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How does thyroid hormone regulate mitochondrial biogenesis in the myocardium?

['L-T3 significantly increased the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone', 'the T(3)-induced phosphorylation of p38 and AMPK in both slow- and fast-twitch skeletal muscles suggests that these events may be important in mediating hormone-induced increases in mitochondrial biogenesis in skeletal muscle.', 'Our findings indicate parallel increases in myocardial mitochondrial bioenergetic capacity, oxygen consumption and markers of mitochondrial biogenesis with 15-day T4', 'The marked, parallel increases in PPARalpha levels suggest its potential involvement in mediating myocardial-specific remodeling of mitochondria in response to T4', 'T3 mediates an early stimulation of enzymes containing mtDNA encoded subunits (e.g. complex IV and V) in contrast to a different regulatory pattern for the entirely nuclear-encoded enzymes', 'Activity of respiratory complexes II, IV, V and citrate synthase (CS), levels of mitochondrial enzyme subunits (e.g. COXI, COXIV) and nuclear-encoded transcription factors, involved in mitochondrial biogenesis (e.g. PGC-1, mtTFA and PPAR-alpha), were significantly elevated with 72 h T3 treatment', 'T(3) increased PGC-1alpha content similarly in both fast- and slow-twitch muscle, as well as in the liver, but not in heart.', "Thyroid hormone [3,5,3'-triiodo-l-thyronine (T(3))] induces phenotypic alterations in cardiac mitochondria, in part by influencing protein import and the expression of the import motor mitochondrial heat shock protein (mtHsp70).", 'These findings indicate that import machinery components are differentially regulated in response to stimuli that induce mitochondrial biogenesis, like T(3) and differentiation.', 'We have previously identified a mitochondrial triiodothyronine receptor (p43) regulating mitochondrial transcription and mitochondrial biogenesis. When overexpressed in skeletal muscle, it increases mitochondrial DNA content, stimulates mitochondrial respiration,', 'Here we show that a p43 depletion in mice decreases mitochondrial DNA replication and respiratory chain activity in skeletal muscle', 'The contribution of TFAM, TFB2M, and helicase Twinkle in thyroid-induced mtDNA biogenesis was assessed. The activation of TFAM and TFB2M expression is shown to be required for the induction of mtDNA biogenesis. The role of helicase Twinkle, the expression induction of which is also observed after triiodothyronine addition, remains unclear. The analysis of factors that activate TFAM and TFB2M expression showed that NRF-1 is the determinative regulator:', 'in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1alpha, NRF-1alpha and Tfam', 'These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.', 'T(3) acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells with mtDNA defects.', 'These findings suggest the existence of compensatory mechanisms operating at the translational and/or post-translational levels which promote proliferation of mitochondria in the hypothyroid liver. However, when the liver mass was considered, hypothyroidism significantly reduced overall mitochondrial proliferation in rat liver.', 'Total liver mitochondrial DNA levels in thyroid-treated animals were greater than age-paired controls by 79% at 7 days but only 67% at 14 days since a small gain occurred in control animals and no further increase occurred in treated rats during the second week.', 'thyroid hormone treatment produces hyperplasia and an increase in mitochondrial number and mass in rat liver', 'It is concluded that T3 exerts a direct, rather than permissive, effect on mitochondrial biogenesis, and that high affinity binding sites for GH are not present in rat liver mitochondria.', 'These data strengthen the view that thyroid hormone regulates synthesis of specific components within each respiratory-chain complex and that these products apparently play key roles in inner-membrane biogenesis and assembly', 'It is concluded that thyroid hormone causes an increase in the mitochondrial mass, mitochondrial cytochrome content, and respiratory rate, and consequently expands the capacity of oxidative metabolism without an uncoupling effect on oxidative phosphorylation.']

['T4 increases myocardial mitochondrial bioenergetic capacity, oxygen consumption and markers of mitochondrial biogenesis. The marked, parallel increases in PPARalpha levels suggest its potential involvement in mediating myocardial-specific remodeling of mitochondria in response to T4. T3 induces mitochondrial biogenesis. In fact, T3 treatment for 72h increases activity of respiratory complexes II, IV, V and citrate synthase (CS), levels of mitochondrial enzyme subunits (e.g. COXI, COXIV) and nuclear-encoded transcription factors, involved in mitochondrial biogenesis (e.g. PGC-1, mtTFA and PPAR-alpha). Furthermore, L-T3 increases the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone.\nThe activation of TFAM and TFB2M expression is shown to be required for the induction of mtDNA biogenesis by T3. Truncated forms of the nuclear receptor TRα1, with molecular weights of 43 kDa (p43) and 28 Kda have been previously identified in mitochondria. P43 is a mitochondrial T3 receptor which stimulates mitochondrial transcription and protein synthesis in the presence of T3. p43 depletion in mice decreases mitochondrial DNA replication and respiratory chain activity.']

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Why are insulators necessary in gene therapy vectors?

['hromatin insulators separate active transcriptional domains and block the spread of heterochromatin in the genome. Studies on the chicken hypersensitive site-4 (cHS4) element, a prototypic insulator, have identified CTCF and USF-1/2 motifs in the proximal 250 bp of cHS4, termed the "core", which provide enhancer blocking activity and reduce position effects.', 'An attractive solution to the problem of oncogene activation is the inclusion of insulators/enhancer-blockers in the viral vectors.', 'We propose the incorporation of chromatin insulators in the design of gene therapy vectors to overcome the problem of position effects. Chromatin insulators are protein-binding DNA elements that lack intrinsic promoter/enhancer activity but shelter genes from transcriptional influence of surrounding chromatin.', 'The design and incorporation of effective chromatin insulator sequences in the next generation of gene therapy vectors should lead to improved and more predictable expression of therapeutic transgenes and constitute an important step toward clinically effective gene therapy.']

['a) They inhibit oncogene activation upon vector integration and b) They maximize the probability of vector expression upon integration in heterochromatinic regions', 'The presence of insulators in gene therapy vectors is necessary because these elements have the ability to help overcome the problem of position effects, caused due to random integration of the therapeutic genes in the host cell genome.']

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Which is the main target of the anti-arrhythmic activity of flecainide?

['flecainide (sodium channel blocker) ', 'Flecainide is a sodium channel blocker with minimal effects expected on ventricular repolarization. ', 'Flecainide, a class I antiarrhythmic drug, inhibits Na(+) and RyR2 channels and prevents CPVT.', ' flecainide, a Class I antiarrhythmic drug, improves left ventricular pressure gradient (LVPG) or symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM).', 'Flecainide is a class 1c antiarrhythmic that acts by blocking sodium channels to reduce intracardiac conduction and is used mainly in the treatment of supraventricular arrhythmias. ', 'Flecainide is a class 1C antiarrhythmic drug especially used for the management of supraventricular arrhythmia', 'Flecainide reduces spark and wave frequency in the intact rat cardiomyocyte at therapeutically relevant concentrations but the mechanism involves I(Na) reduction rather than direct ryanodine receptor (RyR2) inhibition.']

['Flecainide is a class 1c antiarrhythmic that acts by blocking sodium channels and is used mainly in the treatment of supraventricular arrhythmias.']

['The sodium channel']

Which disease can be treated with Delamanid?

['Recently approved anti-Tb drugs (bedaquiline and delamanid) have the potential to induce arrhythmia and are recommended in patients with MDR-Tb when other alternatives fail.', 'Delamanid: a review of its use in patients with multidrug-resistant tuberculosis.', 'Delamanid (Deltyba(®)), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. ', 'In a robust phase\xa0II trial in adult patients with MDR-TB, oral delamanid 100\xa0mg twice daily for 2\xa0months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. ', 'In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB.', 'Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability.', 'This review covers the efficacy and safety of delamanid for MDR-TB.AREA COVERED: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. ', 'EXPERT OPINION: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies.', 'In addition, decreased mortality was observed in MDR-TB patients who received>6 months of delamanid treatment. ', 'Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.', 'Delamanid for multidrug-resistant pulmonary tuberculosis.', 'BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis.METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. ', 'This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. ', 'Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly.', 'Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB.']

['Delamanid is used in patients with multidrug-resistant tuberculosis.']

['tuberculosis']

List available tools for genomic visualisation in comparative genomics

["Insyght: navigating amongst abundant homologues, syntenies and gene functional annotations in bacteria, it's that symbol!", 'Insyght is a comparative genomic visualization tool that combines three complementary displays: (i) a table for thoroughly browsing amongst homologues, (ii) a comparator of orthologue functional annotations and (iii) a genomic organization view designed to improve the legibility of rearrangements and distinctive loci', 'Genomicus: five genome browsers for comparative genomics in eukaryota', 'Genomicus (http://www.dyogen.ens.fr/genomicus/) is a database and an online tool that allows easy comparative genomic visualization in>150 eukaryote genomes', 'Sockeye: a 3D environment for comparative genomics.', 'We have developed a Java-based application called Sockeye that uses three-dimensional (3D) graphics technology to facilitate the visualization of annotation and conservation across multiple sequences.']

['Insyght, Genomicus and Sockeye.']

['Insyght', 'Genomicus', 'Sockeye']

Is lenvatinib effective for thyroid cancer?

['New insights in the treatment of radioiodine refractory differentiated thyroid carcinomas: to lenvatinib and beyond.', 'However, even more impressive responses and progression-free survival benefits were seen in the phase III SELECT trial with lenvatinib, giving even higher hopes for the future management of what was considered just a decade ago an orphan disease. ', 'Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively.', 'A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.', 'CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. ', 'Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer - cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. ', 'Moreover, four of those investigational drugs, vandetanib, cabozantinib, sorafenib and lenvatinib, have reached a phase III clinical trial with favorable results in progression-free survival and overall survival in medullary thyroid carcinoma and differentiated thyroid carcinoma.', 'Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer - cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer', 'BACKGROUND: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor �, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).METHODS: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. ', 'Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC).METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. ']

['Yes, lenvatinib is effective for thyroid cancer.']

['yes']

Which receptor does benralizumab target for allergic asthma treatment and how does it improve outcomes?

['plete blood eosinophils and improve the clinical outcomes of allergic asthma.", "Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5R\\u03b1 itself.", "Benralizumab is an anti-interleukin-5 receptor \\u03b1 monoclonal antibody that depletes blood and airway eosinophils.", "Benralizumab is a monoclonal antibody that targets interleukin-5 receptor \\u03b1 to deplete blood eosinophils and improve the clinical outcomes of allergic asthma.", "Anti-IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies (hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the \\u03b1 subunit of the IL-5R) target the IL-5-signaling in eosinophilic asthma.", "BACKGROUND Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor \\u03b1 monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe, uncontrolled asthma.", "As IL-5 is implicated in disease states that are mediated by eosinophils, benralizumab is an attractive option for use in the management of asthma.", "INTRODUCTION Benralizumab is a monoclonal antibody that binds the \\u03b1 subunit of the receptor to IL-5.", "Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor \\u03b1, immunoglobulin G (IgG) 1 \\u03ba monoclonal antibody.", "We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.", "In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor \\u03b1 monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma.", "Benralizumab, an anti-interleukin-5 receptor \\u03b1 monoclonal antibody, depletes blood and sputum eosinophils."]', 'plete blood eosinophils and improve the clinical outcomes of allergic asthma.", "Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5R\\u03b1 itself.", "Benralizumab is an anti-interleukin-5 receptor \\u03b1 monoclonal antibody that depletes blood and airway eosinophils.", "Benralizumab is a monoclonal antibody that targets interleukin-5 receptor \\u03b1 to deplete blood eosinophils and improve the clinical outcomes of allergic asthma.", "Anti-IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies (hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the \\u03b1 subunit of the IL-5R) target the IL-5-signaling in eosinophilic asthma.", "BACKGROUND Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor \\u03b1 monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe, uncontrolled asthma.", "As IL-5 is implicated in disease states that are mediated by eosinophils, benralizumab is an attractive option for use in the management of asthma.", "INTRODUCTION Benralizumab is a monoclonal antibody that binds the \\u03b1 subunit of the receptor to IL-5.", "Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor \\u03b1, immunoglobulin G (IgG) 1 \\u03ba monoclonal antibody.", "We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.", "In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor \\u03b1 monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma.", "Benralizumab, an anti-interleukin-5 receptor \\u03b1 monoclonal antibody, depletes blood and sputum eosinophils."]']

Benralizumab targets the interleukin-5 receptor α to deplete blood eosinophils and improve the clinical outcomes of allergic asthma.

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What is the relationship between thyroid hormone and inflammatory markers in heart failure patients?

['Considering normal subjects, patients without and with low T3 syndrome, IL-6 and TNFalpha increased progressively from normal to patients with fT3<2 pg/ml (p<0.01 and p<0.01) while CRP only respect to the group with low T3 syndrome (p<0.01). The inflammatory markers were all inversely correlated with FT3 levels.']

['There is an inverse correlation between inflammatory markers (IL-6 and TNF alfa and PCR) and FT3 levels in patients with heart failure']

['There is an inverse correlation between inflammatory markers and FT3 circulating levels']

What is the disease in which patients are sensitive to DNA crosslinking agents, presenting with a high frequency of chromosomal aberrations?

['Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations.', 'Fanconi anemia (FA) is characterized at the cellular level by a high frequency of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal increase in the frequency of chromosomal damage, and semiconservative DNA synthesis is severely inhibited.', 'Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia.', "Cells from patients wtih Fanconi's anemia are unusually sensitive to agents which are capable of crosslinking DNA.", "An elevated frequency of chromosome aberrations, which is further exaggerated by exposure of cells to DNA crosslinking agents, is a general feature of Fanconi's anemia.", 'FA patients exhibit spontaneous chromosome breakage and FA cells are sensitive to DNA interstrand crosslink agents and expresses high frequency of chromosome breakage', 'Fanconi anemia (FA) is characterized at the cellular level by a high frequency of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal increase in the frequency of chromosomal damage, and semiconservative DNA synthesis is severely inhibited', "Cells from patients wtih Fanconi's anemia are unusually sensitive to agents which are capable of crosslinking DNA", 'At the cellular level, FA is characterized by hypersensitivity to DNA cross-linking agents and by high frequencies of induced chromosomal aberrations, a property used for diagnosis', "An elevated frequency of chromosome aberrations, which is further exaggerated by exposure of cells to DNA crosslinking agents, is a general feature of Fanconi's anemia", 'Similarly, Fanconi\'s anemia cells, which are chromosomally sensitive to crosslinking agents, and appear to be defective in the "unhooking" of linked polynucleotide strands [15, 16, 49, 51], are reported to be chromosomally sensitive to ethyl methanesulfonate as well [29], and to be sensitive to ionizing radiation [7, 19, ]0], again implying overlapping repair systems']

['Fanconi anemia (FA) is an autosomal disorder that causes genome instability and manifests by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations.', 'Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations. ', 'Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations.']

['Fanconi anemia']

Is there any link between conserved noncoding elements and alternative splicing in vertebrates?

['Some of the most highly conserved sequences occur in genes encoding RNA binding proteins, particularly the RNA splicing-associated SR genes. Differences in sequence conservation between plants and animals are likely to reflect differences in the biology of the organisms, with plants being much more able to tolerate genomic deletions and whole-genome duplication events due, in part, to their far greater fecundity compared with vertebrates.']

['Yes. Some of the most highly conserved sequences occur in genes encoding RNA binding proteins, particularly the RNA splicing-associated SR genes.']

['yes']

Are the proteins Erbin (LAP2) and Merlin cooperating?

['Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta.', "The results show that the epithelial-enriched protein Erbin controls the function of the NF2 tumor suppressor Merlin by determining the output of Merlin's physical interactions with active PAK2. ", 'Erbin controls Merlin tumor suppressor function by switching the functional valence of PAK2 binding']

['Yes, Erbin and Merlin are cooperating.']

['yes']

What is the drug target for Simtuzumab?

[' These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.', 'These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601', 'These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.', 'Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2.', 'These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.', ' aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, i']

[' These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.', ' these results suggest that loxl2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from gs-607601.', 'Simtuzumab is a humanized monoclonal antibody drug that targets LOXL2']

['LOXL2']

What body parts are also known as phalanges?

['Metacarpal and phalangeal fractures of the long fingers a', ' The anatomical structure of each finger is comprised of four phalanges (distal, middle, proximal, and metacarpal phalange).', 'arious features of the toes, humps in the toe line, phalange marks, flatfoot condition, pits, cracks, corns, etc., were studied.', '802), in which physical injuries are listed, ranging from loss of single phalanges, differentiated between thumb, forefinger, small finger, and the other fingers, to death, is compared with modern grades of disability.', 'They featured a prominent unpaired femur besides paired tibiotarsi, tarsometatarsi and species-specific phalanges of the toes.', 'The bone structure is rarefied at the distal metaphyses of the metacarpals and the proximal metaphyses of the finger basal phalanges.']

['The anatomical structure of each finger is comprised of four phalanges (distal, middle, proximal, and metacarpal phalange). Toes are also known as phalages']

['bones of the digits, fingers or toes']

Which are the plant DNA (cytosine-5) methyltransferase families?

['The topologies of the trees were overall congruent: four monophyletic groups corresponding to the four plant C5-MTase families were clearly distinguished. In addition, sequence analyses of the plant C5-MTase target recognition domain sequences were performed and phylogenetic trees were reconstructed showing that there is good conservation among but not within the plant C5-MTase families.', 'To determine the inheritance of DNA methyltransferase genes and their expression patterns we examined three major DNA methyltransferase families (MET1, CMT3 and DRM) from tobacco and the progenitor species.', 'The comparative investigation of transcription levels of different genes of cytosine DNA methyltransferase family MET (MET1, MET2a, MET2b, MET3) and their methylation patterns shows that there may exist some mechanisms defending the most actively transcribed gene MET1 of this family from methylation mediated silencing. In contrast to DRM2 gene we could not find any adenine methylated GATC sites in the MET1 gene.', "Using the 1kb 3' terminal DNA fragment of the mouse methyltransferase cDNA as a probe and low stringent hybridisation conditions, a new potential methyltransferase (MTase) gene family was isolated from an Arabidopsis thaliana genomic DNA library.", 'The Dnmt3 family of de novo DNA methyltransferases has recently been characterized in animals. Here we describe DNA methyltransferase genes from both Arabidopsis and maize that show a high level of sequence similarity to Dnmt3, suggesting that they encode plant de novo methyltransferases. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity.', 'These results provide the first direct demonstration that DNA-METases of a higher eukaryote are encoded by a gene family.', 'Here we show that Arabidopsis DNA methyltransferase2 (AtDNMT2) is localized in nucleus and associates with histone deacetylation.', 'To explore possible relationships between DNA methylation level and accumulation of DNA-(cytosine-5) methyltransferase (DNMT) transcripts, the full-length coding sequences corresponding to three different DNMT families in oil palm, namely the MET, CMT, and DRM classes, have been isolated and characterized.', 'In Arabidopsis a SWI2/SNF2 chromatin remodeling factor-related protein DDM1 and a cytosine methyltransferase MET1 are required for maintenance of genomic cytosine methylation.', 'Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity.', 'In the present study, the isolation and characterization of two distinct cDNAs that code for carrot DNA (cytosine-5)-methyltransferase (DNA-METase) are reported.', 'The Arabidopsis methylase has eight of the ten conserved sequence motifs found in prokaryote cytosine-5 methyltransferases and shows 50% homology to the murine enzyme in the methyltransferase domain.', 'As deduced form the DNA sequence this protein contains all conserved sequence motifs specific for the 5m cytosine MTases.']

['The plant DNA (cytosine-5)methyltransferases are classified into the families: MET, CMT, and the de novo DRM.']

['MET', 'CMT', 'DRM']

Is signal transducer and activator of transcription-3 (STAT3) critical for tumor angiogenesis progression?

[' (STAT3) is critical for cancer progression by regulating tumor cell survival, proliferation, and angiogenesis. Herein, we investigated the regulation of STAT3 activation and the therapeutic effects of Icaritin, a prenyl flavonoid derivative from Epimedium Genus, in renal cell carcinoma (RCC). ', ' Overall, these results suggest that Icaritin strongly inhibits STAT3 activation and is a potentially effective therapeutic option for the treatment of renal cell carcinoma', 'we have reviewed important signaling pathways that are closely related to radiosensitization, such as cell cycle arrest, tumor angiogenesis, JAK/STAT3 signaling pathway and Mismatch repair', 'Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial-mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis.', 'The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype.', 'STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases', ' EESB treatment could significantly suppress the activation of several CRC-related pathways, including STAT3, Erk, and p38 signalings in tumor tissues, and alter the expression of multiple critical target genes such as Bcl-2, Bax, Cyclin D1, CDK4, and p21. These molecular effects lead to the induction of cancer cell apoptosis and inhibition of cell proliferation. Our findings demonstrate that SB possesses a broad range of antitumor activities because of its ability to affect multiple intracellular targets', 'Western immunoblotting analyses of mouse lung tissues indicated significantly lower level of pSTAT3 and Mcl-1 in the carcinogen plus DMAPT group relative to the group treated with the carcinogen only. Given the evidence that STAT3 is activated in more than half of lung cancers and it regulates genes involved in cell proliferation, survival and angiogenesis, DMAPT is a promising agent for lung cancer chemoprevention in subjects who are at high risk of developing this devastating disease.', '(STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis', 'STAT3) signaling pathway plays important roles in oncogenesis, angiogenesis, immunity, and tumor cell invasion. In the present study, we investigated the association of interleukin ', ' Phosphorylated STAT3 (pSTAT3) regulates many genes that are necessarily expressed in cancer initiation, development, and progression, being involved in proliferation, anti-apoptosis, invasion, angiogenesis, and immune surveillance evasion']

['(STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis']

['yes']

Are Drosophila ultraconserved elements candidate ncRNAs?

['Highly constrained intergenic Drosophila ultraconserved elements are candidate ncRNAs.', 'Here, we report the discovery and characterization of UCEs from 12 sequenced Drosophila species. We identified 98 elements ≥80 bp long with very high conservation across the Drosophila phylogeny. Population genetic analyses reveal that these UCEs are not present in mutational cold spots. Instead we infer that they experience a level of selective constraint almost 10-fold higher compared with missense mutations in protein-coding sequences, which is substantially higher than that observed previously for human UCEs. About one-half of these Drosophila UCEs overlap the transcribed portion of genes, with many of those that are within coding sequences likely to correspond to sites of ADAR-dependent RNA editing. For the remaining UCEs that are in nongenic regions, we find that many are potentially capable of forming RNA secondary structures. Among ten chosen for further analysis, we discovered that the majority are transcribed in multiple tissues of Drosophila melanogaster. We conclude that Drosophila species are rich with UCEs and that many of them may correspond to novel noncoding RNAs.', 'Highly Constrained Intergenic Drosophila Ultraconserved Elements Are Candidate ncRNAs']

['Yes. Highly constrained intergenic Drosophila ultraconserved elements are candidate ncRNAs.']

['yes']

Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?

