Although Ca2+ influx due to strong parallel fiber-triggered dendritic spikes is constrained to branchlets (Hartell, 2+ signals was first shown to increase with distance from the soma in anesthetized rats (Kitamura and Hausser, 2+ channels with distance from the soma. In the physiologically detailed Purkinje cell model with homogeneous distributed Ca2+ channels, dendritic Ca2+ influx increases significantly with distance from the soma and shows significant variations in different branchlets at similar distances (Zang et al., in vivo, including firing state-related availability of K+ channels, concurrent synaptic input and compartment-specific dendritic excitability plasticity (Kitamura and Hausser, 2+ influx implies that both LTP and LTD can occur coincidently at different dendritic branchlets of a Purkinje cell. This spatio-temporal variability can be fine-tuned to modulate the distribution of branchlet-specific synaptic changes, rather than a homogeneous change. Accordingly, the learning capacity of single Purkinje cells can be significantly increased, which may be necessary for complex and arbitrary movement learning (Bouvier et al., Conventionally, dendritic trees are thought to just receive synaptic inputs from presynaptic cells and to convey them to the soma. In recent years, more and more experimental data have uncovered local computation in neuronal dendrites (Branco and H\u00e4usser, Hartell, , informaIn contrast to the idea of climbing fibers as teachers in the Marr-Albus-Ito theory, an alternative view of their role is to provide a \u201cmotor clock\u201d function in the initiation and timing of movements (Welsh et al., via complex spikes (Tang et al., Is there any connection between the \u201cmotor clock\u201d signal and instruction signal? The finding by Mathy et al.  of climbDespite the growing awareness of multisite learning (Gao et al., YZ wrote the initial draft and revised it. ED edited the draft and revised it.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Al3+ has lethal effects on many aspects of the rhizobia/legume symbiosis, which include a decrease in root elongation and root hair formation, lowered soil rhizobial population, and suppression of nitrogen metabolism involving nitrate reduction, nitrite reduction, nitrogenase activity and the functioning of uptake of hydrogenases (Hup), ultimately impairing the N2 fixation process. At the molecular level, Al is known to suppress the expression of nodulation genes in symbiotic rhizobia, as well as the induction of genes for the formation of hexokinase, phosphodiesterase, phosphooxidase and acid/alkaline phosphatase. Al toxicity can also induce the accumulation of reactive oxygen species and callose, in addition to lipoperoxidation in the legume root elongation zone. Al tolerance in plants can be achieved through over-expression of citrate synthase gene in roots and/or the synthesis and release of organic acids that reverse Al-induced changes in proteins, as well as metabolic regulation by plant-secreted microRNAs. In contrast, Al tolerance in symbiotic rhizobia is attained via the production of exopolysaccharides, the synthesis of siderophores that reduce Al uptake, induction of efflux pumps resistant to heavy metals and the expression of metal-inducible (dmeRF) gene clusters in symbiotic Rhizobiaceae. In soils, Al toxicity is usually ameliorated through liming, organic matter supply and use of Al-tolerant species. Our current understanding of crop productivity in high Al soils suggests that a much greater future accumulation of Al is likely to occur in agricultural soils globally if crop irrigation is increased under a changing climate.Recent findings on the effect of aluminium (Al) on the functioning of legumes and their associated microsymbionts are reviewed here. Al represents 7% of solid matter in the Earth\u2019s crust and is an important abiotic factor that alters microbial and plant functioning at very early stages. The trivalent Al (Al Legumes, therefore, play a major role in reducing poverty, improving human health and nutrition and enhancing ecosystem functioning. With more than 78.3\u00a0million\u00a0ha of land planted to legumes, these species provide over 35% of the world\u2019s protein intake  by legumes is therefore a major source of N for agriculture  stress 2+, Al(OH)2+, Al(OH)3 and Al(OH)4\u2212 2+ and Al(OH)2+ species are formed as the soil pH increases 4\u2212] dominates under alkaline conditions  and phosphoenol pyruvate carboxylase (PEPC), which catalyse the formation of carboxylic acids  and Cd (0.3\u20130.5\u00a0mM)  gene clusters have been discovered in Rhizobium leguminosarum bv. viciae and other members of the Rhizobiaceae that are expressed in response to heavy metal concentrations  . We postulate that organic acids (OAs) secreted by roots and cluster roots chelate with active Al to form inactive complexes in the rhizosphere. We also suggest that these OAs inside roots and cluster roots form complexes with incoming active Al ions to form inactive Al-OA complexes that are stored in non-toxic forms in roots and cluster roots. This model could explain why the Al concentrations in below-ground organs such as roots and cluster roots are many folds greater than Al levels in above-ground shoots. In our view, this constitutes the mechanism by which A. linearis can thrive in Al-rich, highly acidic soils in the Cape Fynbos of South Africa. Taken together, these biochemical subtleties in Al tolerance support A. linearis as a natural system for studying metal tolerance in nodulated perennial legumes  the selection and use of legume/rhizobia symbioses resistant to metals, (ii) the use of mixed inoculants containing metal-resistant rhizobia and plant growth-promoting rhizobacteria and (iii) plant inoculation with a mixture of rhizobia and mycorrhizae (Pajuelo et al. Furthermore, the ability of legumes such as 2 fixation of A. linearis (Muofhe and Dakora Interestingly, while there is evidence of acid-tolerant genes in symbiotic rhizobia (Dilworth et al. 2+ to overcome inhibition of root elongation by Al. Thus, even though tap roots might extend into acidic soil zones, development of lateral roots for nutrient and water capture could still be limited (Ferrufino et al. Al phytotoxicity can be amended through liming with calcium carbonate, addition of organic matter and/or by use of Al-tolerant species (Mokolobate and Haynes + and Al+3 activities (Sanzonowicz et al. +3 activity at root cell plasma membrane, thus preventing the disruption of cell expansion and cell division commonly induced by Al toxicity (Kochian Liming has also been found to increase Ca availability to rhizobia and the symbiosis (Hungria and Vargas  Kochian . Similar Kochian . Applied Kochian .Organic matter can also be used to overcome Al toxicity in plants and microbes Foy . During 2 fixation and decreased crop yield. Therefore, selecting legume/rhizobia symbioses that are tolerant of Al toxicity is the easiest way to increase crop yields in Al-rich acidic soils. A better understanding of legume exudation in response to Al toxicity and the mechanisms underlying rhizobial tolerance of Al stress is crucial for increasing yield of grain and pasture legumes. Furthermore, understanding gene expression in the presence of added Al may be a strategy for identifying rhizobial genes and legume traits that permit high N2 fixation in the presence of Al stress.Taken together, Al stress is a major abiotic factor affecting plant growth and productivity. With 40% of the world\u2019s arable land consisting of acid soils and Al toxicity being associated with low pH, global legume production is likely to be hugely constrained. This is because Al toxicity in soils can inhibit root elongation, lateral root development, root hair growth, rhizobial infection of the roots, Nod factor production and nodule development, resulting in low N"}
+{"text": "ARs) are the major mediators of synaptic inhibition in the brain. Aberrant GABAAR activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer\u2019s and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABAARs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABAAR subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABAAR-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABAAR numbers and clustering, modifying neuronal transmission. Interference with GABAAR trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABAAR to AP2 increase the surface concentration of GABAAR clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABAAR accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABAAR modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs.\u03b3-aminobutyric acid type A receptors (GABA ARs) are the principal mediators of phasic and tonic inhibition in the human brain, being a vital part of the molecular machinery that creates cognition, behavior, and consciousness  domain carrying proteins. These showed that through modulation of receptor-scaffolding protein interactions a variety of responses could be achieved, ranging from disruption of glutamate signaling to neuroprotective effects in ischemic brain damage  is a guanine nucleotide exchange factor for Cdc42, a gephyrin binding partner (Kins et al., AR subtypes and GABAAR scaffolds. Neuroligin dysfunction has been implicated in autism (Pettem et al., AR, remain uncharacterized. These molecular insights could greatly contribute to our understanding of the development of the inhibitory synapse, as well as the underlying molecular causes of developmental diseases. Neuroligin family members exert distinct roles in the formation and stabilization of inhibitory and excitatory synapses and display distinct cellular and subcellular distributions. Accordingly, molecules that interfere with their isoform-specific interactions could act as highly cell-type selective modulators of neurotransmission.Proteomic studies (Kang et al., ARs. The loss of gephyrin clusters following the loss of the GABAAR \u03b32 subunit (Essrich et al., AR clusters upon gephyrin deficiency (Kneussel et al., AR subunits could be confirmed (Tretter et al., in-silico studies (Pennacchietti et al., AR complexes and demonstrated that at least the GABAAR \u03b11\u20133 and GlyR \u03b2 subunits bind to an overlapping site within gephyrin in a mutually exclusive fashion (Maric et al., ARs and GlyRs (Specht et al., Gephyrin is a prime candidate for the role of master regulator of neuronal function at inhibitory sites (Tyagarajan and Fritschy, AR diffusion and contributing to input-specific adaptations at postsynaptic sites (Chen et al., AR synapse dynamics remain to be explored in a comprehensive approach that includes an extensive alternative splicing and complex post-translational modification patterns of this region. Identification of the targeted binding pockets and insights into the binding affinities of the modified and unmodified peptide regions within the central region of gephyrin could shed light on the enigmatic molecular mechanisms of gephyrin multimerization, degradation and the tuning of its ligand binding affinities. Additionally, gephyrin isoforms are tissue-specific (Paarmann et al., Gephyrin itself is dynamically regulated, affecting GABAvia gephyrin was achieved more than a decade ago using intrabodies (Zacchi et al., ARs. One such example is artemisinins [AR signaling. Kasaragod et al. (ARs clustering, making artemisinins the first small molecule lead compounds for a new class of inhibitory neurotransmission modulators. Strikingly, the druggable artemisinin-binding pocket overlaps with the universal receptor binding region of gephyrin, which is critical for the interaction with GABAA and glycine receptors (Kasaragod et al., A and glycine receptors that bind to gephyrin. Biomimetic optimization of the \u201chotspots\u201d amino acid sequence, enhanced the affinity of the resulting peptide ligands 46,000-fold compared to the corresponding native peptides (Maric et al., in vitro applications of these new super binder peptide reduced GABAAR \u03b12 conductivity and clustering, providing evidence that GABAAR-associated proteins can be successfully targeted with modified peptides to modulate fast synaptic inhibition (Maric et al., Gephyrin\u2019s crucial role in glycinergic and GABAergic transmission made it a major pharmacological target. The modulation of synaptic responses d et al.  identifiAR trafficking is pivotal for the plasticity (Luscher et al., AR cycling is involved in various neurological disorders (Smith and Kittler, AR sites, that are involved in the trafficking of the receptors, has been identified to control receptor numbers and their concentration at synaptic sites (Comenencia-Ortiz et al., AR trafficking, endocytosis, degradation or recycling, is a promising pharmacological strategy. The proposed direct protein interactors are numerous, among them are muskelin (Heisler et al., GABAAR interaction rapidly modulates synaptic GABAAR numbers, inhibitory synaptic strength, neuronal excitability, and notably, affects animal behavior (Kittler et al., AR subunits (AR derived peptides, that effectively compete with AP2 binding, were successfully used to block the receptor internalization in hippocampal neurons, increasing surface concentration of GABAAR clusters by 50% (Smith et al., AR interactions with its intracellular trafficking partners is an alternative way to influence GABAergic signaling.The AP2-GABAsubunits . Short GAR clustering, like artemisinins or \u201csuper binding peptides,\u201d could reduce the GABAAR synaptic concentration and function. On the other hand, peptides hampering receptor interaction with AP2 trafficking protein increased the synaptic receptor levels. In theory, these approaches could be applied together to achieve bi-directional modulation of inhibitory neurotransmission, promoting a shift in the dynamic equilibrium from phasic to tonic neuronal response.Ongoing research uncovered original, seemingly contrasting, strategies of GABAergic signaling modulation. On the one hand, ligands disrupting gephyrin-GABAAR associated scaffold or trafficking proteins could be applied wherever abnormal GABAergic activity or regulation is involved in pathogenesis. In status epilepticus patients develop a time-dependent pharmacoresistance to GABAergic agents, probably, due to GABAAR internalization (Naylor et al., ARs (Nicholson et al., ARs and both could potentially be alleviated by targeting GABAAR-associated proteins. Stabilization of the gephyrin-receptor scaffolds at inhibitory postsynapses with molecules that mimic the stabilizing action of CB (Saiepour et al., AR loss and preserve inhibitory neurotransmission, alternatively, applying AP2 inhibitors could reduce GABAAR internalization and reverse the loss of postsynaptic GABAARs. Those examples illustrate the potential of GABAergic modulators as adjuvants ameliorating the effect of existing potent drugs, whereas in epilepsy or other diseases involving deregulation of inhibitory neurotransmission they could be applied as stand-alone therapeutics.Those new strategies of GABAergic neurotransmission modulation possess an untapped clinical potential. Agents targeting GABAAR intracellular interactors, accelerated by in-silico predictions and high throughput approaches, will lead to the discovery of novel GABAergic modulators. Affinity, selectivity, bioavailability and immunogenicity of these compounds would have to be optimized for clinical applications, where peptide-based ligands could be further evolved by the introduction of unnatural amino acids, cyclization and other chemical modifications.We expect that the study of GABAMicroscopy is an additional intriguing application of these molecules. The enhanced affinity and specificity of the engineered peptide-based compounds allowed to pioneer their use as fluorescent probes [AR associated proteins could prove to be a versatile pharmacological strategy with clinical potential. Further, we suggested that when combined with state-of-the-art super-resolution microscopy methods, the peptide-based fluorescent probes may resolve the nanoscale architecture of synapses in unprecedented detail. We anticipate that the discovery of additional GABAAR interactors could open the way for the development of new imaging tools and alternative pharmacological approaches.Here, we discussed how the targeting of GABAVK and HM wrote the manuscript and prepared the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In a recent study, Tuuli Karhu and colleagues from Helsinki University compared a set of cell lines for their susceptibility towards eight GATA4 targeting compounds . GATA4 al., 2018; Kikuchial., 2018; Pikkaraal., 2018). The goal., 2018). Of couIn recent years, the development of stem cell based test systems has been a major focus of research (Leist et al., 2017; Godoy ein vivo relevance still remains a major challenge.This approach has been used for developmental neurotoxicity (Waldmann et al., 2014; Meganat"}
+{"text": "Following systematic scrutiny of the evidence in support of the hypothesis that the cardioprotective mechanism of action of dexrazoxane is mediated by a \u2018depletion\u2019 or \u2018downregulation\u2019 of Top2\u03b2 protein levels in heart tissue, the author concludes that this hypothesis is untenable. In seeking to understand how dexrazoxane protects the heart, the outcomes of a customised association rule learning algorithm incorporating the use of antecedent surrogate variables  reveal a previously unknown relationship between dexrazoxane and poly(ADP-ribose) (PAR) polymer. The author shows how this previously unknown relationship explains both acute and long-term cardioprotection in patients receiving anthracyclines. In addition, as a direct inhibitor of PAR dexrazoxane has access to the epigenome and this offers a new insight into protection by dexrazoxane against doxorubicin-induced late-onset damage . Notably, through this review article, the author illustrates the practical application of probing natural language text using an association rule learning algorithm for the discovery of new and interesting associations that, otherwise, would remain lost. Historically, the use of CEME enabled the first report of the capacity of a small molecule to catalyse the hybrid self-assembly of a nucleic acid biopolymer via canonical and non-canonical, non-covalent interactions analogous to Watson Crick and Hoogsteen base pairing, respectively. Dexrazoxane (ICRF-187)  belongs  et al throughout the 1970s and 1980s .\u22123 = \u03bcM) with concentrations in ex vivo tissue mass (\u03bcmol kg\u22121), then using the literature values of IC50 as a measure of toxicity, it can be concluded that for prolonged periods the cardiac concentrations of doxorubicin are sufficient to negatively impact upon cardiomyocyte viability. The limited animal data suggest that cardiotoxic levels of doxorubicin remain significantly above the median IC50 value of 1.67 \u03bcM (see above) for at least 24 hours and decline below this limiting concentration between 24 and 48 hours. In both animals and patients, there is convincing evidence for long-term (days/weeks) retention of doxorubicin within cardiac tissue. Accordingly, given the long-term accumulation of doxorubicin within the heart, if the short pre-administration single infusion of dexrazoxane exerts a cardioprotective effect by depleting Top2\u03b2 protein, then by necessity suppression of the level of Top2\u03b2 protein within the heart must be profound and long lasting. As the author argues, this seems a remote prospect given that by comparison with the slow elimination of doxorubicin, dexrazoxane has a remarkably short half-life. The logical corollary of this substantial difference in pharmacokinetics is twofold. First, dexrazoxane must exert long-lasting suppression that results in maintenance of Top2\u03b2 protein below threshold. Second, in the absence of long-lasting suppression, recovery of suppressed Top2\u03b2 protein (transcription) must be slow.Accepting the proportionality error in comparing concentrations in an aqueous buffer  (t1/2 of 9.3 hours), and to the final hydrolysis product ADR-925 (t1/2 of 23 hours) . Despite the plethora of drugs that degrade Top2\u03b2 protein, dexrazoxane remains the only product that is licenced for the prevention of cardiotoxicity associated with the use of anthracyclines;  et al  ] , and as  et al  triggered the formation of a supramolecular self-assembly consisting of non-covalent interactions between polyacrylate-anchored melamine units and monomeric cyanuric acid.Cyanuric acid catalyses the formation of supramolecular self-assemblies of a naturally occurring adenine-containing nucleotide, polyadenine (poly(A)), in both its DNA and RNA forms; structurally, poly(A) is closely related to PAR. Cyanuric acid-catalysed self-assemblies of poly(A) can be modelled using either canonical Watson\u2013Crick base pairing or a combination of both canonical Watson\u2013Crick and non-canonical Hoogsteen base pairing. Spectral studies suggest that the preferred assembly of poly(A) strands with cyanuric acid monomers is a coiling triplex formation consisting of both canonical and non-canonical base pairing.Cyanuric acid-catalysed self-assembly using a synthetic adenine-containing peptide nucleic acid (PNA) in place of poly(A) has also been demonstrated.Intuitively, it is to be expected that low-energy conformations will exist when there is a maximum separation between the piperazine structures. Conformational analysis undertaken by the author (for details of methods see the appended Supplement) confirm that lower energy conformations are consistent with the maximum spacing between piperazine structures with each adopting a half-chair conformation at methylene carbon atoms 3,5 of each ring structure resulting in an elevated tertiary amine nitrogen atom. As a half-chair conformation, the remainder of the piperazine structure is planar with the keto group at the carbon atom in position 2 of each ring structure in alignment with the tautomeric nitrogen of the secondary amine group of the adenine base of each ADP-ribose unit of PAR , a pilot study was undertaken by the author to investigate the interaction between dexrazoxane and PAR. Using isolated rat liver mitochondria, we demonstrated for the first time that dexrazoxane inhibits PAR-induced release of AIF. Although the details of this methodology are not presented here, the western blots from this study, using anti-AIF antibody (Abcam ab32516) are reproduced in In collaboration with Ritchie et al . Notably, echocardiographic data suggest that dexrazoxane provides long-term cardioprotection, implying that prevention of cardiomyocyte damage during therapy can reduce the incidence of delayed doxorubicin-associated cardiomyopathy in long-term survivors without compromising the chances of oncological cure [The initial application in 2014 of CEME to dexrazoxane revealed an unequivocal signal defining a previously-unknown relationship between dexrazoxane and PAR polymer. Subsequently, the unique property of dexrazoxane to sequester PAR by base pairing was demonstrated using cal cure , 118.What does the proposed association between dexrazoxane and PAR mean to Oncologists?In addressing this important question some historical perspective must be introduced. Dexrazoxane reduces the incidence of anthracycline-induced heart failure by 80% and it is the only drug approved for its prevention . DespiteWhile beyond the scope of this review, the clinical consensus is that dexrazoxane does not compromise anti-tumour therapy. Indeed, in May 2017, the EMA Committee for Medicinal Products for Human Use approved the expansion of the Cardioxane Marketing Authorisation enabling increased use of dexrazoxane within the paediatric population for whom dexrazoxane had been previously contraindicated (dexrazoxane is marketed by Clinigen UK as a branded generic). A review of the evidence that historically led to a reassessment of the European Label for dexrazoxane found that dexrazoxane is not associated with an increased risk of second primary malignancies and that dexrazoxane therapy does not impair anthracycline\u2019s anti-tumour efficacy .Thus, if the above changes and revisions lead to an increase in the use of dexrazoxane throughout different patient populations, then the alert clinician should be responsive to novel/atypical/unexpected clinical benefits and outcomes if dexrazoxane is acting in some part by sequestering PAR by base-pairing. et al propose that impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by disruption of mitochondrial energy production and that this damage is abrogated by dexrazoxane [Indeed, scrutiny of existing clinical outcomes supports an interaction between dexrazoxane and PAR. For example, Lipshultzrazoxane . In a loAt a median follow-up of 7.8 years after treatment, doxorubicin-treated survivors without dexrazoxane had increased PBMC mtDNA copies per cell and concomitant use of dexrazoxane was associated with lower mtDNA copies per cell. The investigators add that mtDNA copies per cell in those who received dexrazoxane were within the normal ranges observed in their previous studies. OXPHOS activity was not different between groups. The investigators propose that in patients treated with doxorubicin alone, impaired mitochondria may undergo clonal expansion of mtDNA that functionally compensates for mutations or deletions that results in normal OXYPHOS and ATP production within the myocardium. They add that their findings support the evidence that dexrazoxane adjuvant therapy in paediatric high-risk ALL patients offers systemic mitochondrial protection and suggest a possible role of dexrazoxane prior to anthracycline therapy as a general protectant of mitochondrial function in other healthy tissues that include the ovaries . et al [Previously, Lebrecht et al  had prop et al .Notwithstanding alternative explanations, can the above effects upon mtDNA be reconciled with an interaction between dexrazoxane and PAR, and in the absence of dexrazoxane can PAR explain the delayed onset of