['his defect does not appear in mouse models with mutations in Dnmt3a and Mthfr genes and, therefore, it is specific for the Dnmt1 gene and is suggestive of a role of DNMT1 in imprint resetting or maintenance in the male germ line.', 'Specificity of Dnmt1 for methylation of hemimethylated CpG sites resides in its catalytic domain.', 'We obtained evidence that some 5-methylcytosine residues in these single-stranded DNAs can stimulate de novo methylation of adjacent sites by murine DNA 5-cytosine methyltransferase as effectively as 5-methylcytosine residues in double-stranded DNA stimulate maintenance methylation.', 'We present in vitro evidence that the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B, but not the maintenance enzyme DNMT1, are also redox-dependent DNA dehydroxymethylases.', 'Direct comparison to met1 plants, deficient in maintenance methyltransferase MET1, showed higher sensitivity of ddm1 plants to NaCl.', 'DNMT1, the major maintenance DNA methyltransferase in animals, helps to regulate gene expression, genome imprinting, and X-chromosome inactivation.', 'Correct establishment and maintenance of methylation patterns at imprinted genes has been associated with placental function and regulation of embryonic/fetal development.', 'Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein-Barr virus restricted latency.', 'Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency.', 'Recent studies demonstrate that UHRF1 is required for DNA methylation maintenance by targeting DNMT1 to DNA replication foci, presumably through its unique hemi-methylated DNA-binding activity and interaction with DNMT1.', 'It is generally accepted that DNA methyltransferases carry out specific and non-overlapping functions, Dnmt3a and Dnmt3b being responsible for the establishment of methylation around the time of implantation and Dnmt1 ensuring that methylation is faithfully copied to daughter cells via what has come to be known as "maintenance methylation."', 'A new model is emerging that takes into account a contribution of the de novo enzymes Dnmt3a and Dnmt3b in the maintenance of the DNA methylation.', 'We propose here observations in support of the hypothesis that the maintenance of methylation and subsequent silencing of a handful of germ line genes requires Dnmt3b but not Dnmt1.', 'DNA methyltransferase 1 (Dnmt1) is the enzyme responsible for maintaining the methylation marks through cell division. However, the de novo methyltransferases, Dnmt3a and Dnmt3b, can also contribute to the maintenance of the methylation pattern.', 'These new data support the notion that de novo DNMTs also have an important role in the maintenance of DNA methylation and suggest that, in addition to acting as oncogenes, they also behave as tumor suppressors.', 'Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1).', 'The DNA methyltransferase Dnmt1 is responsible for the propagation of methylation patterns to the next generation via its preferential methylation of hemimethylated CpG sites in the genome; however, how Dnmt1 maintains methylation patterns is not fully understood.', 'Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1.', 'In mammals Dnmt1 is the DNA methyltransferase chiefly responsible for maintaining genomic methylation patterns through DNA replication cycles, but how its maintenance activity is controlled is still not well understood.', 'DMAP1 is a potent activator of DNMT1 methylation in vitro, suggesting that DMAP1 is a co-repressor that supports the maintenance and de novo action of DNMT1.', 'A group of enzymes, the DNA methyltransferases (DNMTs) tightly regulate both the initiation and maintenance of these methyl marks.', 'Maintenance of DNA methylation depends on DNA methyltransferase 1 (Dnmt1) and intracellular S-adenosylmethionine (SAM) levels, and is inhibited by S-adenosylhomocysteine (SAH).', 'While DNMT3a is mostly involved in de novo methylation, DNMT1 acts as a maintenance methyltransferase.', 'We propose a new model that suggests that the maintenance of DNA methylation relies not only on the recognition of hemimethylated DNA by DNA methyltransferase 1 (DNMT1) but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions that contain methylated DNA.', 'The maintenance methylase, DNMT1 (DNA methyltransferase 1), is a prominent enzyme in the process that is linked to DNA replication and drives the heritable nature of epigenetic modifications.', 'We have shown previously that these drugs selectively and rapidly induce degradation of the maintenance DNA methyltransferase (DNMT) 1 by a proteasomal pathway.', 'Inheritance of epigenetic information encoded by cytosine DNA methylation patterns is crucial for mammalian cell survival, in large part through the activity of the maintenance DNA methyltransferase (DNMT1).', "We and others have shown that DNA methyltransferase 1 (DNMT1), the maintenance methyltransferase, contributes to the cellular response to DNA damage, yet DNMT1's exact role in this process remains unclear.", 'The maintenance function of Dnmt1 is regulated by its large regulatory N-terminal domain that interacts with other chromatin factors and is essential for the recognition of hemi-methylated DNA.', 'In the absence of a human pituitary tumor cell line, small interfering RNA-mediated knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine 5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20.', 'We found that DNA methylation was maintained only when exogenous DNA methyltransferase 1 (DNMT1) and S-adenosyl methionine (SAM) were added to the reaction.', 'We examined the expression of DNMT1 and DNMT3a, representative of a maintenance and de novo methyltransferase respectively, in response to in-vitro depolarization of cortical neurons, using standard techniques such as high potassium (KCl) or the sodium channel agonist veratridine.', 'DNA methyltransferase-1 (DNMT1) has a higher specific activity on hemimethylated DNA than on unmethylated DNA, but this preference is too small to explain the faithful mitotic inheritance of genomic methylation patterns. New genetic studies in plants and mammals have identified a novel factor that increases the fidelity of maintenance methylation.', 'Dnmt1 is the main maintenance methyltransferase in the mouse and its expression is regulated by a splicing mechanism that dictates the expression of stage-specific isoforms.', 'Phosphorylation of serine-515 activates the Mammalian maintenance methyltransferase Dnmt1.', 'DNA methyltransferase 1 methylates hemi-methylated CG sites generated during DNA replication.', 'DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs) including the maintenance enzyme DNMT 1 and de novo methyltransferases DNMT 3a and DNMT 3b.', 'Our data suggest that DNMT1 might be essential for maintenance of DNA methylation, proliferation, and survival of cancer cells.', 'Maintenance DNA methyltransferase (Met1) and silencing of CpG-methylated foreign DNA in Volvox carteri.', 'DNA methylation plays an important role in the gene-silencing network of higher eukaryotes. We have analyzed the 21.5-kb maintenance methyltransferase (M-MTase) gene, met1, of the multicellular green alga Volvox carteri.', 'DNA damage-induced down-regulation of human Cdc25C and Cdc2 is mediated by cooperation between p53 and maintenance DNA (cytosine-5) methyltransferase 1.', 'Methylation at the 5-position of DNA cytosine on the vertebrate genomes is accomplished by the combined catalytic actions of three DNA methyltransferases (DNMTs), the de novo enzymes DNMT3A and DNMT3B and the maintenance enzyme DNMT1.', 'DNA methylation, the major form of epigenetic modifications, is catalyzed by the maintenance DNA methyltransferase (DNMT) 1 and/or the de novo methyltransferases DNMT3A and DNMT3B.', 'The maintenance methylation of hemimethylated CpG sites by the DNA methyltransferase Dnmt1 is the molecular basis of the inheritance of DNA methylation patterns.', 'The allosteric site(s) on Dnmt1 can regulate processes of de novo and maintenance DNA methylation in cells.', 'Dnmt1 (DNA methyltransferase 1) is the principal enzyme responsible for maintenance of cytosine methylation at CpG dinucleotides in the mammalian genome.', 'Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1).', 'In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1.', 'DNA methyltransferases (DNMTs) are essential for maintenance of aberrant methylation in cancer cells and play important roles in the development of cancers.', 'DNA methyltransferase-1 (Dnmt1) is involved in the maintenance of DNA methylation patterns and is crucial for normal mammalian development.', 'DNMT1, which is important for maintenance of methylation, increased across development and stayed high in adult cortex.', 'Our results indicate that DNMT1 plays the main role in maintenance of methylation of CXCR4 promoter, while DNMT3B may function as an accessory DNA methyltransferase to modulate CXCR4 expression in AsPC1 cells.', 'DNA methylation patterns are established and maintained by three DNA methyltransferases: DNMT1, DNMT3A, and DNMT3B.', 'According to their structure and functions, DNA methyltransferases (Dnmts) are divided into two major families in mammalian cells: maintenance methyltransferase (Dnmt1) and de novo methyltransferases (Dnmt3a, Dnmt3b, and Dnmt3L).', 'The 5-LOX DNA methylation increased with the age of the cells.']

['The mammalian DNA (cytosine-5) methyltransferase 1, DNMT1 is the major enzyme responsible for the maintenance of the DNA methylation patterns on the newly synthesized strand after DNA replication. DNMT1 prefers hemimethylated DNA and during DNA replication methylates hemimethylated CpG sites by copying methylation patterns from the parental DNA strand to the newly synthesized daughter strand. The equivalent of DNMT1 in plants is MET1.']

['DNMT1', 'MET1']

Which syndrome is associated with mutations in the LYST gene?

['Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction.', 'Mutations in the CHS1 (LYST) gene result in CHS.', 'Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction.', 'Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429\xa0kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles.', 'Mutations in the CHS1 (LYST) gene result in CHS.', 'Chediak-Higashi syndrome: novel mutation of the CHS1/LYST gene in 3 Omani patients.', 'The CHS1/LYST gene was identified over 10 years ago and homologous CHS1/LYST genes are present in all eukaryotes.', 'We report a novel nonsense mutation of the CHS1/LYST gene in 3 Omani patients.', 'A novel single point mutation of the LYST gene in two siblings with different phenotypic features of Chediak Higashi syndrome.', 'Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations', 'Cloning of bovine LYST gene and identification of a missense mutation associated with Chediak-Higashi syndrome of cattle', 'A frameshift mutation in the LYST gene is responsible for the Aleutian color and the associated Chédiak-Higashi syndrome in American mink', 'Disease-causing mutations in the genes encoding perforin (PRF1, FHL2), munc13-4 (UNC13D, FHL3), syntaxin 11 (STX11, FHL4), and munc18-2 (UNC18-2/STXBP2, FHL5) have been previously identified in Familial Hemophagocyic Lymphohistiocytosis (FHL), whereas mutation in RAB27A and LYST account for Griscelli syndome type 2 and Chediak-Higashi syndrome, respectively', 'Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429\xa0kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles', 'Chediak-Higashi syndrome is a genetic disorder caused by mutations in a gene encoding a protein named LYST in humans (&quot;lysosomal trafficking regulator&quot;) or Beige in mice', 'The Chediak-Higashi syndrome (CHS), a life-threatening autosomal recessive disease with frequent mutations in the LYST gene, and its animal model, the beige mouse, are both characterized by lysosomal defects with accumulation of giant lysosomes', 'Cloning of bovine LYST gene and identification of a missense mutation associated with Chediak-Higashi syndrome of cattle.', 'These data are consistent with LYST being the gene for the human Chediak-Higashi Syndrome and strengthen the synteny relationship between MMU13 and human 1q43.', 'A frameshift mutation in the LYST gene is responsible for the Aleutian color and the associated Chédiak-Higashi syndrome in American mink.', 'Infantile hemophagocytic lymphohistiocytosis in a case of chediak-higashi syndrome caused by a mutation in the LYST/CHS1 gene presenting with delayed umbilical cord detachment and diarrhea.', 'Here, we describe two siblings with CHS due to a novel homozygous R1836X mutation in the LYST gene associated with loss of NK cell degranulation and cytotoxicity. ', 'Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations.', 'Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.']

['Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction.']

['Chediak-Higashi syndrome']

Is Pfh1 a component of the replisome?

['Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity', "Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry.", 'DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase.', 'Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II. ', ' Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites.', 'Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks.', 'Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity.', 'Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites.', 'Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner.', 'Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase.', 'Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks', 'Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II', 'Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites', 'Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks.', 'Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites.', 'Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner.', 'Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity.']

['No. Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity. DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase.']

['no']

Describe the isolation of transcription factor complexes by in vivo biotinylation tagging and direct binding to streptavidin beads, as applied for the case of the essential hematopoietic transcription factor GATA-1.

['Using the biotin tagged erythroid transcription factor GATA-1 as example, we describe several optimization steps for the application of the high affinity biotin streptavidin system in ChIP', 'Isolation and characterization of hematopoietic transcription factor complexes by in vivo biotinylation tagging and mass spectrometry', 'Efficient tagging methodologies are an integral aspect of protein complex characterization by proteomic approaches. Owing to the very high affinity of biotin for avidin and streptavidin, biotinylation tagging offers an attractive approach for the efficient purification of protein complexes. The very high affinity of the biotin/(strept)avidin system also offers the potential for the single-step capture of lower abundance protein complexes, such as transcription factor complexes. The identification of short peptide tags that are efficiently biotinylated by the bacterial BirA biotin ligase led to an approach for the single-step purification of transcription factor complexes by specific in vivo biotinylation tagging. A short sequence tag fused N-terminally to the transcription factor of interest is very efficiently biotinylated by BirA coexpressed in the same cells, as was demonstrated by the tagging of the essential hematopoietic transcription factor GATA-1. The direct binding to streptavidin of biotinylated GATA-1 in nuclear extracts resulted in the single-step capture of the tagged factor and associated proteins, which were eluted and identified by mass spectrometry. This led to the characterization of several distinct GATA-1 complexes with other transcription factors and chromatin remodeling cofactors, which are involved in activation and repression of gene targets. Thus, BirA-mediated tagging is an efficient approach for the direct capture and characterization of transcription factor complexes', 'We have described the application of a simple biotinylation tagging approach for the direct purification of tagged transcription factor complexes, based on the use of artificial short peptide tags that are specifically and efficiently biotinylated by the bacterial BirA biotin ligase, which is co-expressed in cells with the tagged factor. We used this approach to initially characterize complexes formed by the hematopoietic transcription factor GATA-1 in erythroid cells', 'Epitope tags have often been used as more reliable alternatives. In addition, we have employed protein in vivo biotinylation tagging as a very high affinity alternative to antibodies', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes.', 'A short sequence tag fused N-terminally to the transcription factor of interest is very efficiently biotinylated by BirA coexpressed in the same cells, as was demonstrated by the tagging of the essential hematopoietic transcription factor GATA-1.', 'Isolation and characterization of hematopoietic transcription factor complexes by in vivo biotinylation tagging and mass spectrometry.', 'A short sequence tag fused N-terminally to the transcription factor of interest is very efficiently biotinylated by BirA coexpressed in the same cells, as was demonstrated by the tagging of the essential hematopoietic transcription factor GATA-1.', 'The direct binding to streptavidin of biotinylated GATA-1 in nuclear extracts resulted in the single-step capture of the tagged factor and associated proteins, which were eluted and identified by mass spectrometry.', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes.', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes', 'A short sequence tag fused N-terminally to the transcription factor of interest is very efficiently biotinylated by BirA coexpressed in the same cells, as was demonstrated by the tagging of the essential hematopoietic transcription factor GATA-1']

['Owing to the very high affinity of biotin for avidin and streptavidin, biotinylation tagging offers an attractive approach for the efficient purification of protein complexes. The very high affinity of the biotin/(strept)avidin system also offers the potential for the single-step capture of lower abundance protein complexes, such as transcription factor complexes. The identification of short peptide tags that are efficiently biotinylated by the bacterial BirA biotin ligase led to an approach for the single-step purification of transcription factor complexes by specific in vivo biotinylation tagging. A short sequence tag fused N-terminally to the transcription factor of interest is very efficiently biotinylated by BirA coexpressed in the same cells, as was demonstrated by the tagging of the essential hematopoietic transcription factor GATA-1. The direct binding to streptavidin of biotinylated GATA-1 in nuclear extracts resulted in the single-step capture of the tagged factor and associated proteins, which were eluted and identified by mass spectrometry. This led to the characterization of several distinct GATA-1 complexes with other transcription factors and chromatin remodeling cofactors, which are involved in activation and repression of gene targets. Thus, BirA-mediated tagging is an efficient approach for the direct capture and characterization of transcription factor complexes.']

[]

Can Diabetes be caused by a defect in a potassium chanel?

['Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively.', 'To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. ', 'e report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation', 'Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel;', 'We report a case of a 6-week-old infant with diabetes mellitus based on a genetic defect in the sulfonylurea receptor 1 (SUR1), an ATP-sensitive potassium (KATP) channel protein.', 'In diabetes, vascular KATP channel function is impaired.']

['Mutations in the KATP channel can lead to neonatal diabetes.', 'Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively.']

['yes']

When ceritinib used instead of crizotinib?

['Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib-resistant patients, becoming a promising treatment option in this population. ', 'Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib. ', 'Ceritinib has activity in crizotinib-resistant and crizotinib-naïve patients and appears to be a viable alternative for ALK-positive NSCLC.', 'In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented.', 'Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.', 'Preclinical data showed impressive antitumor activity against crizotinib-resistant clones, and based on available data, ceritinib could represent a suitable option in crizotinib-resistant NSCLC.', 'The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.', 'Ceritinib (LDK378): a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer.', 'However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.SIGNIFICANCE: The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. ', 'However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.', 'Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease. The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib.', 'The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented.', 'The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease.', 'In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented. Copyright © 2015 Elsevier Inc.']

['Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC patients that are crizotinib-resistant and crizotinib-naïve.']

['crizotinib-resistant ALK-positive metastatic NSCLC patients', 'crizotinib-naïve ALK-positive metastatic NSCLC patients']

Is metabolic syndrome related with cardiovascular disease?

['The metabolic syndrome (MetS) is characterized by a cluster of risk factors including central obesity, hypertension, dyslipidemia and insulin resistance, The MetS is associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). ', 'As a molecular link between metabolic signals, inflammation, and vascular dysfunction, resistin can be proposed as playing a significant role in the heightened inflammatory state induced by metabolic stress linked to excessive caloric intake, thus contributing to the risk for metabolic syndrome (MetS), type 2 diabetes (T2DM), and cardiovascular disease (CVD). ', 'The metabolic syndrome (MetS) is associated with a higher risk for both, type 2 diabetes mellitus and cardiovascular disease. ', 'arotid intima-media thickness (CIMT) has been widely used as a surrogate marker of atherosclerosis and cardiovascular disease (CVD)']

['The metabolic syndrome (MetS) is characterized by a cluster of risk factors including central obesity, hypertension, dyslipidemia and insulin resistance, The MetS is associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM).']

['yes']

In which condition was protein S100A7 originally identified?

['Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family', 'Psoriasin (S100 A7) was discovered two decades ago as a protein abundantly expressed in psoriatic keratinocytes. ', ' Psoriasin, originally isolated from psoriasis as an overexpressed molecule of unknown function, has recently been identified as a principal Escherichia coli-killing antimicrobial peptide of healthy skin. ', 'Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin)', 'S100A7 (psoriasin) and S100A15 (koebnerisin) were first identified in inflamed psoriatic skin. ', 'Human psoriasin (S100A7) has originally been described as a member of the family of S100 calcium-binding proteins which is overexpressed in patients suffering from psoriasis. ']

['Psoriasin (S100A7) was originally identified in psoriasis.']

['psoriasis']

What pharmacological and non-pharmacological interventions can be considered as prophylactic therapies in Cluster Headache patients?

['The calcium channel blocker verapamil is the drug of choice for CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin, and baclofen.', 'Recently, the therapeutic options for refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation.', 'With the emergence of these novel treatments, the role of ablative surgery in CH has declined.', 'The mainstay of prophylactic therapy is verapamil. Yet, other medications, including lithium, divalproex sodium, topiramate, methysergide, gabapentin, and even indomethacin, may be useful when the headache fails to respond to verapamil.', 'For medically refractory patients, surgical interventions, occipital nerve stimulation, and deep brain stimulation remain an option.', 'The objective of this open single-centre study was to evaluate the efficacy and tolerability of botulinum toxin type-A (BTX-A) as add-on in the prophylactic treatment of cluster headache (CH).', 'These findings provide evidence that BTX-A may be beneficial as an add-on prophylactic therapy for a limited number of patients with chronic CH.', 'There are a variety of different medications for abortive and prophylactic therapy, accompanied by a variable amount of evidence-based medicine.', 'Most procedures are directed against the sensory trigeminal nerve and associated ganglia, eg, anesthetizing the sphenopalatine ganglion.', 'The mainstay of prophylactic therapy is verapamil. Lithium, divalproex sodium, or topiramate may also be useful.', 'Based on our clinical experience, we recommended the combination of nasal sumatriptan for acute attacks and verapamil 240 mg/day for prophylaxis.', 'Topiramate also appears to be well tolerated and useful in the adjunctive treatment of cluster headache.', 'The cornerstone of maintenance prophylaxis is verapamil, yet methysergide, lithium, and divalproex sodium may also be employed. In some patients, melatonin or topiramate may be useful adjunctive therapies.', 'Prophylactic therapy in most cases consisted of verapamil, also with a good response.', 'Patients with chronic cluster headache may achieve good results from long-term treatment with other therapies, including lithium carbonate, verapamil, and ketoprofen.']

['Verapamil, a calcium channel blocker, is considered the mainstay of prophylactic therapy of Cluster Headache patients. Lithium carbonate, topiramate, valproic acid, gabapentin, baclofen, methysergide, melatonin, ketoprofen and indomethacin can also be tried for prophylactic therapy of Cluster Headaches patients. Non-pharmacological prophylactic measures, such as peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation, ablative surgery, and botulinum toxin type-A (BTX-A) injection, can be also considered.']

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Elaborate on the association between Genomic Regulatory Blocks (GRBs) and target genes

['Recent functional studies have demonstrated that many microRNAs (miRNAs) are expressed by RNA polymerase II in a specific spatiotemporal manner during the development of organisms and play a key role in cell-lineage decisions and morphogenesis. They are therefore functionally related to a number of key protein coding developmental genes, that form genomic regulatory blocks (GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning as long-range enhancers that collaboratively regulate the expression of their target genes', "Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene.", 'We show evidence that GRB target genes have properties that set them apart from their bystanders as well as other genes in the genome: longer CpG islands, a higher number and wider spacing of alternative transcription start sites, and a distinct composition of transcription factor binding sites in their core/proximal promoters. Target gene expression correlates with the acetylation state of HCNEs in the region', 'GRB targets are genes with a number of unique features that are the likely cause of their ability to respond to regulatory inputs from very long distances.', 'Insect genomes contain larger blocks of conserved gene order (microsynteny) than would be expected under a random breakage model of chromosome evolution. We present evidence that microsynteny has been retained to keep large arrays of highly conserved noncoding elements (HCNEs) intact. These arrays span key developmental regulatory genes, forming genomic regulatory blocks (GRBs). We recently described GRBs in vertebrates, where most HCNEs function as enhancers and HCNE arrays specify complex expression programs of their target genes.', 'We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes. Bystander genes are not specifically under the control of the regulatory elements that drive the target genes and are expressed in patterns that are different from those of the target genes', 'Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region.', 'BACKGROUND: Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. ', "GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene. The tight regulation of target genes, complex arrangement of regulatory inputs, and the differential responsiveness of genes in the region call for the examination of fundamental rules governing transcriptional activity in GRBs. ", 'Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation.']

["Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene. GRB target genes have properties that set them apart from their bystanders as well as other genes in the genome: longer CpG islands, a higher number and wider spacing of alternative transcription start sites, and a distinct composition of transcription factor binding sites in their core/proximal promoters. Target gene expression correlates with the acetylation state of HCNEs in the region."]

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Is there any role for Pds5b in cohesion establishment?

['Pds5B is required for cohesion establishment and Aurora B accumulation at centromeres.', 'Here, we demonstrate that Pds5 proteins are essential for cohesion establishment by allowing Smc3 acetylation by the cohesin acetyl transferases (CoATs) Esco1/2 and binding of Sororin. While both proteins contribute to telomere and arm cohesion, Pds5B is specifically required for centromeric cohesion. Furthermore, reduced accumulation of Aurora B at the inner centromere region in cells lacking Pds5B impairs its error correction function, promoting chromosome mis-segregation and aneuploidy. Our work supports a model in which the composition and function of cohesin complexes differs between different chromosomal regions.', 'Pds5B is required for cohesion establishment and Aurora B accumulation at centromeres.', 'Here, we demonstrate that Pds5 proteins are essential for cohesion establishment by allowing Smc3 acetylation by the cohesin acetyl transferases (CoATs) Esco1/2 and binding of Sororin.']

['Yes. Pds5 proteins are essential for cohesion establishment by allowing Smc3 acetylation by the cohesin acetyl transferases (CoATs) Esco1/2 and binding of Sororin.']

['yes']

What is the most prominent sequence consensus for the polyadenylation site?

['the cannonical polyadenylation signal sequence AATAAA', 'Two AATAAA motifs are coded in the last exon of this gene', 'The results demonstrate that the intact AAUAAA is not required for RNA polyadenylation but is required for the cleavage step preceding polyadenylation to occur efficiently', 'the early poly(A) consensus signal was mutated from AAUAAA to UGUAAA', "Functional polyadenylation [poly(A)] sites consist of two sequence elements, the AAUAAA and G/U box signals, that closely flank the site of mRNA 3'-end formation", 'the appropriate spacing of the AAUAAA and G/U box signals is critical for poly(A) site function', ' Two AATAAA hexanucleotide sequences are present in the 2092 nucleotide interval. The first one functions as the major polyA signal']

["Functional polyadenylation [poly(A)] sites consist of two sequence elements, the AAUAAA and G/U box signals, that closely flank the site of mRNA 3'-end formation. The canonical polyadenylation signal sequence AATAAA"]

['AATAAA', 'AAUAAA']

Which proteins in the cerebro-spinal fluid can be used for early diagnosis of Alzheimer's disease?

["Alzheimer's disease (AD) patients have reduced amyloid (Aβ 1-42) and elevated total tau (t-tau) and phosphorylated tau (p-tau 181p) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI)", 'although high CSF tau and low CSF Aβ42 are predictive of Alzheimer\'s disease, the criterion "positive CSF tau/Aβ42 ratio" is not well defined. The qualification of biomarkers in the pre-dementia stage of Alzheimer\'s disease will allow better inclusion criteria of patients in pre-dementia trials in which the benefit/risk is higher for treatment with these novel compounds', "investigate the dynamics of four of the most validated biomarkers for Alzheimer's disease (AD), cerebro-spinal fluid (CSF) Abeta 1-42, tau, hippocampal volume, and FDG-PET, in patients at different stage of AD", "Alzheimer's disease (AD) may be facilitated by cerebro-spinal fluid (CSF) biomarkers in combination with imaging and clinical assessments. By determining the concentration of beta amyloid fragments, total tau (t-tau) and phospho-tau (p-tau), it is possible to detect the conversion of mild cognitive impairment (MCI) to AD or distinguish AD vs. pseudo-dementia. However, these markers are poorly sensitive to the progressive disease stages"]

["CSF is a clear fluid that bathes and cushions the brain and spinal cord. Adults have about 1 pint of CSF, which physicians can sample through a minimally invasive procedure called a lumbar puncture, or spinal tap. Research suggests that Alzheimer's disease in its earliest stages may cause changes in CSF levels of tau and beta-amyloid, two proteins that form abnormal brain deposits strongly linked to the disease."]

['phosphorylated tau', 'beta-amyloid']

Is exon skipping correlated with exon circularization?

['Exon Skipping Is Correlated with Exon Circularization', 'We find that circularization of exons is widespread and correlates with exon skipping, a feature that adds considerably to the regulatory complexity of the human transcriptome', 'Exon Skipping Is Correlated with Exon Circularization.', 'We find that circularization of exons is widespread and correlates with exon skipping, a feature that adds considerably to the regulatory complexity of the human transcriptome. <CopyrightInformation>Copyright © 2015 Elsevier Ltd. All rights reserved.</', 'We find that circularization of exons is widespread and correlates with exon skipping, a feature that adds considerably to the regulatory complexity of the human transcriptome. <CopyrightInformation>Copyright © 2015 Elsevier Ltd. All rights reserved.</C', 'Exon Skipping Is Correlated with Exon Circularization.']