anthracycline-associated cardiomyopathy? et al [ et al speculate that by contrast with the well-established positive regulatory role of PARP1 in maintaining nuclear DNA integrity, the addition of PAR groups on mtDNA repair enzymes may uniquely reduce their affinity to bind with DNA and thus may attenuate the rate of mtDNA repair.Using wild-type and PARP1-depleted A549 cells, Szczesny et al  investig et al [ et al [Accepting the new hypothesis that dexrazoxane sequesters PAR by base pairing, then arguably this sequestration state is comparable/equivalent to the PARP1-depleted cells used by Szczesny et al  and that et al . For exa et al . Accordi [ et al  may be a [ et al .A further example serves to illustrate how the existing data can be re-evaluated in the light of an interaction between dexrazoxane and PAR. While the acute cardiotoxic effects of doxorubicin are consistent with a doxorubicin-induced DNA damage response resulting in both PARP1-dependent apoptotic and necrotic cell death , 126, deTwo isoforms of MHC are expressed in the mammalian heart, \u03b1-MHC and \u03b2-MHC. The \u03b1-MHC isoform has a higher ATPase activity than \u03b2-MHC, and the contractile velocity of the heart is correlated with the relative amount of each isoform; hearts expressing greater amounts of \u03b1-MHC having a more rapid contractile velocity \u2013138.The \u03b1- and \u03b2-MHC ratio correlates directly with the overall cardiac performance in both animals and in patients with cardiomyopathy and heart failure \u2013145. PatDe Beer\u2019s Group in the Department of Medical Physiology at Utrecht University observed that long-term administration of doxorubicin resulted in an impairment of the actin-myosin interaction in the hearts of male Wistar rats . Notably et al investigated whether the cardio-protective properties of dexrazoxane involve the prevention of the deleterious effects of doxorubicin upon the actin\u2013myosin contractile machinery [Following their earlier observations of the effects of chronic treatment with doxorubicin upon the contractile function of the heart, de Beerachinery . They ob et al do not support a role for free radicals in mediating the deleterious effects of doxorubicin upon the actin\u2013mysoin contractile machinery [Interestingly, there are no reports within the literature of an association between Top2\u03b2 and MHC isoforms, and additional studies by de Beerachinery . Howeverachinery . MoreoveAre doxorubicin-induced alterations at the epigenome as manifest by a shift in the ratio between MHC isoforms and the effects of dexrazoxane in abrogating this shift, consistent with an interaction between dexrazoxane and PAR? et al in the Division of Cardiovascular Medicine at Stanford University School of Medicine show that Brahma-related gene 1 (Brg1), a chromatin-remodelling ATPase protein subunit of the BRG-1-Associated Factor (BAF complex), interacts with two other classes of chromatin-modifying enzymes, histone deacetylase (HDAC) and PARP, to regulate gene expression during cardiac growth, differentiation and hypertrophy [ et al show that in hypertrophic hearts PARP1 is bound to the proximal promoters of \u03b1-MHC and \u03b2-MHC, and that inhibition of PARP1 activity by the phenanthridinone-based PARP inhibitor PJ34 reduced both Brg1-mediated \u03b1-MHC repression and \u03b2-MHC activation in reporter assays, indicating that Brg1 and PARP1 cooperate to regulate MHC expression [Hangertrophy . In adulertrophy \u2013155. In pression .Mahesh Gupta\u2019s Group in the Department of Cardiothoracic Surgery at The University of Chicago demonstrate that nuclear extracts treated with anti-ADP-ribose antibodies reveal increased poly-ADP-ribosylation (PARylation) of nuclear proteins in failing hearts by comparison with controls, thus confirming the presence of PAR polymer [\u2212/\u2212 mice was also evident from the analysis of hypertrophic marker genes. In PARP+/+ aortic artery-banded mice, the levels of \u03b2-MHC mRNA were highly elevated, whereas \u03b1-MHC levels were repressed, as expected. By contrast, in PARP\u2212/\u2212 aortic artery-banded mice, no repression of \u03b1-MHC levels was observed, and the levels of \u03b2-MHC were increased to a much lesser extent.Notably,  polymer . From thIn their concluding remarks, they propose that PARP inhibitors may be useful agents for managing cardiomyopathies and heart failure.Taken together, these and other data are provocative and indicate that in some part, the cardiotoxic effects of doxorubicin and the cardioprotective effects of dexrazoxane, converge upon the epigenome. By comparison with acute damage, delayed-onset toxicity is consistent with a phenotypic switch that results from doxorubicin alteration(s) at the epigenome. Sequestration of PAR through both canonical Watson\u2013Crick base pairing, and non-canonical Hoogsteen base-pairing provides a mechanism for the cardioprotective effects of dexrazoxane against the toxic effects of doxorubicin in the acute term, and abrogation of delayed-onset cardiomyopathy. et al have previously suggested a possible role of dexrazoxane prior to anthracycline therapy as a general protectant of mitochondrial function in healthy tissues in addition to the heart [ et al [very important neuroprotective properties\u2019.Given the focal role of PAR in an overwhelming number of diseases, it is indeed thought provoking that dexrazoxane offers, for the first time, a unique opportunity to investigate the impact of sequestration of PAR, by comparison with inhibition of PARP, within a remarkably broad context. By way of example, and whilst beyond the scope of this review, the interaction between dexrazoxane and PAR offers the prospect that dexrazoxane can function as a cytoprotectant within other physiological systems (Lipshultzhe heart ). Neurophe heart . In that [ et al  concludepreviously unknown relationships\u2019 within the published literature for a nominated drug within an elected therapeutic category. By comparison with the kind of data stored in structured databases, natural language text within the published literature is unstructured, amorphous and difficult to mine using the traditional algorithms. In practise, the greatest obstacle is missing data within a dataset that is small (thousands of data pieces) by comparison with the much larger size (millions of data pieces) of dataset sets mined using methods traditionally applied in commercial operations such as mining high street supermarket transactions. CEME overcomes the problem of missing data by adapting the use of a statistical method known as \u2018antecedent surrogate variables\u2019. Specifically, in exploring the mechanism of action of dexrazoxane as a cardioprotectant, the task was to characterise as exhaustively as possible cell signalling within all known molecular phenotypes (as determined by extracellular first messengers) of anthracycline-exposed cardiomyocytes. In practise, this is an extremely demanding operation that requires the manual input for all known molecular phenotypes of all known second messengers, enzymes, receptors, transcription factors and so on. To reduce the possibility of a type I error , in addition to dexrazoxane, the CEME process should be repeated for all known cardioprotectants of anthracycline-exposed cardiomyoctes; the list includes beta blockers, angiotensin inhibitors, angiotensin-converting enzyme inhibitors and statins. That is, previously unknown relationships between each cardioprotectant and cell signalling within the anthracycline-compromised cardiomyocyte should be explored. For practical reasons, this was not undertaken.The CEME algorithm is a well-validated methodology that has been successfully applied by McCormack Pharma to many drugs throughout more than three decades \u2013134, 187In silico modelling studies demonstrate that dexrazoxane catalyses the formation of a hybrid self-assembled supramolecular structure between adjacent strands of PAR. These assemblies depict an antiparallel orientation of canonical Watson\u2013Crick base pairing of dexrazoxane with adenine bases. In addition, these in silico studies show that dexrazoxane can also base pair with PAR strands by non-canonical Hoogsteen base pairing. Importantly, these supramolecular structures employing either canonical or non-canonical base pairing and combinations of the two, accord with the theoretical expectation of low-energy thermodynamically stable entities. Moreover, that such supramolecular assemblies are possible is strongly suggested by the work of other groups using molecules that are closely analogous to both dexrazoxane and PAR [in vivo conditions is lacking. Initially, aqueous stability could be explored by utilising in vitro methods such as thermal denaturation using circular dichroism and ultraviolet\u2013visible spectroscopy [ and PAR , 104\u2013107troscopy . These cin vitro study show that consistent with expectation, dexrazoxane prevents PAR-induced AIF release from isolated mitochondria. However, dose-ranging studies are needed, and equilibrium times require investigation. The utilisation of exogenous PAR as used by the author is not a paradigm of a deep compartment for the accumulation of dexrazoxane and consequently does not adequately represent the in vivo situation. Preferably, further studies should incorporate the use of whole cells, such as isolated neonatal rat cardiomyocytes together with the use of ionising radiation to induce DNA damage with subsequent elaboration of endogenous PAR.The results of a preliminary The conformational relationship of the non-covalent interaction between dexrazoxane and PAR was explored using a modified version of Allinger\u2019s Molecular Mechanics MM2 force field (for review see ). Accord"}
+{"text": "With the exponential growth of the Internet of Things (IoT) and cyber-physical systems (CPS), a wide range of IoT applications have been developed and deployed in recent years. To match the heterogeneous application requirements in IoT and CPS systems, many resource-constrained IoT devices are deployed, in which privacy and security have emerged as difficult challenges because the devices have not been designed to have effective security features. With the exponential growth of the Internet of Things (IoT) and cyber-physical systems (CPS), a wide range of IoT applications have been developed and deployed in recent years. To match the heterogeneous application requirements in IoT and CPS systems, many resource-constrained IoT devices are deployed, in which privacy and security have emerged as difficult challenges because the devices have not been designed to have effective security features.Despite many security solutions being developed for the Internet, there are major concerns regarding the resource-constrained environment in IoT, including data encryption, privacy preservation, vulnerabilities, threats, attacks, and controls, among others. To address these privacy and security challenges, appropriate technologies have to be developed for resource-constrained environments in IoT.The basic objective of this Special Issue is to report the most recent research efforts dedicated to strengthening the security and privacy solutions for resource-constrained devices in IoT and CPS systems. Specifically, each manuscript was carefully reviewed by at least two independent experts. All submissions were evaluated for their rigor and quality and their relevance to the topics proposed in this Special Issue. After a rigorous review process, 16 high-quality papers were accepted and included in this Special Issue. We will now briefly introduce the accepted papers.In the paper entitled \u201cA Lightweight Cipher Based on SALSA20 for Resource-Constrained IoT Devices\u201d , Lara etIn the paper entitled \u201cAn Incentive Mechanism in Mobile Crowdsourcing Based on Multi-Attribute Reverse Auctions\u201d , Hu et aBouaynaya et al. investigated formal methods to quantify and evaluate the risks associated with information systems in the paper \u201cExploring Risks Transferred from Cloud-Based Information Systems: A Quantitative and Longitudinal Model\u201d . FurtherThe paper entitled \u201cEfficient Privacy-Preserving Access Control Scheme in Electronic Health Records System\u201d focused on the constrained device access control in e-health records (HER) systems by reducing the computational resources . The proSun et al focused on a compressed-sensing-based fault-tolerant data aggregation in the paper \u201cCS-FCDA: A Compressed Sensing-Based on Fault-Tolerant Data Aggregation in Sensor Networks\u201d . The effIn the paper entitled \u201cBeeKeeper 2.0: Confidential Blockchain-Enabled IoT System with Fully Homomorphic Computation\u201d , Zhou etRahman et al. focused on the joint relay selection and power allocation for cooperative cognitive radio networks in the paper entitled \u201cJoint Relay Selection and Power Allocation through a Genetic Algorithm for Secure Cooperative Cognitive Radio Networks\u201d , which iAlromih et al. investigated a randomized watermarking technique for resource-constrained devices in the paper \u201cA Randomized Watermarking Technique for Detecting Malicious Data Injection Attacks in Heterogeneous Wireless Sensor Networks for Internet of Things Applications\u201d . The expFang, Yang, and Wu went through secure cost-aware data communication in IoT in the paper entitled \u201cSecurity Cost Aware Data Communication in Low-Power IoT Sensors with Energy Harvesting\u201d . In thisLuo et al. focused on the low-cost security and data integrity scheme in an air quality monitoring system in the paper entitled \u201cOn the Security and Data Integrity of Low-Cost Sensor Networks for Air Quality Monitoring\u201d .Alabdulkarim et al. developed a privacy-preserving single decision tree algorithm for resource-constrained IoT devices in the paper entitled \u201cPPSDT: A Novel Privacy-Preserving Single Decision Tree Algorithm for Clinical Decision-Support Systems Using IoT Devices\u201d . This woLara-Nion et al. investigated efficient scalar multiplication for resource-constrained devices in the paper \u201cEnergy/Area-Efficient Scalar Multiplication with Binary Edwards Curves for the IoT\u201d . In thisIn the paper entitled \u201cFPGA Modeling and Optimization of a SIMON Lightweight Block Cipher\u201d , Abed etQin et al. proposed a lightweight anomaly detection system for IoT in the paper titled \u201cIMLADS: Intelligent Maintenance and Lightweight Anomaly Detection System for Internet of Things\u201d . This woAl-Otaibi et al. aimed at developing a privacy-preserving vehicular rogue node detection scheme for light devices in IoT and fog computing in the paper entitled \u201cPrivacy-Preserving Vehicular Rogue Node Detection Scheme for Fog Computing\u201d . The simShifa et al. proposed a lightweight cipher for H.264 video in IoT in the paper entitled \u201cLightweight Cipher for H.264 Videos in the Internet of Multimedia Things with Encryption Space Ratio Diagnostics\u201d . This woIn this Special Issue, a wide range of topics are reported that cover ongoing research interests regarding security and privacy solutions for resource-constrained devices in IoT and CPS systems. The team hopes that this Special Issue will make contributions to encouraging IoT security and privacy issues.In conclusion, we sincerely thank all researchers for their sharing of their research works to this special issue and the reviewers for volunteering their time and expertise to carefully reviewing and commenting on all submissions. We would like to thank the sensors EIC and the admin team for their continuous support and guidance."}
+{"text": "Current developments and challenges for serial sample delivery at synchrotrons and X-ray free-electron lasers are reviewed, including the new megahertz repetition-rate machines, with an emphasis on liquid injection and high-viscosity extrusion. The high peak brilliance and femtosecond pulse duration of X-ray free-electron lasers (XFELs) provide new scientific opportunities for experiments in physics, chemistry and biology. In structural biology, one of the major applications is serial femtosecond crystallography. The intense XFEL pulse results in the destruction of any exposed microcrystal, making serial data collection mandatory. This requires a high-throughput serial approach to sample delivery. To this end, a number of such sample-delivery techniques have been developed, some of which have been ported to synchrotron sources, where they allow convenient low-dose data collection at room temperature. Here, the current sample-delivery techniques used at XFEL and synchrotron sources are reviewed, with an emphasis on liquid injection and high-viscosity extrusion, including their application for time-resolved experiments. The challenges associated with sample delivery at megahertz repetition-rate XFELs are also outlined. This type of mixing, combined with SFX data collection from a GDVN-generated liquid jet, has been used to capture structural intermediates of a riboswitch binding its ligand \u223c10\u2005s after reaction initiation , the mixing process must take place close to the injector tip such that the travel time of the sample from the point of reaction initiation to the X-ray interaction region is short. Moreover, the effect of a non-uniform velocity profile on sample transport must be minimized downstream of the reaction initiation. Interestingly, an investigation of microcrystal flow through capillaries indicated the presence of a depletion zone containing no crystals near the capillary wall, which introduces an intrinsic cutoff of low-speed tails and alleviates flow smearing . High pressures are generally required for this, often in excess of those that can be supplied by an HPLC-based liquid-delivery system. A piston-driven sample reservoir must then be installed between the HPLC and the nozzle, with the piston serving both as a pressure amplifier and as the means of separating the sample from the hydraulic fluid . The high viscosity of an HVE sample precludes GDVN gas focusing, meaning that the extruded free stream is roughly equal in diameter to the inner diameter of the sample capillary, which is typically 50\u2013100\u2005\u00b5m. Sample flow rates can be as low as tens of nanolitres per minute; thus, sample efficiency is much higher and sub-milligram sample quantities can be sufficient  exposure time. Thus, the diffraction patterns are not \u2018smeared out\u2019 by crystal movement, as shown recently at the SLS  or shorter lipids such as MAG 7.9 , (i) the very same segment must be in the X-ray interaction region simultaneously with the X-ray pulse and not yet have travelled beyond or not yet have reached it, and moreover (ii) it must have passed beyond the interaction region before the next probe pulse. For ultrafast time delays \u0394t, the jet is essentially still during \u0394t and only (ii) needs to be considered. For longer time delays  both points (i) and (ii) matter. Point (ii) sets a minimal jet-speed limit and depends on the optical laser diameter and position. Point (i) sets the maximal and potentially another minimal jet speed and/or the distance between reaction initiation and X-ray interaction. For successful TR measurements, the jet speed must therefore be known and, together with other experimental parameters, adjusted where possible. Generally, the jet speed limits TR measurements in the free jet to a maximal time delay of at most a few microseconds for GDVNs, whereas a few seconds may be achieved with HVE.Jet speed is also important for optically triggered TR experiments as it can determine the accessible time delays  and microscopic jet size, which means that tracking a feature over time requires fast time resolution both to prevent blurring and to capture the feature at two or more successive positions. Pulsed (laser) illumination of sufficiently short duration (a few nanoseconds or less) can be used to deliver sharp images of liquid jets  and the displacement of a feature  can be tracked without difficulties using a camera with a reasonable frame rate and magnification  whether they can be used at room or cryogenic temperature.Fixed-target techniques are another means of serially delivering fresh sample for each X-ray exposure. Here, the crystals are immobilized on a substrate, which is then scanned through the X-ray beam. An inherent advantage of this approach is that in principle the geometry and crystal distribution can be arranged such that every crystal on the substrate is probed. Each step in a raster scan must clearly move beyond the area affected by previous probe pulses, which is particularly important at an XFEL. Numerous solid-support approaches have been developed over the years and, depending on the design, they mainly vary in (i) the X-ray background, which can be caused by the substrate itself and by excess mother liquor, (ii) the extent to which they support high-throughput data collection in terms of maximal data-collection rate and high hit rate, (iii) whether only specific crystal sizes or shapes can be accommodated, (iv) crystal handling, et al., 2014et al., 2016et al., 2019Goniometer-based approaches using standard loops and micromeshes or specialized high-density sample-mounting grids have successfully been used at XFELs with larger microcrystals (>20\u2005\u00b5m) at cryogenic temperature  etched into silicon and crystals mixed with Paratone N \u2018painted\u2019 onto the remaining 50\u2005nm layer of silicon nitride as a support . These windows can be endowed with modified surface properties  to promote random crystal orientations within a silicon mesh and thereby provide an efficient sampling of reciprocal space (Zarrine-Afsar et al., 2015et al., 2016et al., 2017et al., 2015et al., 2015et al., 2015et al., 2015et al., 2016et al., 2015et al., 2016et al., 2017et al., 2015et al., 2016et al., 2017et al., 2015et al., 2017et al., 2016et al., 2017et al., 2017et al., 2018et al., 2018To reduce background scattering even further, silicon chips can incorporate microscopic \u2018wells\u2019 (Mueller 4.Despite the increasing variety of sample-delivery techniques, there is no universal technique of choice for serial crystallo\u00adgraphic data collection at XFEL or synchrotron sources. Instead, the suitability of a specific technique strongly depends on the investigated system and the experimental aim and conditions. We expect serial sample delivery to remain a rapidly developing field as the number of next-generation synchrotrons and XFELs is increasing, as will the user community."}
+{"text": "The structures provide insight into the regulation and specificity of mirolysin, and hint at how it might be inhibited for therapeutic effect.Guevara, Rodriguez-Banqueri  Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia. These pathogens release \u2018virulence factors\u2019, molecules that aid their colonization and survival in the subgingival niche and their evasion of the host immune response. Synergistic interactions of the pathogenic microbes with normal oral microbiota lead to a sustained host inflammatory response, degrading periodo\u00adntal tissues, eroding bone, and ultimately leading to tooth loss. Severe periodo\u00adntitis affects around 10% of the human population, and health implications are not limited to oral health; the chronic inflammatory conditions precipitated by the disease can extend to systemic manifestations, contributing to risk of cardiovascular and respiratory diseases, diabetes, rheumatoid arthritis, and cancer (Hajishengallis, 2015et al., 2017Periodo\u00adntitis, commonly known as gum disease, is a chronic inflammatory disease characterized by dysregulation of the oral microbiota in the subgingival space below the gum line (Hajishengallis, 2015T. forsythia. Mirolysin cleaves multiple components of the complement pathway to protect the pathogen against complement-mediated killing, and degrades the antimicrobial peptide LL-37, a human host defense peptide secreted by epithelial and immune cells at sites of infection (Jusko et al., 2015et al., 2017T. forsythia survival and immune evasion, mirolysin offers a potential therapeutic target, yet until now the structural basis for its latency, activation and substrate specificity have not been defined.Proteases are amongst the most abundant virulence factors produced by periodo\u00adntal pathogens. These enzymes degrade host proteins to feed bacterial growth, and also serve as key mediators of immune-subversive mechanisms, for example by degrading or inactivating endogenous antimicrobial peptides and components of the host complement system (Hajishengallis, 2015IUCrJ, Guevara, Rodriguez-Banqueri et al. report high-resolution crystal structures of promirolysin, defining the mechanism of latency of the precursor protein (Guevara et al., 2020et al., 2018et al., 1999et al., 2018In this issue of 2 between these structural elements, greater than the average buried surface area for protein\u2013protein complexes, which is remarkable given the small size of the 34-residue pro-segment. The pro-segment and catalytic domain interact through a balance of favorable hydro\u00adphobic interactions complemented by an array of hydrogen bonds and salt bridges, the same forces that shape affinity and selectivity of intermolecular protein\u2013protein interactions (Xu et al., 1997in trans, and serving as a template for engineering protein-based mirolysin inhibitors of therapeutic utility. Similar approaches have shown promise for engineering therapeutic inhibitors of ADAM family metallopeptidases, based upon their much larger pro-domains (Moss et al., 2007et al., 2016While this basic cysteine switch mechanism of latency is well precedented, the promirolysin structure reveals a surprisingly extensive interface between the pro-segment and the catalytic domain. The zymogen structure reveals a buried surface area of 2302\u2005\u00c5et al. further report a high-resolution structure of active mirolysin bound to a peptide product, providing insight into determinants of substrate specificity of the protease (Guevara et al., 2020et al., 2017et al., 2019Guevara, Rodriguez-Banqueri"}
+{"text": "Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age\u2010related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy\u2010dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise\u2010induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity. Accrual and aggregation of these defunct components result in disruption of cellular homeostasis, progressive degeneration, and increases the risk of cell death  is a central regulatory kinase that regulates cellular growth and protein synthesis. This complex is stimulated by nutrient availability , mechanical stress, and growth factors  and is inhibited by nutrient deprivation, energetic stress, and the macrocyclic polyketide rapamycin  has been shown to be a reliable method of lifespan extension and/or moderator of age\u2010related disease through modulation of autophagic activity in numerous model species ranging from yeast to humans     is one of two functionally and compositionally distinct multi\u2010protein TOR complexes; the second being TOR complex 2 (TORC2). Both complexes are highly conserved in all known eukaryotic cells  (Honjoh, Yamamoto, Uno, & Nishida, This evidence suggests that normal levels of autophagy may be sufficient to maintain cytosolic proteostasis if the rate of protein and organelle synthesis is reduced; however, it may also be possible that the reduced levels of autophagy observed in older cells may not be linked to aging, but simply offer an indirect reflection of excess TORC1 activity Pani, . At pres4S.\u00a0cerevisiae and C.\u00a0elegans to rodents and primates, including humans (Figure Lifespan extension via autophagy has been closely linked to CR (Bergamini, Cavallini, Donati, & Gori, s Figure  (Colman s Figure , and reps Figure . Calorics Figure .Even modest implementations of CR, such as intermittent fasting protocols, can promote health (Brandhorst et al., +\u2010dependent protein deacetylase also sensitive to energetic challenges, has been implicated in mediating the aging process (Salminen & Kaarniranta, Indeed, it has been observed that long\u2010term CR is a strong physiological promoter of autophagy, resulting in an upregulation of a number of autophagy\u2010related modulators and transcripts (Mercken et al., ++ is released from the lysosome into the cytosol, activating calcineurin which dephosphorylates TFEB and promotes its translocation to the nucleus where it initiates the transcription of a number of Atgs and proteins (Palmieri et al., Additionally, TFEB, a transcription factor involved in coordinating the expression of lysosomal and autophagic genes, has been shown to be activated during energy deprivation (Medina et al., Increasingly, autophagic activity has been shown to act as a key mediator of the observed impact of CR on lifespan (Bergamini et al., Some of the first data of long\u2010term CR on autophagic function in humans were collected from 15 lean and weight\u2010stable members of the Calorie Restriction Society who had practiced 30% CR for an average of 9.6\u00a0years. Upregulation of a number of autophagy modulators and gene and protein expression was noted including AMPK and SIRT family transcripts, ULK1, ATG101, APG12, GAPRAP/GATE\u20106, beclin\u20101, autophagin\u20101, and LC3 gene expression, as well as protein expression of FOXOs, PGC1\u03b1, beclin\u20101, and LC3 compared to age\u2010matched controls practicing a typical Western diet (Mercken et al., It is also interesting to note that suppression of the TORC1 pathway has been shown to potentiate longevity beyond the maximum extension achieved with CR alone (Bjedov et al., 5As discussed, energetic stress is a potent stimulator of autophagy; accordingly, exercise has been shown to augment acute autophagic activity in skeletal muscle (Jamart, Benoit, et al., While some data do exist relating to other forms of autophagy (Li et al., +, and ROS levels also are strong instigators of autophagic activity (Vainshtein & Hood, During exercise, autophagy mediates the clearance of proteins and organelles damaged by heat, pH changes, or mechanical stress which likely acts to prevent accumulation of these cytosolic components and maintain myocyte function (Schwalm et al., +, respectively. AMPK and SIRT1 both act to upregulate expression of Atgs by activating FOXO1 and FOXO3, increasing PGC1\u2010\u03b1 activity, and inhibiting mTORC1 (Vainshtein & Hood, In part, exercise acts to initiate autophagy in skeletal muscle through the same pathways as CR; namely, AMPK and SIRT1 are sensitive to alterations in AMP and NAD++\u2010dependent calcineurin where it then activates the CLEAR gene network and the transcription of Atgs and proteins.mTORC1 has also been implicated in regulating autophagy activity through mediating TFEB localization which may be subsequently modulated by exercise and nutrient deprivation (Medina et al., In addition to serving as a means to meet the energetic demands of exercise, autophagy is understood to facilitate exercise in numerous ways in skeletal muscle (Dokladny et al., While exercise\u2010induced skeletal muscle autophagy is presently the most studied, there are data showing enhanced autophagic activity in other tissues, thus demonstrating acute exercise is capable of instigating a global autophagic response Figure  He, Bas. In theiThese noted systemic autophagic effects suggest exercise could possess a role in modulating some of the age\u2010related pathologies that autophagy has been reported to be implicated in, which include type 2 diabetes (Gonzalez et al., 6Emerging evidence suggests that the autophagic response to exercise may occur in a biphasic manner in that acute cellular perturbations induce a precipitous increase in autophagic flux occurring acutely following insult and is mediated by posttranslational protein modification (Vainshtein & Hood, 2max has been shown to stimulate autophagic activity in skeletal muscle (Jamart, Benoit, et al., 2max (Moller et al., 2peak (Schwalm et al., Aerobic exercise for 60\u00a0min or greater at 55%\u201370% VO2max did not alter autophagic activity in healthy adults (Masschelein et al., 2max induced autophagy (Moller et al., 2max did not produce a response (Tachtsis et al., Conversely, 20\u00a0min of cycling at ~50% VOThese findings help highlight the importance of exercise duration and intensity in stimulating autophagic induction and point to a threshold for activation, likely involving AMPK\u2010mediated determination of energy insufficiency. Importantly, the extreme elevations in autophagic activity observed with ultra\u2010endurance performance are likely indicative of excessive muscle damage and energetic protein catabolism, thus offering intriguing implications regarding the J\u2010shaped relationship observed between mortality and exercise participation (Arem et al., 7Currently, the long\u2010term effects of exercise on autophagic activity are ill\u2010characterized; however, they appear mediated by activation of a transcriptional program (Vainshtein & Hood, Skeletal muscle autophagy has been studied following regular exercise. In mice, 3\u00a0months of endurance exercise has been reported to produce no changes in resting levels of LC3\u2010II/LC3\u2010I ratio within skeletal muscle (Grumati et al., It is also interesting to note that autophagic activity appears to be necessary for the normal adaptations of skeletal muscle (He, Bassik, et al., Given aging is an organismal phenomenon, it is pertinent to establish the global effects of long\u2010term exercise on autophagy and determine its role beyond exercised skeletal muscle. While evidences exist demonstrating acute exercise is capable of upregulating autophagic activity and/or Atg expression in a number of tissues apart from skeletal muscle including heart (He, Bassik, et al., Ghareghani et al.  reported8Investigation into the mechanisms underpinning lifespan and longevity shows that the appropriate maintenance of the proteome and organelle population is key in the augmentation of lifespan and/or mitigation of many pathologies associated with the aging process (Balch, Morimoto, Dillin, & Kelly, None declared."}
+{"text": "Neurobiological models of stress and stress-related mental illness, including post-traumatic stress disorder, converge on the amygdala and the prefrontal cortex (PFC). While a surge of research has reported altered structural and functional connectivity between amygdala and the medial PFC following severe stress, few have addressed the underlying neurochemistry.in vivo MR-spectroscopy (1H-MRS) measurements of glutamate in 26 survivors from the 2011 Norwegian terror attack and 34 control subjects.We combined resting-state functional magnetic resonance imaging measures of amygdala connectivity with et al., 2017) and together suggest long-term impact of a traumatic experience on glutamatergic pathways. Importantly, local glutamatergic metabolite levels predicted the individual amygdala\u2013aMCC and amygdala\u2013vmPFC functional connectivity, and also mediated the observed group difference in amygdala\u2013aMCC connectivity.Traumatized youths showed altered amygdala\u2013anterior midcingulate cortex (aMCC) and amygdala\u2013ventromedial prefrontal cortex (vmPFC) connectivity. Moreover, the trauma survivors exhibited reduced levels of glutamate in the vmPFC which fits with the previous findings of reduced levels of Glx (glutamate + glutamine) in the aMCC (Ousdal Our findings suggest that traumatic stress may influence amygdala\u2013prefrontal neuronal connectivity through an effect on prefrontal glutamate and its compounds. Understanding the neurochemical underpinning of altered amygdala connectivity after trauma may ultimately lead to the discovery of new pharmacological agents which can prevent or treat stress-related mental illness. Twenty-six survivors from the terror attack at Ut\u00f8ya and 34 healthy control subjects between 16 and 25 years were included in the study after giving written informed consent. All data were collected between 21 and 33 months after the terror attack. This study is part of a larger project assessing the effects of traumatic stress during late adolescence on cognition, behaviour and biological measures.et al., et al., The trauma survivors were recruited through written invitation sent out from the Resource Centre for Violence, Traumatic Stress and Suicide Prevention, Western Norway (64% response rate). The control sample was an age-, sex- and education-matched group, who were not involved in the trauma, and were not otherwise related to any of the survivors. In order to obtain information concerning participants\u2019 mental health, the Mini International Neuropsychiatric Interview . All volumes were realigned to the first volume . We used the software default measures, which included (1) >1.5% variance in global signal from scan to scan and (2) >0.5\u00a0mm/TR frame-wise displacement. Volumes that exceeded one of these cut-offs were replaced via interpolation. Subjects with more than 20% bad volumes in total were excluded . After artefact correction, all images were spatially normalized to a standard EPI template based on the Montreal Neurological Institute (MNI) reference brain . This method calculated the temporal correlation between brain activation from our seed region and all other brain areas using a General Linear Model (GLM) approach. Following the CompCor strategy as implemented in CONN, nuisance covariates including CSF, white-matter signals and the individual realignment parameters were modelled and regressed out from the analysis. In addition, the data were band-pass filtered (0.008\u20130.09\u00a0Hz).The goal of our analysis was to assess amygdala\u2013prefrontal resting-state connectivity due to the importance of these neurocircuits in stress-related psychiatric disorders -corrected significance of p\u00a0<\u00a00.05 at the cluster level. In addition, as we had a priori hypotheses regarding amygdala\u2013dACC/aMCC and amygdala\u2013vmPFC connectivity, small volume correction (svc) based on anatomically defined aMCC and vmPFC ROIs and peak-level FWE-corrected p values were used. The anatomically defined ROIs were created using the SPM Wake Forest University (WFU) Pickatlas toolbox .We tested for statistical significance using an initial voxel-wise threshold of et al., a priori for measurements of glutamate levels and related compounds. We obtained 1H-spectra from the vmPFC and the aMCC using a single voxel point resolved spectroscopy (PRESS) sequence. Glx data from the aMCC and the vmPFC voxels have been published previously  were used from the LCModel output. There was an association between Glu/Cr and white as well as grey matter in the vmPFC MRS voxel (see online Supplementary Methods), thus we controlled for voxel white and grey matter in all analyses of the vmPFC Glu/Cr data. We did not obtain aMCC 1H-MRS spectra from three of the controls. Furthermore, vmPFC 1H-spectra data from one trauma survivor and two controls had to be excluded due to poor data quality. Thus, the final sample size for the aMCC 1H-MRS data included 24 controls and 23 trauma survivors, and for the vmPFC 1H-MRS data, 25 controls and 22 trauma survivors.The amygdala is closely connected to the vmPFC and the dACC/aMCC , amygdala\u2013dorsolateral PFC  and amygdala\u2013cerebellum  connectivity. The location of the aMCC cluster accords with a recent meta-analysis which showed that hyperactivity in the aMCC is among the most consistent finding in traumatized subjects which develop PTSD  and amygdala connectivity while controlling for comorbid PTSD and panic disorder. The group differences were robust to adjustments for comorbidity (see online Supplementary Table S2). Except for the group difference in amygdala\u2013dorsolateral PFC connectivity, we also replicated the findings in un-scrubbed data (see online Supplementary Table S3). Thus, the main findings were not dependent on any adjustments made by the ArtRepair software. Finally, a comparison of BA31 functional connectivity between the groups revealed no whole-brain or small-volume significant clusters.Amygdala functional connectivity maps across groups are presented in online Supplementary Fig. S1 with corresponding statistics in online Supplementary Table S1. We observed whole-brain significant group differences in amygdala\u2013aMCC connectivity \u00a0=\u00a04.54, p\u00a0=\u00a00.04, partial \u03b72\u00a0=\u00a00.10, t45\u00a0=\u00a00.38, p\u00a0=\u00a00.71) in the aMCC. Mean Glu/Cr values for the vmPFC and the aMCC voxels are presented in online Supplementary Table S4.post-hoc analyses, we explored whether the glutamatergic compounds which displayed significant group differences also predicted inter-individual differences in amygdala functional connectivity. In the first analysis, we regressed individual vmPFC Glu scores onto the individual functional connectivity maps while controlling for vmPFC white and grey matter. The analysis revealed a negative association between vmPFC Glu and amygdala\u2013vmPFC functional connectivity , and should therefore be interpreted with caution. Based on a previous finding of reduced levels of aMCC Glx in the trauma survivors  after controlling for the effect of group.In two separate r\u00a0=\u00a0\u22120.51, p\u00a0=\u00a00.02), supporting that the reduction of vmPFC Glu developed over time. Previous analyses revealed no association between aMCC Glx and time elapsed since the traumatic event . A second regression showed that the group was associated with aMCC Glx . aMCC Glx was also associated with amygdala\u2013aMCC connectivity . Importantly, adding the aMCC Glx levels as a second predictor of the amygdala\u2013aMCC connectivity removed the effect of the group , and the indirect effect of aMCC Glx on amygdala\u2013aMCC connectivity was significant  and the amygdala in the aftermath of significant stress exposure (Gee et al., et al., et al., et al., et al., et al., et al., et al., In addition to reduced negative connectivity between vmPFC and the amygdala, we found significantly reduced positive connectivity between the amygdala and aMCC in the trauma survivors. The result is in line with studies in subclinical and clinical PTSD groups also finding compromised resting-state amygdala\u2013dACC/aMCC connectivity (Thomason et al., et al., et al., et al., et al., et al., et al., et al., 1H-MRS, which restricts measurements to \u2018bulk\u2019 levels of metabolites, and the technical challenges especially related to acquisitions in the most ventral parts of the PFC (de Matos et al., et al., et al., Mounting evidence from animal studies suggests that acute and chronic stress affect Glu neurotransmission in the PFC (Popoli et al., et al., The directionality of the associations is worth reiterating. We have previously reported that traumatic stress was associated with a reduction of aMCC Glx (Ousdal et al., et al., et al., per se. As such, future studies should investigate potential associations between vmPFC Glu and amygdala connectivity in both PTSD patients and trauma-exposed control groups, to understand the association between stress exposure, stress-related psychopathology and amygdala\u2013vmPFC glutamatergic connections. Finally, the association between amygdala functional connectivity and prefrontal glutamatergic metabolites were based on correlations, which do not imply causation. Thus, the present results should be interpreted with caution, bearing in mind the study design and analytic approaches.We acknowledge a potential limitation of the present study rests in the relative small group sizes and the heterogeneity related to the trauma group. This is always likely to be a problem in these types of studies given the variability of response to stressors. Furthermore, we acknowledge that the use of an amygdala ROI and not an independent component analysis when processing the rsfMRI data may be less sensitive to physiological noise (Van Dijk In conclusion, we found that traumatic stress influences functional connectivity between amygdala and medial prefrontal cortical regions, which are regions implicated in emotion generation and regulation. More specifically, trauma-exposed individuals had less positive amygdala\u2013aMCC connectivity and less negative amygdala\u2013vmPFC connectivity compared with a matched group without any trauma exposure. Overall, the results support a model in which traumatic stress is associated with reduced regulation of amygdala responses, both directly and indirectly. The amygdala\u2013aMCC connectivity pattern was mediated by Glx, suggesting that the compromised connectivity in trauma survivors may be secondary to trauma-induced changes in prefrontal glutamatergic pathways. Identifying the neurochemical underpinning of the observed connectivity changes in trauma-exposed individuals may ultimately contribute to new pharmacological treatments of stress-related mental illness."}
+{"text": "Capripoxvirus-induced diseases of cattle and sheep, respectively. Despite the extensive vaccination program adopted by Egyptian veterinary authorities, LSD and sheep pox are still prevalent and spread throughout the whole country. The current study was designed for molecular characterization and phylogenetic analysis of LSD virus (LSDV) and Sheep pox virus (SPPV) recovered from field cases in Egypt along with vaccinal strains to assess their genetic relatedness.Lumpy skin disease (LSD) and sheep pox are economically important Skin biopsies were collected from naturally infected cases of LSD in Ismailia (n=3 farms) and Beni-Suef (n=2 farms) Governorates and sheep pox in Beni-Suef (n=1 flock). Virus isolation was carried out on primary ovine fetal kidney and heart cell cultures. DNA was extracted from infected materials  as well as LSDV Neethling vaccine strain and Romanian SPPV vaccine strain. Polymerase chain reaction was performed using oligonucleotide primers targeting the entire open reading frame of G protein-coupled receptors (GPCR) gene and gene sequences were analyzed.Virus isolation on primary ovine fetal kidney and heart cell culture revealed a cytopathic effect at the third passage characterized by rounding of infected cells and margination of nuclear chromatin. Comparative sequence analysis of GPCR gene revealed that Egyptian LSDV isolated from Ismailia and Beni-Suef shared 99:100% nucleotide and amino acid (AA) identities with each other. In comparison to the vaccinal strains, Egyptian LSDV isolates shared 98:99 nucleotide and AA identities with LSDV Neethling vaccine strain and 93:94% with SPPV Romanian vaccine strain. No differences at the nucleotide or AAs were observed between the SPPV vaccine and virulent strains (100% identity). Phylogenetic analyses revealed that LSDV Neethling vaccine strain is more related to field Egyptian LSDV and clustered within the LSDV group while Romanian SPPV vaccine strain clustered in a separate clade with SPPV field isolates.Comparative sequencing and phylogenetic analyses of the GPCR gene reveal a minimal genetic variation between LSDV field isolates from different locations and a close relationship between virulent field strains and homologous vaccines. Capripoxvirus (CaPV)-induced diseases of cattle and sheep, respectively. LSD virus (LSDV) and Sheep pox virus (SPPV) are categorized within the genus CaPV in the family Poxviridae [Lumpy skin disease (LSD) and sheep pox are economically important xviridae .LSD is an acute to subacute disease of cattle characterized by fever, rapid eruption of numerous circumscribed skin nodules, and generalized lymphadenitis -5. The cSheep pox is a highly contagious disease of small ruminants  characteThere is no doubt that vaccination is the most effective way to control CaPV diseases . Due to In Egypt, the Kenyan SGP O-240 vaccine was used during LSD incursion in 2005-2006 . At presIn the current study, G protein-coupled receptors (GPCR) gene was used for molecular characterization and phylogenetic analysis of LSDV and SPPV circulating in the field along with vaccinal strains to assess their genetic relatedness.All animal handling procedures, as well as samples collection and disposal, were approved by the animal care and use committee of the Faculty of Veterinary Medicine, University of Sadat City, Egypt, according to the guidelines and recommendations of the European Communities Council Directive 1986 (86/609/EEC).From June 2015 to September 2016, LSD and sheep pox were suspected among dairy cattle herds located in private farms belonging to Ismailia (n=3) and Beni-Suef (n=2) Governorates and one sheep flock in Beni-Suef Governorate, respectively. All farms were clinically examined and a total of five nodular skin lesions were collected from diseased cattle with skin eruption all over the body while skin lesions were collected and pooled from infected sheep pox flock showing generalized pock lesions. The collected samples were kept at \u221220\u00b0C for virus isolation and polymerase chain reaction (PCR).4 TCID50 of freeze-dried, live, attenuated virus (SIS Neethling-type)from the Republic of South Africa and Romanian SPPV vaccine strain provided from the Pox Department, Veterinary Serum and Vaccine Research Institute, Abbassia, Cairo, Egypt, was used in the molecular study (103 TCID50/ml).South African Neethling vaccine strain  each 1 mL (1 dose) of the vaccine contains 10et al. [Skin biopsies were used for the isolation of LSDV and SPPV according to Tuppurainen et al. . BrieflyDNA was extracted from skin lesions, infected cell culture, LSDV Neethling vaccine strain, and Romanian SPPV strain using a DNA/RNA Extraction Kit  according to the manufacturer\u2019s instructions.et al. [The primers were developed to amplify the entire GPCR gene at position 6961-8119 according to Le Goff et al. . The priet al. [http://Zwww.ncbi.nlm.nih.gov/blast) was initially implemented to establish sequence identity to GenBank accessions. Phylogenetic tree and sequence alignments were generated using MEGAVersion X software. The tree was generated by the neighbor-joining method based on 1000 bootstrapped data sets [PCR amplicons were purified using QIAquick PCR Purification Kit and dispatched to Macrogen\u2122, Seoul, Korea, for DNA sequencing using two additional primers(5\u00b4-GATGAGTATTGATAGATACCTAGCTGTAGTT-3\u00b4and 5\u00b4-TGAGACAATCCAAACCACCAT-3\u00b4) according to Le Goff et al. . BLAST aata sets .Fever, skin lesions scattered in different parts of the body , and enlVirus isolation revealed CPE at the third passage on primary ovine fetal kidney and heart cells, characterized by retraction of the cell membrane from surrounding cells, rounding of cells, and margination of the nuclear chromatin .Using primer sequences targeting the entire GPCR gene, a fragment of 1158 bp has been amplified from all DNA extracts . SequencRegarding Romanian SPPV vaccine strain, it was found that AA residues situated in position 10-16 (SATMYNS) in LSDV field isolates are missed in SPPV vaccine; moreover, there are 27 variances in AA motifs between LSDV field isolates and SPPV vaccines were observed along GPCR gene  and 2. OTo represent the evolutionary relationships among field and vaccinal strains of LSDV and SPPV sequenced in this study and available CaPVs in the database, a GPCR-based phylogenetic tree was generated using the neighbor-joining method on nucleic acid sequences. The tree showed three tight genetic clusters  . LSDV faCapripoxviruses field and vaccinal strains based on sequence analysis of GPCR gene.LSD and sheep pox diseases are now considered as endemic diseases in Egypt. Despite the extensive vaccination program adopted by Egyptian veterinary services, LSD and sheep pox are still prevalent and spread throughout the whole country, thereby the present study provides a molecular characterization of LSDV and SPPV recovered from field cases in Egypt and a comparison of A total of five LSDV and one SPPV were isolated from naturally infected animals with typical clinical features of LSD and sheep pox, respectively, after being confirmed by PCR.The complete open reading frames of the GPCR gene of isolated viruses were sequenced along with vaccine strains. Comparative sequence analysis revealed that all of the five LSDV isolates are closely related to each other with a nucleotide and AA identity ranged from 99% to 100% in between confirming the circulation of the same virus strain.Egyptian LSDV field isolates were found more related to LSDV Neethling vaccine where it differs only in four AA substitutions and an AA deletion at positions 30-33.et al. [et al. [The comparative sequence analysis revealed that the 5-end of GPCR gene of SPPV vaccine was characterized by deletion of 21 nucleotides (7-aa) when it compared with LSDV field isolates. This sheep pox gap was recorded in all isolates and vaccine strains located in the database and was considered as a specific signature for SPPV as reported previously by Le Goff et al. . Many va [et al.  and El-T [et al. . Intereset al. [et al. [et al. [Phylogenetically, CaPV was delineated into three clades LSDV, GTPV, and SPPV as previously reported by Rouby et al. , Rouby [et al. , Rouby aet al. , and Maf [et al. . LSDV fa [et al. . The oth [et al.  and rece [et al. .Comparative sequencing and phylogenetic analyses of GPCR gene revealed a minimal genetic variation between different LSDV isolates from different locations and a close relationship between LSDV Neethling vaccine strain and Egyptian field LSDV isolates. GPCR gene possesses specific signatures for LSDV and SPPV at both nucleotide and AA sequences level and cluster them separately according to their host origin.ME designed the study. SRR and AB performed PCR, sequence analysis, and wrote the initial draft of the manuscript. MW and ME revised the manuscript. All authors read and approved the final manuscript."}