['Yes. Circularization of exons is widespread and correlates with exon skipping, a feature that adds considerably to the regulatory complexity of the human transcriptome.']

['yes']

Which are the subunits of the transcription factor NF-kappaB in the canonical pathway activation?

['In this study, we demonstrated that the HSV-1 UL42 protein, a DNA polymerase processivity factor, was a novel antagonism of the canonical NF-κB signaling pathway. UL42 was shown to significantly suppress TNF-α mediated NF-κB activation. Co-immunoprecipitation experiment revealed that UL42 bound to the NF-κB subunits p65 and p50. ', 'Thus, it was first time we demonstrated that HSV-1 UL42 appeared to prevent NF-κB-dependent gene expression by retaining p65 and p50 in the cytoplasm, and UL42-dependent transcriptional activation were inherently coupled to promote HSV-1 lytic replication, which also may contribute to immune evasion and pathogenesis of HSV-1.', 'The review describes NF-κB and its two pathways: the canonical, mediated by the p65 and p50 subunits, and the non-canonical, mediated by the subunits RelB, p52 and p50. ', 'The function of the TTV open reading frame (ORF) in the nuclear factor kappaB (NF-kappaB) pathway has not yet been established. In this study, we found for the first time that the TTV ORF2 protein could suppress NF-kappaB activity in a dose-dependent manner in the canonical NF-kappaB pathway. By Western blot analysis, we proved that the TTV ORF2 protein did not alter the level of NF-kappaB expression but prevented the p50 and p65 subunits from entering the nucleus due to the inhibition of IkappaBalpha protein degradation.', 'Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-α-induced NF-κB activation by interacting with p65/RelA and p50/NF-κB1.']

['The NF-κB canonical pathway is mediated by the p65/relA and p50 subunits.']

['p65', 'RelA', 'p50', 'NF-κB1']

Is indicated the use of antioxidant supplements in patients at risk for coronary artery disease?

['We and others have published observational epidemiologic studies in support of vitamins in the primary prevention of CVD, but the results from intervention studies are mixed.', 'For vitamin E, observational data suggest benefit at doses of 100 to 400 IU/d. Results from recent large-scale trials are mixed, with some showing modest benefit but others suggesting no benefit, especially for secondary prevention. Results for B vitamins are also mixed and further complicated by the recent folate fortification of the flour supply. If greater B vitamin intake does reduce CVD, the benefits are likely to be greatest for primary prevention and in populations with intake below dietary reference standards. ', 'In the dose-response meta-analysis, each 30 mg/day increase in vitamin C, 30 IU/day increase in vitamin E, and 1 mg/day increase in beta-carotene yielded the estimated overall relative risk for CHD of 1.01 (95% CI, 0.99-1.02), 0.96 (95% CI, 0.94-0.99), and 1.00 (95% CI, 0.88-1.14), respectively. CONCLUSIONS: Our findings in this meta-analysis suggest that an increase in dietary intake of antioxidant vitamins has encouraging prospects for possible CHD prevention.', 'High levels of α-tocopherol in serum were associated with 30% lower CAD risk in another study (HR 0.71; 95%CI 0.53-0.94). Among minerals (zinc, selenium, and chromium), an inverse association between zinc and CAD was observed; levels lower than 14.1 µmol/L were associated with an increased risk for CAD (RR 1.70; 95%CI 1.21-2.38).', 'The information available on this issue is scarce. Further prospective studies are needed to elucidate the role of these nutrients in the cardiovascular risk of patients with diabetes.', 'Coenzyme Q10 supplementation at a dosage of 150 mg appears to decrease the inflammatory marker IL-6 in patients with CAD.', ' Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative stress and increase antioxidant enzyme activity in patients with CAD. A higher dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable antioxidation in patients with CAD.', 'Alpha-tocopherol or beta-carotene supplementation has no protective effect on macrovascular outcomes or total mortality of diabetic male smokers.', 'Sodium selenite supplementation increases GPx-1 activity in endothelial cells and in CAD patients. Future studies have to demonstrate whether long-term CAD outcome can be improved.', 'After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.', ' In this population-based study, vitamin E use was unrelated to mortality, but this apparently null finding seems to represent a combination of increased mortality in those with severe cardiovascular disease and a possible protective effect in those without.', ' In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality. ', 'The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials', 'Recent studies show that supplementation with antioxidant vitamins E and C have benefits in CHD prevention; however, supplementation with beta-carotene may have deleterious effects and is not recommended. Current evidence suggests that patients with CHD would probably benefit from taking vitamin E in a dosage of 400 IU per day and vitamin C in a dosage of 500 to 1,000 mg per day. Clinicians may also want to consider vitamin supplementation for CHD prevention in high-risk patients. Folate lowers elevated homocysteine levels, but evidence for routine supplemental use does not yet exist. ', 'In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.']

['antioxidant supplementation \nHowever there are no clear evidencies on the clinical and prognostic benefit of this supplementation. \nCurrently there areno recommendation for the antioxidant therapy in patients with coronary artery disease.\nCurrently the American Heart Association recommends consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but does not recommend antioxidant supplementation for the general population.']

['no']

What is Neisseria adhesin A?

['Exploiting chimeric human antibodies to characterize a protective epitope of Neisseria adhesin A, one of the Bexsero vaccine components.', 'Neisseria adhesin A (NadA) is one of the antigens of Bexsero, the recently licensed multicomponent vaccine against serogroup B Neisseria meningitidis (MenB). NadA belongs to the class of oligomeric coiled-coil adhesins and is able to mediate adhesion and invasion of human epithelial cells. As a vaccine antigen, NadA has been shown to induce high levels of bactericidal antibodies', 'A new vaccine (the 4CMenB 4-component protein vaccine [Bexsero], which includes PorA, factor H-binding protein [fHbp], neisserial heparin-binding antigen [NHBA], and Neisseria adhesin A [NadA]) against serogroup B meningococci has recently been approved for use in people older than age 2 months in Europe, Australia, and Canada. ', 'Serum bactericidal activity using human complement (hSBA) was measured against three reference strains 44/76-SL, 5/99 and NZ98/254, selected to express one of the vaccine antigens; Neisseria adhesin A (NadA), factor H binding protein (fHbp) and porin A (PorA) containing outer membrane vesicle (OMV), respectively.', 'Isolates were genotyped by analysis of their 4CMenB vaccine antigen genes of PorA, factor H binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisseria Adhesin A (NadA).', 'Vaccine components were typed by sequencing for factor H-binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA) and Neisseria adhesin A (NadA). ', 'Neisseria adhesin A (NadA), involved in the adhesion and invasion of Neisseria meningitidis into host tissues, is one of the major components of Bexsero, a novel multicomponent vaccine licensed for protection against meningococcal serogroup B in Europe, Australia, and Canada. NadA has been identified in approximately 30% of clinical isolates and in a much lower proportion of carrier isolates. Three protein variants were originally identified in invasive meningococci and named NadA-1, NadA-2, and NadA-3, whereas most carrier isolates either lacked the gene or harbored a different variant, NadA-4. Further analysis of isolates belonging to the sequence type 213 (ST-213) clonal complex identified NadA-5, which was structurally similar to NadA-4, but more distantly related to NadA-1, -2, and -3. At the time of this writing, more than 89 distinct nadA allele sequences and 43 distinct peptides have been described. ', 'The main features of this new scheme include (i) the grouping of the previously named NadA-2 and NadA-3 variants into a single NadA-2/3 variant, (ii) the grouping of the previously assigned NadA-4 and NadA-5 variants into a single NadA-4/5 variant, (iii) the introduction of an additional variant (NadA-6), and (iv) the classification of the variants into two main groups, named groups I and II. ', 'To broaden the scope of its protection, the multicomponent vaccine (4CMenB) incorporates a PorA-containing outer membrane vesicle (OMV) alongside relatively conserved recombinant protein components, including factor H-binding protein (fHbp), Neisseria adhesin A (NadA), and neisserial heparin-binding antigen (NHBA). ', 'Nine N. meningitidis isolates (eight MenB and one MenY) were found to possess at least one gene that encoded for an antigen that matched exactly with protein variants in the 4CMenB vaccine. Two MenB expressed PorA antigen P1.4 and possessed the nhba gene for peptide 2; four other MenB were predicted to have NHBA peptide 2; another two MenB were predicted to encode fHbp peptide 1.1; and a single MenY was found to have nadA gene for NadA peptide 8.', 'Isolates were genotyped by analysis of their 4CMenB vaccine antigen genes of PorA, factor H binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisseria Adhesin A (NadA).Of the 263 IMD isolates analysed, 229, 16, 10, 7, and 1 belonged to MenB, MenY, MenW, MenC, and MenX, respectively', 'We analyzed the sequence variability of factor H-binding protein (fHbp), Neisserial Heparin-Binding Antigen (NHBA) and Neisseria adhesin A (NadA), three major antigens in the multicomponent meningococcal serogroup B vaccine 4CMenB', 'To broaden the scope of its protection, the multicomponent vaccine (4CMenB) incorporates a PorA-containing outer membrane vesicle (OMV) alongside relatively conserved recombinant protein components, including factor H-binding protein (fHbp), Neisseria adhesin A (NadA), and neisserial heparin-binding antigen (NHBA)', 'Novartis Vaccines has developed a vaccine for the prevention of MenB disease that contains four antigenic components: factor H binding protein (fHbp), neisserial adhesin A (NadA), Neisseria heparin binding antigen (NHBA) and outer membrane vesicles from a New Zealand epidemic strain (which provides PorA)', 'The Oca (Oligomeric coiled-coil adhesin) family is a subgroup of the bacterial trimeric autotransporter adhesins, which includes structurally related proteins, such as YadA of Yersinia enterocolitica and NadA of Neisseria meningitidis', 'Here we elucidate a novel phase variable mechanism for NadA, an adhesin and invasin of Neisseria meningitidis', 'Neisseria meningitidis adhesin NadA targets beta1 integrins: functional similarity to Yersinia invasin.', 'Human monocytes/macrophages are a target of Neisseria meningitidis Adhesin A (NadA).', 'We have previously shown that NadA also promotes bacterial internalization in a heterologous expression system. ', 'Its recombinant form NadA(Δ351-405,) devoid of the outer membrane domain, is an immunogenic candidate for an anti-MenB vaccine able to stimulate monocytes, macrophages and dendritic cells. ', 'Role of ARF6, Rab11 and external Hsp90 in the trafficking and recycling of recombinant-soluble Neisseria meningitidis adhesin A (rNadA) in human epithelial cells.', 'A new vaccine (the 4CMenB 4-component protein vaccine [Bexsero], which includes PorA, factor H-binding protein [fHbp], neisserial heparin-binding antigen [NHBA], and Neisseria adhesin A [NadA]) against serogroup B meningococci has recently been approved for use in people older than age 2 months in Europe, Australia, and Canada.', 'Neisseria adhesin A (NadA), involved in the adhesion and invasion of Neisseria meningitidis into host tissues, is one of the major components of Bexsero, a novel multicomponent vaccine licensed for protection against meningococcal serogroup B in Europe, Australia, and Canada.', 'With the aim of studying the molecular diversity of the antigens of a new recombinant vaccine against meningococcus serogroup B, the three genes coding for the main vaccine components GNA (Genome-derived Neisseria Antigen) 1870 (fHbp, factor H Binding Protein), GNA1994 (NadA, Neisseria adhesin A) and GNA2132 were sequenced in a panel of 85 strains collected worldwide and selected as representative of the serogroup B meningococcal diversity.', 'To broaden the scope of its protection, the multicomponent vaccine (4CMenB) incorporates a PorA-containing outer membrane vesicle (OMV) alongside relatively conserved recombinant protein components, including factor H-binding protein (fHbp), Neisseria adhesin A (NadA), and neisserial heparin-binding antigen (NHBA).', '4CMenB vaccine antigens, PorA, factor H binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA) were molecularly typed by sequencing.', 'Vaccine components were typed by sequencing for factor H-binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA) and Neisseria adhesin A (NadA).', 'Isolates were genotyped by analysis of their 4CMenB vaccine antigen genes of PorA, factor H binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisseria Adhesin A (NadA).Of the 263 IMD isolates analysed, 229, 16, 10, 7, and 1 belonged to MenB, MenY, MenW, MenC, and MenX, respectively.', 'Neisseria adhesin A (NadA) is one of the antigens of Bexsero, the recently licensed multicomponent vaccine against serogroup B Neisseria meningitidis (MenB).', 'Neisseria adhesin A (NadA) is present on the meningococcal surface and contributes to adhesion to and invasion of human cells.', 'Isolates were genotyped by analysis of their 4CMenB vaccine antigen genes of PorA, factor H binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisseria Adhesin A (NadA).', 'We analyzed the sequence variability of factor H-binding protein (fHbp), Neisserial Heparin-Binding Antigen (NHBA) and Neisseria adhesin A (NadA), three major antigens in the multicomponent meningococcal serogroup B vaccine 4CMenB.']

['Neisseria adhesin A (NadA) is one of the antigens of Bexsero, the recently licensed multicomponent vaccine against serogroup B Neisseria meningitidis (MenB). NadA belongs to the class of oligomeric coiled-coil adhesins and is able to mediate adhesion and invasion of human epithelial cells. As a vaccine antigen, NadA has been shown to induce high levels of bactericidal antibodies. More than 89 distinct NadA allele sequences and 43 distinct peptides have been described.']

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Is Tuberous Sclerosis a genetic disease?

['Tuberous sclerosis complex (TSC) is a genetic disease', 'Tuberous sclerosis is a rare genetic disease', 'Tuberous sclerosis complex (TSC) is a multisystem genetic disease', 'Tuberous sclerosis complex (TSC) is a genetic disease', 'The disease is caused by mutational inactivation of the tumor suppressor gene tuberous sclerosis complex 1 (TSC1) or TSC2.', 'mTOR inhibitors have antiepileptogenic and antiseizure effects in animal models of the genetic disease, tuberous sclerosis complex.', 'Tuberous sclerosis (TSC) is an autosomal-dominant genetic disease', 'Tuberous sclerosis is a rare genetic disease', 'Tuberous Sclerosis Complex (TSC) is a genetic disease', 'Tuberous sclerosis complex (TSC) is a multiorgan genetic disease', 'Tuberous sclerosis complex (TSC) is a genetic disease', 'Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease', 'Tuberous sclerosis complex (TSC) is a genetic disease', 'Tuberous sclerosis complex (TSC) is a multiorgan genetic disease', 'In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated.', 'Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease.', 'The tuberous sclerosis gene 2 product tuberin is an important regulator of the mammalian target of rapamycin (mTOR).', 'Tuberous sclerosis complex (TSC) is a genetic disease', 'Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease', 'Tuberous sclerosis complex (TSC) is a relatively rare autosomal dominant disorder', 'Tuberous sclerosis is a genetic disease with autosomal dominant inheritance,', 'PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway.', 'Tuberous sclerosis complex (TSC) is a multiorgan genetic disease', 'Tuberous sclerosis complex (TSC) is a genetic disease', 'Tuberous sclerosis is a rare genetic disease', 'Tuberous sclerosis complex (TSC) is a genetic disease', 'Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2.', 'Tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in either TSC1 or TSC2 tumor suppressor genes.', 'Mutation in either the TSC1 or TSC2 tumor suppressor gene is responsible for the inherited genetic disease of tuberous sclerosis complex.', 'Tuberous sclerosis (TSC) is a frequent autosomal-dominant condition (affecting 1 in 6000 individuals) caused by various mutations in either the hamartin (TSC1) or the tuberin gene (TSC2).', 'Tuberous sclerosis is a rare genetic disease', 'Tuberous sclerosis (TS) is a genetic disease with prominent cutaneous and brain involvement ', 'TSC was recognized to be a genetic disease with autosomal dominant inheritance', 'On average TSC families are very small; in most cases there are fewer than two informative meioses. The size distribution of chromosome 9 linked families was similar to that of non-linked families.', 'The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC).', 'Tuberous sclerosis is a dominant hereditary disease', 'Many of these advances originated from studies of the genetic disease tuberous sclerosis complex (TSC)']

['Tuberous sclerosis is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and incomplete penetrance. Two thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. Current genetic tests have difficulty locating the mutation in approximately 20% of individuals diagnosed with the disease. So far it has been mapped to two genetic loci, TSC1 and TSC2.\nTSC1 encodes for the protein hamartin, is located on chromosome 9 q34 and was discovered in 1997. TSC2 encodes for the protein Tuberin, is located on chromosome 16 p13.3 and was discovered in 1993. TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with TSC who also develop PKD in childhood. TSC2 has been associated with a more severe form of TSC. However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 80-90%.', 'Yes, Tuberous Sclerosis is a genetic disease, caused by mutations in the TSC1 or TSC2 gene.']

['yes']

Which drug is considered as the first line treatment of fibromyalgia?

['Multimodal approaches seem to be the treatment of choice in fibromyalgia', 'A multidisciplinary program was developed and implemented for patients with fibromyalgia in the primary care setting. The program included education (seven sessions) and physical therapy (25 sessions).', 'Amitriptyline for neuropathic pain and fibromyalgia in adults.', 'Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage) and fibromyalgia, and is recommended in many guidelines. ', 'Amitriptyline should continue to be used as part of the treatment of neuropathic pain or fibromyalgia, but only a minority of patients will achieve satisfactory pain relief.', 'Valproic acid and its sodium salt (sodium valproate) are antiepileptic drugs that are sometimes used to treat chronic neuropathic pain and fibromyalgia, although they are not licensed for this use. ', 'Oral pregabalin, a calcium channel alpha(2)delta-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia.', 'Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.']

['Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.']

['Pregabalin']

Describe the applicability of Semantic MediaWiki in the case of FANTOM5

['To make the heterogeneous data set accessible and useful for investigators, we developed a web-based database called Semantic catalog of Samples, Transcription initiation And Regulators (SSTAR). SSTAR utilizes the open source wiki software MediaWiki along with the Semantic MediaWiki (SMW) extension, which provides flexibility to model, store, and display a series of data sets produced during the course of the FANTOM5 project. Our use of SMW demonstrates the utility of the framework for dissemination of large-scale analysis results. SSTAR is a case study in handling biological data generated from a large-scale research project in terms of maintenance and growth alongside research activities', 'SSTAR utilizes the open source wiki software MediaWiki along with the Semantic MediaWiki (SMW) extension, which provides flexibility to model, store, and display a series of data sets produced during the course of the FANTOM5 project.', 'SSTAR utilizes the open source wiki software MediaWiki along with the Semantic MediaWiki (SMW) extension, which provides flexibility to model, store, and display a series of data sets produced during the course of the FANTOM5 project.']

['To make the heterogeneous data set accessible and useful for investigators, a web-based database called Semantic catalog of Samples, Transcription initiation And Regulators (SSTAR) has been developed. SSTAR utilizes the open source wiki software MediaWiki along with the Semantic MediaWiki (SMW) extension, which provides flexibility to model, store, and display a series of data sets produced during the course of the FANTOM5 project. The use of SMW demonstrates the utility of the framework for dissemination of large-scale analysis results. SSTAR is a case study in handling biological data generated from a large-scale research project in terms of maintenance and growth alongside research activities']

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Is TNNI3K a cardiac-specific protein?

['cardiomyocyte-specific kinase TNNI3K ', 'We report that cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase,', 'TNNI3K, a cardiac-specific kinase, ', ' The cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific kinase, is associated with cardiomyocyte hypertrophy', 'Human cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific functional kinase that can bind to cTnI in a yeast two-hybrid screen. ', 'Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunctio', 'Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown', ' Cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific kinase gene', ' a novel cardiac-specific kinase gene (TNNI3K),', ' TNNI3K is a novel cardiac troponin I-interacting kinase gene and its overexpression may promote cardiac myogenesis, ', 'TNNI3K is a new cardiac-specific MAP kinase whose gene is localized to 1p31.1 and that belongs to a tyrosine kinase-like branch in the kinase tree of the human genome.', 'The cardiac ankyrin repeat kinase (CARK) gene, also named TNNI3K for its interaction with cardiac troponin I, is both a unique expression and heart-enriched gene', 'Molecular cloning of cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac-specific protein kinase containing seven N-terminal ankyrin (ANK) repeats followed by a protein kinase domain and a C-terminal Ser-rich domain, has previously been reported.', ' TNNI3K is highly expressed in heart, but is undetectable in other tissues. Immunohistochemical analysis predominantly localized TNNI3K in the nucleus of cardiac myocytes. ']

['Yes, TNNI3K is highly expressed in heart but is undetectable in other tissues.']

['yes']

What is the role of TAD protein domain?

[' Thus, nuclear ERK5 activates transcription factors by either direct phosphorylation or acting as co-activator thanks to a unique transcriptional activation TAD domain located at its C-terminal tail. ', 'Although lacking kinase activity, these forms activate transcription by interacting with transcription factors through the TAD domain. ', 'Myc has an N-terminal transcription activation domain (TAD) that interacts with various coactivators and a C-terminal basic-helix-loop-helix-leucine zipper (bHLHZip) domain required for E box-specific DNA-binding and heterodimerization with its obligatory bHLHZip protein partner Max. ', 'p300 worked synergistically with MRTF-A to activate the transcription of MYH9, MYL9 and CYR61. As identified by co-IP, p300 interacted with the C-terminal TAD domain of MRTF-A.', 'To investigate further the role of cytoplasmic sequestration of p53 in its inhibition by the E1B 55-kDa protein we systematically examined domains in both the Ad12 55-kDa protein and p53 that underpin their colocalization in the cytoplasmic body and show that the N-terminal transactivation domain (TAD) of p53 is essential for retaining p53 in the cytoplasmic body.', 'Physical interaction between the transactivation domain (TAD) of the mixed-lineage leukemia protein (MLL) and the KIX domain of the cyclic-AMP response element binding protein (CREB) binding protein (CBP) is necessary for MLL-mediated transcriptional activation.', 'The IE62 possesses several domains essential for trans-activation, including an acidic trans-activation domain (TAD), a serine-rich tract (SRT), and binding domains for USF, TFIIB, and TATA box binding protein (TBP)', 'To investigate further the role of cytoplasmic sequestration of p53 in its inhibition by the E1B 55-kDa protein we systematically examined domains in both the Ad12 55-kDa protein and p53 that underpin their colocalization in the cytoplasmic body and show that the N-terminal transactivation domain (TAD) of p53 is essential for retaining p53 in the cytoplasmic body.', 'We have characterized two transcription activation domains (TADs) in Da, called activation domain 1 (AD1) and loop-helix (LH), and have evaluated their roles in promoting peripheral neurogenesis.', 'Particularly, the intrinsic histone acetyltransferase (HAT) activity and transactivation domains (TAD) play essential roles for their coactivating function.']

['TAD domain is a transcription activation domain found in transcription factors.']

['transcription activation domain', 'transactivation domain', 'trans-activating domain']

How are looped genes identified in yest?

["Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB.", 'Instead, activators physically interacted with the general transcription factor TFIIB when the genes were activated and in a looped configuration.']

["Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB.", "gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as tfiib.", "Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB", "Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB. . . . . "]

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What is the localization of the protein encoded by the gene DNAJC11?

[' DnaJC11, respectively. The first three are outer membrane proteins, CHCHD3 has been assigned to the matrix space, and the other two proteins have not been described in mitochondria previously.']

['mitochondrial inner membrane']

['mitochondrial inner membrane']

What are the effects of ILK ablation?

['ILK knockdown had no effect on the viability or survival pathway activity pattern of MM cells.', 'We conclude that ILK does not play a prominent role in the promotion or sustenance of established MM.', 'Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts', 'Here, we show that fibroblast-restricted inactivation of ILK in mice leads to impaired healing due to a severe reduction in the number of myofibroblasts, whereas inflammatory infiltrate and vascularization of the granulation tissue are unaffected.', 'in fibroblasts, ILK is crucial for limiting RhoA activity, thus promoting TGFβ1 production, which is essential for dermal repair following injury.', 'Our results show that ILK is important for the function, but not the differentiation, of osteoclasts.', 'Osteoclast-specific inactivation of the integrin-linked kinase (ILK) inhibits bone resorption.', 'ack of ILK in the hepatocytes imparts prolonged proliferative response not only to stimuli related to liver regeneration but also to xenobiotic chemical mitogens, such as PB.', 'Liver-specific ablation of integrin-linked kinase in mice results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration.', 'Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase.', 'ILK deficiency caused an aberrant distribution of nephrin and alpha-actinin-4 in podocytes, whereas the localization of podocin and synaptopodin remained relatively intact.', 'Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure.', 'Here we show that targeted ablation of the integrin-linked kinase (ILK) expression results in spontaneous cardiomyopathy and heart failure by 6 wk of age.', 'Together, these results suggest that ILK plays a central role in protecting the mammalian heart against cardiomyopathy and failure.', 'Our results show for the first time in vivo the significance of ILK and hepatic ECM-signaling for regulation of hepatocyte proliferation and differentiation.', 'Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly.']