+{"text": "The aim of this review was to summarize key developments in classification and diagnosis of the idiopathic inflammatory myopathies (IIMs).The recently published European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for the IIMs provide a comprehensive, accurate and data-driven approach to identification of IIM cases appropriate for inclusion in research studies. Further, recent studies have advanced understanding of clinical manifestations of the IIMs and delineated the role of imaging, particularly magnetic resonance.The recent publication of the EULAR/ACR classification criteria will potentially greatly improve IIM research through more accurate case identification and standardization across studies.Future inclusion of newly recognized clinical associations with the MSAs may further improve the criteria's accuracy and utility. Clear and comprehensive understanding of associations between clinical manifestations, prognosis and multisystem involvement can aid diagnostic assessment; recent advances include delineation of such associations and expansion of the role of imaging. The idiopathic inflammatory myopathies (IIMs) are a group of autoimmune diseases characterised by chronic muscle inflammation (myositis), internal organ inflammation and significant morbidity and mortality . The widThis article aims to summarize recently published research pertinent to advances in IIM classification and diagnosis. A Medline search for research articles published between January 2017 and May 2018 was carried out using the MeSH term \u2018myositis\u2019. Articles primarily focussing on myositis-specific autoantibodies were excluded, as they will be reviewed in detail in a separate article.\u00a0The IIMs have traditionally been classified and diagnosed according to the criteria by Bohan and Peter Table  since pu\u25aa\u25aa]. Initial methodology identified 93 candidate variables for inclusion in the classification criteria. Variable domains included pattern of weakness, dermatological manifestations, disease course, systemic manifestations, response to treatment, pattern of muscle biopsy abnormalities, presence of MSAs, electromyogram (EMG) and MRI features.These drawbacks have limited accurate identification of well defined populations suitable for IIM research studies. Therefore, in 2004, the International Myositis Classification Criteria Project (IMCCP) was established with the aim of developing new IIM classification criteria. The IMCCP working committee was formed of experts from adult and paediatric rheumatology, neurology, dermatology, epidemiology and biostatistics. In 2017, the newly developed European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria were published [4Using data from 976 IIM cases and 624 comparators, the combination of candidate variables that could most accurately distinguish between IIM and non-IIM participants was identified. The variables included in the final classification criteria are displayed in Table The likely IIM subtype of each case can also be ascertained, according to the published classification tree Fig. . Subtypeet al. [et al. [www.imm.ki.se/biostatistics/calculators/iim.The EULAR/ACR criteria demonstrated high sensitivity 93%) and specificity 88%) when muscle biopsy data were included. Sensitivity and specificity also remained high when muscle biopsy data were not included: 87 and 82%, respectively. The accuracy of the newly created classification criteria was compared against previously developed criteria, including those by Bohan and Peter [% and speet al. , Targoff [et al. , Dalakas8% when mThe criteria have a number of major strengths. Their development methodology included a large IIM population with non-IIM comparators and considered inclusion of a wide variety of candidate variables. The ease of use and provision of a website-based calculator are also major strengths. Drawbacks include the fact that a majority of the development population were white, thus potentially limiting the criteria's validity in Asian and African populations. Further, MRI and electromyography data were only available in 38 and 29% of cases, thus potentially excluding these variables from the criteria only due to missing data. A limitation of subtype identification is the inability to separately identify IMNM and ASS cases. The inclusion of only one myositis-specific autoantibody (anti-Jo-1) in the classification criteria is a major limitation, as recent studies have illustrated the important and distinctive clinical and subtype associations . TherefoIn summary, the newly developed EULAR/ACR classification criteria for the IIMs provide an accurate method through which clearly defined study populations can be formed, thus potentially improving validity of IIM research.The newly developed classification criteria provide robust methods for identifying IIM cases for research purposes; however, their use is not designed nor recommended for use in clinical practice.Accurate diagnosis of an IIM is key to appropriate treatment instigation, prognostication and prevention of complications. However, diagnosis and subtype identification in clinical settings can be challenging, in part due to potential multisystem involvement and wide variations between subtype manifestations. Currently, no clear diagnostic criteria for the IIMs exist. However, findings from clinically focused research studies can aid a clinician's diagnostic accuracy, identification of factors associated with prognosis and guide investigation of multisystem involvement.et al.[N\u200a=\u200a2145). Interestingly, seven of the nine cases also fulfilled criteria for ASS and six cases were positive for anti-Jo-1 antibodies. This study highlights the importance of foot examination in IIM cases when trying to identify cutaneous manifestations. Mamyrova et al.[et al.[Findings from epidemiological and observational studies can inform clinical practice and guide the diagnostic process. A number of observational studies have recently been published and these will be summarized, with a particular focus upon potential clinical applications. Cox et al. recentlyva et al.\u25aa identifA recent study compared the utility of muscle testing via hand-held dynamometry against manual muscle testing in myositis cases . They reet al.[et al.[\u221703, thus indicating a genetic interaction with smoking and IIM development. These studies therefore highlight the importance of ascertaining a patient's smoking history due to its potential diagnostic utility and estimation of ILD risk.Interstitial lung disease (ILD) is an important extramuscular manifestation to consider during the diagnostic process and subsequent assessments. A number of studies have recently investigated risk factors for ILD. A recent study by Schiffenbauer et al. has highl.[et al. in 2012,et al.[et al.[Investigation for predictors of poor survival in 497 IIM-associated ILD cases was carried out by Sato et al.. They idl.[et al. reportedThe role of imaging in IIM diagnosis has expanded in recent years and has a number of capabilities. Imaging techniques, such as MRI, can help identify the presence of myositis, delineate its extent and assess treatment response, through serial scans and also help focus appropriate areas for muscle biopsy, limiting the likelihood of a false negative sample.et al.[et al.[et al.[Studies by both Yao et al.\u25aa and Andl.[et al. have recl.[et al.\u25aa also coet al.[et al.[Pinal-Fernandez et al. reportedl.[et al. in 12 biet al.[et al.[Focused MRI scanning can identify focal areas on myositis; however, whole-body MRI offers the ability to completely delineate all muscle groups affected and potentially identify secondary organ involvement and the presence of associated malignancy. Whole-body MRI, as opposed to focused imaging, was advocated by Elessawy et al.\u25aa as the l.[et al. also repet al.[Other imaging modalities also offer utility in IIM diagnosis. Burlina et al.\u25aa recentlet al.[Computed tomography (CT) scanning offers detailed assessment of the presence of ILD. A recent study by Ungprasert et al. investiget al.[et al.[The ability to identify cardiac involvement (an uncommon but important extramuscular manifestation) and distinguish from other heart disease has undergone advances recently. The utility of MRI in identifying cardiac involvement has been confirmed in recent years by a small number of studies ,29. Receet al. have recl.[et al. aimed toet al.[Huber et al.\u25aa confirmAccurate case identification is key to IIM research and the recent publication of the EULAR/ACR classification criteria will potentially greatly improve IIM research through accurate case identification and standardization across studies. Clear diagnosis of the IIMs is important to ensure appropriate diagnosis and treatment instigation. Recent advances in knowledge of clinical features will aid the clinician in prognostication, treatment stratification and investigation for multisystem involvement.None.This work was supported by Medical Research Council (MRC) UK grant MR/N003322/1. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.There are no conflicts of interest.\u25aa of special interest\u25aa\u25aa of outstanding interestPapers of particular interest, published within the annual period of review, have been highlighted as:"}
+{"text": "To conduct advanced psychometric analysis of Primary Care Assessment Tool (PCAT) in Tibet and identify avenues for metric performance improvement.Measuring progress toward high-performing primary health care can contribute to the achievement of sustainable development goals. The adult version of PCAT is an instrument for measuring patient experience, with key elements of primary care. It has been extensively used and validated internationally. However, only little information is available regarding its psychometric properties obtained based on advanced analysis.We used data collected from 1386 primary care users in two prefectures in Tibet. First, iterative confirmatory factor analysis examined the fit of the primary care construct in the original tool. Then item response theory analysis evaluated how well the questions and individual response options perform at different levels of patient experience. Finally, multiple logistic regression modeling examined the predicative validity of primary care domains against patient satisfaction.A best final structure for the PCAT-Tibetan includes 7 domains and 27 items. Confirmatory factor analysis suggests good fit for a unidimensional model for items within each domain but doesn\u2019t support a unidimensional model for the entire instrument with all domains. Non-parametric and parametric item response theory analysis models show that for most items, the favorable response option (4 = definitely) is overwhelmingly endorsed, the discriminability parameter is over 1, and the difficulty parameters are all negative, suggesting that the items are most sensitive and specific for patients with poor primary care experience. Ongoing care is the strongest predictor of patient satisfaction. These findings suggest the need for some principles in adapting the tool to different health system contexts, more items measuring excellent primary care experience, and update of the four-point response options. Values were also imputed for the \u2018not sure/don\u2019t remember\u2019 response option as an alternative to attributing the pre-set value of 2.5. In general, estimates produced with listwise deletion are less efficient than other methods of handling missing data. Therefore, we reported only results using database with ML imputation  imputation method was used to replace the missing values; match age, sex, education, self-rated health status; 295 respondents were excluded because of missing values for the matching variables, leaving 1091 respondents in subsequent analyses. Those excluded were more likely to be female and less educated. To examine the robustness of our conclusion, we excluded all respondents who had at least one missing value on any item (listwise deletion) and repeated all data analyses  by domain was conducted to flag items with low correlations (Pearson <0.20) or low factor loading (<0.30) for potential deletion. We repeated the exploratory factor analysis after deleting each item with low factor loading until all retained items had a factor loading of at least 0.30. The results of exploratory factor analysis guided subsequent confirmatory factor analysis.Then confirmatory factor analysis using structural equation modeling was used to test the goodness of fit of the items to the theoretical domains of the original PCAT. Subsequently, confirmatory factor models were adjusted iteratively based on fit and judgment until the goodness-of-fit statistics were optimized. We also assessed the entire instrument including all domains in our data analysis. First, we included all domains in confirmatory factor analysis. Then we only included the four core domains  in confirmatory factor analysis. The following goodness-of-fit statistics were used: normed fit index (NFI) \u22650.9 indicating good fit, comparative fit index (CFI) \u22650.9 indicating good fit, standardized root mean square residual (SRMR) \u22640.05 indicating acceptable fit.For each domain confirmed as being unidimensional, we examined the distribution of response options of individual items within each domain based on domain performance using nonparametric item response theory analysis. However, we cannot get the exact information of each item performance. To be more precise, two parameter estimates (discriminability and difficulty) were subsequently generated using Samejima\u2019s  grade reWe estimated the correlations between domains to examine how domains were related and whether they demonstrated distinctiveness.Finally, we used logistic regression modeling to examine how primary care domains were associated with patients\u2019 satisfaction with service attitude (one item) and perceived technical quality (one item) of their primary care provider. The five-point Likert response scale for the two items was dichotomized to indicate satisfaction (very satisfied or satisfied) versus dissatisfaction. All domains were put in the same model, and age, sex, education, and self-rated health status were included in the model as covariates. Education level was categorized into three groups: illiterate, primary school, junior high school and above. Self-rated health status was measured by a visual analogue scale with end points of 0 and 100, where 0 corresponds to \u2018the worst health status\u2019, and 100 corresponds to \u2018the best health\u2019.Descriptive, correlation, and exploratory factor analysis were conducted with SPSS 22.0. ML imputation and confirmatory factor analysis were conducted with LISREL9.1. Nonparametric and parametric item response theory analyses was conducted with SPSS 22.0 and MULTILOG 7.03.Table S1.For first contact access, two of the six items were deleted because of the unacceptable goodness-of-fit statistics (FCA5 and FCA6); and two items fit better in first contact utilization (FCA1 and FCA4), leaving only two items in first contact access and four in first contact utilization. In the eight-item ongoing care, two items were deleted because of unacceptable goodness-of-fit statistics (OC1 and OC7); and a further item (OC8) was removed to improve the goodness-of-fit statistics, leaving a five-item ongoing care scale. The eight-item comprehensiveness subscale showed unacceptable goodness-of-fit statistics on a single factor ; and after removing four of the poorest fitting items, a final four-item comprehensiveness subscale demonstrated good fit . There is no change in items in other domains. The detailed iterative process to finalize the original factor structure was reported in Supplemental Table Table However, either the model including all domains  or the model including only the four core domains  shows unacceptable goodness-of-fit statistics on a single factor, which suggest that the domains included in original PCAT may not measure a common single construct in Tibet context, and it is not appropriate to report a total score.\u03b1 is over 0.70, indicating good internal consistency of items for all domains except first contact access (0.66) and ongoing care (0.66).The mean of each domain score is lower than the median and negatively skewed, indicating most of patients reporting favorable response answers. The first contact utilization score is the highest (3.66\u00b10.48), while the first contact access score is the lowest (2.94\u00b10.95). Cronbach Non-parametric item response theory graphs were modeled on each unidimensional domain to provide further insight into item performance and reliability. In most items, the option characteristic curve for the response option \u20182 = Probably not\u2019 is overshadowed by other options  and ongoing care (0.60). First contact utilization is also highly correlated with family centeredness (0.54) and ongoing care (0.55). First contact access, comprehensiveness, and community orientation have lower correlation with other domains.The Pearson correlations between the domains indicate the distinctiveness of each domain. Correlation coefficients between domains range from 0.23 to 0.61 and are lower than Cronbach Finally, Table This advanced psychometric analysis of the PCAT-Tibetan versions provides further insight into some of the problematic psychometric properties found in the initial validation analysis, and it suggests avenues to improve the metric performance of the tool. Despite the metric problems, the PCAT-Tibetan domains of first-contact, ongoing care, and coordination with specialists are associated with an increased likelihood of patient satisfaction. This illustrates the potential of the PCAT and underlines the importance of improving the tool to address some of the metric problems. Some of the problems, such as the skewness of item response distribution found in many items, are shared with the original PCAT and other versions; and our results suggest some solutions that could improve performance. Others may be specific to the PCAT-Tibetan version \u2013 such as the non-optimal resolution of items relating to First Contact constructs \u2013 suggest the need for some principles in adapting the tool to different health system contexts.et al., et al., et al., et al., et al., et al., et al., et al., The widespread use of the PCAT to evaluate primary care in many countries provides an opportunity to compare primary care across different contexts and to support a worldwide movement to improve primary care. Our results show not only the association of the PCAT-Tibetan with patient satisfaction but also other analysis that demonstrated the capacity to distinguish between health-care organizations in Tibet and other regions in China (Wang et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The negative skewness of item response distribution in many items was noted in the original validation of the long PCAT version (Shi et al., et al., et al., et al., et al., et al., et al., Another metric issue results from offering the \u2018not sure/don\u2019t remember\u2019 option. The high rate of endorsing this response option is common in many language versions, especially in Asian countries including Korean, Japanese and Chinese. (Lee et al., et al., et al., et al., et al., \u03b1 was only 0.38 (Mei et al., et al., et al., et al., et al., et al., et al., Collaborative international work could also address principals for measuring and/or comparing domains that affected health system specificities, for instance, in the access domain. First contact in the PCAT-Tibetan fails to meet optimal psychometric standards of construct validity and internal consistency. Similar problems were also found in other PCAT validation studies in China (Yang et al., et al., et al., In contrast, the domain of ongoing care most strongly predicts patient satisfaction with primary care provider in Tibet. This is consistent with a previous systematic review showing that the most important determinants of satisfaction are the interpersonal relationships and their related aspects of care (Crow This study contributes to the growing international work supporting the relevance and need for valid and reliable measures of the patient experience of health care. Several lessons from PCAT-Tibetan validation study may be shared with our colleagues in low- and middle-income countries. First, the items or content of instruments from developed countries may not be appropriate in other countries. Some specific features of local primary care system may not be reflected in the translated instruments. For example, no items in PCAT could reflect the feature of geographical accessibility, which is a major aspect in Tibet. Some items in comprehensiveness domain are not appropriate in Tibet. Therefore, instead of adapting existed instrument directly, qualitative research is needed to understand the local population preference of primary care first. Second, more items to measure excellent primary care experience should be developed. Most existing items have adequate capacity to discriminate between poor and average performance on different primary care domains. However, items that discriminate clearly between average and good primary care are needed. Further research is required to explore the characteristics of some exemplars with good primary care experience and what the good primary care is from their narratives. Third, the choice of response categories should be careful. The current four-point response scale and its wording in PCAT may not be appropriate in some countries. Several factors could be considered when exploring the appropriate response categories, such as literacy level, response tendency, and judgment making of local population. This could be done through qualitative research.Finally, a summary score of overall primary care experience including all domains, which is often the most used metric when assessing a health system, is not supported by our analysis of PCAT-Tibetan version. However, this psychometrically validated 27-item Tibetan version of PCAT will be useful in monitoring and evaluating the performance of primary care system in Tibet in specific areas, especially in accessibility, continuity, and coordination, which are the priorities of current health reform efforts in Tibet. The health service research is underdeveloped in Tibet, and there is no instrument measuring patient experience that could be used when this study was conducted. We hope this study could bring more researchers\u2019 attention into primary care performance evaluation in Tibet. We also recognize that different policy interventions to achieve primary care functions are inter-related, but each policy has its own priorities. For example, the family doctor contract service model is being developed and expanded now to improve performance in accessibility and continuity; and the transformation of tiered health service delivery system aims to promote collaboration between different health-care providers and to improve coordination. Under this context, PCAT-Tibetan version is a potential useful instrument to evaluate the effectiveness of these policy interventions."}
+{"text": "Hyaluronan and proteoglycan link protein 2 (Hapln2) is important for the binding of chondroitin sulfate proteoglycans to hyaluronan. Hapln2 deficiency leads to the abnormal expression of extracellular matrix (ECM) proteins and dysfunctional neuronal conductivity, demonstrating the vital role of Hapln2 in these processes. Studies have revealed that Hapln2 promotes the aggregation of \u03b1-synuclein, thereby contributing to neurodegeneration in Parkinson\u2019s disease (PD), and it was recently suggested to be in intracellular neurofibrillary tangles (NFTs). Additionally, the expression levels of Hapln2 showed lower in the anterior temporal lobes of individuals with schizophrenia than those of healthy subjects. Together, these studies implicate the involvement of Hapln2 in the pathological processes of neurological diseases. A better understanding of the function of Hapln2 in the central nervous system (CNS) will provide new insights into the molecular mechanisms of these diseases and help to establish promising therapeutic strategies. Herein, we review the recent progress in defining the role of Hapln2 in brain physiology and pathology. Parkinson\u2019s disease (PD), Alzheimer\u2019s disease (AD) and schizophrenia are neurological diseases characterized by the dysfunction of certain types of neurons , is vital for neuronal conductivity and the formation of the extracellular matrix (ECM), and besides its potential role in the UPP, it has been identified as a contributor to the pathological processes in several neurological disorders. For example, Martins-de-Souza et al.  showed tHAPLN2 revealed seven exons encoding a polypeptide with an estimated molecular mass of 38 kDa (Hirakawa et al., The structure and roles of Hapln2 in the CNS have been studied since around the turn of this century, when an analysis of the gene now known as The hyaluronan and proteoglycan link family of proteins consists of four members: Hapln1, Hapln2, Hapln3, and Hapln4 (Spicer et al., HAPLN2 mRNA is expressed at high levels in the human hippocampus, medulla oblongata, putamen, SN, thalamus, and spinal cord but at lower levels in the cerebellum, cerebral cortex, frontal lobe, and nucleus accumbens. By in situ hybridization, we detected high expression levels of Hapln2 mRNA in the SN, olfactory bulb, red nucleus, cerebellum, brain stem, and hippocampus but relatively weak signals in the cerebral cortex of adult rat brain (Wang et al., Northern blot analyses by Hirakawa et al.  showed tLecticans such as brevican and aggrecan mainly bind to the hyaluronans, which are the major components of the ECM in the brain (Yamaguchi, + channels antibody (Oohashi et al., + channels and the contactin-associated protein (Rasband et al., Northern blot analyses have shown that Hapln2 expression in the mouse brain begins at 20 days after birth and increases with age (Hirakawa et al., + channel clustering coincides with myelination (Bekku et al., + channels. Of note, the clustering of Na+ and K+ channels is critical for saltatory conduction (Oohashi et al., + and K+ channels, flash visual evoked potentials had a longer latency and smaller amplitude in recordings from Hapln2 knockout mice compared with those from wild-type mice (Bekku et al., + channels (Susuki et al., + channel, nodes formation and AP propagation. However, more studies should be performed to clarify the details about the relationship between Hapln2 and the paranodal barriers or the CS in these processes during the development.As NaAs mentioned above, Hapln2 deficiency decreased the expression of ECM-associated proteins (Bekku et al., PD is characterized by the formation of Lewy bodies and selective loss of dopamine neurons in the SN (Liu et al., via proteasome inhibition resulted in the degeneration of dopaminergic neurons in vitro and in vivo (Kikuchi et al., Flow cytometry and immunostaining analyses showed that the overexpression of Hapln2 increased the death of MES23.5 and primary neuronal cells (Wang et al., Immunostaining analysis of MES23.5 cells overexpressing Hapln2 also showed an accumulation of \u03b1-synuclein, aggregates of which were found to colocalize with Hapln2 (Wang et al., A variety of environmental and genetic factors have also been implicated in the pathology of AD (Chin-Chan et al., via disruptions of the UPP. Postmortem tissue samples from the hippocampus, superior and middle temporal gyri, parahippocampal gyri, and the inferior parietal lobes of AD patients exhibit signs of reduced proteasome activity compared with those from control subjects (Keller et al., Notably, both AD and PD are age-associated neurodegenerative diseases with characteristic protein aggregates (Bridi and Hirth, in situ hybridization (Wang et al., Although high levels of Hapln2 in the hippocampus were measured by via the degradation of particular substrate proteins (Tsukamoto and Yokosawa, Although the pathophysiology of schizophrenia has not been fully defined, genetic factors, epigenetic elements, and abnormal neurotransmission in the hippocampus are important contributors (Kim et al., Moreover, it has been reported that ECM plays important roles in regulating neurogenesis, axonal outgrowth, synaptogenesis and cell migration (Bandtlow and Zimmermann, As a brain specific-hyaluronan and proteoglycan link protein, Hapln2 plays vital physiological roles in the formation and maintenance of the ECM scaffold. Studies in knockout mice have also revealed that Hapln2 influences neuronal conductivity. Several studies have revealed the involvement of Hapln2 in the pathogenesis of neurological diseases including PD, AD and schizophrenia, which provided new insights into the underlying molecular mechanisms of brain disorders .Current research suggested that Hapln2 was involved in the formation of \u03b1-synuclein aggregates in PD pathology and study in AD suggested that Hapln2 might be the component of NFTs aggregates (Minjarez et al., QW, CW, BJ, and CY wrote the manuscript. JC and JZ edited the manuscript. All the authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The mental and physical health of individuals with a psychotic illness are typically poor. Access to psychosocial interventions is important but currently limited. Telephone-delivered interventions may assist. In the current systematic review, we aim to summarise and critically analyse evidence for telephone-delivered psychosocial interventions targeting key health priorities in adults with a psychotic disorder, including (i) relapse, (ii) adherence to psychiatric medication and/or (iii) modifiable cardiovascular disease risk behaviours.Ten peer-reviewed and four grey literature databases were searched for English-language studies examining psychosocial telephone-delivered interventions targeting relapse, medication adherence and/or health behaviours in adults with a psychotic disorder. Study heterogeneity precluded meta-analyses.Twenty trials [13 randomised controlled trials (RCTs)] were included, involving 2473 participants . Five of eight RCTs targeting relapse prevention and one of three targeting medication adherence reported at least 50% of outcomes in favour of the telephone-delivered intervention. The two health-behaviour RCTs found comparable levels of improvement across treatment conditions.Although most interventions combined telephone and face-to-face delivery, there was evidence to support the benefit of entirely telephone-delivered interventions. Telephone interventions represent a potentially feasible and effective option for improving key health priorities among people with psychotic disorders. Further methodologically rigorous evaluations are warranted. Life expectancy is 12\u201319 years shorter than that of the general population Laursen, , with CVet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Importantly, increasing evidence supports the role of psychological interventions  for improving symptoms . The focus of this review will be on person-delivered interventions using the spoken word  and one or more psychological strategies  and the protocol has been published  were assessed against the 11 item Physiotherapy Evidence Database (PEDro) scale  was assessed using the Collaboration's Risk of Bias tool, as described in the A study was considered to have a positive outcome if more than 50% of the reported outcome measures (primary and secondary) demonstrated a between-group difference in favour of the telephone group at the treatment end. Positive maintenance outcome(s) were identified when this effect was evident at short and/or medium and/or long-term follow-up .Comparability of study design and outcome measures across studies was assessed by a consultant statistician to determine the possibility of conducting meta-analyses on RCTs to examine effects on relapse, medication adherence and smoking and other health behaviours and CVD risk. A narrative synthesis of the findings was conducted, structured around intervention type, outcome, population and methodological quality. As Clinical Guidelines recommend an improved focus on personally meaningful recovery  relative to traditional clinical outcomes (e.g. symptoms and relapse) in mental health care, to help inform clinical practice, the assessment, reporting and/ or change in these additional outcomes is also central to the structure of the review.Across all studies, the total number of participants was 2473, with 867 in relapse prevention, 1273 in medication adherence and 333 in smoking and/or other health risk behaviour studies (see online Supplementary Table S1). The average age was 40.7 years . Overall, the percentage of males across the studies was 50.1%. However, there was a higher percentage of males in studies of schizophrenia samples (64.5%) compared with studies of bipolar (37.7%) and mixed samples (44.2%). No study used a first episode sample.et al.  in favour of TAU  has been argued to be a sufficient alternative (Hansson"}
+{"text": "In the present contribution, we introduce the eLignin database, use its dataset to map the reported ecological and biochemical diversity of the lignin microbial niches, and discuss the findings.Lignin is a heterogeneous aromatic biopolymer and a major constituent of lignocellulosic biomass, such as wood and agricultural residues. Despite the high amount of aromatic carbon present, the severe recalcitrance of the lignin macromolecule makes it difficult to convert into value-added products. In nature, lignin and lignin-derived aromatic compounds are catabolized by a consortia of microbes specialized at breaking down the natural lignin and its constituents. In an attempt to bridge the gap between the fundamental knowledge on microbial lignin catabolism, and the recently emerging field of applied biotechnology for lignin biovalorization, we have developed the eLignin Microbial Database ( The eLignin database was launched online in March 2017 and aims to bring together the bibliome of this field in one self-contained searchable platform, and thus fill a gap presently not covered by other online biological databases, as well as to demonstrate the high diversity of this microbial niche , as these play an important role in microbial degradation of native lignin and can be applied for enzymatic depolymerzation of technical lignins . Due to the nature of the data collection for eLignin (scientific publications), there will be some overlap with other biological databases such as MetaCyc , manually curated and supplemented with links to relevant entries in other well-established biological and chemical databases  and two fungal phyla (Ascomycota and Basidiomycota) (see Tables Proteobacteria (114 species/strains), Basidiomycota (58 species/strains),\u00a0Actinobacteria (31 species/strains), Ascomycota (27 species/strains), and Firmicutes (22 species/strains) (Tables Euryarchaeota) is also beginning to emerge  lignin signified by its brown color (hence the name of this group of wood degraders); they are primarily found in softwood ecosystems  currently listed in eLignin are distributed between ta Table . The cliWhen it comes to lignin-degrading activity, fungi tend to be more studied than bacteria because of their higher prevalence of lignolytic secretomes , with Proteobacteria dominating the list with its 114 entries , followed by \u03b2-Proteobacteria (27 species/strains), \u03b1-Proteobacteria (18 species/strains), and \u03b4-Proteobacteria (3 species/strains), again highlighting that certain types of microbes are greatly enriched in the eLignin bibliome. It can also be noted that many of the organisms in this particular niche have undergone one or several taxonomical reclassifications since they were first isolated and described , with the remainder being Gram-positive (46 species/strains) and unknown/Gram-indeterminate (4 species/strains). This may have implication on studies focusing on, e.g., transport of compounds over membranes (discussed in a separate section below), or when expanding a species\u2019 substrate range by metabolic engineering. In the latter case, the difference in total GC content in the genome that is in general seen between Gram-positives and Gram-negatives (Muto and Osawa Although fungi are known as the main degraders of the lignin macropolymer (as described in the previous subsection), there are a substantial number of studies that describe delignifying bacteria. Tian et al. reviewed the topic and performed phylogeny on 57 lignin-degrading and 463 laccase-encoding prokaryotes that led them to propose that screening for laccases genes may be a good way to detect new lignin-degrading species  extension of the lignin microbial niche.Five archaeal isolates\u2014classified in niche subgroup 2  via acetyl-CoA  to evaluate the physiology of the microbial niche  monoaromatic compounds tend to be more commonly studied across all phyla. Note that there are no Acidobacteria or Spirocheates in the eLignin bibliome that have been reported to degrade natural/technical lignins and di-/oligoaromatics.Similar to how fundamental and applied studies on lignin focus on a few model organisms, many studies use a few common model aromatic model compounds that represent different funneling pathways  , coniferyl alcohol , and p-coumaryl branch (no methoxy groups)  they catabolize: the sinapyl branch (two methoxy groups), coniferyl branch (one methoxy group), and the see Fig. . Within see Fig. . Funnelisee Fig. , is anotIn a lot of bibliome studies, the substrate specificity of a species is presented without going into the intracellular conversion mechanisms nor reporting evidence of a specific funneling pathway. Therefore, in order to be able to use the eLignin dataset to look at pathway diversity, we developed a prediction algorithm to infer funneling branches from reported substrates from the literature. This is possible since many of the funneling branches are linear, e.g., ferulic acid is degraded via vanillin, and any species that have been reported to grow on these compounds and their intermediates can then be theoretically inferred to have the coniferyl branch Fig. . Cinnamip-coumaric (H) branches seem by far to be the most abundant in niche 2. This might be correlated to the number of methoxy groups -derived monomers. Spruce lignosulfonate has for instance been reported to yield vanillin, guaiacol, acetovanillone, and vanillic acid (P\u00e9rez and Tuck Amycolatopsis sp. ATCC 39116 (Pometto III et al. Comamonas sp. B-9 (Chen et al. Rhodotorula rubra IFO 889 (Huang et al. Sphingobium sp. SYK-6 (Katayama et al. Acetobacterium woodii NZva16 (Bache and Pfennig Rhizobium sp. YS-1r (Jackson et al. Oceanimonas doudoroffii JCM21046T (Numata and Morisaki Exophiala jeanselmei CBS 658.76 (Middelhoven Many lignin valorization studies apply chemical depolymerization since microbial enzymatic breakdown of lignin is a very slow process taking many weeks (Fackler et al. Although the chemical structure of many aromatic compounds allow them to passively diffuse through the lipid bilayers of biological membranes (Engelke et al. Acinetobacter baylyi ADP1 (Collier et al. Bradyrhizobium japonicum USDA110 (Michalska et al. Klebsiella pneumoniae M5a1 (Xu et al. Pseudomonas putida KT2440 (Nishikawa et al. Rhodopseudomonas palustris CGA009 (Giuliani et al. Sinorhizobium meliloti 1024 (Michalska et al. Sphingobium sp. SYK-6 (Mori et al. Corynebacterium glutamicum ATCC 13032 (Chaudhry et al. Lactobacillus plantarum WCFS1 (Rever\u00f3n et al. Rhodococcus jostii RHA1 (Otani et al. Pseudomonas isolate that excreted vanillyl alcohol during growth on vanillin as a tolerance mechanism to handle excess vanillin that was not catabolized to vanillic acid fast enough, but the mechanism by which vanillyl alcohol was transported out of the cell has not been elucidated yet (Ravi et al. Current knowledge on bacterial aromatic transporters mostly focuses on Gram-negative bacteria which have a cell envelope with two lipid bilayers separated by a periplasmic space: the outer and the inner membrane Nikaido . Some GrThe interest for lignin as an underexploited carbon source has markedly increased during the last two decades, as evidenced by the exponential increase in published papers on lignin valorization (Abej\u00f3n et al. The microbiological aspects of lignin and aromatics degradation have a long history with a vast bibliome, and the need for resources such as the eLignin database will continue to grow as the field expands. In the future, we expect to further implement in eLignin a number of discussed features including improved prediction algorithms, lignolytic communities, and substrates that cannot be converted by a given organism. Economically feasible lignin valorization will require advanced metabolic engineering and thorough knowledge on microbial physiology. In that context, the objective of eLignin is not only to generate new overviews of the field but also to fuel new research ideas and engineering strategies and thus become an operational tool for studies on the microbiological aspect of lignin degradation, catabolism, and valorization."}
+{"text": "Synapse loss has detrimental effects on cellular communication, leading to network disruptions within the central nervous system (CNS) such as in Alzheimer\u2019s disease (AD). AD is characterized by a progressive decline of memory function, cognition, neuronal and synapse loss. The two main neuropathological hallmarks are amyloid-\u03b2 (A\u03b2) plaques and neurofibrillary tangles. In the brain of AD patients and in mouse models of AD several morphological and functional changes, such as microgliosis and astrogliosis around A\u03b2 plaques, as well as dendritic and synaptic alterations, are associated with these lesions. In this review article, we will summarize the current literature on synapse loss in mouse models of AD and discuss current and prospective treatments for AD. Synapse loss has harmful effects on cellular communication, leading to network disruption in the central nervous system (CNS). The communication of billions of neurons within the mammalian brain generates and controls memory, thoughts and emotions. In a neuronal network with different cells, the transfer of information is coordinated at specialized compartments such as the synapse. Synapses are contact points between two neurons, where they communicate by passing ions or neurotransmitter across the synaptic cleft. Synapses can have excitatory or inhibitory effects on the target cells, depending on the released signals. The formed synapses are not rigid but rather dynamic and can either strengthen, shrink or even get lost. Considering the critical role of synapses under physiological conditions, it is not surprising that a severe loss of synaptic integrity can cause substantial disorders such as neurodegenerative diseases  which currently affects 46 million people worldwide Prince, . Over a Besides aging, new genetic risk factors for AD were reported recently in GWAS, such as ApoJ/Clusterin, PICALM, complement receptor 1 (CR1), TREM2 and sialic-binding immunoglobulin (Ig)-like lectin CD33  (Kuchibhotla et al., Astrocytes represent the most abundant cell type in the brain. They are involved in synapse formation and elimination, synaptic plasticity and activity. Due to their essential role in brain function it is likely that astrocyte dysfunction results in progression of neurodegenerative diseases. Similar to microglia, reactive astrocytes surround senile A\u03b2 plaques in the brain of AD patients and in mouse models of AD. They become reactive as indicated by their hypertrophic processes and increased expression of GFAP (Wisniewski and Wegiel, Further investigations of neuron-glia signaling pathways and their disruption in neurodegenerative diseases are necessary for the development of new successful therapies that are promising due to the early involvement of glia in the disease process.Although our knowledge regarding the mechanism underlying AD pathogenesis has improved over the last decades, there is still no cure available. Moreover, open questions concerning memory and synapse loss, as well as gliosis and related neuronal damage, still remain (De Strooper and Karran, In vivo imaging of 3xTg-AD mice revealed spine loss on dystrophic dendrites positive for hyperphosphorylated tau in areas without plaques (Bittner et al., Most current therapeutic approaches focused on the reduction of A\u03b2 levels and A\u03b2 plaque load by inhibiting or modifying the generation of A\u03b2. Other attempts tried to target the tau protein instead (Roberson et al., In vivo 2-photon imaging allows to explore structural plasticity of synapses in living mice, even for long-time periods (Grutzendler et al., in vivo 2-photon imaging and followed dendritic spines and axonal boutons over the course of several weeks in APPS1 mice. Pre- and postsynaptic structures showed an enhanced instability in the vicinity of A\u03b2 plaques (Grutzendler and Gan, Prime targets for AD therapies are \u03b2- and \u03b3-secretase inhibitors. Numerous inhibitors currently undergo clinical trials (May et al., in vivo imaging experiments (Filser et al., Unfortunately, the inhibition of BACE1 is known for its mechanism-based side-effects. Conditional deletion of BACE1 in 5xFAD mice resulted in reduced A\u03b2 plaque load and improved synaptic function, determined by LTP and contextual fear conditioning experiments (Hu et al., The oligomeric form of A\u03b2 is often considered as the toxic form. Immunotherapy against A\u03b2 oligomers had little effect on synapse loss in the vicinity of A\u03b2 plaques but abolished synapse loss further away from plaques (Dorostkar et al., To date, it remains an open question whether such A\u03b2 lowering strategies will be successful. Therefore, alternative treatment options should be considered. Mice exposed to an environmental enrichment developed enhanced numbers of new dendritic spines, excitatory synapses and dendritic branches on pyramidal neurons (Mora et al., Besides the physical degeneration of synapses in AD and other neurodegenerative diseases, it is unclear which role glial cells play during the process of synapse loss. Further research will hopefully provide more insights into the role of glial cells and their contribution to synapse loss, in particular at earlier pre-depositing stages when synapses are already vulnerable. Future preclinical treatment approaches should combine pharmacological, non-pharmacological and behavioral studies.SZ-W and MM-L contributed equally to this work, wrote the manuscript, read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ocular surface disease is an umbrella term that includes a variety of complex pathologies such as Stevens\u2013Johnson syndrome, mucous membrane pemphigoid, limbal stem cell insufficiency, dry eye disease, and ocular graft-versus-host disease. Regardless of the underlying disease process, ocular surface failure may result in inflammatory and infectious complications and potentially devastating visual loss. Early diagnosis and appropriate treatment of ocular surface disease require a high level of expertise as these conditions can be extremely challenging even for experienced clinicians. Although key issues in the management of patients with complex ocular surface disease still remain controversial, recent advances in diagnostics and therapeutics have enhanced our armamentarium and allow for improved clinical outcomes.in vivo confocal microscopy, the morphology of two types of vortex keratopathy: amiodarone-induced keratopathy and the Fabry disease-associated keratopathy. Finally, Moschos et al. explore the psychological aspects and the incidence of depression in patients with symptomatic keratoconus.In our special issue on ocular surface disease, Wr\u00f3bel-Dudzi\u0144ska et al. report on the clinical efficacy of platelet-rich plasma in the management of neurotrophic corneal ulcer, showing promising clinical results. Hazarbassanov et al. assess the effect of osmoprotection in the management of dry eye disease after refractive surgery in a randomized controlled double-blind clinical trial, while Moussa et al. investigate the effect of different prostaglandin analogues on the ocular surface of patients with primary open-angle glaucoma. Krysik et al. report on indications, outcomes, and complications of penetrating keratoplasty for ocular surface disease-related pathologies in a tertiary referral center, whereas Sun et al. analyze the therapeutic effects of corneal debridement combined with intrastromal voriconazole in a patient series with recalcitrant fungal keratitis. Ikegawa et al. investigate, with the aid of Zisis GatzioufasSamer HamadaSotiria PaliouraThe authors declare that they have no conflicts of interest."}
+{"text": "Innate immunity against pathogen infection by membrane-localized receptors is evolutionarily conserved among eukaryotes  and receptor-like proteins (RLPs) ; and (2) VIGS in N. benthamiana avoids gene function redundancy and allows for simultaneous silencing of multiple homologous genes (Wang et al., The VIGS-based approach for identification of PRRs has advantages over methods that rely on map-based cloning and Arabidopsis T-DNA insertion lines (Zipfel et al., N. benthamiana recognizes XEG1, a widely distributed MAMP in microbial taxa (N. benthamiana can identify XEG1 family proteins secreted by various microbes. Therefore, RXEG1 could potentially be used to protect a broad range of plants, especially other solanaceous plant species such tomatoes, whereby high disease resistance might be achieved through genetic engineering or by spraying.In addition to identifying and characterizing PRRs, elucidating the mechanisms by which PRRs perceive microbial attack will significantly advance our understanding of plant innate immunity. The comprehensive and intensive work of Wang et al.  revealedial taxa . When miial taxa . Wang etial taxa  demonstrWang et al.  identifiCurrently, the recognition of certain MAMPs remains restricted to solanaceous plants (Wang et al., WW drafted the manuscript. SW and WW revised the manuscript. SW draw The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Geriatrics infusion and transformation of community-based settings to support \u201caging in place\u201d is complex. It requires a customized approach that engages multiple stakeholders who are invested in systems redesign and process change. Rowan University School of Osteopathic Medicine\u2019s NJ Geriatrics Workforce Enhancement Program, in partnership with an affordable housing facility operated by Fair Share Housing/Northgate II, and Rutgers University School of Nursing (RSoN), implemented a Resident Health Risk Assessment (RHRA) tool as part of an interprofessional community-based training experience for health professions students. The goal was to identify health risks that impact a resident\u2019s ability to age in place and implement a person-centered intervention plan. Multi-level stakeholder engagement and ongoing rapid cycle quality improvement catalyzed changes in structure and process for all partners. Results included refinement of an interprofessional clinical rotation, introduction of competency attainment into the orientation process, and resource reallocation to support data collection."}