['Depending on the tissue or cell where ILK is ablated we see different effects:\nAblation of ILK in heart results in dilated cardiomyopathy and spontaneous heart failure\nAblation of ILK in fibroblasts leads to impaired healing due to a severe reduction in the number of myofibroblasts\nAblation of ILK in osteoclasts inhibits bone resorption\nAblation of ILK in liver results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration and in abnormal histology\nAblation of ILK in podocytes caused an aberrant distribution of nephrin and alpha-actinin-4']

['Ablation of ILK in heart results in dilated cardiomyopathy and spontaneous heart failure', 'Ablation of ILK in fibroblasts leads to impaired healing due to a severe reduction in the number of myofibroblasts', 'Ablation of ILK in osteoclasts inhibits bone resorption', 'Ablation of ILK in liver results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration and in abnormal histology', 'Ablation of ILK in podocytes caused an aberrant distribution of nephrin and alpha-actinin-4']

How Flaviviridae family of viruses infects vertebrates?

['(WNV) is a neurotropic flavivirus that cycles between mosquitoes and birds but that can also infect humans, horses, and other vertebrate animals. In most humans, WNV infection remains subclinical. However, 20%-40% of those infected may develop WNV disease, with symptoms ranging from fever to meningoencephalitis. A large variety of WNV strains have been described worldwide', 'can be parasitized by Ixodid ticks, which may be infected with tick-borne pathogens, like Borrelia spp., Babesia spp., Anaplasma, Rickettsia/Coxiella, and tick-borne encephalitis virus. The prevalence of ticks on birds varies over years, season, locality and different bird species. The prevalence of ticks on different species depends mainly on the degree of feeding on the ground. In Europe, the Turdus spp., especially the blackbird, Turdus merula, appears to be most important for harboring ticks. Birds can easily cross barriers, like fences, mountains, glaciers, desserts and oceans, which would stop mammals, and they can move much faster than the wingless hosts. Birds can potentially transport tick-borne pathogens by transporting infected ticks, by being infected with tick-borne pathogens and transmit the pathogens to the ticks, and possibly act as hosts for transfer of pathogens between ticks through co-feeding.', 'The dengue viruses (DENVs) are mosquito-borne flaviviruses transmitted by infected Aedes mosquitoes. Illness manifests across a clinical spectrum with severe disease characterized by intravascular volume depletion and hemorrhage. Recent estimates on the burden of DENV infection determined that there are 390 million dengue infections per year, three times the current estimate by the WHO', '(WNV), an arbovirus maintained in a bird-mosquito enzootic cycle, can infect other vertebrates including humans', '(WNV), a mosquito-borne flavivirus in the Japanese encephalitis antigenic group, has caused sporadic outbreaks in humans, horses and birds throughout many of the warmer regions of Europe for at least 20 years. Occasional cases of West Nile encephalitis have also been associated with infected blood transfusions and organ donations', 'Dengue is the most important vector-borne disease in many different parts of the world and is expanding into other areas of the globe without hindrance. The morbidity and mortality due to dengue complications are increasing globally at an alarming rate. Although transmission of the dengue virus has been documented in well-characterized areas of Pakistan, its incidence in Khyber Pakhtunkhawa has not been characterized', ' A rising incidence of acute hepatitis C virus (HCV) in HIV-infected MSM has been observed since 2000 in Europe, Australia, USA and Asia. Transmission appears to occur through the permucosal rather than the more usual parenteral route. Although often multifactorial, permucosal risk factors can be classified as behavioural (sexual practices and mucosally administered drugs) and biological (HIV and sexually transmitted infections). This review will describe the epidemiology of HCV infection in this cohort. Current and future treatment strategies will also be outlined in the context of novel, orally bioavailable, directly acting antiviral therapies', 'The genus Flavivirus currently consists of approximately 80 single-strand positive-sense RNA viruses. These replicate in a range of hosts including myriad vertebrate, insect, and tick species. As a consequence of this broad host range, the majority of flaviviruses can be propagated in most vertebrate and insect cell cultures. This ability to infect arthropods and vertebrates usually is essential for maintenance of these viruses in nature. But recently, there has been the discovery of a number of flaviviruses that infect mosquitoes but not vertebrates. It remains largely unknown why certain flaviviruses infect vertebrates and mosquitoes while others infect mosquitoes or vertebrates exclusively', 'Hepatitis C virus (HCV) transmission among people who inject drugs remains a challenging public health problem. We investigated the risk of HCV transmission by analyzing the direct association of HCV with filters, water to dilute drugs, and water containers', ' is a mosquito-borne disease caused by four closely related dengue virus (genus Flavivirus)serotypes (DENV-1–4)', ' West Nile viruses are enveloped RNA viruses that belong to genus Flavivirus (family Flaviviridae) and are considered important mosquito-borne viral pathogenic agents worldwide', ' (JEV) is a mosquito-borne pathogenic flavivirus responsible for acute viral encephalitis in humans', 'Hepatitis C virus infection (HCV) is not infrequent among haemodialysis patients. Most published reports suggest that patient-to-patient spread, either directly or indirectly, is the most common mode of transmission in renal units', 'POWV) is a rare tick-borne agent of encephalitis in North America. Historically, confirmed cases occurred mainly in the northeastern United State', '(WNV) is a zoonotic arthropod-borne pathogen with continued geographical expansion in Europe. We present and evaluate data on the temporal, spatial and bird species focus of the WNV surveillance programme in dead wild birds in Great Britain ', 'YFV) is historically one of the most important viruses to affect human populations. Despite the existence of highly effective vaccines for over 70 years, yellow fever remains a significant and re-emerging cause of morbidity and mortality in endemic and high-risk regions of South America and Africa. The virus may be maintained in sylvatic enzootic/epizootic, transitional and urban epidemic transmission cycles with geographic variation in terms of levels of genetic diversity, the nature of transmission cycles and patterns of outbreak activity.', 'is a systemic arthropod-borne viral disease of major global public health importance. At least 2.5 billion people who live in areas of the world where dengue occurs are at risk of developing dengue fever (DF) and its severe complications, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). ', ' is a mosquito-transmitted infection that poses significant global health risks for travelers and individuals living in the tropics and subtropics.', '(WNV) (Flaviviridae: Flavivirus) is transmitted from mosquitoes to birds, but can cause fatal encephalitis in infected humans.', 'West Nile virus (WNV) is a member of the genus Flavivirus within the Japanese encephalitis antigenic complex. The enzootic virus cycle involves transmission between avian hosts and ornithophilic mosquitoes, whereas humans and horses are considered dead-end hosts', ' four major flavivirus clades are transmitted by mosquitoes, ticks, directly between vertebrates or directly between arthropods, respectively, but the molecular determinants of mode of transmission in flaviviruses are unknown. ', ' Tick-borne encephalitis virus (TBEV), one of the most prevalent arboviruses in Europe and in many parts of Asia. Transmission of TBEV to humans usually occurs by bite of an infected tick or rarely by ingestion of unpasteurized milk products of infected livestock. ', "Most alphaviruses and flaviviruses survive in nature by replicating alternately in a vertebrate host and a hematophagous arthropod (mosquitoes or, for some flaviviruses, ticks). Arthropod vectors acquire the viral infection by biting a viremic host, and after an extrinsic incubation period during which the virus replicates in the vector's tissues, they transmit virus through salivary secretions to another vertebrate host", 'Western Hemisphere have drawn attention to West Nile virus (WNV) as an international public health problem. Of particular concern has been the ability for the virus to cause outbreaks of disease in highly populated urban centers. Incrimination of Australian mosquito species is an essential component in determining the receptivity of Australia to the introduction and/or establishment of an exotic strain of WNV and can guide potential management strategies. Based on vector competence experiments and ecological studies, we suggest candidate Australian mosquito species that would most likely be involved in urban transmission of WNV, along with consideration of the endemic WNV subtype, Kunjin']

['A wide range of about 500 different viruses is transmitted by arthropods such as ticks, mosquitoes and sandflies. These arboviruses multiply in the arthropod vector, and for each virus there is a natural cycle involving vertebrates (various birds or mammals) and arthropods. The virus enters the arthropod when the latter takes a blood meal from the infected vertebrate, and passes through the gut wall to reach the salivary gland where replication takes place. Once this has occurred, 1–2 weeks after ingesting the virus, the arthropod becomes infectious, and can transmit the virus to another vertebrate during a blood meal. Certain arboviruses that infect ticks are also transmitted directly from adult tick to egg (transovarial transmission), so that future generations of ticks are infected without the need for a vertebrate host.']

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Is Beta-Thalassemia is associated with a mutation or deletion of the gene that codes for alpha globin?

['Beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of β-globin chains', 'The beta-thalassemia syndromes are a heterogeneous group of genetic disorders characterized by reduced or absent expression of the beta-globin gene']

['Beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of β-globin chains', 'beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of β-globin chains.', 'Beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of -globin chains. ', 'Beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of β-globin chains.']

['no']

Which are the biotracers used for detection of Alzheimer's disease using PET?

['(18)F-flutemetamol PET and structural MRI provided additive information in the diagnostic classification of aMCI subjects, suggesting an amyloid-independent neurodegenerative component among aMCI subjects in this sample.', 'This pooled analysis of four studies determined the level of association between uptake of the fibrillar amyloid β positron emission tomography (PET) imaging agent [(18)F]flutemetamol (Pittsburgh Compound B analog with a 5.5 times longer half-life to enable it to be used in the clinical setting) ', "is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ dep", "g biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now exte", 'Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE T', "ol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as 'normal' versus 'Alzheimer-like', is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how (18)F-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed (18)F-flutemetamol scans and volumetric MRI scans from 72 cases from the (18)F-flutemetamol phase 2 study (27 clinically probable Alzheimer's disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the (18)F-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The (18)F-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the (18)F-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the (18)F-flutemetamol- and the gray matter volume-based classifiers were identical (85.2%), albeit with discordant classification in three cases. Specificity of the (18)F-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI ", "disease (AD) is defined histologically by the presence of extracellular β-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. The diagnosis of dementia, along with the prediction of who will develop dementia, has been assisted by magnetic resonance imaging and positron emission tomography (PET) by using [(18)F]fluorodeoxyglucose (FDG). These techniques, however, are not specific for AD. Based on the chemistry of histologic staining dyes, several Aβ-specific positron-emitting radiotracers have been developed to image neuropathology of AD. Among these, [(11)C]PiB is the most studied Aβ-binding PET radiopharmaceutical in the world. The histologic and biochemical specificity of PiB binding across different regions of the AD brain was demonstrated by showing a direct correlation between Aβ-containing amyloid plaques and in vivo [(11)C]PiB retention measured by PET imaging. Because (11)C is not ideal for commercialization, several (18)F-labeled tracers have been developed. At this time, [(18)F]3'-F-PiB (Flutemetamol), (18)F-AV-45 (Florbetapir), and (18)F-AV-1 (Florbetaben) are undergoing extensive phase II and III clinical trials. This article provides a brief review of the amyloid biology and chemistry of Aβ-specific (11)C and (18)F-PET radiopharmaceuticals. Clinical trials have clearly documented that PET radiopharmaceuticals capable of assessing Aβ content in vivo in the brains of AD subjects and subjects with mild cognitive impairment will be important as diagnostic agents to detect in vivo amyloid brain pathology. In addition,", "is well known that many clinical and genetic factors have been associated with beta-amyloid deposition, few studies have examined the interactions of such factors across different stages of Alzheimer's pathogenesis. METHODS: We used 18F-florbetapir F18 PET imaging to quantify neuritic beta-amyloid plaque density across four cortical regions in 602 elderly (55-94 years) subjects from the national ADNI biomarker study. The group comprised of 194 normal elderly, 212 early mild cognitive impairment [EMCI], 132 late mild cognitive impairment [LMCI], and 64 mild Alzheimer's (AD). FINDINGS: In a model incorporating multiple predictive factors, the effect of apolipoprotein E ε4 and diagnosis was significant on all four cortical regions. The highest signals were seen in cingulate followed by frontal and parietal with lowest signals in temporal lobe (p<0.0001). The effect of apolipoprotein E ε4 (Cohen's D 0.96) on beta-amyloid plaque density was approximately twice as large as the effect of a diagnosis of AD (Cohen's D 0.51) and thrice as large as the effect of a diagnosis of LMCI (Cohen's D 0.34) (p<0.0001). Surprisingly, ApoE ε4+ normal controls had greater mean plaque density across all cortical regions than ε4- EMCI and ε4- LMCI (p<0.0001, p=0.0009) and showed higher, though non-significant, mean value than ε4- AD patients (p<0.27). ApoE ε4+ EMCI and LMCI subjects had significantly greater mean plaque density across all cortical regions than ε4- AD patients (p<0.027, p<0.0001). INTERPRETATION: Neuritic amyloid plaque load across progressive clinical stages of AD varies strongly by ApoE4 genotype. These findings support the need for better pathology-based and supported diagnosis in routine practice. Our data als", "sitron emission tomography (PET) radiotracers, fluorodeoxyglucose F 18 ((18)F-FDG) is the compound most widely used in the diagnosis of neurodegenerative dementias. However, this compound shows a level of specificity and sensitivity for early Alzheimer's disease detection that is lower than that provided by high-affinity ligands for β-amyloid (Aβ). Among the new widely available fluorine 18 ((18)F)-labeled Aβ ligands, florbetapir F 18 ((18))F-AV-45; Amyvid™) showed clear qualitative and quantitative correlations between in vivo PET imaging and postmortem histopathologic analysis of Aβ. Florbetapir F 18 stands out for its high Aβ affinity and its pharmacokinetic properties that allow 10-minute PET scan imaging within 90 minutes after administration (dose = 370 MBq). Importantly, no safety concerns for florbetapir F 18 were found in preclinical studies. In 2012, the U.S. Food and Drug Administration (FDA) approved Amyvid as a radiotracer helpful for excluding the presence of Aβ in the brain. It was the", " (Abeta) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Abeta imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Abeta-specific ligands. (18)F-BAY94-9172 is an Abeta ligand that, due to the half-life of (18)F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD. METHODS: 15 "]

["Pittsburgh compound B (PIB) was the first radiotracer capable of highlighting deposits of beta-amyloid—one pathological hallmark of Alzheimer's disease—in living individuals during a PET scan. The Alzheimer's Association helped fund early PIB development. The Association in 2006 also awarded a $2.1 million grant to the Alzheimer's Disease Neuroimaging Initiative (ADNI) to expand this long-term, nationwide study to include PIB-PET imaging.\n\n18F flutemetamol (flute), another radiotracer that highlights beta-amyloid in a PET scan, is structurally identical to PIB except for one fluorine atom in place of a carbon atom. That small chemical change enables flutemetamol to remain stable significantly longer than does PIB, potentially increasing its usefulness outside research settings. In phase II study results reported in the Annals of Neurology, flutemetamol performed similarly to PIB. Additional testing is under way.\n\nFlorbetapir F 18 (18F-AV-45) is also a radiotracer that highlights brain beta-amyloid during a PET scan. At the 2010 Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD), florbetapir's developer first reported data, later published in the JAMA, showing nearly perfect correlation between brain amyloid levels detected by florbetapir PET scans in study volunteers and levels found in autopsies of the same individuals a few months later. The developer has sought Food and Drug Administration (FDA) approval to market florbetapir under the brand name Amyvid. The FDA has said it will withhold approval until the developer establishes a professional training program to ensure accuracy and consistency in reading and interpreting Amyvid scans.\n\nFlorbetaben (BAY 94-9172) is another radiotracer designed to detect beta-amyloid during a PET scan. Phase II study results and other florbetaben data were reported at the 2010 Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD). Phase II data were also later published in Lancet Neurology. Further studies are now under way."]

['Pittsburgh compound B', 'Florbetaben (BAY 94-9172)', 'Florbetapir F 18 (18F-AV-45)', '18F flutemetamol (flute)']

List clinical trials that have directly compared microsurgical clipping with endovascular coiling for treatment of ruptured brain aneurysms?

['The authors report the 3-year results of the Barrow Ruptured Aneurysm Trial (BRAT). The objective of this ongoing randomized trial is to compare the safety and efficacy of microsurgical clip occlusion and endovascular coil embolization for the treatment of acutely ruptured cerebral aneurysms and to compare functional outcomes based on clinical and angiographic data. ', 'We report the design of the FIAT study, a clinical care trial aiming to compare angiographic and clinical outcomes following treatment with a Flow-Diverter or with the best conventional treatment option. The FIAT study will include both a randomized and a registry portion. Patients will be proposed randomization to either FD stenting or best conventional treatment option (observation, coiling, stenting, or clipping) as determined by the treating physician. ', 'The effect of clipping and coiling in acute severe subarachnoid hemorrhage after international subarachnoid aneurysmal trial (ISAT) results.', 'A critical appraisal of the ISAT of microsurgical clipping versus coiling is used for comparison of our results.', 'International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion.', 'International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial.']

['Barrow Ruptured Aneurysm Trial (BRAT) and international subarachnoid aneurysmal trial (ISAT) have directly compared microsurgical clipping with endovascular coiling for treatment of ruptured brain aneurysms. FIAT study, a clinical care trial aiming to compare angiographic and clinical outcomes following treatment with a Flow-Diverter or with the best conventional treatment option (including clipping) is underway.']

['Barrow Ruptured Aneurysm Trial (BRAT)', 'international subarachnoid aneurysmal trial (BRAT)', 'FIAT study']

How does apolipoprotein E in HDL help with anti-inflammatory and anti-atherogenic effects?

['[" have previously reported that apolipoprotein E (apoE), a protein component of very-low-density lipoproteins (VLDL) and high-density lipoproteins and a potent plasma-borne atheroprotective factor, exerts anti-inflammatory activity in macrophages by switching the activation profile from M1 (\\"classic\\") to M2 (\\"alternative\\") in a process involving signaling via low-density lipoprotein receptor ", "anti-inflammatory activity in macrophages ", "Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE ", "Apolipoprotein (apo) E-containing high-density lipoprotein (HDL) has antioxidant, anti-inflammatory and anti-atherogenic properties"]', '[" have previously reported that apolipoprotein E (apoE), a protein component of very-low-density lipoproteins (VLDL) and high-density lipoproteins and a potent plasma-borne atheroprotective factor, exerts anti-inflammatory activity in macrophages by switching the activation profile from M1 (\\"classic\\") to M2 (\\"alternative\\") in a process involving signaling via low-density lipoprotein receptor ", "anti-inflammatory activity in macrophages ", "Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE ", "Apolipoprotein (apo) E-containing high-density lipoprotein (HDL) has antioxidant, anti-inflammatory and anti-atherogenic properties"]']

Apolipoprotein (apo) E-containing high-density lipoprotein (HDL) has antioxidant, anti-inflammatory and anti-atherogenic properties

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Does HuR protein regulate the splicing process?

['HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA', 'Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances', 'HuR increased SIRT1-∆Exon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-∆Exon8 mRNA levels. ', 'HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress', 'Hu antigen R (HuR) regulates stress responses through stabilizing and/or facilitating the translation of target mRNAs', 'We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs', 'Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. ', 'Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus', "Furthermore, significant changes can be observed in nuclear alternative polyadenylation and splicing events on cellular pre-mRNAs as a result of sequestration of HuR protein by the 3' UTR of transcripts of this cytoplasmic RNA virus.", 'Here we demonstrate that expression of 2A(pro) induces a selective nucleo-cytoplasm translocation of several important RNA binding proteins and splicing factors. Subcellular fractionation studies, together with immunofluorescence microscopy revealed an asymmetric distribution of HuR and TIA1/TIAR in 2A(pro) expressing cells, which modulates splicing of the human Fas exon 6', 'knockdown of HuR or overexpression of TIA1/TIAR, leads to Fas exon 6 inclusion in 2A(pro)-expressing cells', 'The differential expression levels of T-cell intracellular antigens (TIA) and Hu antigen R (HuR) are concomitant with a splicing switch in apoptosis receptor Fas in HCT-116 cells', 'overexpression and knockdown of HuR led to Fas exon 6 skipping and inclusion, respectively. These results suggest that the TIA and HuR cellular ratio influences cell-type specific Fas exon 6 splicing pattern.', 'Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition', 'antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer', 'ELAV/Hu proteins bind to AU-rich elements (ARE) in mRNAs and regulate their stability from splicing to translation, and the ubiquitous HuR protein has been implicated in cancerous cell growth.', 'The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability.', 'Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition.', 'I report that antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer. ', 'Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus.', 'Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. ', 'HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA.', 'HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress.', 'The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability. ', 'Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. Taken together, these results support a functional link between HuR as repressor of alternative Fas splicing and the molecular mechanisms modulating programmed cell death.', 'We are interested in interactions involving hnRNP proteins participating in several steps of mRNA processing (mainly pre-mRNA splicing) and HuR with an established role in stability/translation of associated mRNAs. hnRNP and HuR proteins have a major nucleoplasmic localization and ability to shuttle between nucleus and cytoplasm. We report here on interactions between hnRNP and HuR proteins that were identified in the context of isolated hnRNP and mRNP complexes. ', 'Despite the fact that HuR sites are observed in intronic regions, our data do not support a role for HuR in regulating splicing.']

['Recent research demonstrated that SIRT1 pre-mRNA undergoes alternative splicing to produce different isoforms, such as SIRT1 full-length and SIRT1-∆Exon8 variants. Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances: HuR increased SIRT1-∆Exon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-∆Exon8 mRNA levels. This study provides novel insight into how the alternative splicing of SIRT1 pre-mRNA is regulated, which has fundamental implications for understanding the critical and multifunctional roles of SIRT1. Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively.', 'HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA', 'Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition. HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances. Overexpression and knockdown of HuR led to Fas exon 6 skipping and inclusion, respectively. These results suggest that the TIA and HuR cellular ratio influences cell-type specific Fas exon 6 splicing pattern.']

['yes']

Is the protein β1-integrin recycled?

['Pathways selectively regulating β1-integrin recycling are implicated in cancer invasion and metastasis,', 'integrin-positive early and recycling endosomes ', 'LPA-induced recycling of β1 integrin,', 'RCP-mediated recycling of α5β1 integrin ', 'CycD1 overexpression increased β1 integrin recycling ', 'inhibition of autophagy slowed down the lysosomal degradation of internalized β1 integrins and promoted its membrane recycling', 'recycling pathway for β1-integrin', ' β1 integrin recycling', ' β1 integrin recycling', ' controlling β1 integrin recycling to the plasma membrane ', 'integrin recycling pathway', 'Distinct recycling of active and inactive β1 integrins.', 'Integrin functions are controlled by regulating their affinity for ligand, and by the efficient recycling of intact integrins through endosomes.', ' β1 integrins, resulting in their recycling to the cell surface where they can be reused.']

['Yes, the β1-integrin is recycled.']

['yes']

Which ApoE isoform is associated with atherosclerosis and Alzheimer's disease?

["Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer's disease (AD). ", "Homozygosity for ApoE epsilon4 is associated with atherosclerosis and Alzheimer's disease whereas ApoE epsilon2 and epsilon3 tend to be protective.", "Importantly, lipoproteins containing the apoE3 isoform had higher TGF-beta levels and bioactivity than those containing apoE4, a major genetic risk factor for atherosclerosis and Alzheimer's disease. ", "ApoE4 is positively associated with atherosclerosis and late-onset and sporadic Alzheimer's disease (AD). ", "Isoform (allele)-specific effects include the association of apoE2 with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis and the association of apoE4 with increased risk for both atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth; isoform-specific differences in cellular signaling events may also exist. ", 'Although APOE-epsilon3 is considered a longevity gene, APOE-epsilon4 is a dual risk factor to atherosclerosis and Alzheimer disease.', 'The apolipoprotein E (apoE) type epsilon 4 isoform specifies increased cerebral and cerebrovascular accumulation of amyloid-beta protein (A beta) and contributes to the genetic susceptibility underlying a large proportion (approximately 60%) of typical, sporadic Alzheimer disease.', 'The structural preference of apoE4 to remain functional in solution may explain the enhanced opportunity of apoE4 isoform to display its pathophysiologic functions in atherosclerosis and Alzheimer disease.', "The apolipoprotein E (APOE) E4 allele is associated with Alzheimer's disease, cardiovascular disease, and decreased longevity.", "The apolipoprotein E type 4 allele is a susceptibility gene for late-onset Alzheimer's disease.", 'The apolipoprotein E (ApoE) ε4 allele is the strongest risk factor of sporadic Alzheimers disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE ε2, ε3, ε4) remain controversial', 'Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimers disease (AD)', 'Homozygosity for ApoE epsilon4 is associated with atherosclerosis and Alzheimers disease whereas ApoE epsilon2 and epsilon3 tend to be protective', "Homozygosity for ApoE epsilon4 is associated with atherosclerosis and Alzheimer's disease whereas ApoE epsilon2 and epsilon3 tend to be protective. ", 'Although APOE-epsilon3 is considered a longevity gene, APOE-epsilon4 is a dual risk factor to atherosclerosis and Alzheimer disease. ', "The apoE4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. ", "Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer's disease (AD).", "Homozygosity for ApoE epsilon4 is associated with atherosclerosis and Alzheimer's disease whereas ApoE epsilon2 and epsilon3 tend to be protective.", "Importantly, lipoproteins containing the apoE3 isoform had higher TGF-beta levels and bioactivity than those containing apoE4, a major genetic risk factor for atherosclerosis and Alzheimer's disease.", "Isoform (allele)-specific effects include the association of apoE2 with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis and the association of apoE4 with increased risk for both atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth; isoform-specific differences in cellular signaling events may also exist.", "The decreased antioxidant activity of E4 could contribute to its association with Alzheimer's disease, cardiovascular disease and decreased longevity.", "The isoform apoE4 is associated with an increased risk of Alzheimer's disease and it has been postulated that high intracellular cholesterol levels promote the amyloidogenic processing of amyloid precursor protein.", 'Among three ɛ2, ɛ3, ɛ4 alleles, ɛ4 allele is associated with the increase in cholesterol level, risk of atherosclerosis and Alzheimer disease, while ɛ2 allele is associated with the decrease in cholesterol level and risk of atherosclerosis.', 'Although APOE-epsilon3 is considered a longevity gene, APOE-epsilon4 is a dual risk factor to atherosclerosis and Alzheimer disease.', 'The structural preference of apoE4 to remain functional in solution may explain the enhanced opportunity of apoE4 isoform to display its pathophysiologic functions in atherosclerosis and Alzheimer disease..']