+{"text": "Fungi are eukaryotic heterotrophs present in virtually every environment, with potentially more than 5 million individual species . DespiteThe constant exposure of humans to both commensal and environmental fungi requires a competent immune system for tolerance, protection, and/or clearance, while limiting collateral damage caused by excessive or detrimental inflammation. Innate responses to fungal pathogens are initiated by fungal component recognition via an array of pathogen-associated molecular pattern recognition receptors (PRRs) \u201311. RecoIncreased understanding of these host-fungal interactions and the mechanisms that favor protective immunity over immune pathology could provide targets for novel therapeutic approaches that complement the limited repertoire of existing antifungal drugs. The aim of this research topic is to explore the host and fungal pathways that program innate and adaptive immunity and the immune cells, molecules, and regulatory pathways that comprise protective or detrimental responses to fungal exposure or infection. Researchers from 15 countries in North and South America, Europe, Asia, and Australia contributed 36 review and original research articles that cover a wide range of fungal pathogens, disease models, and effector and regulatory cell and molecular pathways of host immune responses to fungal exposure and infection. Here, we present an outline of the findings, perspectives, and reviews contained in this research topic.Tang et al.. Although the important role of the \u03b2-1,3-glucan receptor dectin-1 in antifungal immunity is well appreciated, the \u03b1-mannan-binding dectin-2 and dectin-3 also influence responses to fungal exposure and infection and their roles are less clear. In support of these studies, Preite et al. show that dectin-2 and dectin-3 mediate antifungal activity and cytokine secretion of human plasmacytoid dendritic cells (pDCs) in response to the endemic dimorphic fungal pathogen Paracoccidioides brasiliensis via a pathway mediated by the CLR-associated signaling molecule Syk. In addition, de Castro et al. show that mouse bone marrow-derived macrophages (BMMs) and DCs (BMDCs) produce IL-1\u03b2 and IL-18 in response to Fonsecaea pedrosoi, the main causative agent of chromoblastomycosis, in a dectin\u22121, \u22122, and \u22123-dependent manner. A role for the NOD-Like Receptor P3 (NLRP3), an intracellular protein complex that controls activation of inflammatory caspases and cytokine production, is shown by Feriotti et al. as important for the development of protective immunity to pulmonary infection with P. brasiliensis. \u03b2-glucan stimulation of NLRP3 inflammasome-mediated IL-1\u03b2 secretion in B cells reported by Ali et al. shows innate antifungal cytokine production in an adaptive lymphocytes that were also capable of producing IgM in an NLRP3-dependent manner.The major class of pattern recognition receptors, the C-type lectin receptors (CLRs), including molecules critical for the initiation of inflammation and the development of adaptive immunity to fungi, are reviewed by Aspergillus fumigatus . Circulating monocytes are subsequently recruited to sites of infection in response to inflammatory signals produced by tissue-resident macrophages. T\u00f3th et al. report that the exposure of hyphae of the dematiaceous mold Curvularia lunata to human THP-1 monocytes resulted in increased inflammatory IL-8 and regulatory/anti-inflammatory IL-10, suggesting a possible mechanism for the ability of this species to cause chronic infections in immune competent individuals. Landgraf et al. report that dihydrolipoyl dehydrogenase secreted by P. brasiliensis may act as an exoantigen that enhances macrophage phagocytosis. Mukaremera et al. report that hypha of the yeast Candida albicans induced low levels of cytokine secretion from human monocytes, with the highest levels from yeast and intermediate levels from pseudohypha, and cell wall mannan depletion partially reversed these responses. Using fluorescence yeast cell wall-labeling to measure yeast division within macrophages, Dagher et al. show that activation of the tyrosine kinase Syk is critical for macrophage control of phagocytosed C. glabrata. Together, these studies provide new insights into the roles for monocytes and macrophages in induction and regulation of antifungal inflammation and fungal clearance.PRR-expressing tissue-resident macrophages are part of the first line of defense against fungal infections  cells in innate antifungal immunity is reviewed by Schmidt et al.. These works further illustrate diverse mechanisms and roles for innate myeloid and lymphoid cells in antifungal immunity.Inflammatory cytokine production by macrophages leads to localized inflammation with production of chemokines that attract additional innate immune cells. Maldonado and Fitzgerald-Bocarsly. Xu et al. investigated the role of macrophage receptor with collagenous structure (MARCO) on pDC recruitment and induction of antifungal adaptive immunity to C. neoformans infection, and report that expression of MARCO promoted recruitment of lymph node DCs and skewed local and systemic T helper cell responses away from protective Th1 responses and toward non-protective Th2 responses. Wong et al. demonstrate a role for leucine-rich repeat kinase 2 (LRRK2) in translocation of NFAT to the nucleus in DCs in the early stages of the non-canonical autophagic response to A. fumigatus conidia, thus connecting LRRK2 with NFAT-mediated IL-2 expression in early antifungal immunity. Hellmann et al. compared immune responses to A. fumigatus in human and mouse DCs, macrophages, and neutrophils, and observed that human DCs exhibited more significant increases in maturation markers and phagocytic ability than murine DCs, while murine neutrophils and macrophages displayed more reactive oxygen species production after A. fumigatus exposure. Collectively, these works provide support for additional mediators of DC function that shape antifungal adaptive immunity, and suggest distinct roles for these cells in human fungal disease and experimental animal models.Dendritic cells (DCs) are multifaceted professional antigen presenting cells that integrate antigen uptake and local inflammatory signals in order to effectively prime adaptive antifungal immune responses upon migration to site-draining lymph nodes . The rolTrist\u00e3o et al. report that these cytokines, along with the IL-17 receptor A, were necessary for protective lung granuloma formation in mice infected with P. brasiliensis. IL-1\u03b1/\u03b2 also influence adaptive immune responses to fungi, such as the dimorphic Cryptococcus spp., as Shourian et al. observed that IL-1 receptor type 1-deficient mice had increased cryptococcal burden, eosinophilia, M2 macrophage polarization, and recruitment of CD4+IL-13+ T cells, with a concomitant reduction in pro-inflammatory Th1 and Th17 cytokines. However, excessive inflammation and Th1 activation in C. neoformans infection is also detrimental, and was reported by Fa et al. to be mediated by the cell death regulatory genes FADD (Fas-associated death domain) and RIP3K (receptor interacting protein kinase 3). The results of these studies support roles for Th1 and Th17 responses in antifungal immunity, as well as a requirement for regulation of cell death to limit excessive inflammation.After DCs migrate to draining lymph nodes, they present fungal antigen to na\u00efve T cells, inducing antifungal adaptive immunity. This process is influenced by cytokines in the microenvironment. Formation of the antifungal Th17 subset of T helper cells is promoted by the inflammatory cytokines IL-6 and IL-23, and A. fumigatus; findings that shed light on this host-pathogen dynamic are reviewed by Choera et al.. De Ara\u00fajo et al. report that DCs from an infected P. brasiliensis-susceptible mouse strain exhibit IDO activity and promote inflammation, while DCs from resistant mice phosphorylate IDO and promote a tolerogenic phenotype. The same group further compared P. brasiliensis infection in IDO-deficient and wild-type mice, and observed increased mortality, fungal burden, histopathology, and Th17 cell recruitment and activation in IDO-deficient mice with concomitant decreases in Th1 and Treg cells de Ara\u00fajo et al.. In addition to the enzymatic activity and signaling by IDO, antifungal immune responses are regulated at the post-transcriptional level by microRNAs (miRNAs); these molecules and their associated pathways are reviewed by Croston et al.. Zimmerman et al. report that patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) exhibit decreased levels of the signaling molecule STAT1, in contrast with patients with STAT1 gain-of-function mutations, despite similar disease phenotypes. These works highlight findings of enzymatic, post-translational, and signal transduction in the regulation of antifungal immunity and fungal disease susceptibility.Cell and molecular regulation of immunity occurs at multiple levels from induction to resolution of immune responses. An enzyme that limits available tryptophan and thus dampens immune cell proliferation and effector function, indoleamine 2,3-dioxygenase (IDO), is produced by mammalian hosts and the fungal pathogen Kernien et al. review host immune recognition of fungal biofilms and biofilm properties that inhibit host recognition and clearance. Zhang et al. explore how immune interactions with respiratory and gastrointestinal fungal microbiota contribute to chronic airway inflammatory disease. Sparber and LeibundGut-Landmann more specifically discuss host immune responses to skin-colonizing Malassezia species, yeasts that are involved in a variety of skin disorders. Finally, Casadevall et al. review the evidence that C. neoformans mediates host damage at the molecular, cellular, tissue, and organism levels, in some instances with formation of large fungal masses in brain tissue. These reviews highlight emerging areas of fungal immunology that consider fungal interactions with the host immune system beyond the level of cell and molecular recognition.Although spore/hyphal recognition by innate cells drives the development of immunity to fungal pathogens, host-fungal pathogen interactions are also considered at the macroscopic level of microbial communities  and host tissues. Elsegeiny et al. review studies of immune pathology in cryptococcal infection and discuss the need for immune targeting therapies that suppress immune-mediated damage without further compromising host protection. Van Dyke et al. demonstrate that combining non-lethal C. neoformans challenge with local IFN-\u03b3 production elicits an immune response that protects mice from subsequent lethal infection. Tso et al. summarize efforts and obstacles in the development of anti-Candida vaccines, and discuss the potential use of trained immunity in the development of strategies against opportunistic fungal infections. Finally, Kumaresan et al. review the development of CD8+ T cell therapy for the control of invasive fungal infections, with a focus on the use of chimeric antigen receptor (CAR) T cells that target \u03b2-glucan. These reviews underscore the importance of current and future efforts to enhance immune protection while limiting immune pathology in patients that may not respond to traditional antifungal therapies.Despite significant advances in our understanding of host immunity to fungal exposure and infection, treatment of fungal diseases has not progressed beyond the use of a limited repertoire of antifungal drugs that are rendered increasingly ineffective by emerging fungal resistance. Since appropriate antifungal immunity is critical for protection from fungal disease, complementary therapies that target immune pathways represent areas of considerable interest for fungal immunologists. Collectively, the studies described in original research and review articles in this topic provide optimism for the future of antifungal immune therapy. Recent advances by fungal immunologists have greatly increased our understanding of the basic mechanisms of innate immune recognition, inflammation, adaptive immunity, and regulation of antifungal immune responses at molecular, cell, tissue, and organismal levels. We hope these articles will stimulate further research with the ultimate goal of improving outcomes for patients with fungal diseases.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "People with diabetes mellitus (DM) have a higher-than-average risk of having a heart attack or stroke , 2. In fDe Rosa et al., from Magna Graecia University, elegantly illustrated fundamental genetic and epigenetic mechanisms linking cardiovascular disease and DM; similarly, Pordzik et al. identified the functional role of specific platelet-related microRNAs in the pathophysiology of cardiovascular events in high-risk populations, including diabetic patients.Soares Felicio et al. demonstrated an association between reduced levels of Vitamin D and the presence and severity of diabetic kidney disease in type 1 DM (T1DM); the molecular mechanisms underlying diabetic nephropathy have been also explored by Zou et al. in streptozotocin-induced DM. Arcangeli et al. found a significant association between the number of circulating endothelial progenitor cells (cEPCs) and the age and duration of the disease in T1DM patients: indeed, young T1DM patients have significantly higher levels of cEPCs compared to adult T1DM patients; of note, such difference is also maintained when the disease lasts for more than 10 years. The Authors propose that maintaining a high number of cEPCs, possibly through an efficient glycemic control, would contribute to contain the cardiovascular burden in T1DM. Notably, in vitro experiments performed by Lin et al. at New York University have shown how to ameliorate purification and maturation of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes through means of culture in glucose-depleted medium supplemented with fatty acids (oleic acid and linoleic acid) and 3,3\u2032,5-triiodo-L-thyronine (T3).Infante et al. revealed a greater severity of coronary artery disease in type 2 diabetes (T2DM) patients compared to non-diabetic individuals; equally important, van Bussel et al. from Maastricht University Medical Center, highlighted the actual advantages of multiparametric neuroimaging in the clinical evaluation of cognitive decline in T2DM.Applying comprehensive analyses based on imaging and molecular biology, Orosz et al. in subjects with impaired glucose tolerance, a prediabetic condition, have shown that prediabetes is associated with repolarization instability, indicated by elevated values of beat-to-beat short-term QT interval variability, thereby suggesting that an impaired autonomic control precedes the actual onset of diabetes. Last but not least, Altara et al. validated the key importance of targeting microvascular disease, common in both diabetes and obesity, in order to treat heart failure with preserved ejection fraction (HFpEF). Microvascular disease is a growing public health problem, accounting for approximately half of hospital admissions of individuals with heart failure (The studies performed by  failure , 11, 12.In summary, the present Research Topic indicates that the exceptional advances achieved in the last decade in understanding the molecular alterations involved in the pathophysiology of both DM and cardiovascular disease are opening new therapeutic opportunities for the treatment of these disorders and, potentially, their future application to the clinical scenario might result to further enhancements in patient care. Furthermore, the exciting findings discussed herein might foster community awareness of these important diseases and stimulate further research in the field.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Numerous studies have shown that infiltration of lymphocytes into tumor tissue is associated with better prognosis (Bindea et al., 2013; SchmidtThis result is of relevance, because it shows that immune modifiers have different roles in NSCLC of smokers and non-smokers. It will be important to consider this difference in therapy studies targeting the PD-1/PD-L1 axis. Predicting prognosis and response to therapy remains a challenging task (Hellwig et al., 2016; Lohr etThe author declares no conflict of interest."}
+{"text": "Cervico-vaginal mucus (CVM), the product of epithelial cells lining the uterus, cervix and vagina, is secreted to facilitate uterine lubrication and microbial clearance. Predominantly composed of water and mucins, CVM also contains high levels of immuno-active proteins such as immunoglobulin A (IgA), lactoferrin and lysozyme which protect against infection by blocking adhesion and mediating microbial killing. The repertoire of cytokines, chemokines and antimicrobial peptides is predominantly generated by the secretions of endometrial epithelial cells into the uterine lumen and concentrated in the CVM. The quantity and relative proportions of these inflammatory biomarkers are affected by diverse factors including the estrus cycle and health status of the animal and therefore potentially provide important diagnostic and prognostic indicators. We propose that measuring molecular signatures in bovine CVM could be a useful approach to identifying and monitoring genital tract pathologies in beef and dairy cows. Cervico-vaginal mucus (CVM) represents a mixture of vaginal, cervical and uterine mucus and is composed of 92\u201395% of water, ions and 5\u20138% solid matter   multiplication in the uterus  are secreted directly into the endometrial lumen while TNF-\u03b1, IL-1 and IL-8 are concentrated in uterine mucus after infiltrating through uterine wall (Carneiro et al. IL8 in the endometrium 2\u00a0weeks after calving, and intrauterine infusion of exogenous IL-8 reproduces the disease (Chapwanya et al. IL-1 is the key mediator of uterine inflammation that is secreted as a result of tissue damage associated with parturition (Adnane et al. E. coli infection (Chapwanya et al. E. coli have high systemic levels of AGP at 21 and 28 DPP (Williams et al. Trichomonas foetus or endometritis (Adnane et al. APPs are highly responsive proteins, secreted by the liver in response to injury or infection in an effort to restore homeostasis. Extra-hepatic sources of APPs have also been identified, including in endometrial cells (Chapwanya et al. Members of the S100 family chelate calcium and therefore regulate many cellular processes including microbial viability (Corbin et al. Here we reviewed the measurement of inflammatory biomarkers in CVM early postpartum as an alternative method for the prognosis of genital tract pathology in cows and other species. CVM molecular signatures are specific to uterine health status may also reflect local microbiome diversity. They provide a convenient, cost effective and welfare-friendly method for timely detection of uterine inflammation in order to reduce the impact of endometritis on dairy cow production. CVM therefore is a potentially valuable resource to investigate the diversity of bacteria in cows with uterine disease as many of these bacteria are trapped by the mucus structure."}
+{"text": "DiMarco et al., Chem. Sci., 2018, DOI: 10.1039/c7sc03839a.Correction for \u2018Dye-sensitized electron transfer from TiO The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage.Demographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model  but no significant differences when VT was used .In total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's In conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes. However, findings have been inconsistent and so far they have only been partially reviewed quantitatively . In order to extract data from studies where data were available only in a plot format, we have used the plot digitiser software (http://plotdigitizer.sourceforge.net/).The main outcome measure was the difference in the TSPO imaging index between patients with schizophrenia-spectrum disorders and healthy controls. For all studies, we extracted the following variables: authors, year of publication, subject characteristics for the patient and healthy control group , imaging characteristics  and modelling method. The estimation of pooled standard deviation was performed using the statstodo software  . The DVR method used in this study is not equivalent to the measures used in the other studies. Also Ottoy et al.  . Therefore, the main analysis of VT values included six studies using the 2TCM model.The main outcome measure was the effect size determined using the TSPO tracer measure and quantified by either BPd Hickie , and alt  express both mixed affinity for TSPO (MAB), while those without the polymorphism (HH) have high-affinity binding (HAB) for TSPO . Leave-one-out sensitivity analyses were conducted to investigate the potential effect of an individual study on the outcome measure. A p value <0.05 (two-tailed) was taken as a significance level. The statistical analysis of the extracted data was conducted using the R statistical programming language version 3.2.2 with the \u2018metafor\u2019 package.Publication bias was assessed using visual inspection of funnel plots as well as regression test. Where potential publication bias was suspected, trim and fill analysis was conducted to correct for putatively missing studies. Heterogeneity was estimated using the The PubMed, EMBASE and PsycINFO databases were searched without language restrictions. The electronic search using EMBASE and PsycINFO were carried out together using Ovid. The following keywords were used: \u2018(Positron Emission Tomography OR PET OR Single photon emission tomography OR SPET OR Single Photon Emission Computed Tomography OR SPECT) AND (schizophrenia OR schizophreniform OR psychosis) AND \u2019. Review papers were also screened to search for additional studies.The inclusion criteria were: original studies in (1) patients with a diagnosis of schizophrenia or related psychotic diagnoses , (2) reporting PET measures using a TSPO-specific ligand and (3) reporting data for the whole grey matter or grey matter regions. Studies that did not have a control group were excluded. Where there was sample overlap between studies, we included the largest one and excluded the other to avoid double counting.VT). As these give different information, we conducted separate meta-analyses of these outcomes. The studies that used BP as an outcome measure have used either values obtained using microparameters from Simplified Reference Tissue Model  or volume of distribution  0.02\u20130.6] . Visual inspection of the funnel plot suggested asymmetry . The regression test was significant . The trim and fill analysis showed three putatively missing studies on the left side. The results were not significant after correcting for these studies . The results were significant in two out of six in the leave-one-out analysis, with effect sizes varying from 0.27 to 0.47. Five out of the six studies used the [11C]-PK11195 ligand, with the sub-analysis of these studies revealing a significant elevation of BP in patients with schizophrenia with an effect size of 0.35  .Six studies reported outcome measures as BP. Our results showed that BP was significantly elevated in patients with schizophrenia when compared with healthy controls with an effect size of 0.31 [Hedge's .02\u20130.6] . The I2 VT. VT in patients with schizophrenia when compared with healthy controls . The I2 test revealed moderate\u2013high heterogeneity . Visual inspection of funnel plot suggested asymmetry . However, the regression test was not significant . Trim and fill analysis showed two missing studies in the right side. The effect sizes varied from \u22120.08 to \u22120.37 in the leave-one-out analysis. We extracted data for high- (HABs) and mixed-affinity binders (MABs) separately from these studies to conduct a sub-analysis stratified by genotype. Bloomfield et al. reported only one patient who was a MAB, precluding accurate estimation of the effect size. Thus, this study was not included in the sub-analysis of MAB subjects . However, there was a significant difference in the MAB .Six studies reported the outcome measure as g\u00a0=\u00a00.31; p\u00a0=\u00a00.03), but there is no significant difference when the tracer volume of distribution (VT) is used as the outcome measure . In the following section, we consider methodological factors and the implications of our findings.Our main findings are that TSPO PET tracer binding is significantly elevated in patients with schizophrenia relative to controls when BP is used as an outcome measure, with a small-to-moderate effect size  is negative, the results using this tracer are not an outlier, suggesting findings may not entirely be accounted for by tracer differences. It has been suggested that TSPO expression may change during the course of the disorder, which could account for the differences in findings between studies  measures the tracer binding in the tissue of interest relative to another brain region selected to have negligible specific binding, to give specific binding in the region of interest  measures the total amount of tracer in the brain region relative to that in the blood  that are known to be elevated in schizophrenia (Telford et al., et al., et al., VT, and potentially mask an elevation in the patients\u2019 brain as compared with controls. There is inconsistency in findings in schizophrenia, with one study showing elevation in the plasma concentration levels of [11C]-PBR28 in patients with schizophrenia relative to controls (Bloomfield et al., 18F]-FEPPA and [11C]-PBR28 show no differences in plasma concentration levels (Hafizi et al., et al., et al., et al., et al., VT values in the disorder, but it should be recognized that there is no direct evidence that plasma binding alters VT values in humans (Cumming et al., VT changes are not explained by an effect of protein binding (Collste et al., VT in schizophrenia. Nevertheless, while this is a potential concern for studies using VT as the outcome measure, blood binding should not affect the studies that use a ratio approach, as these methods report tracer uptake relative to another brain region rather than blood. Furthermore, TSPO is expressed on the endothelial cells of brain blood vessels as well as on the outer layer of mitochondria in microglia (Rizzo et al., et al., The non-displaceable BP (BPet al., et al., et al., et al., et al., Taken together, our meta-analytic findings suggest an elevation in TSPO tracer binding in total grey matter relative to other brain tissue, but not relative to blood, with the caveat that the relative increase is largely based on studies using PK11195, which has a lower specific signal. Thus, this could reflect an increase in TSPO in grey matter or a reduction in TSPO in the reference region, or altered non-specific binding in the brain (Cumming VT as the outcome measure, showed a reduction in VT in patients relative to healthy controls (Plaven-Sigray et al., VT in our meta-analysis, our meta-analysis included one more second-generation study showing no differences in VT between schizophrenia patients and healthy controls (Ottoy et al., in utero and early development may predispose to schizophrenia (Meyer, VT approach (Bloomfield et al., VT as the outcome measure, using the tracer [18F]-FEPPA and [11C]-PK11195, showed no differences in TSPO binding between healthy controls and in individuals at ultra high risk of psychosis for psychosis (Hafizi et al., et al., et al., et al. (et al. (et al. (Our different findings depending on the outcome measure used point towards the existence of potential methodological problems in TSPO imaging, raising questions over the interpretation of the elevation in grey matter TSPO binding relative to a reference region in patients with schizophrenia when compared with healthy controls. A recent individual participant data meta-analysis of second-generation radioligand studies, with a Meyer, . However, et al.  and van  (et al.  suggest  (et al. b using tVT is the outcome measure used. These results suggest that potential methodological differences between TSPO studies need to be accounted for and addressed in future studies and keep open the discussion over the existence of an increase in microglia activity in patients with schizophrenia-spectrum disorders.In conclusion, there is evidence for a moderate effect size elevation in TSPO tracer binding in grey matter in schizophrenia-spectrum disorders when using BP as an outcome measure, but no changes when"}
+{"text": "Purified proteins offer a homogeneous population of biological nanoparticles, equipped in many cases with specific binding sites enabling the directed self-assembly of envisaged one-, two- or three-dimensional arrays. These arrays may serve as nanoscale biotemplates for the preparation of novel functional composite materials, which exhibit potential applications, especially in the fields of nanoelectronics and optical devices. This review provides an overview of the field of protein-mediated biotemplating, focussing on achievements made throughout the past decade. It is comprised of seven sections designed according to the size and configuration of the protein-made biotemplate. Each section describes the design and size of the biotemplate, the resulting hybrid structures, the fabrication methodology, the analytical tools employed for the structural analysis of the hybrids obtained, and, finally, their claimed/intended applications and a feasibility demonstration (whenever available). In conclusion, a short assessment of the overall status of the achievements already made vs. the future challenges of this field is provided. Purified proteins offer a homogeneous population of biological nanoparticles, equipped in many cases with specific binding sites enabling directed self-assembly into one-, two- or three-dimensional arrays. These arrays may serve as biotemplates for the preparation of novel functional composite materials on the nanoscale, using either specific or site-directed chemical binding, with the potential for expansion by genetic or chemical manipulations.The potential inherent in protein-mediated biotemplating has attracted much attention throughout the past two decades . SeveraThis review provides an overview of the field of protein-mediated nanoscale biotemplating, focused on the achievements made throughout the past decade. The review is organized into sections according to the size and configuration of the protein-made biotemplate ranging from single protein soluble molecules and supramolecular protein \u201ccages\u201d to two-dimensional (2D) protein arrays, protein fibers and tubes, viral envelopes, three-dimensional (3D) protein crystals, and fragments of microbial cells.Each section describes the structure and size of the biotemplates employed, the fabrication methodology, the analytical tools used for its structural analysis, its claimed/intended applications and a feasibility demonstration (whenever available).Dagan-Moscovich et al.  initiateThe construction of a conducting metallic silver coating on the surface of the oxidoreductase enzyme glucose oxidase (GOx), a 5 \u00d7 8 nm \u2018peanut-like\u2019 dimer, enabled the nanowiring of its active site to platinum electrodes, resulting in the oxygen-independent direct determination of glucose by electrochemical biosensors , as scheThe biotemplating approach for electroless metal deposition directed to the surface of single soluble protein molecules was readily expanded from silver deposition to the deposition of other metals . GlucoseBy changing the biologically active protein core from GOx to the binding protein avidin, which is capable of specifically binding the vitamin biotin, additional applications of metallic silver-coated soluble protein molecules became available: imaging by HRTEM without staining. Mor et al.  demonstrThe range of applications of silver\u2013enzyme hybrids was expanded further to antimicrobial applications aiming at the prevention of microbial biofilm formation, by affecting the on-site enzymatically attenuated release of silver ions, generating in situ antimicrobial activity. \u2018Zone of inhibition\u2019 antimicrobial studies demonstrated the feasibility of using these hybrids as wide-spectrum antimicrobial agents, especially as potential antifungal agents against skin and hair fungal contaminations .Veelders and Essen  demonstr2S nanoparticles (NPs) ~20 nm in diameter, enabled by RNase A capping, as hollow or full spheres with a claimed potential application as a drug delivery vehicle. The structural characterization of the QDs and Ag2S NPs thus obtained was carried out by high-resolution electron microscopy and spectral analysis.Kong et al.  describeThree recent reports have described biomineralization processes directed by protein molecules and designed for biomedical applications, including (i) the formation of albumin-mediated platinum nanocrystals for tomography imaging ; (ii) siFerritin\u2014a natural, spherical, protein-made nanoscale \u201ccage\u201d\u2014serves as an iron storage protein in bacteria, plants, animals and humans. In eukaryotic cells, ferritin is comprised of 24 subunits forming a hollow spherical shell with an inner diameter of 8 nm ,18). TheThe currently available biochemical data on the molecular mechanisms involved in these processes has inspired an exploration of the potential biomedical applications of a series of ferritin and mutated ferritin as protein cages for the preparation of hybrids by biotemplating. The templating of metals, alloys and metal ion salts, including iron, silver, gold, palladium, cadmium, cobalt, platinum and copper, were described . It Listeria innocua [The demonstrated feasibility of using the cavity, 7 nm in diameter, of natural ferritin for biotemplating has triggered efforts to develop analogous, smaller protein cages made of other proteins, resulting in CdS and CdSe NPs biotemplated inside the 4.5 nm diameter cavity of a cage-shaped protein derived from  innocua ,24, as wThe use of the cage-forming protein clathrin as a biotemplate for the synthesis of metallic NPs was also described, enabling the preparation of either homogeneous or bimetallic silver\u2013gold or silver\u2013copper NPs, albeit in sizes larger than those available by ferritin-mediated biotemplating (characterized by HRTEM) .2 molecules by using a small de novo designed protein, self-assembled as a \u201cnanoreactor\u201d for biomineralization. Behrens et al. [Voet et al.  demonstrs et al.  describeZhou et al.  describeThe pioneering work of Slytr et al.  on the iThe elucidation of the mechanism underlying the biotemplating of FePt NPs from the gas phase into a 2D array on the surface of a bacterial S-layer was presented by Queitsch et al.  and veriValero et al.  demonstrTwo-dimensional protein arrays other than bacterial S-layers were also used as biotemplates: Shindel and coworkers ,38,39 ex2 nanotubes enabled directed gold deposition, resulting in a hybrid exhibiting enhanced electron transfer between heme proteins and electrodes [Bovine serum albumin adsorbed as a 2D monolayer on the surface of TiOectrodes .Magnetospirillum magneticum for biotemplating of magnetic nanoparticle arrays; characterized by TEM, SEM and AFM, with potential applications in the manufacture of electric circuits.Galloway et al.  and BirdThe data available in the literature on self-assembly of proteins into fibers and tubes has paved the way for the exploitation of the inherent potential of using a series of readily available self-assembled protein fibers as biotemplates.Colby et al.  describeMalisauskas et al.  describeMethanocaldococcus jannaschii as a biotemplate decorated with silver, gold, palladium or platinum NPs, by electroless deposition using NaBH4 as a reducer of pre-adsorbed metal ions. The coated protein filaments thus obtained were characterized by TEM, spectral and electrical analysis, with the intended application of metal nanowires of defined length.Slocik et al.  describeIonov et al.  describep-nitrophenol to p-aminophenol by NaBH4. The gold nanoparticle-decorated lysozyme fibrils obtained were subjected to structural analysis by TEM and X-ray diffraction (XRD) analysis, and the feasibility of their use as a catalyst was demonstrated by kinetic spectrophotometric analysis.Juarez et al.  describeLeroux et al.  demonstr3O4\u2013protein hybrids thus obtained were characterized by HRTEM, XRD and Fourier transform infrared spectroscopy (FTIR) analysis, and the feasibility of their magnetization demonstrated, leading towards potential applications as MRI contrast agents.The preparation of magnetic nanowires was also described by Juarez et al. . The coaGeobacillus stearothermophilus into tubular structures serving as biotemplates for the chemical deposition of platinum. The resulting hybrid was characterized by HRTEM, SEM and fluorescence analysis, in preparation for an intended application as nanowires.Korkmaz et al.  describe2 and TiO2 nanowires were grown on the biotemplate by monomer polymerization. The structures obtained were characterized by TEM and field-emission scanning electron microscopy (FESEM), and the feasibility of their use for biosensors based on the enzymatic activity of acetylcholine esterase was demonstrated and characterized.Padalkar et al.  describep-nitrophenol by NaBH4 to 4-aminophenol was described by Batzli and Love [Insulin fibers were coated with palladium by electroless deposition. The nanostructure and electrical properties of the palladium hybrids thus obtained were characterized by AFM, TEM, X-ray photoelectron spectroscopy (XPS) and scanning capacitance microscopy (SCM) analysis . The useand Love ; see alsand Love .Methanocaldococcus jannaschii, and its use as the major component of a biotemplate has been constructed in combination with other protein-made connecting units .The highly-ordered 3D protein envelopes of viruses, especially of plant viruses and bacteriophages, offer a \u2018natural\u2019 biotemplating tool, which is available in several geometrical shapes and sizes , used as a biotemplate for electroless deposition mediated by reduction with NaBH4 of cobalt and platinum ions within the channel. Nanowires ranging from 50 to 100 nm were identified by HRTEM analysis, as well as by EDXS and magnetometry measurements.Tsukamoto et al.  describe2 nanocrystals biotemplated onto the surface of M13 bacteriophages, significantly improving parameters such as operational and storage stability.Neltner et al.  describeLim et al.  describeThe production of 3 nm aligned magnetic NPs within the central channel of mutated tobamovirus was described by Kobayashi et al. . Energy-Nuraje et al.  demonstrThe controlled preparation of a 3D super lattice of metallic nanocrystals was demonstrated by Alloyeau et al. , combiniZhou et al.  describeFlexible electroactive nanomaterials were prepared by Vera-Robles et al.  by biote2+ cations [Piezoelectric nanowires were biotemplated on a genetically engineered M13 bacteriophage coating protein surface, displaying triglutamate residues for the periodical positioning of Pb cations . A latti cations  and tuna cations .As the structural complexity degree of biotemplated arrays grows, it should be mentioned that new characterization tools are also gradually becoming available for the biotemplating arena, as demonstrated by the recent report by Carreno-Fuentes et al.  on the cProtein crystals, routinely prepared for the elucidation of protein 3D structures by X-ray crystallography, present a highly ordered 3D array of protein molecules. Along with the formation of this array, a complementary 3D array of nanosize voids is also formed; with patterns, geometry and dimensions depending on the protein \u2018building block\u2019 and its mode of \u2018packaging\u2019 within the crystal .The composites obtained by \u2018filling\u2019 these voids of protein crystals as biotemplates have potential in providing nanostructured, 3D, highly accurate arrays of hybrid materials for applications in fields such as electronic devices  and speThe exploitation of the potential inherent to 3D protein crystal biotemplating calls for the availability of complex infrastructures, including the means, know-how, and the control of protein crystallization and protein crystal stabilization to prevent crystal dissolution; as well as structural analysis by XRD and related advanced spectrophotometric methods in order to monitor the preservation of the parent 3D crystalline structure throughout the templating procedure, and the prevention of distortion resulting from the impact on the template array by the templated material.The feasibility of using such an infrastructure for the monitoring of the stability of a crosslinked lysozyme crystal throughout biotemplating of a crosslinked hydrogel inside its internal voids array was successfully demonstrated in our laboratory . FollowiStabilization of protein crystals by chemical crosslinking is a pre-requisite to controlled 3D biotemplating, as the stability of the crystalline protein template should be preserved throughout the process. This stabilization is mostly affected by glutaraldehyde crosslinking . In vieThe elucidation of the glutaraldehyde crosslinking mechanism and an understanding of its progress throughout the protein crystal structure paved the way for the potential inherent to site-preferred partial crosslinking, enabling the isolation of the homogeneous population of protein products  \u201cliberated\u201d from partially crosslinked crystals by re-dissolution, as demonstrated in our laboratory .A large spectrum of 3D void arrays, exhibiting different shapes and sizes, is available for exploitation from the Protein Data Bank (PDB). Their use is, however, often limited by the commercial availability of an envisaged protein or tedious crystallization procedures and their structural analysis. An alternative route for fishing data out from the PDB might be the use of a \u201cparent\u201d protein building block for the preparation of a series of protein crystals, each exhibiting a different 3D void array. This approach may be materialized by affecting different crystallization conditions: (i) modification of salt and alcohol concentrations, (ii) \u201cdirecting\u201d the crosslinking of binding proteins by bi-ligand as demonstrated by crosslinking of concanavalin A, yielding \u2018diamond-like\u2019 crystals by crosslinking with monosaccharide bi-ligands ; or (iiiAcetivibrio cellulolyticus) as illustrated in To illustrate the feasibility of the latter approach, Wine and coworkers ,83 used An alternative route to affect parent protein\u2013protein molecular interactions affecting crystal \u201cpacking\u201d was demonstrated by Cohen-Hadar et al. , using tTakeda et al.  suggeste4, indicating the superiority of smaller crystals for this application.He and colleagues ,87 demonThe feasibility of using bacterial flagella, either extracted from bacterial cells or re-assembled from purified flagellin, was demonstrated by several groups.Salmonella typhimurium . Oxide formation on the surface of a series of biological templates, including flagella mechanically detached from S. typhimurium was also demonstrated by this laboratory [Mao and colleagues  demonstrboratory , using cS. typhimurium flagella reconstructed from isolated and purified flagellin. The hybrid obtained was characterized by HRTEM, X-ray and Raman spectroscopy, followed by electrochemical I-V measurements, indicating that electrical conductivity of the hybrid prepared from reconstructed flagella was superior to the conductivity exhibited by directly extracted flagella.Gopinathan et al.  demonstrProtein-mediated biotemplating has attracted much attention throughout the past decade, culminating in data proving the feasibility of a wide spectrum of biotemplating systems demonstrated in one, two and three dimensions. All these data are supported by advanced, state-of the-art characterization technologies.The preliminary feasibility demonstrations of several applications made available by protein-mediated biotemplating was also demonstrated with an emphasis on nanoelectronics and biosensing. It appears, however, that most protein-mediated biotemplating systems described so far did not culminate in feasibility demonstrations for their potential applications. Therefore, it appears that protein-mediated biotemplating-related research and development (R+D) efforts should address the challenges of the identification and demonstration of new applications, and focus on further developing the already described initiations.Future advancement of such a technology should also aim to solve important practical aspects as bringing results from bench to practice, including the provision of the means of contact or connection of the hybrids thus obtained to working/detecting systems, as well as data on storage and operational stability. The process of coping with future R+D challenges may benefit from further exploitation of the potential inherent to the incorporation of additional protein engineering and chemical modification-based methods for the manipulation and performance improvement of protein templates."}
+{"text": "The hypothalamic non-apeptide oxytocin (OT) has several physiological functions, ranging from lactation to social attachment  neurons, showed that OT induces membrane hyperpolarization and consequently inhibits the nociceptive transmission by Ca2+-dependent mechanisms  neurons and ex vivo patch-clamp as well as behavioral analyses, suggest that OT inhibits the nociceptive input either directly , for which OT has a physiologically relevant affinity, cannot be ruled out  abolished the OT-induced Ca2+ influx. These results were confirmed by replicating both the nociceptive DRG neurons isolated from wild-type animals and the modest OT-induced analgesia observed in TRPV1 knock-out mice. Further electrophysiological, planar lipid bilayer, and in silico experiments showed that OT acts as a partial agonist of TRPV1 channels and induces a strong desensitization of these channels, under nociceptive stimulation. This pioneering study strongly suggests that at peripheral level, OT-induced analgesia passes at least in part, through a direct TRPV1 interaction.Nersesyan et al. was first to show that aversive behaviors induced by an intracutaneous (i.c.) injection of capsaicin into an animal hindpaw, were reduced in animals concomitantly treated with i.c. OT. One can therefore propose that the OT effect is a result of OTR activation at the peripheral nerve endings  mediated by GABA. These data suggest that OT recruits GABAergic interneurons, which in turn, activate GABAB receptors and consequently inhibit the capsaicin-sensitive neurons. Interestingly, TRPV1 and GABAB receptors were found to be coexpressed in primary nociceptive neurons. Additionally, the TRPV1 spinal cord expression was enhanced in neuropathic rats, an up-expression corrected by intrathecal OT treatment. Accordingly, the OT-induced analgesia was partially reduced in TRPV1 knockout mice. Like the proposal of Nersesyan et al., this study points out that OT-induced analgesia may rely on both GABA release and modulation of TRPV1 activity.To further explore if OT-induced analgesia in neuropathic pain may occur via TRPV1, Sun et al. first confirmed that intrathecal OT diminishes the aversive behavior in neuropathic animals (Miranda-C\u00e1rdenas et al., B receptors, which in turn modulate the TRPV1 function during neuropathic pain. This finding is in line with the observation that GABAB receptors revert the TRPV1 sensitization by noncanonical signaling under pathological pain (Hanack et al., In the past decades, OT has slowly emerged as an important mediator of endogenous analgesia (Poisbeau et al., An intriguing point in Sun et al. study is how exactly, at the spinal level, OT engages the intracellular machinery to modulate the TRPV1 expression. At least two mechanisms can be proposed. The first might be a direct action of OT on TRPV1, as suggested by Nersesyan et al. The second might be that the OT-induced activation of OTR, leads to an intracellular cascade capable of modulating the expression or epigenetic modifications of TRPV1, as suggested by Sun et al. It remains unclear however, how exactly OT modulates the TRPV1 functions and whether it remains true at physiological concentrations. Indeed, while Nersesyan et al. clearly show a direct interaction between OT and TRPV1, neither them nor Sun et al. were able to reveal a strong, behaviorally relevant, OT-mediated TRPV1 modulation. Since OTR was recently involved in functional heterodimers, such as vasopressin or dopamine receptors (Terrillon et al., Finally, although the sources of OT and its spinal effects are neuronal and seem to play a role in endogenous analgesia (Eliava et al., In conclusion, a collection of evidence, briefly explained here, suggests that a triad between OT, GABA, and TRPV1 does exist and sheds a light on new mechanisms involved in OT-induced analgesia, which ultimately is much more complex than initially expected.