["The ApoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer's disease (AD)."]

['ApoE4 isoform', 'Apolipoprotein E4 isoform']

How do histone methyltransferases cause histone modification?

['Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage.', 'This approach identified Txr1p as a histone methyltransferase in Tetrahymena thermophila and characterized the relationships of the Txr1p and Ezl2p methyltransferases to histone H3 modification.', 'Histone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1-MLL4) whose specific functions are largely unknown. ', 'Epigenetic regulation of gene expression by covalent modification of histones is important for germ line cell development. In mammals, histone H3 lysine 9 (H3K9)-specific histone methyltransferases (HMTases), such as G9a, SETDB1, and SUV39H, play critical roles, but the contribution of H3K9-specific HMTases in Drosophila remains to be clarified, especially in male sperm.', 'By analyzing the distribution of histone modifications in nuclei using quantitative fluorescence microscopy, we found that H4K16 acetylation (H4K16ac) is underrepresented and H4K20 monomethylation (H4K20me1) is enriched on hermaphrodite X chromosomes in a DCC-dependent manner. ', ' Here, we found the epigenetic modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. ', 'Although DNA methyltransferases have been shown to interact with histone methyltransferases such as EZH2 (which methylates histone H3 on lysine 27) and G9a (which methylates histone H3 on lysine 9), the relationship between DNA methylation and repressive histone marks has not been fully studied. ', 'Methylation of histone H4 lysine 20 (H4K20me) plays critical roles in diverse cellular processes such as gene expression, cell cycle progression and DNA damage repair, with each of the three degrees of methylation (mono-, di- and tri-methylation) making a unique contribution. ', 'Histone H3-lysine (K) 4, H3-K9 and H3-K27 modifications in all these four genes were examined by chromatin immunoprecipitation (ChIP) assay in HCC cell lines. ', 'The histone H4 N-terminal tail has long been regarded as a major regulator in chromatin structure and function.', 'Gene transcription is critically influenced by chromatin structure and the modification status of histone tails. Methylation of lysine residues in histone tails is dynamically regulated by the opposing activities of histone methyltransferases and histone demethylases.', 'The SAS3-dependent NuA3 histone acetyltransferase complex was originally identified on the basis of its ability to acetylate histone H3 in vitro.', 'SU(VAR)3-9 like histone methyltransferases control heterochromatic domains in eukaryotes.', 'Methylation of position-specific lysine residues in histone N termini is a central modification for regulating epigenetic transitions in chromatin. Each methylatable lysine residue can exist in a mono-, di-, or trimethylated state, thereby extending the indexing potential of this particular modification. ', 'One of these modifications, histone lysine methylation, has been shown to be highly stable and to represent an epigenetic alteration.', 'Primarily because of the recent discovery of the SET domain-depending H3-specific histone methyltransferases SUV39H1 and Suv39h1, which selectively methylate lysine 9 of the H3 N terminus, this posttranslational modification has regained scientific interest.', 'Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation.', 'Our results suggest that the methylation of histone tails can have distinct effects on transcription, depending on its chromosomal location, the combination of posttranslational modifications, and the enzyme (or protein complex) involved in the particular modification.', 'Among the different groups of enzymes known to catalyze the covalent modification, the most recent additions are the histone methyltransferases (HMTases), whose functions are now being characterized.']

['Histone methyltransferases (HMTs) are responsible for the site-specific addition of covalent modifications on the histone tails, which serve as markers for the recruitment of chromatin organization complexes. There are two major types of HMTs: histone-lysine N-Methyltransferases and histone-arginine N-methyltransferases. The former methylate specific lysine (K) residues such as 4, 9, 27, 36, and 79 on histone H3 and residue 20 on histone H4. The latter methylate arginine (R) residues such as 2, 8, 17, and 26 on histone H3 and residue 3 on histone H4. Depending on what residue is modified and the degree of methylation (mono-, di- and tri-methylation), lysine methylation of histones is linked to either transcriptionally active or silent chromatin.']

[]

Which are the bioinformatics tools for gene structure prediction?

["The prediction of the complete structure of genes is one of the very important tasks of bioinformatics, especially in eukaryotes. A crucial part in the gene structure prediction is to determine the splice sites in the coding region. Identification of splice sites depends on the precise recognition of the boundaries between exons and introns of a given DNA sequence. This problem can be formulated as a classification of sequence elements into 'exon-intron' (EI), 'intron-exon' (IE) or 'None' (N) boundary classes.", 'The proposed WPSS method poses efficient results compared with the performance of many methods proposed in the literature.', 'SCGPred: a score-based method for gene structure prediction by combining multiple sources of evidence.', 'Moreover, computational gene finding in newly sequenced genomes is especially a difficult task due to the absence of a training set of abundant validated genes. Here we present a new gene-finding program, SCGPred, to improve the accuracy of prediction by combining multiple sources of evidence.', 'Therefore, SCG-Pred can serve as an alternative gene-finding tool for newly sequenced eukaryotic genomes. The program is freely available at http://bio.scu.edu.cn/SCGPred/.', 'Incorporation of splice site probability models for non-canonical introns improves gene structure prediction in plants.', 'We pursued one such approach and describe the training and implementation of GC-donor splice site models for Arabidopsis and rice, with the goal of exploring whether specific modeling of non-canonical introns can enhance gene structure prediction accuracy.', 'Source code for the updated versions of GeneSeqer and SplicePredictor (distributed with the GeneSeqer code) isavailable at http://bioinformatics.iastate.edu/bioinformatics2go/gs/download.html. Web servers for Arabidopsis, rice and other plant species are accessible at http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/AtGDBgs.cgi, http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/OsGDBgs.cgi and http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/PlantGDBgs.cgi, respectively. A SplicePredictor web server is available at http://bioinformatics.iastate.edu/cgi-bin/sp.cgi. Software to generate training data and parameterizations for Bayesian splice site models is available at http://gremlin1.gdcb.iastate.edu/~volker/SB05B/BSSM4GSQ/', 'Prediction of splice sites with dependency graphs and their expanded bayesian networks.', 'A crucial part in the gene structure prediction is to determine the precise exon-intron boundaries, i.e. the splice sites, in the coding region.', 'Software (a program called DGSplicer) and datasets used are available at http://csrl.ee.nthu.edu.tw/bioinf/ BACKGROUND: [email protected].', 'Gene structure prediction from consensus spliced alignment of multiple ESTs matching the same genomic locus.', 'Accurate gene structure annotation is a challenging computational problem in genomics.', 'The splice site prediction tool (SplicePredictor) is distributed with the GeneSeqer code. A SplicePredictor web server is available at http://bioinformatics.iastate.edu/cgi-bin/sp.cgi', 'We have developed a software tool, Transcript Assembly Program (TAP), to delineate gene structures using genomically aligned EST sequences.', 'GeneBuilder: interactive in silico prediction of gene structure.', 'In the case of low homology, GeneBuilder is still able to predict the gene structure. The GeneBuilder system has been tested by using the standard set (Burset and Guigo, Genomics, 34, 353-367, 1996) and the performances are: 0.89 sensitivity and 0.91 specificity at the nucleotide level.', 'The computer program SeqHelp organizes information from database searches, gene structure prediction, and other information to generate multiply aligned, hypertext-linked reports to allow for fast analysis of molecular sequences.', 'Identification of human gene structure using linear discriminant functions and dynamic programming.', 'Development of advanced technique to identify gene structure is one of the main challenges of the Human Genome Project.', 'A gene structure prediction system FGENE has been developed based on the exon recognition functions.', 'Analysis of uncharacterized human sequences based on our methods for splice site (HSPL, RNASPL), internal exons (HEXON), all type of exons (FEXH) and human (FGENEH) and bacterial (CDSB) gene structure prediction and recognition of human and bacterial sequences (HBR) (to test a library for E. coli contamination) is available through the University of Houston, Weizmann Institute of Science network server and a WWW page of the Human Genome Center at Baylor College of Medicine.', 'In the bioinformatics field, many computer algorithmic and data mining technologies have been developed for gene prediction, protein-protein interaction analysis, sequence analysis, and protein folding predictions, to name a few.', 'The accurate prediction of intron boundaries largely facilitates the correct prediction of gene structure in nuclear genomes.']

['The in silico prediction of the complete structure of genes is one of the main challenges of bioinformatics. A critical part in the gene structure prediction is to identify the boundaries between exons and introns (i.e. splice sites) in the coding region. Several advanced bioinformatics tools have been developed for the precise delineation of a given gene structure: WPSS, SCGPred, TICO, GLIMMER, MetWAMer, WebScipio, GeneSeqer, SplicePredictor, DGSplicer, Transcript Assembly Program (TAP), GeneBuilder, SeqHelp, HSPL, RNASPL, HEXON, CDSB, HBR, FGENE and FGENEH for human genes.', 'SCGPred: a score-based method for gene structure prediction by combining multiple sources of evidence. MetWAMer.gthXML is a special-purpose variant of the software, specifically tailored to refine gene structure predictions generated by the GenomeThreader [30] and GeneSeqer [31] programs for spliced alignment-based gene structure annotation. WebScipio: an online tool for the determination of gene structures using protein sequences. ']

['WPSS', 'SCGPred', 'TICO', 'GLIMMER', 'MetWAMer', 'WebScipio', 'GeneSeqer', 'SplicePredictor', 'DGSplicer', 'TAP', 'GeneBuilder', 'SeqHelp', 'FGENE', 'FGENEH', 'HSPL', 'RNASPL', 'HEXON', 'CDSB', 'HBR']

Are long non coding RNAs spliced?

['Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths.', 'For alternative exons and long noncoding RNAs, splicing tends to occur later, and the latter might remain unspliced in some cases.', 'bosome-mapping data to identify lncRNAs of Caenorhabditis elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or multiexonic structures that did not overlap protein-coding transcripts, and about sixty antisense lncRNAs (ancRNAs), which were complementary to protein-coding transcripts', 'We introduce an approach to predict spliced lncRNAs in vertebrate genomes combining comparative genomics and machine learning.', 'Owing to similar alternative splicing pattern to mRNAs, the concept of lncRNA genes was put forward to help systematic understanding of lncRNAs. ', 'Our synthesis of recent studies suggests that neither size, presence of a poly-A tail, splicing, direction of transcription, nor strand specificity are of importance to lncRNA function.']

['Long non coding RNAs appear to be spliced through the same pathway as the mRNAs']

['yes']

Which are the methods for in silico prediction of the origin of replication (ori) among bacteria?

['Based on the Z-curve theory, we have developed a web-based system Ori-Finder to predict oriCs in bacterial genomes with high accuracy and reliability by taking advantage of comparative genomics', 'we have applied a combination of multiple in silico approaches - Z curve, the cell division cycle (cdc6) gene location and location of consensus origin recognition box (ORB) sequences for location of origin of replication', 'Using features that have been previously experimentally verified in the alpha-Proteobacterium Caulobacter crescentus, the origin of DNA replication (ori) regions were identified in silico for Wolbachia strains and eleven other related bacteria belonging to Ehrlichia, Anaplasma, and Rickettsia genera. These features include DnaA-, CtrA- and IHF-binding sites as well as the flanking genes in C. crescentus.', 'The sequences of the ori regions described here are only similar among closely related bacteria while fundamental characteristics like presence of DnaA and IHF binding sites as well as the boundary genes are more widely conserved.', 'We propose a correlation measure and show that it is correctly able to predict the origin of replication in most of the bacterial genomes. When applied to Methanocaldococcus jannaschii, Plasmodium falciparum apicoplast and Nicotiana tabacum plastid, this correlation based method is able to correctly predict the origin of replication whereas the generally used GC skew measure fails.', 'DNA base composition asymmetry is the basis of numerous in silico methods used to detect the origin and terminus of replication in prokaryotes.', 'These analyses include finding the dnaA gene and its binding sites; making BLAST analyses of the intergenic sequences compared to related species; studying the gene order around the origin sequence; and studying the distribution of the genes encoded in the leading versus the lagging strand.', 'DnaA binds a single DnaA box as a monomer', 'In silico comparative analysis of sequenced mollicute genomes indicated the lack of conservation of gene order in the region containing the predicted origin of replication (oriC) and the existence, in most of the mollicute genomes examined, of putative DnaA boxes lying upstream and downstream from the dnaA gene.', 'In this paper we have applied a combination of multiple in silico approaches - Z curve, the cell division cycle (cdc6) gene location and location of consensus origin recognition box (ORB) sequences for location of origin of replication in Thermococcus onnurineus, Thermococcus gammatolerans and other Themococcales and compared the results to that of the well-documented case of Pyrococcus abyssi.', 'DNA base composition asymmetry is the basis of numerous in silico methods used to detect the origin and terminus of replication in prokaryotes.', 'It increases the prediction accuracy of the replication termini compared with previously documented methods based on genomic base composition.', 'Using compositional skews such as the GC skew, replication origin and terminus can be predicted in silico by observing the shift points.', 'Here, we summarize the recent advances of in silico prediction of oriCs in bacterial and archaeal genomes using the Z-curve based method', 'DNA base composition asymmetry is the basis of numerous in silico methods used to detect the origin and terminus of replication in prokaryotes', 'Recent Advances in the Identification of Replication Origins Based on the Z-curve Method.', 'We present a web-based tool Ori-Finder 2 to predict oriCs in the archaeal genomes automatically, based on the integrated method comprising the analysis of base composition asymmetry using the Z-curve method, the distribution of origin recognition boxes identified by FIMO tool, and the occurrence of genes frequently close to oriCs']

['Several in silico methods have been applied for prediction of the origin of replication (ori). DNA base composition asymmetry, such as GC skew, is the basis of numerous in silico methods used to detect the ori in prokaryotes. The Z curve analysis is also used for ori identification. Comparative genomics, by BLAST analyses of the intergenic sequences compared to related species have been applied in ori prediction. The finding of the dnaA gene and its binding sites, DnaA boxes, as well as the finding of the binding sites of other proteins, such as CtrA and IHF, are fundamental characteristics used for in silico prediction of the ori. Also, the localization of boundary genes, such as cell division cycle (cdc6) gene, and consensus origin recognition box (ORB) sequences have been employed for ori detection. The study of the gene order around the origin sequence and the distribution of the genes encoded in the leading versus the lagging strand are also used for in silico detection of the ori.']

['GC skew analysis', 'Z curve analysis', 'comparative genomics', 'dnaA gene location', 'localization of dnaA binding sites (DnaA boxes)', 'localization of CtrA binding sites', 'localization of IHF binding sites', 'localization of cell division cycle (cdc6) gene', 'localization of other boundary genes', 'localization of other consensus origin recognition box (ORB) sequences', 'the gene order around the ori', 'gene distribution in leading versus lagging strand']

Is there a genome-wide technique for the detection of R-loop formation?

['Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops', 'We have used a bisulfite-sensitivity assay to demonstrate genome-wide increase in the occurrence of RNA-DNA hybrids (R-loops), including from antisense and read-through transcripts, in a nusG missense mutant defective for Rho-dependent termination.', 'The results demonstrate a key function of FACT in the resolution of R-loop-mediated transcription-replication conflicts, likely associated with a specific chromatin organization.', 'Previous work revealed that GC skew and R-loop formation associate with a core set of unmethylated CpG island (CGI) promoters in the human genome']

['Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops. Here we show that recombination factors are required for the survival of yeast FACT mutants, consistent with an accumulation of DNA breaks that we detected by Rad52 foci and transcription-dependent hyperrecombination. The latter pathway operates on nascent transcripts that are not simultaneously translated and requires factors Rho, NusG, and NusA, each of which is essential for viability of WT Escherichia coli. DNA replication in Escherichia coli is normally initiated at a single origin, oriC, dependent on initiation protein DnaA.', 'Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops\nA bisulfite-sensitivity assay may demonstrate genome-wide increase in the occurrence of RNA-DNA hybrids (R-loops).']

['yes']

Is Bladder training an effective method to treat urge incontinence ?

['Mindfulness-based stress reduction appears to be a treatment worthy of further study, as in the short term, it is as effective as historical studies of drug treatment and bladder training in reducing urge incontinence and incontinence-related quality of life.', 'All patients, irrespective of the results of cystometry were subsequently treated with oxybutynin 2.5 mg twice daily along with bladder training.', 'Of the 29 patients with stable bladder and symptoms of OAB, 100% cure rate was achieved in 20 (68.9%) and 06 (20.6%) patients respectively. While in 3 patients in both groups, decrease of symptoms upto 75% after 6 months of treatment was observed.', 'Both urodynamically proven unstable and stable bladder showed nearly equal improvement with treatment', 'There are 3 types of urine incontinence (urge-, stress-, and overflow-incontinence). Another standardization of urinary incontinence follows dysfunctions of the pelvic floor: detrusor muscle-dependent, due to sphincter spasm, prostate gland dependent. Urge incontinence with a dysfunction of the detrusor muscle is the most common type. Mixed types are frequent. Non-drug measures (e.g. pelvic muscle training, bladder training, toilet training are first choice treatments.', 'Treatment of stress, urge and mixed incontinence can usually be commenced in primary care; pelvic floor exercises and bladder training are preferred. If bladder training is not effective for urge incontinence, anticholinergic drugs should be considered.', 'Sixty patients (age 8 to 12 years) with urge incontinence or dysfunctional voiding were evaluated. After a no-treatment control period (average 6 months), patients underwent a 6-day bladder training course', 'Six months after training completion, 64.1% and 64.7% of the inpatient and outpatient groups with daytime wetting and 51.5% and 17.7% of the inpatient and outpatient groups with nighttime wetting were cured or had improved', 'Of the inpatient group with urge incontinence, the functional bladder capacity increased by 15%.', 'To compare the efficacy of tolterodine plus simplified bladder training (BT) with tolterodine alone in patients with an overactive bladder.', 'CONCLUSIONS: Tolterodine 2 mg twice daily is an effective and well tolerated treatment for an overactive bladder, the effectiveness of which can be augmented by a simplified BT regimen.', 'Bladder training is a modification of bladder drill that is conducted more gradually on an outpatient basis and has resulted in significant reduction of incontinence in older, community-dwelling women.', 'OBJECTIVE: To evaluate the long-term effect of treatment of female incontinence by the general practitioner (pelvic floor exercises, and bladder training) in female urinary incontinence.', 'Stress incontinence and urge incontinence were treated by means of pelvic floor exercises and bladder training respectively, while a mixed incontinence was treated by bladder training followed by pelvic floor exercises. T', 'The treatment consisted of training of pelvic muscles in stress incontinence and bladder training in urge incontinence', 'RESULTS: After 3 months the mean frequency of urine loss per week diminished from 21 to 8, and after 12 months to 6 times.', 'Some elders suffering from urge incontinence prefer pelvic muscle exercises to bladder training as the behavioral intervention of choice', 'for eight out of nine women their continence had improved, both subjectively and objectively.', 'Bladder training is a simple, safe, and effective treatment in the management of mild to moderate forms of urinary incontinence in outpatient populations. It can be used as a first-line treatment or in combination with such other interventions as pelvic muscle exercises, bladder pressure biofeedback, electrical stimulation, and drug therapy', 'Treatment consisted of pelvic floor exercises in the case of stress incontinence and bladder training in the case of urge incontinence.', 'After 3 months about 60% of the patients were either dry or only mildly incontinent', 'terodiline group shows this drug to be a valuable adjunct to a bladder regimen in children with urge incontinence', 'Basing on our experience with 39 patients with severe urge incontinence (in one-quarter of the cases pure urge incontinence, in one-half of the cases mixed incontinence and in a further quarter of the cases neurogenic bladder disorders) a supervised programme (mictiogram) and a well-tried therapy (especially in the Anglo-Saxon countries) consisting of the triad hospitalisation/bladder training/medication therapy are presented. After an average hospitalisation period of 14 days, we were able to achieve a symptom-free state in 94% of the patients.', 'Anamnestic and urodynamical results are evaluated before and after bladder retraining drill (BRD) in women suffering from urge incontinence.', 'We could state that the BRD is a good possibility to realize multistep-therapy of female incontinence.', 'Twenty consecutive female patients with urge incontinence and stable detrusor function on provocative rapid fill CO2-cystometry were treated as out-patients with a bladder training programme and with terodiline/placebo in a double-blind cross-over design.', 'In conclusion, female patients with idiopathic urge incontinence and stable detrusor function did respond to treatment as do female patients with urge incontinence and proven instability.', 'The results of in-patient bladder training in 65 women with frequency, urgency and urge incontinence are reported. There was a good initial response in 88%. By 6 months the response rate had fallen to 38%.', 'Patients with sensory urgency appeared to do better than those with detrusor instability and it is suggested that bladder training may be indicated as primary treatment in sensory urgency.', 'Bladder training and/or biofeedback techniques were used to treat 75 patients with frequency, urgency, nocturia and urge incontinence. Significant improvement or cure was obtained in 70 per cent of enuretic children, and 66 per cent of men and 74 per cent of women with unstable detrusor function.']

['Yes. Bladder training is a simple, safe, and effective treatment in the management of mild to moderate forms of urinary incontinence in outpatient populations. It can be used as a first-line treatment or in combination with such other interventions as pelvic muscle exercises, bladder pressure biofeedback, electrical stimulation, and drug therapy. Quoted results vary from 26 to 90% . Patients with sensory urgency appeared to do better than those with detrusor instability and it is suggested that bladder training may be indicated as primary treatment in sensory urgency.']

['yes']

What is the function of caspases?

['Caspases are the ultimate executors of the apoptotic programmed cell death pathway.', 'Members of the caspase family of cysteine proteases coordinate the morphological and biochemical events that typify apoptosis. ', 'Caspase function is known to be essential for cell death by apoptosis,', 'Caspases, initially identified as a family of proteases regulating cell death, have been found to have nonapoptotic functions as well.', '. As in other organisms, apoptosis is executed by caspases.', 'Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation. ', 'Apoptosis is dependent upon caspase activation leading to substrate cleavage and, ultimately, cell death.', 'Caspases are a family of evolutionarily conserved cysteine proteases that constitute the effector arm of the apoptotic machinery.', 'Caspases are critical mediators of apoptosis, the principle mechanism by which extra and harmful cells are eliminated to ensure proper development and maintain cellular homeostasis in all multicellular organisms. ', "Caspases (cysteine-containing aspartate-specific proteases) are at the core of the cell's suicide machinery. These enzymes, once activated, dismantle the cell by selectively cleaving key proteins after aspartate residues. ", 'Programmed cell death plays an important role in maintaining homeostasis during animal development, and has been conserved in animals as different as nematodes and humans. ']

['Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation.']

['Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation.']

Has silicon been used in treatment of incontinence ?

['an artificial anal sphincter. Worldwide, there are two established devices on the market: the artificial bowel sphincter® (ABS) from A. M. S. (Minnetonka, MN, USA) and the soft anal band® from A. M. I. (Feldkirch, Austria). How to implant the artificial anal sphincter? Both devices consist of a silicon cuff which can be filled with fluid.', 'The InVance™ system uses a silicon-coated polyester sling positioned under the bulbar urethra via a perineal incision.', 'Through a perineal incision three titanium screws with a polipropylene suture were inserted in each ischiopubic rami, and a silicon/polipropylene mesh (Invance) is affixed to them, compressing the bulbar urethra', 'surgical treatment of female stress urinary incontinence with a trans-obturator sub-urethral tape of Uratape (Porgés). METHODS: Treatment and follow up of their complication were performed at the CHRU of Lille. RESULTS: In both cases, this complication is related to prolonged vaginal exposition of the tape. Vaginal erosion always occurs next to the silicon coated section of the tape', 'A non-elastic, polypropylene tape (UraTape, Mentor-Porgès) with a silicon coated central part was placed under the mid-urethra.', ' Stress incontinence is a rare complication in men, usually following prostatic surgery. It can be treated conservatively with pelvic floor training and alpha-adrenergic receptor agonists and if necessary surgically with submucosal collagen or silicon injections in the sphincter area or implantation of a sphincter prosthesis', 'The Femassist is a medical-grade silicon dome-shaped device, worn over the urethra and held securely via suction and a commercially available adhesive lotion.', 'To examine the performance of a silicon urinary control device for nonsurgical management of women with genuine stress incontinence', 'The "FemAssist" is a dome-shaped medical grade silicon device intended to be worn over the external urethral meatus and held in place by suction and an adhesive gel. Thirty eight women with varying degrees of genuine stress urinary incontinence (GSUI) or mixed incontinence on multichannel urodynamic testing were fitted with one of two sizes of "FemAssist']

['Yes']

['yes']

Show results of randomised controlled trials for certolizumab pegol.