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Rhodovulum sulfidophilum, a marine purple non-sulfur bacterium. Several types of artificial RNAs have been successfully produced in R. sulfidophilum. Purple photosynthetic bacteria produce hydrogen via nitrogenase, and genetic engineering strategies have been investigated to enhance the hydrogen production. This mini review describes the microbial production of these high-value compounds using purple photosynthetic bacteria as the host microorganism.Photosynthetic microorganisms can serve as the ideal hosts for the sustainable production of high-value compounds. Purple photosynthetic bacteria are typical anoxygenic photosynthetic microorganisms and are expected to be one of the suitable microorganisms for industrial production. Purple photosynthetic bacteria are reported to produce polyhydroxyalkanoate (PHA), extracellular nucleic acids and hydrogen gas. We characterized PHA production as a model compound in purple photosynthetic bacteria, especially focused on marine strains. PHA is a family of biopolyesters synthesized by a variety of microorganisms as carbon and energy storage materials. PHA have recently attracted attention as an alternative to conventional petroleum-based plastics. Production of extracellular nucleic acids have been studied in  Cyanobacteria, algae and plants have two photosystems (photosystem I and II), extract electrons from water, and evolve oxygen as a byproduct , extracellular nucleic acids and hydrogen gas as shown in Cupriavidus necator, a hydrogen-oxidizing bacterium, is the most studied bacterium for PHA production and produced about 90% of dry cell weight (wt%) PHA  through three enzyme reactions . KetothiA. vinosum, a purple sulfur bacterium, has Class III type PhaC and extensively studied its biological activity  was produced by a cell free protein expression system and characterized its activity -3-hydroxybutyryl-CoA (3HB-CoA) and did not saturate, suggesting that the PhaCRs was not saturated due to low affinity for the substrate. Generally, PhaC is thought to exist as monomeric and dimeric forms in equilibrium and dimerization of PhaC induced by substrate binding facilitate the PHA polymerization  affect the cell growth and PHA production in R. sulfidophilum  among three types of wavelengths we studied. We found that marine purple non-sulfur bacteria strains hardly accumulated PHA (<5 wt%) under aerobic conditions in the presence of malate and pyruvate. Interestingly, the addition of acetate induced high PHA production (33 wt%) under aerobic conditions. The expression of isocitrate dehydrogenase in the tricarboxylic acid (TCA) cycle decreased under aerobic conditions in the presence of malate and pyruvate and upregulated by the addition of acetate. Considering these results, we proposed that low PHA production under aerobic conditions is caused by low activity of the TCA cycle and its activity was enhanced by the addition of acetate. We found that the expression of PdhR, which is a transcriptional repressor of the pyruvate dehydrogenase complex, was upregulated upon the addition of acetate. The changes in the metabolic state might be induced by the addition of acetate under aerobic conditions and PdhR is involved in this regulation.PHA production was examined in marine purple non-sulfur bacteria under various growth light and oxygen conditions  [P(3HB-co-3HV)], has a lower melting temperature and higher biodegradability compared to P(3HB) depending on the polymer composition  and 3-hydroxyvalerate (3HV). PHA composition affects the mechanical and thermal properties of PHA. Poly(3-hydroxybutyrate) [P(3HB)], homopolymer of 3HB, is a highly crystalline and brittle material. Melting temperature of P(3HB) is around 180\u00b0C Rehm, . The copE. coli that do not have PHA degradation pathway  have been found in natural conditions such as freshwater, seawater, and soil and it is reported that some bacteria produced nucleic acids extracellularly  are considered to be involved in the production of extracellular nucleic acids in in vitro transcription . Purple non-sulfur bacteria is known to produce hydrogen via nitrogenase    (Franchi et al., A variety of kinds of large-scale photobioreactor has been investigated for industrial photohydrogen production in purple non-sulfur bacteria. Reactor design, culture light condition and nutrient sources have been investigated and are reviewed elsewhere (Eroglu and Melis, 2, N2 and sunlight energy can be used as a culture medium, biological sources and energies. Genetic tools such as synthetic promoter and transformation method have not been fully established yet in marine purple photosynthetic bacteria, even though we recently developed a transformation method using chemical competent cells of marine purple photosynthetic bacteria (Higuchi-Takeuchi et al., Marine purple photosynthetic bacteria are environmentally friendly microorganisms and can produce high-valuable compounds such as PHA, extracellular nucleic acids, and hydrogen gas. Previously, we demonstrated that marine purple photosynthetic bacteria were able to produce PHA even in seawater (Higuchi-Takeuchi et al., MH-T and KN conceptualized and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Electronic health  tools are becoming increasingly popular for helping patients\u2019 self-manage chronic conditions. Little research, however, has examined the effect of patients using eHealth tools to self-report their medication management and use. Similarly, there is little evidence showing how eHealth tools might prompt patients and health care providers to make appropriate changes to medication use.The objective of this systematic review was to determine the impact of patients\u2019 use of eHealth tools on self-reporting adverse effects and symptoms that promote changes to medication use. Related secondary outcomes were also evaluated.MEDLINE, EMBASE, and CINAHL were searched from January 1, 2000, to April 25, 2018. Reference lists of relevant systematic reviews and included articles from the literature search were also screened to identify relevant studies. Title, abstract, and full-text review as well as data extraction and risk of bias assessment were performed independently by 2 reviewers. Due to high heterogeneity, results were not meta-analyzed and instead presented as a narrative synthesis.A total of 14 studies, including 13 randomized controlled trials (RCTs) and 1 open-label intervention, were included, from which 11 unique eHealth tools were identified. In addition, 14 RCTs found statistically significant increases in positive medication changes as a result of using eHealth tools, as did the single open-label study. Moreover, 8 RCTs found improvement in patient symptoms following eHealth tool use, especially in adolescent asthma patients. Furthermore, 3 RCTs showed that eHealth tools might improve patient self-efficacy and self-management of chronic disease. Little or no evidence was found to support the effectiveness of eHealth tools at improving medication recommendations and reconciliation by clinicians, medication-use behavior, health service utilization, adverse effects, quality of life, or patient satisfaction. eHealth tools with multifaceted functionalities and those allowing direct patient-provider communication may be more effective at improving patient self-management and self-efficacy.Evidence suggests that the use of eHealth tools may improve patient symptoms and lead to medication changes. Patients generally found eHealth tools useful in improving communication with health care providers. Moreover, health-related outcomes among frequent eHealth tool users improved in comparison with individuals who did not use eHealth tools frequently. Implementation issues such as poor patient engagement and poor clinician workflow integration were identified. More high-quality research is needed to explore how eHealth tools can be used to effectively manage use of medications to improve medication management and patient outcomes. Use of the internet has increased considerably since the early 1990s. The World Bank reports that almost 44% of people across the globe used the internet in 2015, compared with 0.25% in 1993 , while aWell-functioning eHealth tools can help patients better understand their health  and may The ability of patients to use eHealth tools to better manage medication by reporting feedback on symptoms and use of medications directly to health care providers has not been comprehensively explored in the literature. Similarly, there is little evidence showing how eHealth tools might provide prompts to patients and health care providers to make appropriate changes to medication use based on this feedback. A synthesis of this literature will provide greater understanding of what eHealth tool design features may be helpful in patient reporting of medication-related experiences and outcomes.The objective of this systematic review was to determine the impact of patients\u2019 use of eHealth tools on self-reporting adverse effects and symptoms that promote changes to medication use. The PICO model was used to focus the objective of the review, as seen in This systematic review was performed following steps outlined by Cochrane\u2019s Effective Practice and Organization of Care group and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement . A totalFor the purposes of this review, an eHealth tool was considered to be any internet-based intervention, including mobile health apps, used by patients for clinical purposes that focused on improving patient health and clinical outcomes. The term PHR refers to an eHealth tool wherein a patient has access to and can enter or edit their own health data. The population investigated was community-dwelling individuals of any age in an outpatient setting.For a study to be included, the eHealth tool must have allowed patients (or caregivers) to enter information directly ; included self-reporting functionalities focusing on medication monitoring, contain a medication monitoring or use component, or specifically incorporating the option for the patient or caregiver to enter symptoms including adverse effects; and needed to focus specifically on medication use, clinical outcomes, or symptom reporting following use of the eHealth tool. Any eHealth tools involving changes in medication reconciliation and recommendations made to changes in drug therapy were also included.Exclusion criteria were conference abstracts; qualitative studies; articles without a comparator group; articles that did not report on at least one medication-related outcome; articles where self-management strategies focused on lifestyle modification, behavioral interventions, or nondrug interventions; articles focused solely on the validation of an eHealth tool; articles focused on methodological or technical aspects of eHealth interventions; articles containing nonempirical information; articles that synthesized information about multiple eHealth tools in an article ; and eHealth tools used by regulatory agencies to report adverse drug events (ADEs).All potentially relevant articles were uploaded into DistillerSR software, which was used throughout the selection process. Potentially relevant articles underwent title, abstract, and full-text review. Articles that met inclusion criteria proceeded to data abstraction and risk of bias assessment. Articles not meeting inclusion criteria were excluded at both levels. Title and abstract review were performed independently by 2 reviewers from a pool of 5 reviewers. Of these, 1 reviewer went through the reference lists of all the articles included in this study. Another reviewer went through reference lists of relevant systematic reviews identified during the literature search. Potentially relevant articles were identified. These articles went through abstract review by 2 reviewers. Studies found not to fit inclusion criteria after abstract review were excluded. Full-text review was performed independently by 5 reviewers. The kappa scores were calculated to determine agreement among reviewers who conducted review of titles and abstracts. All kappa scores calculated were greater than .93. Conflicts were resolved by consensus.Data extraction and risk of bias assessment were performed for each study independently by 2 reviewers. Data extracted included study design and setting, participant demographics, number of participants in each group, intervention components, comparator group components, eHealth tool functionality measured, and results and significance levels for each outcome measure. Conflicts in data extraction were resolved by consensus. Risk of bias assessment used questions recommended by the Agency for Healthcare Research and Quality\u2019s 2014 publication Methods Guide for Effectiveness and Comparative Effectiveness Reviews  and was The primary and secondary outcomes are listed in Subgroup analyses were performed to investigate differences in treatment effect present because of (1) age of participants, (2) patients with specific conditions targeted by intervention, and (3) different features and functionalities of the included eHealth tools.A total of 3515 articles were generated from database and reference searching, resulting in 2489 potential articles that were screened based on their titles and abstracts, after duplicates were removed. Furthermore, 75 full-text articles were assessed for eligibility, of which 14 were included in this systematic review  -31 and 1Of the 13 RCTs included in this review, 2 studies were cluster RCTs ,26. The A total of 4 RCTs focused on pediatric and adolescent asthma patients ,23-25; 1double-dummy style intervention, where both groups used Web-based PHRs to record information that differed only in content. Cho et al [In 3 studies, use of an eHealth tool in the intervention group was compared with usual care plus links to relevant websites ,25,28. Sho et al  comparedho et al  utilizedho et al  used a sho et al  developeho et al  used a mho et al . Carlsenho et al  used an From the 14 included studies, 11 unique eHealth tools were described. The 2 RCTs by Joseph et al ,25 utiliAll 11 eHealth tools from all 14 studies included a component where patients could self-report medication management information or changes, including symptoms, health data, adverse effects, or ADEs. A total of 12 studies included Web-based patient questionnaires or surveys ,21,23-32The results of each study by outcome can be seen in A total of 6 RCTs -22,24,27P=.035). A nonsignificant trend approaching significance was seen for decreased number of over-the-counter medications used in the eHealth tool group (P=.05) [P<.001). They also found that a significantly higher proportion of patients in the intervention group had medications initiated or dosages changed for hypertension  and hyperlipidemia .Chrischilles et al  found a  (P=.05) . Grant e (P=.05)  found a P=.01). Simon et al [21=10.5, P=.001). Carlsen et al [P<.001) [Joseph et al  found thon et al  found then et al  showed ten et al  showed t[P<.001) .P=.36). Fiks et al [In contrast, Cho et al  found noks et al  provided1c) [A total of 9 RCTs ,27,30,311c) , and 2 fP=.001) and that the active group had less frequent flare-ups . Gustafson et al [P=.01).Fiks et al  reportedon et al  found anP=.009), symptom days , days of restricted activity , and school days missed . In another study, Joseph et al [P=.01). Following subgroup analysis, it was found that teenagers with moderate to severe asthma had fewer symptom days , total school days missed , school days missed because of asthma , and days of restricted activity .Joseph et al  found thph et al  reportedP=.04). Ahmed et al [1c ; however, they did find a statistically significant decrease in waist circumference between intervention and control . Cho et al [1c in the active group  at 30 months. Grant et al [1c and for percentage of patients at target HbA1c levels. Similarly, Carlsen et al [P=.18).Simon et al  reporteded et al  reporteded et al  found noho et al  did findnt et al  found noen et al  found noA total of 5 RCTs measured this outcome ,23,26,30P=.01). They also found a positive significant effect of intervention on ACQ score when mediated by information competence . Schnipper et al [P<.001). Ahmed et al [Gustafson et al  found ther et al  found thed et al  found thed et al  found thed et al  found noA total of 3 RCTs measured this outcome, all using measures of medication adherence as a surrogate for medication use behavior ,23,24. NP=.01). In addition, Schnipper et al [P=.04). The number of medication discrepancies per patient with the potential for harm approached significance as a result of using eHealth tools (P=.05) [A total of 3 RCTs reported on this outcome ,20,26. OCho et al  acknowleP value: .02 to <.001) relative to usual care. Descriptive evidence from Fiks et al [A total of 1 open-label intervention  and 5 RCks et al  showed 1ks et al  providedks et al  or ADEs ks et al ,28 foundP=.01). The remaining 5 studies [A total of 6 RCTs reported health service utilization outcomes ,27,28,30 studies ,27,28,30A total of 4 studies measured this outcome ,30-32, a21=8.38, P=.004). Fiks et al [A total of 2 RCTs ,27 and 1ks et al  providedA total of 4 RCTs investigated the use of eHealth tools in children and teens with asthma ,23-25. TSubgroup analysis also found that multifaceted interventions combining use of eHealth tools with clinician support or case management and eHealth tools utilizing direct patient-provider communication might be more effective at improving some aspects of patient self-management and self-efficacy ,26,30,31Many studies reported barriers to the implementation of eHealth tools. The most common barrier was lack of participant engagement, resulting in low eHealth tool utilization rates. This was reported by 9 of the 14 studies -27,31,32Evidence from 4 RCTs and 1 open-label intervention ,24,27,32Evidence was found that eHealth tools improved the outcome of patient self-management and self-efficacy. Subgroup analysis found that eHealth tools that allow patients and clinicians to communicate directly, and multifaceted interventions combining eHealth tools with clinician support and case management might lead to greater increases in patient self-management and self-efficacy. It is notable that more significant improvements were found for more objective outcome measures, such as number of medication changes and clinical signs, and less were found for more subjective outcome measures such as self-management and self-efficacy. It may also be that sample sizes were too small to detect differences, particularly if this was not the primary objective for these studies. It is likely that the eHealth tools under investigation either did not provide effective content or functionalities to help participants improve self-management and medication management in participants or the tools used to measure these outcomes were not able to detect any differences between groups. Another possibility is the lack of patient understanding of chronic disease and poor perception of health goals.It was thought that eHealth tools that focus on improvement of patient self-efficacy and self-management might lead to improved medication-use behavior, which in turn may lead to changes in medication use, identification of real or potential ADEs, improvement in signs and symptoms, and overall improvement in HRQoL. However, there is not enough evidence to draw conclusions as to the effectiveness of eHealth tools for identification of adverse effects, improving medication-use behavior, increasing recommendations to medication therapies and improving medication reconciliation, improving health service utilization, and improving overall health status and patient satisfaction. Only a small number of included studies investigated these outcomes; it is likely that with such a small overall sample size, it was not possible to find differences between groups.As with most systematic reviews on the subject of eHealth tools ,33,54-57A 2012 systematic review by Ammenwerth et al found that use of patient portals linked to a PHR led to significant increases in medication adjustments in diabetic patients . Other rOverall, this review supports findings by Ammenwerth et al  that intTo our knowledge, this is the first systematic review of eHealth interventions focusing on patient self-reporting of symptoms and adverse effects. The review\u2019s search strategy was augmented by reference searching. This review was limited to studies that included medication-related outcomes. The majority of studies included in this review were RCTs, most of which were of moderate quality.eHealth and believe future research should focus on establishing better consensus for this term. There was considerable variety among the interventions in the studies, some of which included features such as direct health care provider follow-up, thus making it more complicated to determine which outcomes could be specifically attributable to using an eHealth tool. As this review also examined different populations of varying sample sizes and medical conditions for eHealth tools, it may be difficult to detect differences and generalize findings and conclusions. We did not include qualitative studies in our review because the goal of our study was to better understand the effectiveness and impact of changes to medication regimens based on quantifiable differences in using eHealth tools for self-reporting adverse effects and symptoms that promote changes to medication use versus a comparator. We value the insight of qualitative studies that have been investigated elsewhere [This review also has a number of weaknesses. It was limited to studies published in English, which may have excluded relevant articles. No searching of grey literature was performed, as we focused on empirical work published in academic journals, and so it is possible that some early non\u2013peer-reviewed reports may have been missed. We acknowledge the lack of definitional clarity surrounding the term lsewhere ,60. AddiWhere possible, health care providers should encourage patient use of eHealth tools for symptom and adverse effect self-reporting. eHealth tools may be especially useful for reducing symptoms in certain populations, for example, children and teenagers with asthma. eHealth tools might also encourage patients to improve self-management behaviors and participate in shared decision making with clinicians. Having information from the EMR entered directly into the eHealth tool may reduce the burden on the patient to routinely update their clinical information (something that only highly motivated patients are likely to do regularly) . CliniciThere is a paucity of primary research articles investigating eHealth tools and their impact on medication use. Studies are generally small and of moderate quality. Large-scale RCTs focusing on the use of eHealth tools for medication and symptom management should be undertaken to establish more high-quality evidence. This is especially important given how ubiquitous the use of medication is. Furthermore, the effects of patient self-management and self-efficacy on medication use and symptom experience are not well studied; more research in this area could help drive creation of medication-focused eHealth tools. Low patient engagement and eHealth tool utilization were commonly noted implementation barriers; it could be that patients were not engaged in eHealth tool use enough for them to feel an impact on their satisfaction with health care or overall quality of life. Descriptive evidence shows low proportions of patients felt that eHealth tools improved their care or communication with providers, indicating that development of eHealth tools should focus on functionalities and outcomes that are important to the patient. This may be achieved by utilizing research on patient motivation and behavior change to increase patient engagement ,24,25.The results of this review show initial and promising findings that specialized eHealth tools can be used for reporting and monitoring of symptoms and medication-related adverse effects and some evidence that use of eHealth tools have the potential to identify instances where changes in medication use may be appropriate. A modest amount of mixed evidence was found, demonstrating that eHealth tools can improve patient self-management and self-efficacy. Very little or no evidence was found to demonstrate that use of eHealth tools could increase numbers of medication recommendations or improve medication-taking behavior, health services utilization, identification of adverse effects, overall health status, and patient satisfaction. eHealth tools may be more effective at promoting medication changes and improving patient self-management and self-efficacy if they provide mechanisms for direct patient-provider communication and may be more effective in certain populations such as children and teenagers with asthma."}
+{"text": "Recently Christian Hudert and colleagues from the Charit\u00e9 in Berlin published a study about genetic determinants in pediatric non-alcoholic liver disease . Non-alDue to the current increase in the incidence of liver diseases a better understanding of their pathophysiology is of major importance (Jansen et al., 2017; Vartak"}
+{"text": "Sci., 2019, DOI: ; 10.1039/c8sc05721d.Correction for \u2018Facile N-functionalization and strong magnetic communication in a diuranium( The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Alzheimer's disease (AD), the most common type of dementia among the elderly, is caused by progressive neural death that results in impaired memory, thinking skills and, eventually, the ability to carry out simple tasks. Unfortunately, approximately 5% of people over the age of 65 suffer from AD, and the prevalence of AD increases with aging (Udeochu et al., Investigators have proposed that the onset and progression of AD is contributed by pathogenic microbes although definitive evidence has not been presented (Sjogren et al., Based on unbiased approaches and large-scale data sets from several brain banks and cohort studies, this is the first study to provide strong evidence supporting the controversial hypothesis that viruses play an essential role in regulatory genetic networks that are believed to lead to AD. Identifying links to viruses may help scientists interested in developing potential new treatment strategies.Several important questions are raised from this phenomenal study. First, does herpes virus cause the onset or progression of AD? Eimer and colleagues recently reported that A\u03b2 traps herpes viruses in insoluble amyloid, and active herpes infections in brain accelerate amyloid deposition, indicating that herpes infection may promote AD pathology directly via amyloid-mediated pathological pathways (Eimer et al., Second, whether herpesviruses regulate, or are regulated by AD-associated genes? Will anti-herpes drugs be effective against early onset of AD? This study established a strong connection between multiple viruses, especially HHV-6A, and AD risk genes, including PSEN1, BACE1, and APBB2 which are implicated in regulation of A\u03b2 production. Besides, several recent studies show that A\u03b2 is an antimicrobial protein of the body's innate immune system, capable of providing immediate, effective protection from infection with pathogens like herpes viruses in both cultured human brain cells and animal models of AD (Kumar et al., Third, is miR-155 a regulator of anti- or pro-viral activity in early AD? Could miR-155 gain-of-function help with A\u03b2 clearance and neuroprotection in AD? MiR-155 has been reported as an important regulator of T cell and microglia in response to neurodegeneration (Song and Lee, Lastly, there remain some open issues that future studies will need to address about the Readhead et al. findings. For example, HHV-6A/B and HHV-7 are considered lymphotropic rather than neurotrophic (Berneman et al., X-WS drafted an initial version of this commentary. C-ML and Z-QT revised and finalized the text. All authors approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}