['RESULTS: 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY).', 'As well as displaying clinical efficacy, there is evidence to suggest that CZP has unique characteristics, including reduced transfer across the placenta and reduced frequency of injection site reactions. Furthermore, randomised controlled trials (RCTs) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA.', 'To assess the effectiveness and safety of certolizumab pegol (CDP870) in patients with RA who have not responded well to conventional disease modifying anti-rheumatic drugs (DMARDs', ' With an overall high grade of evidence this review revealed an improvement of clinical results (ACR50, 28 joint disease activity score (DAS-28) remission and HAQ scores) with certolizumab pegol.\xa0Adverse events were more frequent with certolizumab; there was a statistically significant increase in the number of serious adverse events, infections and hypertension.', "The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 patients and RAPID 2 24 weeks with 619 patients. Evidence for clinical effectiveness of CZP in mono-therapy came from the 24-week FAST4WARD trial with 220 patients that compared CZP (400 mg every 4 weeks) versus placebo. The three key RCTs demonstrated statistically significant superiority of CZP + MTX versus placebo + MTX and of CZP versus placebo with respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect comparison meta-analyses, the manufacturer suggested that CZP may be at least as effective as other 'biological' DMARD (bDMARD) comparators and, in a few ACR measures at 3 and 6 months, more effective. CZP is an effective therapy for adult RA patients whose disease has failed to respond adequately to cDMARDs including MTX or who are intolerant of MTX. The cost-effectiveness of CZP relative to other bDMARDs is unclear because the economic modelling undertaken may have ignored relevant effectiveness data and potential differences between trial populations, and so may have included effectiveness results that were biased in favour of CZP"]

['Improvement of clinical results (ACR50, 28 joint disease activity score (DAS-28) remission and HAQ scores) with certolizumab pegol. Adverse events were more frequent with certolizumab; there was a statistically significant increase in the number of serious adverse events, infections and hypertension.\nRandomised controlled trials (RCTs) of CZP have demonstrated rapid improvements in workplace and home productivity.']

[]

How is active neurotoxin of Clostridium botulinum detected?

['The neurotoxin detection is based on the mouse lethality assay. ', 'which could be shown by bioassay to produce biologically active type B toxin in culture.', 'Human induced pluripotent stem cells (hiPSC) hold great promise for providing various differentiated cell models for in vitro toxigenicity testing. ', 'A direct comparison of BoNT detection using primary rat spinal cord cells and hiPSC-derived neurons showed equal or increased sensitivity', 'BoNT/A intoxication studies demonstrate that the hiPSC-derived neurons reproducibly and quantitatively detect biologically active BoNT/A with high sensitivity (EC(50) ∼0.3 U).', ' these data suggest that neurons derived from hiPSCs provide an ideal and highly sensitive platform for BoNT potency determination, neutralizing antibody detection and for mechanistic studies.', 'Detection of botulinum neurotoxin-A activity in food by peptide cleavage assay.', 'his study reports the successful use of an enzymatic assay employing an internally quenched fluorogenic peptide as a fast, simple and inexpensive alternative to the mouse bioassay. ', 'BoNT endopeptidase assays', "in vivo mouse bioassay has for years been the 'gold standard' assay used for this purpose", 'Cell-based assays are currently the only in vitro alternative that detect fully functional BoNTs in a single assay and have been utilized for years for research purposes.', 'mouse bioassay (MBA) is traditionally used to confirm the presence of toxin in serum or food', 'A novel FDC (functional dual coating) microtitre plate immuno-biochemical assay,', 'This report demonstrates a novel assay that utilises the endopeptidase activity of the toxin to detect Botulinum neurotoxin in a pharmaceutical sample. The cleaving of SNAP-25 is monitored via UV-Visible spectroscopy with a limit of detection of 373 fg/mL and has been further developed into a high throughput method using a microplate reader detecting down to 600 fg/mL of active toxin. ']

['Active neurotoxin of Clostridium botulinum can be detected by:\nmouse lethality assay\nby mass spectrometry\nbioassay\ndifferentiated cell models\npeptide cleavage assay\nFDC (functional dual coating) microtitre plate immuno-biochemical assay\nendopeptidase activity monitored via UV-Visible spectroscopy']

['mouse lethality assay', 'by mass spectrometry', 'bioassay', 'differentiated cell models', 'peptide cleavage assay', 'FDC (functional dual coating) microtitre plate immuno-biochemical assay', 'endopeptidase activity monitored via UV-Visible spectroscopy']

The protein NONO forms heterodimers. With which proteins?

['The paraspeckle component 1 (PSPC1) and non-POU-domain-containing octamer-binding protein (NONO) heterodimer is an essential structural component of paraspeckles,', 'PSPC1-NONO heterodimer.', 'Crystallization of a paraspeckle protein PSPC1-NONO heterodimer', 'difficult heterodimeric complex of two human proteins, paraspeckle component 1 (PSPC1) and non-POU domain-containing octamer-binding protein (NONO), that are involved in gene regulation and the structural integrity of nuclear bodies termed paraspeckles is described.', 'SFPQ (PSF) and NONO (p54) are nuclear proteins that interact with each other and have diverse roles in nucleic acids metabolism. The SFPQ/NONO heterodimer was previously found to enhance DNA strand break rejoining in vitro.', 'We identified a heterodimer, p54nrb and PSF,', 'P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner.', 'e demonstrated that the PSF heterodimer partner, p54nrb (non-POU-domain-containing, octamer binding protein), can also function as a transcription corepressor, independent of PSF.', 'The PSPC1/NONO heterodimer has a right-handed antiparallel coiled-coil', 'Structure of the heterodimer of human NONO and paraspeckle protein component 1']

['The protein NONO forms heterodimers with PSPC1, SFPQ.']

['PSPC1', 'SFPQ']

Which intraflagellar transport (IFT) motor protein has been linked to human skeletal ciliopathies?

['Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies', 'Cytoplasmic dynein-2 is the motor for retrograde intraflagellar transport (IFT), and mutations in dynein-2 are known to cause skeletal ciliopathies', 'Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS)', 'Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies', 'All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS).', 'Cytoplasmic dynein-2 is the motor for retrograde intraflagellar transport (IFT), and mutations in dynein-2 are known to cause skeletal ciliopathies.', 'Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies.', 'All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS)', 'All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). ', 'Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. ', 'Cytoplasmic dynein-2 is the motor for retrograde intraflagellar transport (IFT), and mutations in dynein-2 are known to cause skeletal ciliopathies. ', 'Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. ', ' Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS).', 'All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease.', ' Cytoplasmic dynein-2 is the motor for retrograde intraflagellar transport (IFT), and mutations in dynein-2 are known to cause skeletal ciliopathies. Here, we define for the first time the composition of the human cytoplasmic dynein-2 complex.', 'The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies.', 'All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS).', 'Cytoplasmic dynein-2 is the motor for retrograde intraflagellar transport (IFT), and mutations in dynein-2 are known to cause skeletal ciliopathies.', 'Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies.']

['Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies', 'Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS).']

['Intraflagellar transport (IFT) motor protein DYNC2H1']

Does nimotuzumab improve survival of glioblastoma patients?

['The survival times were similar to those seen in historical data of standard therapy.', 'The survival time of a matched population treated at the same hospital with irradiation alone was decreased (median 8.0 and 12.2 mo for GBM and AA patients, respectively) compared with that of the patients who received nimotuzumab and curative-intent radiotherapy.', 'This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients.', 'The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. CONCLUSIONS: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.', 'Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis.', ' Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment.', 'CONCLUSIONS: Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation.', 'It has been evaluated in malignant brain tumors in adults and children, and shown to be therapeutically safe and effective in terms of increased survival and improved quality of life. ', 'Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. ', 'Nimotuzumab prolongs survival in patients with malignant gliomas: A phase I/II clinical study of concomitant radiochemotherapy with or without nimotuzumab.', 'Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature.', 'This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients', 'Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature', 'A multicenter exploratory study combining nimotuzumab and radiotherapy showed disease control and an overall patient survival similar to previous experiences along with an improvement in the quality of patient survival and no severe side effects.', 'Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab therapy may slightly improve tumor control and overall survival']

['Yes. Nimotuzumab improves survival of adult and pediatric patients diagnosed with glioblastoma and with other high-grade gliomas.']

['yes']

To which family does the Zika virus belong?

['Zika virus (ZIKV; genus Flavivirus, family Flaviviridae) ']

['The Zika virus belongs to the family Flaviviridae.']

['Flaviviridae']

what is the role of GATA-4 in regeneration of the heart after myocardial infarction?

['TGF-beta conducted the myogenic differentiation of CD117+ stem cells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the intramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively assisted the myocardial regeneration and induced therapeutic angiogenesis, contributing to functional cardiac regeneration.', 'G-CSF treatment also led to activation of signal transducer and activator of transcription-3 and induction of GATA-4 and various sarcomeric proteins such as myosin heavy chain, troponin I and desmin. ', 'We describe here the identification of a subpopulation of primitive cells from rat heart, processing stem cell marker, c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, and cardiac specific proteins, troponin-I, alpha-sarcomeric actinin and connexin-43. They exhibited a high in vitro proliferative potential. These findings strongly suggest that these cells are putative cardiomyocyte precursors. After transplantation, they were able to be retained and proliferate (13.63 +/- 5.97% after 2 weeks) within the ischemic heart. Progeny of implanted cells migrated along the infarcted scar, reconstituted regenerated cardiomyocytes with incorporation into host myocardium, and inhibited cardiac remodeling with decreased scar formation. ', 'Histological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of human specific alpha-cardiac actin. Human alpha cardiac actin-positive cells also expressed cardiac nuclear factors; nkx2.5 and GATA-4. Our results suggest that intracoronary artery transplantation of hCLCs is a potentially effective therapeutic strategy for future cardiac tissue regeneration.', 'This pattern of colocalization was also found in developing embryonic myocardium. Cardiac transcription factors Nkx-2.5 and GATA-4 were strongly expressed in the muscle bundles. ', 'After hypergravity and 5-Aza treatment, BMSCs showed positive for the early muscle and cardiac markers GATA-4, MEF-2, and Nkx2-5 with RT-PCR', 'Experiments in murine models of myocardial infarction (MI) demonstrated population of VSELs expressed also early markers of cardiac and endothelial lineages (GATA-4, Nkx2.5/Csx, VE-cadherin, von Willebrand factor) which migrated to stromal-derived factor-1 (SDF-1) and other chemoattractant gradient and underwent rapid mobilization into peripheral blood in experimental MI mice models.', 'We conclude that GATA-4 overexpression in MSCs increased both MSC survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct remodeling.', 'These cardiac c-kit+AT2+ cells, represented approximately 0.19% of total cardiac cells in infarcted heart, were characterized by upregulated transcription factors implicated in cardiogenic differentiation (Gata-4, Notch-2, Nkx-2.5) and genes required for self-renewal (Tbx-3, c-Myc, Akt). ', 'these findings suggest G-CSF administration could be an effective approach to treating chronic heart failure following a large MI.']

['GATA-4 is implicated in cardiogenic differentiation of cardiac c-kit+AT2+ cells that represent approximately 0.19% of total cardiac cells in infarcted heart. GATA-4 overexpression in mesenchymal stem cells increases both survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct regenaration. In addition, interventions, such as hypergravity and 5-Aza treatment, induce expression of early muscle and cardiac markers like GATA-4 in BMSCs. A subpopulation of primitive cells from rat heart, expressing c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, exhibit a high in vitro proliferative potential. Progeny of these implanted cells have been shown to migrate along the infarcted scar, reconstitute regenerated cardiomyocytes with incorporation into host myocardium, and inhibit cardiac remodeling with decreased scar formation. In another study, TGF-beta has been shown to conduct the myogenic differentiation of stem cells by upregulating GATA-4 and NKx-2.5 expression and the intramyocardial implantation of TGF-beta-preprogrammed stem cells effectively assisted the myocardial regeneration. Furthermore, G-CSF treatment in postinfarcted murine hearts appears to be an effective approach for treating heart failure and also leads to induction of GATA-4 resulting in expression of various sarcomeric proteins.']

[]

Which are the main NMD factors in Saccharomyces cerevisiae?

['In addition to their well-documented roles in the promotion of nonsense-mediated mRNA decay (NMD), yeast Upf proteins (Upf1, Upf2/Nmd2, and Upf3) also manifest translational regulatory functions, at least in vitro, including roles in premature translation termination and subsequent reinitiation', 'In Saccharomyces cerevisiae, nonsense-mediated mRNA decay (NMD) requires Upf1p, Upf2p, and Upf3p to accelerate the decay rate of two unique classes of transcripts: (1) nonsense mRNAs that arise through errors in gene expression, and (2) naturally occurring transcripts that lack coding errors but have built-in features that target them for accelerated decay (error-free mRNAs)', "In Saccharomyces cerevisiae, rapid degradation of nonsense-containing mRNAs requires the decapping enzyme Dcp1p, the 5'-to-3' exoribonuclease Xrn1p, and the three nonsense-mediated mRNA decay (NMD) factors, Upf1p, Nmd2p, and Upf3p", 'Our results indicate that Upf1p, Nmd2p, and Upf3p regulate decapping and exonucleolytic degradation of nonsense-containing mRNAs. In addition, we show that these factors also regulate the same processes in the degradation of wild-type mRNAs', 'This quality control pathway depends on the NMD-specific factors, Upf1p, Upf2p/Nmd2p, and Upf3p, as well as the two release factors, eRF1 and eRF3 (respectively designated Sup45p and Sup35p in yeast)', 'In addition to their well-documented roles in the promotion of nonsense-mediated mRNA decay (NMD), yeast Upf proteins (Upf1, Upf2/Nmd2, and Upf3) also manifest translational regulatory functions, at least in vitro, including roles in premature translation termination and subsequent reinitiation. ', 'Association of yeast Upf1p with direct substrates of the NMD pathway', ' Translation termination factors eRF1 (Sup45) and eRF3 (Sup35) participate not only in the last step of protein synthesis but also in mRNA degradation and translation initiation via interaction with such proteins as Pab1, Upf1, Upf2 and Upf3.', 'From these results, we conclude that sup111, sup112 and sup113 are mutant alleles of UPF2, UPF3 and UPF1, respectively, and thus attribute suppressor activity of these mutations to defects in the NMD (nonsense-mediated mRNA decay) machinery.', 'In Saccharomyces cerevisiae, nonsense-mediated mRNA decay (NMD) requires Upf1p, Upf2p, and Upf3p to accelerate the decay rate of two unique classes of transcripts: (1) nonsense mRNAs that arise through errors in gene expression, and (2) naturally occurring transcripts that lack coding errors but have built-in features that target them for accelerated decay (error-free mRNAs).', "In Saccharomyces cerevisiae, rapid degradation of nonsense-containing mRNAs requires the decapping enzyme Dcp1p, the 5'-to-3' exoribonuclease Xrn1p, and the three nonsense-mediated mRNA decay (NMD) factors, Upf1p, Nmd2p, and Upf3p.", 'To date, human (h) Upf1 protein (p) (hUpf1p), a group 1 RNA helicase named after its Saccharomyces cerevisiae orthologue that functions in both translation termination and NMD, has been the only factor shown to be required for NMD in mammalian cells.', 'In Saccharomyces cerevisiae, rapid degradation of nonsense-containing mRNAs requires the decapping enzyme Dcp1p, the 5-to-3 exoribonuclease Xrn1p, and the three nonsense-mediated mRNA decay (NMD) factors, Upf1p, Nmd2p, and Upf3p.', 'In Saccharomyces cerevisiae, three trans-acting factors (Upf1p to Upf3p) are required for NMD.', 'Interactions between Upf1 and the decapping factors Edc3 and Pat1 in Saccharomyces cerevisiae.', 'In yeast Saccharomyces cerevisiae, the activity of this pathway depends on the recognition of the PTC by the translational machinery and interaction of translation termination factors eRF1 and eRF3 with Upf1, Upf2 and Upf3 proteins.', 'In yeast Saccharomyces cerevisiae, the activity of this pathway depends on the recognition of the PTC by the translational machinery and interaction of translation termination factors eRF1 and eRF3 with Upf1, Upf2 and Upf3 proteins', 'NMD activation is also enabled by the absence of the poly(A)-binding protein, Pab1p, downstream of a termination event', 'Of those, a group of weak and recessive suppressors, sup111, sup112 and sup113, is of particular interest because of their dependency on [PSI+], a yeast prion.']

['Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that accelerates the degradation of mRNAs containing premature translation termination codons. This quality control pathway depends on the NMD-specific factors, Upf1p, Upf2p/Nmd2p, and Upf3p, as well as the two release factors, eRF1 and eRF3 (respectively designated Sup45p and Sup35p in yeast). NMD activation is also enabled by the absence of the poly(A)-binding protein, Pab1p, downstream of a termination event', 'In Saccharomyces cerevisiae, rapid degradation of nonsense-containing mRNAs requires the three nonsense-mediated mRNA decay (NMD) factors, Upf1p, Nmd2p, and Upf3p.', 'In addition to their well-documented roles in the promotion of nonsense-mediated mRNA decay (NMD), yeast Upf proteins (Upf1, Upf2/Nmd2, and Upf3) also manifest translational regulatory functions, at least in vitro, including roles in premature translation termination and subsequent reinitiation']

['Upf1p', 'Nmd2p', 'Upf3p']

What is the effect of Allopurinol on asphyxia in neonates?

['Potential neuroprotective strategies targeting different pathways leading to neuronal cell death in response to hypoxic-ischemic insult have been investigated: hypothermia, erythropoietin, iminobiotin, deferioxamine, magnesium, allopurinol, xenon, melatonin and statins.', 'Allopurinol reduces the formation of free radicals, thereby potentially limiting the amount of hypoxia-reperfusion damage.', 'There were no differences in long-term outcome between the allopurinol-treated infants and controls. However, subgroup analysis of the moderately asphyxiated group showed significantly less severe adverse outcome in the allopurinol-treated infants compared with controls (25% vs 65%; RR 0.40, 95%CI 0.17 to 0.94).', 'The reported data may suggest a (neuro)protective effect of neonatal allopurinol treatment in moderately asphyxiated infants.', 'The asphyxiated newborns treated with allopurinol had better neurologic and neurodevelopmental outcome at 12 or more months of age.', 'In newborn infants, allopurinol is being tested as a free radical scavenger to prevent brain damage caused by reperfusion and oxygenation after perinatal hypoxia and ischemia (birth asphyxia).', 'Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia.', 'The analysis showed an unaltered (high) mortality and morbidity in the infants treated with allopurinol.', 'Allopurinol treatment started postnatally was too late to reduce the early reperfusion induced free radical surge.', 'One randomized trial of allopurinol showed short-term benefits but was too small to test death or disability.', 'No toxic side effects of ALLO were detected.', 'This study suggests a beneficial effect of ALLO treatment on free radical formation, CBV, and electrical brain activity, without toxic side effects.']

['Allopurinol was shown in a number of clinical trial to be safe and effective for treatment of neonatal asphyxia. Allopurinol improves short-term and long-term clinical outcomes of neonatal asphyxia. Allopurinol should be administered as soon as possible. Postulated mechanism of allopurinol action in this setting is prevention of hypoxia-perfusion injury by reduction of free radical formation.']

[]

Which are the most under-represented oligonucleotides in higher eukaryote genomes?

['Unusual frequencies of certain alternating purine-pyrimidine runs in natural DNA sequences', 'Octanucleotides are the most deficient, occurring at only 60% of the frequency expected in random sequences. An unexpectedly high proportion of these octamers consists of alternating tetramers with the repeat structure (PuPyPuPy)2 or (PyPuPyPu)2', 'For dinucleotides, TA is almost universally under-represented, with the exception of vertebrate mitochondrial genomes, and CG is strongly under-represented in vertebrates and in mitochondrial genomes', 'For trinucleotides, GCA.TGC tends to be under-represented in phage, human viral, and eukaryotic sequences, and CTA.TAG is strongly under-represented in many prokaryotic, eukaryotic, and viral sequences', 'The dinucleotide CpG is significantly under-represented in vertebrate DNA and is usually methylated', 'One such pattern recognition system is based on unmethylated CpG dinucleotides in particular sequence contexts (CpG motifs); these motifs are common in bacterial DNA but are under-represented ("CpG suppression") and methylated in vertebrate DNA', 'We argue that the significant under-represented motif pattern of CpG in an AU context--which is found in both the ssRNA viruses and innate genes, and has decreased throughout the history of H1N1 influenza replication in humans--is immunostimulatory and has been selected against during the co-evolution of viruses and host innate immune genes']

['The oligonucleotides containing the CG and TA dinucleotide are generally under-represented in higher eukaryote genomes', 'TpA is the most underepresented dinucleotide followed closely by CpG. For trinucleotides, GCA/TGC tends to be under-represented in phage, human viral, and eukaryotic sequences, and CTA/TAG is strongly under-represented in many prokaryotic, eukaryotic, and viral sequences. For higher lengts alternating Purine/Pyrimidine tracts are underepresented up to 60%.', 'Oligonucleotides containing CG and TA dinucleoides']

['TA', 'CG', '(PuPy)n', 'GCA/TGC', 'CTA/TAG']

What is the effect of the absence of Saccharomyces cerevisiae Rrm3p?

['Twice as many pause sites were identified in rrm3 compared with wild-type cells, as pausing in this strain occurred at both highly transcribed RNA polymerase II genes and the previously identified protein DNA complexes. ORFs of highly transcribed RNA polymerase II genes are a class of natural pause sites that are not exacerbated in rrm3 cells', 'The DNA helicase Rrm3 promotes replication fork progression through >1000 discrete genomic regions and represses the cDNA-mediated mobility of the Ty1 retrotransposon. We explored the connection between DNA replication and Ty1 retromobility by investigating the basis of increased retromobility in an rrm3 mutant. Even though Ty1 cDNA levels are increased in the absence of RRM3, neither the level nor target-site specificity of cDNA integration was altered', 'We propose that RNA:DNA hybrid regions within nascent retrotransposition events block replication in an rrm3 mutant, leading to chromosome breaks within Ty1 sequences', 'We demonstrate that the inefficient mtDNA replication process of mutant yeast cells lacking the PIF1 DNA helicase is partly rescued in the absence of the DNA helicase RRM3. The rescue effect is likely due to the increase in the deoxynucleoside triphosphates (dNTPs) pool caused by the lack of RRM3', ' However, the essential nuclear function of Pfh1p could be supplied by Rrm3p. Expression of Rrm3p suppressed the accumulation of DNA damage foci but not the hydroxyurea sensitivity of cells depleted of nuclear Pfh1p. Together, these data demonstrate that Pfh1p has essential roles in the replication of both nuclear and mitochondrial DNA', ' In the absence of the Rrm3p helicase, there was a slight enhancement of fork arrest at the Ter sites. Simultaneous deletions of the TOF1 (or CSM3), and the RRM3 genes restored fork arrest by removing both the fork-releasing and fork-protection activities', "Rrm3p is a 5'-to-3' DNA helicase that helps replication forks traverse protein-DNA complexes. Its absence leads to increased fork stalling and breakage at over 1,000 specific sites located throughout the Saccharomyces cerevisiae genome", 'These data suggest a model in which the stalled and broken forks generated in rrm3 cells activate a checkpoint response that provides time for fork repair and restart', 'Lack of the yeast Rrm3p DNA helicase causes replication defects at multiple sites within ribosomal DNA (rDNA), including at the replication fork barrier (RFB)', "The Saccharomyces cerevisiae RRM3 gene encodes a 5' to 3' DNA helicase. While replication of most of the yeast genome was not dependent upon Rrm3p, in its absence, replication forks paused and often broke at an estimated 1400 discrete sites, including tRNA genes, centromeres, inactive replication origins, and transcriptional silencers. These replication defects were associated with activation of the intra-S phase checkpoint. Activation of the checkpoint was critical for viability of rrm3Delta cells, especially at low temperatures", 'These data indicate that the Rrm3p DNA helicase helps replication forks traverse protein-DNA complexes, naturally occurring impediments that are encountered in each S phase', "In wild-type Saccharomyces cerevisiae, replication forks slowed during their passage through telomeric C(1-3)A/TG(1-3) tracts. This slowing was greatly exacerbated in the absence of RRM3, shown here to encode a 5' to 3' DNA helicase", ' Loss of Rrm3p also resulted in replication fork pausing at specific sites in subtelomeric DNA, such as at inactive replication origins, and at internal tracts of C(1-3)A/TG(1-3) DNA', 'Local chromatin structure at the ribosomal DNA causes replication fork pausing and genome instability in the absence of the S. cerevisiae DNA helicase Rrm3p.']

["The Saccharomyces cerevisiae RRM3 gene encodes a 5' to 3' DNA helicase. While replication of most of the yeast genome was not dependent upon Rrm3p, in its absence, replication forks paused and often broke at an estimated 1400 discrete sites, including tRNA genes, centromeres, inactive replication origins, and transcriptional silencers. These replication defects were associated with activation of the intra-S phase checkpoint. Activation of the checkpoint was critical for viability of rrm3Delta cells, especially at low temperatures.", 'The Saccharomyces cerevisiae RRM3 gene encodes a 5 to 3 DNA helicase. While replication of most of the yeast genome was not dependent upon Rrm3p, in its absence, replication forks paused and often broke at an estimated 1400 discrete sites, including tRNA genes, centromeres, inactive replication origins, and transcriptional silencers. These replication defects were associated with activation of the intra-S phase checkpoint. Activation of the checkpoint was critical for viability of rrm3Delta cells, especially at low temperatures ']

['Lack of the yeast Rrm3p DNA helicase causes replication defects at multiple sites within ribosomal DNA (rDNA), including at the replication fork barrier (RFB).']

Is the circadian clock involved in ribosome biogenesis?

['The circadian clock coordinates ribosome biogenesis.', 'Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis.', 'Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation', 'The circadian clock coordinates ribosome biogenesis', 'Here we show that the circadian clock exerts its function also through the regulation of mRNA translation', 'Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation.']

['Yes. The circadian clock coordinates ribosome biogenesis. It influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation.']

['yes']

Is LPS a microbial product?

['and microbial translocation [lipopolysaccaride (LPS), microbial 16S rDNA and sCD14] ', 'Lipopolysaccharide sensing an important factor in the innate immune response to Gram-negative bacterial infections', 'bacterial lipopolysaccharide (LPS)', 'sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota']

['Yes, the lipopolysaccharide (LPS) is a component of the bacterial cell wall.']

['yes']

What is Dravet syndrome?

['Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures.', 'BACKGROUND: Dravet syndrome is a severe form of epilepsy.', 'Dravet syndrome, a severe infantile epilepsy syndrome, is typically resistant to anti-epileptic drugs (AED).', 'Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions.', 'Dravet syndrome is an epileptic encephalopathy characterized by multiple types of seizures.', 'Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death', 'Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours', 'Dravet syndrome, or as it was called in the past severe myoclonic epilepsy in infancy, is a drug-resistant epilepsy first described by Charlotte Dravet in 1978', 'Dravet syndrome is a severe form of epilepsy.', 'Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for whose treatment stiripentol (STP) has been recently licensed for add-on use.To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) as therapy for patients with SMEI.We searched the Cochrane Epilepsy Group Specialised Register (15 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4 of 12, The Cochrane Library, April 2013), MEDLINE (1', 'Dravet syndrome is a severe infantile-onset epileptic encephalopathy associated with mutations in the sodium channel alpha-1 subunit gene SCN1A.', 'Dravet syndrome is a rare form of epilepsy largely refractory to current antiepileptic medications. ', 'Dravet syndrome is a rare epileptic encephalopathy characterized by treatment-resistant polymorphic seizures. ', 'Dravet syndrome is a severe form of epileptic encephalopathy characterized by early onset epileptic seizures followed by ataxia and cognitive decline.', 'Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. ', 'Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI) is a baleful epileptic encephalopathy that begins in the first year of life. ', 'Dravet syndrome is a severe infantile onset epilepsy syndrome with multiple seizure types, developmental slowing and poor outcome', 'Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life.', 'Dravet syndrome is an epileptic syndrome of infancy and early childhood.', 'Dravet syndrome is an epileptic syndrome of infancy.', "patients with severe myoclonic epilepsy of infancy (Dravet's syndrome)", 'Dravet syndrome is a severe infantile epileptic encephalopathy caused in approximately 80% of cases by mutations in the voltage gated sodium channel subunit gene SCN1A']

['Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy.', 'dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality.', 'Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures.', 'Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality.', 'Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and is associated with high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures.']

['A severe epilepsy of chidhood']

Which is the third subunit of the TSC1-TSC2 complex upstream of mTORC1?

['The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth.', 'Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity.', 'TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome.', 'Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.']

['TBC1D7 was identified as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. It was demonstrated that TSC1-TSC2-TBC1D7 (TSC-TBC) is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity to negatively regulate mTORC1 activity. In agreement with this, TBC1D7 knockdown was shown to result in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.']

['TBC1D7']

What is Bexsero?

['A capsular group B meningococcal vaccine - 4CMenB (Bexsero) - has recently been licensed in the European Union, Canada and Australia.', 'The 4-component meningococcal serogroup B vaccine 4CMenB (Bexsero) is the first vaccine against this serogroup and has been approved by licensing authorities in Europe, Canada and Australia. ', "Implementation of meningococcal B vaccination (Bexsero®) in France: Physicians' perceptions and experiences of a few months after marketing approval", 'In December 2013, the French public health authorities recommended the use of Bexsero® (meningococcus B vaccine) in areas with endemic risk and for patients at risk for invasive meningococcal B disease. ', 'Bexsero, a novel vaccine against meningococcus', 'Meningococcus B is the most prevalent Neisseria meningitidis serogroup isolated in Hungary. Bexsero is one of the vaccines developed against it, which has been available in Hungary since the summer of 2014. ', 'Vaccinating Italian infants with a new multicomponent vaccine (Bexsero®) against meningococcal B disease: A cost-effectiveness analysis.', 'The European Medicines Agency has approved a multicomponent serogroup B meningococcal vaccine (Bexsero®) for use in individuals of 2 months of age and older.', 'Our results suggest that vaccinating infants in Italy with Bexsero® has the ability to significantly reduce meningococcal disease and, if the probable underestimation of disease incidence is considered, routine vaccination is advisable.', 'Since the antigens selected for Bexsero® are also harbored by meningococci belonging to other serogroups there may be the potential for Bexsero® to offer a certain level of protection against non-B serogroups.', '[Bexsero, a novel vaccine against meningococcus].', 'The new available vaccines are Bexsero® and Trumenba®.', 'Surface-expressed protein antigens such as factor H-binding protein (fHbp), Neisserial adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and Porin protein A (PorA); all express sequence variability that can affect their function as protective immunogens when used in meningococcal serogroup B vaccines like the recently-approved 4CMenB (Bexsero(®)).', 'Proteinaceous meningococcal B vaccines are under development, and the most advanced, Bexsero, is currently being evaluated by the European Medicines Agency.', 'Among them, the Reverse Vaccinology approach was successfully applied to the development of an innovative vaccine against Neisseria meningitidis serogroup B, now available on the market with the commercial name BEXSERO® (Novartis Vaccines).', 'Recently, a vaccine, 4CMenB (Bexsero(®)), containing three recombinant proteins, and outer membrane vesicles (OMV) derived from a serogroup B meningococcal strain (MenB) has been licensed in Europe and Australia and is indicated for persons aged 2 mo or older.', 'Multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero(®)) is a unique vaccine containing four main immunogenic components: three recombinant proteins combined with outer membrane vesicles derived from meningococcal NZ98/254 strain', 'Recently, a universal serogroup B meningococcal vaccine, Bexsero(®), was licensed in Europe, Australia and United States, following several clinical studies demonstrating its immunogenicity and safety', 'Like any drug, Bexsero(®) and Trumemba(®) will require close observation to assess their impact on meningococcal epidemiology. <CopyrightInformation>Copyright © 2015 Elsevier Masson SAS', 'Bexsero, a new vaccine against Neisseria meningitidis serogroup B (MenB), is composed of 3 main recombinant proteins and an outer membrane vesicle component', 'The meningococcal 4CMenB vaccine (Bexsero; Novartis) contains four antigens that can elicit serum bactericidal activity, one of which is factor H (FH)-binding protein (FHbp)', 'In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB)', 'Bexsero® is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany', 'Re-evaluating cost effectiveness of universal meningitis vaccination (Bexsero) in England: modelling study.', 'Bexsero: a multicomponent vaccine for prevention of meningococcal disease.', 'OBJECTIVE: To use mathematical and economic models to predict the epidemiological and economic impact of vaccination with Bexsero, designed to protect against group B meningococcal disease, to help inform vaccine policy in the United Kingdom.DESIGN: Modelling study.SETTING: England.POPULATION: People aged 0-99.INTERVENTIONS: Incremental impact of introductory vaccine strategies simulated with a transmission dynamic model of meningococcal infection and vaccination including potential herd effects. ', 'Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero(�)).', 'Modelled evaluation of multi-component meningococcal vaccine (Bexsero®) for the prevention of invasive meningococcal disease in infants and adolescents in the UK.', 'BACKGROUND: 4CMenB (Bexsero), a vaccine developed against invasive meningococcal disease caused by capsular group B strains (MenB), was recently licensed for use by the European Medicines Agency. ', 'Bexsero is the first meningococcal B vaccine to be approved in the European Union. ', 'Quantification by LC-MS(E) of outer membrane vesicle proteins of the Bexsero® vaccine.', 'We previously demonstrated the immunogenicity and tolerability of the serogroup B meningococcal vaccine, 4CMenB (Bexsero), in 11-17 y-olds randomized to receive 1, 2, or 3 doses at 1, 2, or 6 mo intervals. ', 'This policy statement provides recommendations for the prevention of serogroup B meningococcal disease through the use of 2 newly licensed serogroup B meningococcal vaccines: MenB-FHbp (Trumenba; Wyeth Pharmaceuticals, a subsidiary of Pfizer, Philadelphia, PA) and MenB-4C (Bexsero; Novartis Vaccines, Siena, Italy).', 'An outbreak of Neisseria meningitidis serotype B infection occurred at a small residential university; public health announced an organizational vaccination program with the 4-component Meningococcal B (4CMenB) vaccine (Bexsero(TM), Novartis/GlaxoSmithKline Inc.) several days later.', 'Bexsero, a new vaccine against serogroup B meningococcal disease (MenB), was licensed in Europe in January 2013.', 'Recently approved in the EU, US, Australia, and Canada, 4CMenB (Bexsero(®), GSK Vaccines) is a multi-component meningococcal B (MenB) vaccine containing 3 surface exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) containing PorA 1.4.', 'In Germany, Bexsero is recommended for persons at increased risk of invasive meningococcal disease, but not for universal childhood vaccination.', 'To support decision making we adapted the independently developed model for England to the German setting to predict the potential health impact and cost-effectiveness of universal vaccination with Bexsero(®) against MenB disease.', 'This has resulted in a multicomponent, recombinant, meningococcal serogroup B vaccine: 4CMenB (Bexsero(®), Novartis Vaccines & Diagnostics, NC, USA), containing four main immunogenic components: two recombinant fusion proteins (Neisseria heparin-binding antigen-GNA1030 and factor H-binding protein-GNA2091); recombinant Neisserial adhesion A; and detergent-treated outer membrane vesicles derived from the meningococcal NZ98/254 strain, where porin A 1.4 is the major immunodominant antigen.', 'BACKGROUND: 4CMenB (Bexsero), a vaccine developed against invasive meningococcal disease caused by capsular group B strains (MenB), was recently licensed for use by the European Medicines Agency.', 'In January 2015, FDA licensed a second MenB vaccine (MenB-4C [Bexsero, Novartis Vaccines]) as a 2-dose series.', 'Bexsero, a new vaccine against Neisseria meningitidis serogroup B (MenB), is composed of 3 main recombinant proteins and an outer membrane vesicle component.', 'Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero(®)).', '[Bexsero, a novel vaccine against meningococcus].', "Modelling the cost-effectiveness of catch-up 'MenB' (Bexsero) vaccination in England.", 'Re-evaluating cost effectiveness of universal meningitis vaccination (Bexsero) in England: modelling study.', 'The novel vaccine Bexsero (previously 4CMenB) has been developed and proven safe and immunogenic in clinical trials.', 'Multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero(®)): a review of its use in primary and booster vaccination.', 'Bexsero, the recently licensed multicomponent vaccine against serogroup B Neisseria meningitidis (MenB).', 'Recommendation for anti-meningococcal vaccination among these workers has been recently updated upon the licensure in Europe of Bexsero® vaccine.', 'Clinical recommendations for the use of Bexsero have been published in several countries. ']

['Bexsero is a 4-component vaccine against capsular Meningococcus serogroup B (4CMenB), which has recently been licensed in Europe, Canada and Australia.', 'Bexsero is amulticomponent vaccine against serogroup B Neisseria meningitidis (MenB).']

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Which gene is most commonly associated with severe congenital and cyclic neutropenia?

['Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital neutropenia (CN) and cyclic neutropenia (CyN)', 'We screened CN (n\xa0=\xa0395) or CyN (n\xa0=\xa092) patients for ELANE mutations and investigated the impact of mutations on mRNA expression, protein expression, and activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN patients, 69 of them were novel', 'Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype', 'Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other', 'One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype', 'Three familial cases of each of severe congenital neutropenia (SCN) and cyclic neutropenia (CN) in addition to 3 sporadic cases of SCN were analyzed for neutrophil elastase (Ela2) gene mutation', 'Three cases of familial SCN (P13L, R52P, and S97L), 2 of familial CN (W212stop and P110L), and 1 of sporadic SCN (V72M) were shown to have heterozygous mutations in the Ela2 gene', 'Recent studies have elucidated a role for the unfolded protein response in mediating the pathogenic effects of ELA2 mutations, the most common mutation in severe congenital neutropenia (SCN) as well as cyclic neutropenia', 'Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis', 'Heterozygous mutations of the gene encoding neutrophil elastase (ELA2) have been associated with cyclic neutropenia (CN) and severe congenital neutropenia (SCN).', 'The observation that mutations in the neutrophil elastase gene, which cause cyclic and severe congenital neutropenia, are associated with protease maldistribution gives some clue as to the potential importance of inhibitor proteins.', 'All cases of cyclic neutropenia and most cases of severe congenital neutropenia result from heterozygous germline mutations in the gene encoding neutrophil elastase, ela2.', 'Mutations in the neutrophil elastase gene were identified in all patients with cyclic neutropenia and most of the patients with severe congenital neutropenia.', 'Mutations in the neutrophil elastase gene were identified in all patients with cyclic neutropenia and most of the patients with severe congenital neutropenia', 'Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital neutropenia (CN) and cyclic neutropenia (CyN)', 'This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia', 'Mutations in ELA2 encoding the neutrophil granule protease, neutrophil elastase (NE), are the major cause of the 2 main forms of hereditary neutropenia, cyclic neutropenia and severe congenital neutropenia (SCN)', 'Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis', 'Heterozygous mutations of the gene encoding neutrophil elastase (ELA2) have been associated with cyclic neutropenia (CN) and severe congenital neutropenia (SCN)']

['Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital neutropenia (SCN) and cyclic neutropenia (CN).', 'Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other ']

['The neutrophil elastase gene (ELANE)']

What is the role of TRH in hypertension?

['We recently showed that diencephalic TRH may mediate the central leptin-induced pressor effect', 'that central TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity.', 'Five polymorphisms in five genes, CAST(calpastatin), LIPC (hepatic lipase), SLC4A1 (band 3 anion transporter), TRH (thyrotropin-releasing hormone), and VWF (von Willebrand factor), were significantly associated with both blood pressure variation and hypertension.', 'We previously reported that thyrotropin-releasing hormone (TRH) precursor gene overexpression induces hypertension in the normal rat and that spontaneously hypertensive rats have central TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number.', 'We propose that because leptin produces central TRH synthesis and release, obesity may induce hypertension through TRH system activation and that the TRH-leptin interaction may thus contribute to the strong association between hypertension and obesity.', 'We have described that TRH overexpression induces hypertension in a normal rat, which was reversed by TRH antisense treatment. ', 'his treatment also reduces the central TRH hyperactivity in spontaneously hypertensive rats and normalizes blood pressure.', 'Our findings support the hypothesis that the TRHR gene participates in the etiopathogenesis of essential hypertension.', 'Recently, we described that the TRH precursor gene overexpression induces hypertension in the normal rat. In addition, we published that spontaneously hypertensive rats (SHR) have central extrahypothalamic TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number.', 'the encephalic renin-angiotensin system seems to be crucial in the development and/or maintenance of hypertension in SHR, we investigated the effect of antisense inhibition of TRH on that system and found that TRH antisense treatment significantly diminished the elevated diencephalic angiotensin II (Ang II) content in the SHR without any effect in control animals, suggesting that the Ang II system is involved in the TRH cardiovascular effects.', 'he central TRH system seems to be involved in the etiopathogenesis of hypertension in this model of essential hypertension', 'ong-term treatment with enalapril (5 mg/kg twice daily), which was effective in inhibiting serum angiotensin-converting enzyme activity by more than 50%, decreased arterial blood pressure and preoptic area TRH content of SHR, whereas another vasodilator, diltiazem (10 mg/kg every 8 hours), failed to produce a similar change', 'the pressor effect of intravenous TRH is mediated primarily by a stimulation of alpha-adrenergic receptors. Adrenal medullectomy appears to enhance the blood pressure response to intravenous TRH. Activation of cardiac beta-adrenoceptors seems to contribute to the blood pressure increasing effect of intravenous TRH in medullectomized animals.', 'Centrally administered thyrotropin-releasing hormone exerts a well documented hypertensive effect.', 'These results provide evidence for a role of endogenous brain thyrotropin-releasing hormone in the maintenance of hypertension in spontaneously hypertensive rats.', 'in spontaneously hypertensive (SHR) rats the development of hypertension paralleled increases in brain receptors for thyrotropin-releasing hormone (TRH)', 'The results suggest that in addition to the brain, TRH receptors in the spinal cord of SHR rats are also up-regulated and may also play an important role in the regulation of blood pressure.', 'The results provide, for the first time, evidence for a parallel increase in the density of brain TRH receptors with elevation of blood pressure, and suggest that brain TRH receptors may play an important role in the pathophysiology of hypertension.']

['TRH gene overexpression induces hypertension in normal rats and spontaneously hypertensive rats have central TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. TRH antisense treatment reduces hypertension.\ncentral TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity.\nthe pressor effect of intravenous TRH is mediated primarily by a stimulation of alpha-adrenergic receptors. Activation of cardiac beta-adrenoceptors seems to contribute to the blood pressure increasing effect of intravenous TRH. Ang II system is involved in the TRH cardiovascular effects. \nPolymorphisms in TRH (thyrotropin-releasing hormone) are significantly associated with both blood pressure variation and hypertension.\nTRH may mediate the central leptin-induced hypertension effect\nA parallel increase in the density of brain TRH receptors with elevation of blood pressure has been shown and suggests that brain TRH receptors may play an important role in the pathophysiology of hypertension. TRH Receptor gene participates in the etiopathogenesis of essential hypertension.']

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Neurostimulation of which nucleus is used for treatment of dystonia?

['Bilateral globus pallidus internus (GPi) DBS was performed in five SD patients and unilateral ventralis oralis anterior and posterior (Voa/Vop) nucleus of the thalamus DBS in two post-stroke hemiballismus patients. ', 'BACKGROUND: Deep brain stimulation of the internal pallidum (GPi-DBS) is effective for various types of drug-refractory primary dystonias. ', 'METHODS: In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life.', 'INTERPRETATION: 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia.', 'We describe a patient who received bilateral globus pallidus internus DBS for dystonia with initially good clinical response, but the device eventually failed. ', 'Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.', 'Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. ', 'INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. ', 'Pallidal deep-brain stimulation in primary generalized or segmental dystonia.', 'BACKGROUND: Neurostimulation of the internal globus pallidus has been shown to be effective in reducing symptoms of primary dystonia. ', 'CONCLUSIONS: Bilateral pallidal neurostimulation for 3 months was more effective than sham stimulation in patients with primary generalized or segmental dystonia.', 'OBJECTIVE: To assess the effects of bilateral pallidal deep brain stimulation (DBS) on mood and cognitive performance in patients with dystonia before surgery (at baseline, while patients received their usual treatment) and 12 months postoperatively (while patients received neurostimulation and their medications) in a multicenter prospective study. ', 'CONCLUSIONS: Bilateral pallidal stimulation has a good benefit-to-risk ratio as it did not negatively affect cognitive performance and mood in primary dystonia, while a significant motor improvement was obtained.', 'Despite that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favored intervention for patients with medically intractable dystonia, the pathophysiological mechanisms of dystonia are largely unclear. In eight patients with primary dystonia who were treated with bilateral chronic pallidal stimulation, we correlated symptom-related electromyogram (EMG) activity of the most affected muscles with the local field potentials (LFPs) recorded from the globus pallidus electrodes. ', 'Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia.', 'METHODS: We performed a prospective, controlled, multicenter study assessing the efficacy and safety of bilateral pallidal stimulation in 22 patients with primary generalized dystonia. ', 'CONCLUSIONS: These findings support the efficacy and safety of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.', 'Bilateral pallidotomy or pallidal stimulation may provide major benefit especially in patients with generalized, disabling dystonia with the most dramatic improvements in dystonia type 1 patients.', 'This suggests that neurostimulation of the VIM may be an effective treatment for myoclonus in pharmacologically intractable IMDS.', 'We report on the effects of bilateral neurostimulation of the ventral intermediate thalamic nucleus (VIM) in a patient with medically intractable and progressing inherited myoclonus dystonia syndrome (IMDS). ', 'Neurostimulation of the ventral intermediate thalamic nucleus in inherited myoclonus-dystonia syndrome.', 'Pallidal and thalamic neurostimulation in severe tardive dystonia.', 'After informed consent, a bilateral stereotactic electrode placement targeting the ventral intermediate thalamic nucleus (VIM) and the globus pallidus internus (GPi) was performed.', 'Stimulation of the VIM did not improve the hyperkinetic movements and simultaneous stimulation of both the GPi and the VIM did not result in any additional benefit. ', 'Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP.', '3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia.', ' This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia.', 'INTERPRETATION: 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia.', 'This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia.', 'Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP', '3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia']

['Neurostimulation of globus pallidus internus is effective for treatment of dystonia. Ventral intermediate thalamic nucleus has also been tested for neurostimulation in dystonia patients.']

['globus pallidus internus']

Is triadin involved in cardiac function?

['Junctin (JCN), a 26-kd sarcoplasmic reticulum (SR) transmembrane protein, forms a quaternary protein complex with the ryanodine receptor, calsequestrin, and triadin in the SR lumen of cardiac muscle. Within this complex, calsequestrin, triadin, and JCN appear to be critical for normal regulation of ryanodine receptor-mediated calcium (Ca) release.', 'Recent studies have uncovered functional roles of both JCN and triadin in the mouse heart, using transgenic overexpression strategies, which exhibit varying phenotypes including mild SR structural alterations, prolongation of Ca transient decay, impaired relaxation, and cardiac hypertrophy and/or heart failure.', 'Triadin is involved in the regulation of cardiac excitation-contraction coupling. ', 'Thus the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function.', 'Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR) is regulated by a complex of proteins, including the ryanodine receptor (RyR), calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD).', 'Impaired sarcoplasmic reticulum (SR) Ca release has been suggested to contribute to the depressed cardiac function in heart failure. The release of Ca from the SR may be regulated by the ryanodine receptor, triadin, junctin, calsequestrin, and a histidine-rich, Ca-binding protein (HRC).']

['Yes, triadin is involved in the regulation of cardiac excitation-contraction coupling.']

['yes']

which are the risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy?

['Cardiac magnetic resonance (CMR) is used in the diagnosis and risk stratification of hypertrophic cardiomyopathy (HCM) and can detect myocardial replacement fibrosis (anindependent predictor of adverse cardiac outcomes) using late gadolinium enhancement (LGE). ', 'J wave is associated with increased risk of sudden cardiac arrest in patients with hypertrophic cardiomyopathy.', 'The J wave may be a risk factor for SCA in patients with HCM.', 'Extreme left ventricular hypertrophy was the most common risk factor present (alone or in combination with other markers) in patients experiencing primary prevention interventions (17 of 26 [65%]).', 'Extreme left ventricular hypertrophy was most frequently associated with appropriate interventions.', 'In conclusion, it is demonstrated that LGE has incremental value in addition to clinical risk factors for risk stratification and management of patients with HC.', 'Fibrosis as detected by CMR should be evaluated as an additional risk factor to further delineate risk of SCD in carriers of an HCM causing mutation.', 'Nonsustained VT was the only predictive risk factor (RF) for an appropriate ICD intervention in the PP (positive predictive value 22%, negative predictive value 96%).', 'Nonsustained ventricular tachycardia seems to be the most predictive RF for appropriate device discharges. ', 'However, LGE was strongly associated with surrogates of arrhythmia and remained a significant associate of subsequent SCD and/or ICD discharge after controlling for other variables. If replicated, LGE may be considered an important risk factor for sudden death in patients with HCM.', 'In conclusion, our cohort study results do not support LVOTO as an independent risk factor for SD in patients with hypertrophic cardiomyopathy.', 'The appearance of a "hump" at the ST segment during exercise testing appears to be a risk factor for SCD in patients with HCM. However, further studies are necessary to validate this finding in larger populations and to elucidate the mechanism of the appearance of the "hump."', 'The ICD is definitely indicated for secondary prevention of sudden death in patients with HCM who have survived a cardiac arrest with documented ventricular fibrillation, or experienced one or more episodes of sustained ventricular tachycardia.', 'A number of risk markers are used to assess the magnitude of risk, including family history of premature sudden death; extreme left ventricular (LV) hypertrophy (> 30 mm) in young patients; nonsustained ventricular tachycardia on Holter electrocardiographic recording; unexplained (not neurally mediated) syncope, particularly in young patients; and blood pressure decrease or inadequate increase during upright exercise.', 'Measured risk factors for sudden death included family history of sudden death, massive left ventricular hypertrophy, nonsustained ventricular tachycardia on Holter monitoring, and unexplained prior syncope.', 'The following risk factors were analyzed: 1) previous cardiac arrest or sustained ventricular tachycardia; 2) family history of sudden cardiac death; 3) high-risk genetic mutations; 4) syncope; 5) non-sustained ventricular tachycardia; 6) hypotensive response to exercise; and 7) marked left ventricular hypertrophy.', 'Family history of sudden death was associated with a positive predictive value of 25% for appropriate therapies, 40% for syncope and 50% for non-sustained ventricular tachycardia. ', 'In patients with an implantable cardioverter-defibrillator for primary prevention, non-sustained ventricular tachycardia was the risk factor with the highest predictive value. ', 'It is concluded that there is an association of the mutation Arg719Trp in the beta-myosin heavy chain with sudden cardiac death in a young child. ']

['The following risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy have been identified: 1) previous cardiac arrest; 2) sustained ventricular tachycardia; 3) family history of sudden cardiac death; 4) high-risk genetic mutations; 5) unexplained syncope; 6) non-sustained ventricular tachycardia; 7) hypotensive response to exercise; 8) marked left ventricular hypertrophy; 9) J-wave on ECG and 10) myocardial fibrosis using late gadolinium enhancement']

['myocardial fibrosis using late gadolinium enhancement', 'J-wave on ECG', 'Extreme left ventricular hypertrophy (>30mm)', 'Nonsustained ventricular tachycardia', 'Sustained ventricular tachycardia', 'previous cardiac arrest', 'family history of sudden cardiac death', 'unexplained syncope', 'hypotensive response to exercise', 'high-risk genetic mutations']

Which protein mediates gene loop formation in the yeast S. cerevisiae?

['A transcription-independent role for TFIIB in gene looping.', 'Moreover, looping is dependent upon the general transcription factor TFIIB: the E62K (glutamic acid 62 -->lysine) form of TFIIB adversely affects looping at every gene tested, including BLM10, SAC3, GAL10, SEN1, and HEM3', "TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP", "We present a high-resolution genome-wide map of TFIIB locations that implicates 3' NFRs in gene looping.", 'Instead, activators physically interacted with the general transcription factor TFIIB when the genes were activated and in a looped configuration. TFIIB cross-linked to both the promoter and the terminator regions during the transcriptionally activated state of a gene. ', ' We propose that the activators facilitate gene looping through their interaction with TFIIB during transcriptional activation of genes.', 'Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, requires transcription factor IIB (TFIIB).', 'We have earlier demonstrated association of TFIIB with the distal ends of a gene in an activator-dependent manner', 'Furthermore, TFIIB interaction with the CF1 complex and Pap1 is crucial for gene looping and transcriptional regulation.', 'TFIIB also cross-links to terminator regions and is required for gene loops that juxtapose promoter-terminator elements in a transcription-dependent manner.', 'These results define a novel, functional interaction between TFIIB and Ssl2 that affects start site selection and gene looping.', "Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB.", "Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB."]

["Moreover, looping is dependent upon the general transcription factor TFIIB: the E62K (glutamic acid 62 --> lysine) form of TFIIB adversely affects looping at every gene tested, including BLM10, SAC3, GAL10, SEN1, and HEM3. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP.", "Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP", 'Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, requires transcription factor IIB (TFIIB).', 'A transcription-independent role for TFIIB in gene looping.']

['TFIIB']

Has proteomics been used in the study of the dry eye syndrome?

['Tear proteomic analysis of patients with type 2 diabetes and dry eye syndrome by two-dimensional nano-liquid chromatography coupled with tandem mass spectrometry.', 'Dry eye syndrome in diabetic patients is associated with aberrant expression of tear proteins, and the findings could lead to identification of novel pathways for therapeutic targeting and new diagnostic markers.', ' 2D electrophoresis (2DE) and Differential gel electrophoresis (DIGE) was done to identify differentially expressed proteins. ', 'Two dimensional electrophoretic analysis of human tears: collection method in dry eye syndrome.', 'Identification of tear fluid biomarkers in dry eye syndrome using iTRAQ quantitative proteomics.', 'This study demonstrated that iTRAQ technology combined with 2D-nanoLC-nanoESI-MS/MS quantitative proteomics is a powerful tool for biomarker discovery.']

['Yes, tears obtained from patients with the dry eye syndrome have been analyzed using different proteomic technologies.']

['yes']

Is there a role of proton beam therapy in medulloblastoma treatment?

['All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma.', 'There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas.', 'Cost-effectiveness analysis of cochlear dose reduction by proton beam therapy for medulloblastoma in childhood.', 'BACKGROUND: The aim of this study is to evaluate the cost-effectiveness of proton beam therapy with cochlear dose reduction compared with conventional X-ray radiotherapy for medulloblastoma in childhood.METHODS: We developed a Markov model to describe health states of 6-year-old children with medulloblastoma after treatment with proton or X-ray radiotherapy.', 'Evaluation of permanent alopecia in pediatric medulloblastoma patients treated with proton radiation.', 'BACKGROUND: To precisely calculate skin dose and thus to evaluate the relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with proton beams.', 'CONCLUSIONS: Our results based on 12 patients provide a relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with protons. ', 'Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma.', 'PURPOSE: Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma.', 'CONCLUSIONS: This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. ', 'Dilemmas concerning dose distribution and the influence of relative biological effect in proton beam therapy of medulloblastoma.', 'OBJECTIVE: To improve medulloblastoma proton therapy.', 'The aim of this study is to evaluate the cost-effectiveness of proton beam therapy with cochlear dose reduction compared with conventional X-ray radiotherapy for medulloblastoma in childhood.', 'The aim of this study is to evaluate the cost-effectiveness of proton beam therapy with cochlear dose reduction compared with conventional X-ray radiotherapy for medulloblastoma in childhood.We developed a Markov model to describe health states of 6-year-old children with medulloblastoma after treatment with proton or X-ray radiotherapy', 'All patients completed therapy without interruption.Our proton-beam technique for craniospinal irradiation of pediatric medulloblastoma has successfully reduced normal-tissue doses and acute treatment-related sequelae', 'Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuro-ectodermal tumors: spinal theca irradiation', 'For 6 MV x-rays > 60% of the dose prescribed to the target was delivered to 44% of the heart volume, while the proton beam was able to completely avoid the heart, the liver, and in all likelihood the thyroid and gonads as well.The present study demonstrates a potential role of proton therapy in decreasing the dose (and toxicity) to the critical structures in the irradiation of the spinal neuraxis in medulloblastoma/PNET', 'Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume', 'This review describes the role of radiation in general and proton therapy in particular for the treatment of medulloblastoma, central nervous system primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, and the recently described embryonal tumor with multilayered rosettes', 'Reducing toxicity from craniospinal irradiation: using proton beams to treat medulloblastoma in young children.', 'Intensity-modulated radiotherapy did show more bladder dose reduction than the other techniques in pelvic sarcoma irradiation.CONCLUSIONS: In the diseases studied, using various techniques of 3D-CRT, electrons, IMRT, and protons, protons are most optimal in treating retinoblastomas, medulloblastomas (posterior fossa and craniospinal), and pelvic sarcomas.', 'For 6 MV x-rays>60% of the dose prescribed to the target was delivered to 44% of the heart volume, while the proton beam was able to completely avoid the heart, the liver, and in all likelihood the thyroid and gonads as well.CONCLUSION: The present study demonstrates a potential role of proton therapy in decreasing the dose (and toxicity) to the critical structures in the irradiation of the spinal neuraxis in medulloblastoma/PNET.', 'In medulloblastoma, three posterior fossa irradiation techniques were analyzed: 3D-CRT, IMRT, and protons.', 'Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuro-ectodermal tumors: spinal theca irradiation.', 'Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume.', 'The present study demonstrates a potential role of proton therapy in decreasing the dose (and toxicity) to the critical structures in the irradiation of the spinal neuraxis in medulloblastoma/PNET.', 'Cost-effectiveness analysis of cochlear dose reduction by proton beam therapy for medulloblastoma in childhood.', 'Dilemmas concerning dose distribution and the influence of relative biological effect in proton beam therapy of medulloblastoma.', 'To improve medulloblastoma proton therapy.', 'Our proton-beam technique for craniospinal irradiation of pediatric medulloblastoma has successfully reduced normal-tissue doses and acute treatment-related sequelae.', 'Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques?']

['Yes, proton beam therapy is used for treatment of medulloblastoma.']

['yes']

Is edema a symptom of nephrotic syndrome?

['Nephrotic syndrome (NS) is a common clinical disease with four main clinical manifestations: hypoalbuminemia (<30 g/L), macro-proteinuria (>3.5 g/24 h), edema, and hyperlipidemia. ', 'Nephrotic syndrome is an unusual manifestation of IgA Nephropathy (IgAN).', 'Twelve patients with IgAN with steroid-responsive nephrotic syndrome were evaluated and followed up. All patients presented with generalized edema. ', 'The clinical features of sudden onset of generalized edema, initial heavy proteinuria and initial severe hypoalbuminemia might help identify the subset of patients, especially in low grade IgAN.', 'Most patients presented within 3 months duration (61.4%) and the most common symptom was puffiness of face (98.45%) followed by pedal edema (91%). ', 'We analyzed medical records of 290 patients with diagnosis of nephrotic syndrome as defined by International Study of Kidney Disease in Children (ISKDC), between January 1987 and December 2000, at the Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar. ', 'He was admitted because of systemic edema and dyspnea on effort Laboratory data revealed renal failure and nephrotic syndrome, whereas there was no symptom of diabetic retinopathy.', 'Nephrotic syndrome: more than just oedema.', 'Oedema is the commonest presenting symptom and sign in nephrotic syndrome. ', 'One of these five clinical syndromes is the nephrotic syndrome, which is characterized by proteinuria > 3.5 g/day accompanied by hypalbuminemia, hyperlipoproteinemia and pronounced edema', 'Tolvaptan therapy for massive edema in a patient with nephrotic syndrome', 'Nephrotic syndrome (NS) is characterized by water and sodium retention, which leads to edema', 'The non-osmotic stimulation of arginine vasopressin release from the pituitary gland has been implicated as one of the important factors in abnormal water retention in patients with NS.We present the initial description of a patient with massive edema caused by refractory nephrotic syndrome, which was effectively treated with tolvaptan, a selective oral vasopressin V2 receptor antagonist.Tolvaptan is effective for the treatment of massive edema caused by NS', 'We report a child with steroid-resistant nephrotic syndrome with diuretic-resistant nephrotic edema treated successfully using acute peritoneal dialysis as a means of UF', 'Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies', 'The treatment of edema in patients with nephrotic syndrome is generally managed by dietary sodium restriction and loop diuretics', 'Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome', 'Blessed were the days when it all made sense and the apparent mechanism for edema formation in nephrotic syndrome was straightforward: the kidneys lost protein in the urine, which lowered the plasma oncotic pressure', 'The nephrotic syndrome is characterized by a combination of pathological lab values and clinical symptoms, i. e. pronounced proteinuria (usually more than 3 - 3,5 g protein/24 h), hypoalbuminemia, edema and hyperlipidemia.', 'The patient was admitted with edema of both legs, and the nephrotic syndrome was discovered, leading to the diagnosis of AA amyloidosis on kidney biopsy.', 'Linear regression to relate measures.Other signs and symptoms of nephrotic syndrome at baseline (serum albumin < 3.5 g/dL, serum total cholesterol > 260 mg/dL or use of a statin, and edema or use of a loop diuretic); progression of chronic kidney disease during follow-up (doubling of baseline serum creatinine level or requirement for dialysis or kidney transplantation).', 'A case of interstitial shadows associated with oral cyclophosphamide therapy in a 32-month-old girl with steroid-resistant nephrotic syndrome, who was admitted to the Nishi-Kobe Medical Center with systemic edema, is reported.', 'Nephrotic syndrome represents a constellation of symptoms including hyperalbuminuria, hypoalbuminemia, edema formation, hypercholesterolemia, hypertension, hypercoagulopathy, and increased infection risk.', 'Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease.', 'To study the evidence-based therapy of edema in nephrotic syndrome by analyzing the literatures systematically.', 'Edema is the prominent feature of nephrotic syndrome and initially develops around the eyes and legs.', 'Intussusception should be considered in the differential diagnosis of abdominal pain in patients with nephrotic syndrome, especially in patients exhibiting prolonged edema.', 'Oedema is the commonest presenting symptom and sign in nephrotic syndrome.', 'Other signs and symptoms of nephrotic syndrome at baseline (serum albumin < 3.5 g/dL, serum total cholesterol > 260 mg/dL or use of a statin, and edema or use of a loop diuretic); progression of chronic kidney disease during follow-up (doubling of baseline serum creatinine level or requirement for dialysis or kidney transplantation).']

['Yes, edema is the commonest presenting symptom and sign in nephrotic syndrome.']

['yes']

Is apremilast effective for psoriasis?

['CONCLUSION: Apremilast reduces the severity of nail/scalp psoriasis.', 'CONCLUSIONS: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52\u2005weeks.', 'Apremilast: A Novel Drug for Treatment of Psoriasis and Psoriatic Arthritis.', 'In those that involved doses of 30 mg twice daily, a significantly greater percentage of patients receiving apremilast (28.8% to 40.9%) compared with placebo (5.3% to 5.8%) achieved at least 75% improvement from baseline in Psoriasis Area and Severity Index score at 16 weeks.', 'CONCLUSIONS: Apremilast has a novel mechanism of action and is safe and effective for the management of psoriasis and psoriatic arthritis. At this time, apremilast should be reserved for patients unable to take disease-modifying antirheumatic drugs.', 'Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1).', 'More recently, three larger double-blinded, and randomized multicenter studies demonstrate that apremilast is efficacious in the treatment of psoriasis and PsA, with significantly higher numbers of apremilast-treated patients achieving endpoints of a 75% reduction compared to baseline in Psoriasis Area and Severity Index (PASI-75) or American College of Rheumatology-20 scores, relative to placebo.', 'No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period.Data were limited to 52 weeks and may not generalize to nonplaque psoriasis.Apremilast was effective in moderate to severe plaque psoriasis.<CopyrightInformation>Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.</', 'Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediator production.Assess apremilast efficacy and safety in moderate to severe plaque psoriasis.Phase II, 12-week, multicenter, double-blind, placebo-controlled, parallel-group, dose-comparison study of 259 subjects randomized 1 : 1 : 1 to placebo, apremilast 20 mg QD or apremilast 20 mg BID.More subjects receiving apremilast 20 mg BID achieved ≥ 75% reduction in Psoriasis Area and Severity Index (PASI-75) vs. placebo (24.4% vs. 10.3%; P = 0.023)', 'Apremilast, a specific inhibitor of phosphodiesterase 4, modulates pro-inflammatory and anti-inflammatory cytokine production.Apremilasts effect on patient-reported outcomes (PROs) in patients with moderate to severe psoriasis was evaluated in a phase IIb randomized, controlled trial (NCT00773734).In this 16-week, placebo-controlled study, 352 patients with moderate to severe plaque psoriasis received placebo or apremilast (10, 20, or 30 mg BID)', 'Although further longer-term and comparative efficacy and tolerability data would be beneficial, the current clinical data indicate that apremilast is an effective and well tolerated option for the management of psoriasis and PsA in adults', 'More recently, three larger double-blinded, and randomized multicenter studies demonstrate that apremilast is efficacious in the treatment of psoriasis and PsA, with significantly higher numbers of apremilast-treated patients achieving endpoints of a 75% reduction compared to baseline in Psoriasis Area and Severity Index (PASI-75) or American College of Rheumatology-20 scores, relative to placebo', 'No deaths or opportunistic infections were reported.Apremilast 20 mg BID for 12 weeks was effective and well tolerated in subjects with moderate to severe plaque psoriasis.<CopyrightInformation>© 2012 The Authors', 'In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis.', 'Although further longer-term and comparative efficacy and tolerability data would be beneficial, the current clinical data indicate that apremilast is an effective and well tolerated option for the management of psoriasis and PsA in adults.', 'No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period.Data were limited to 52 weeks and may not generalize to nonplaque psoriasis.Apremilast was effective in moderate to severe plaque psoriasis.<CopyrightInformation>Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.</C', 'Several drug peculiarities, such as the low frequency of adverse events and the oral route of administration, make apremilast an innovative treatment for moderate-to-severe psoriasis.', 'Two new oral medications, apremilast and tofacitinib, have been developed for their immunomodulatory properties, and their potential efficacy in treating psoriasis is being evaluated.We reviewed phase III randomized, placebo-controlled clinical trial results for apremilast and tofacitinib for efficacy and safety in psoriasis.Psoriasis Area and Severity Index (PASI) 75 after 16 weeks for apremilast was between 28.8% and 33.1%.', 'Apremilast was effective in moderate to severe plaque psoriasis..', 'Both new oral medications, apremilast and tofacitinib, appear to be effective in treating psoriasis.', 'Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52\xa0weeks..', 'Apremilast is an effective and well-tolerated option in treating moderate-to-severe plaque psoriasis.', 'Apremilast has a novel mechanism of action and is safe and effective for the management of psoriasis and psoriatic arthritis.', 'Apremilast 20 mg BID for 12 weeks was effective and well tolerated in subjects with moderate to severe plaque psoriasis..', 'Apremilast for the treatment of psoriasis.', 'Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical trials in patients with moderate to severe psoriasis.']

['Yes, apremilast is effective for treatment of psoriasis.']

['yes']

How many tissue kallikrein genes are present in the human genome?

['Tissue kallikreins are a group of closely related serine proteinases that are represented by multigene families in mice and rats.', 'Our map specifies the distance between genes to one base pair accuracy, the relative location, and the direction of transcription of all 15 genes.', 'The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis.', 'The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions.', 'The 15 human and 24 mouse kallikreins have been implicated in pathophysiology of brain, kidney, and respiratory and reproductive systems and often are used as cancer biomarkers.', 'Kallikrein gene families have been identified previously in genomes of the human, the mouse, and the rat, and individual kallikrein-like genes have been found in many more species.', 'The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes.', 'The tissue kallikrein gene family consists of 15 genes tandemly arranged on human chromosome 19q13.4.', 'Human kallikreins are a cluster of 15 serine protease genes located in the chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors, including pancreatic cancer.', 'Tissue kallikrein genes (KLKs) are found on chromosome 19q13.3-4 as a gene cluster encoding 15 different serine proteases.', 'Project to perform in silico analyses of the expression pattern of the 15 human KLK genes in normal and cancerous ovarian tissues and cell lines.', 'Novel kallikrein genes were cloned recently, and it was shown that the human kallikrein family contains 15 genes tandemly aligned on chromosomal locus 19q13.3-q13.4.', 'The human kallikrein gene family consists of 15 serine proteases.', 'We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes.', 'The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles.', 'that forms the largest cluster of contiguous protease genes in the human genome.', 'Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases encoded by the largest uninterrupted cluster of protease-encoding genes within the human genome.', 'In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins.', 'The human tissue kallikrein gene family is the largest contiguous family of proteases in the human genome, containing 15 genes.', 'Human tissue kallikrein genes represent the largest contiguous group of proteases within the human genome.', 'Human tissue kallikreins (hKs), which are encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles.']

['Tissue kallikreins (KLKs) are a group of closely related serine proteinases that are represented by multigene families in the human genome. The human tissue kallikrein gene family consists of 15 genes, denoted KLK1–KLK15, tandemly arranged on chromosomal locus 19q13.4.']

['15']

Which are currently available software tools for detecting rare codon clusters in coding sequences?

['Our program Sherlocc, detects statistically relevant conserved rare codon clusters and produces a user-friendly HTML output.', 'LaTcOm: a web server for visualizing rare codon clusters in coding sequences', "We present LaTcOm, a new web tool, which offers several alternative methods for 'rare codon cluster' (RCC) identification", 'three RCC detection schemes are implemented: the recently described %MinMax algorithm and a simplified sliding window approach, along with a novel modification of a linear-time algorithm for the detection of maximally scoring subsequences tailored to the RCC detection problem', 'The PAUSE software has been developed as a new tool to study translational control over protein targeting. This makes it possible to correlate the position of clusters of rare codons in a gene, predicted to cause a translational pause, with the position of hydrophobic stretches in the encoded protein, predicted to span a membrane or to act as a cleavable signal for targeting to the secretory pathway.']

['Rare codon clusters (RCCs) correspond to regions along mRNA sequences where among the possible choices of synonymous codons those with lower usage are observed. Due to the fact that relative codon frequencies have been shown to correlate with their cognate tRNA frequencies, RCCs indicate possible translational attenuation sites. A few tools specific for this task have been described in the literature, namely: LaTcOm, %MinMax, PAUSE, Sherlocc, Sliding Window (RiboTempo)']

['LaTcOm', '%MinMax', 'PAUSE', 'Sherlocc', 'Sliding Window', 'RiboTempo']

Is cytisine superior to nicotine replacement therapy for smoking cessation?

['The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men.', 'CONCLUSIONS: When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.']

['Yes, one clinical trial that directly compared smoking cessation rates with cytisine versus nicotine replacement therapy reported that cytisine was superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.']

['yes']

What is situs inversus?

['Situs inversus totalis is a relatively rare condition and is an autosomal recessive congenital defect in which an abdominal and/or thoracic organ is positioned as a "mirror image" of the normal position in the sagittal plane.', 'Situs inversus totalis (SIT) represents a total vertical transposition of the thoracic and abdominal organs which are arranged in a mirror image reversal of the normal positioning.', 'The patient had dextrocardia situs inversus totalis with a mirror-image reversal of the thoracic and abdominal organs.', 'Situs inversus totalis (SIT) is characterized by complete mirroring of gross cardiac anatomy and position combined with an incompletely mirrored myofiber arrangement, being normal at the apex but inverted at the base of the left ventricle (LV).', 'Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs. ', ' Situs inversus totalis (SIT) is an uncommon congenital syndrome, which refers to a reversal mirror-image of the normal thoracoabdominal organs position.']

['Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs.']

['Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs.']

Which clotting factor is inhibited by betrixaban?

['Evaluation of the oral direct factor Xa inhibitor - betrixaban.', 'Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. ', 'Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717.', 'Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). ', 'They must be modified and standardized for the measurement of direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban and others). ', 'Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. ', ' These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). ', 'Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa.', 'The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717.', 'Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. ', 'EXPERT OPINION: A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban.', 'Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies.', 'Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. ', 'Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments.', 'Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. ', 'Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation.', 'Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. ', 'Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa.', '[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban].', 'Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE).', 'A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT).', 'Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion.', 'Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism.', 'Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)].', 'Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban.', 'Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban.', 'Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists.', 'Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity.', 'Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux).', 'Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor.', 'Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome.', 'Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa', 'These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin)', 'These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin)', 'Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE)', 'Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion.', 'Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism', 'Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban.', 'Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa']

['Betrixaban is an orally administered direct clotting factor Xa inhibitor.']

['Xa']

What do hamartin and tuberin gene products do and how are they connected to the mTOR pathway?

['["The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2.", "The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently", "Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors", "Ten years ago, a mutation in the TSC2 gene was identified in the Eker rat at Fox Chase Cancer Center by Yeung and Knudson, and in Tokyo by Kobayashi and Hino.", "Here, we will review the clinical association of RCC in TSC, consider the factors that have led to its under-emphasis within the RCC field, address the cellular and biochemical mechanisms that may contribute to RCC in cells with TSC1 or TSC2 mutations, and finally discuss the ways in which the TSC signaling pathways may be linked to sporadic RCC in the general population.", "Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype.", "The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways", "Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. ", "TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease.", "We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis.", "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis", "The disease can be caused by mutations in either of two genes, TSC2, identified in 1993, and TSC1, only recently identified.", "Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis (Tsc2)", "We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat", "Tuberous sclerosis complex is a genetic disorder caused by mutations in either the TSC1 or TSC2 gene that can result in the growth of hamartomas in multiple organ systems", "Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway. ", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway.", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13."]', '["The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2.", "The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently", "Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors", "Ten years ago, a mutation in the TSC2 gene was identified in the Eker rat at Fox Chase Cancer Center by Yeung and Knudson, and in Tokyo by Kobayashi and Hino.", "Here, we will review the clinical association of RCC in TSC, consider the factors that have led to its under-emphasis within the RCC field, address the cellular and biochemical mechanisms that may contribute to RCC in cells with TSC1 or TSC2 mutations, and finally discuss the ways in which the TSC signaling pathways may be linked to sporadic RCC in the general population.", "Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype.", "The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways", "Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. ", "TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease.", "We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis.", "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis", "The disease can be caused by mutations in either of two genes, TSC2, identified in 1993, and TSC1, only recently identified.", "Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis (Tsc2)", "We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat", "Tuberous sclerosis complex is a genetic disorder caused by mutations in either the TSC1 or TSC2 gene that can result in the growth of hamartomas in multiple organ systems", "Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway. ", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway.", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13."]']

The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently. Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival.

[]

What is the typical outer diameter of microtubules (tubulin heterodimers)?

['microtubules are highly anisotropic structures built from tubulin heterodimers. They are hollow cylindrical shells with a ∼ 25\xa0nm outer diameter', 'single microtubules (diameter 25 nm', 'The individual microtubules measured about 24 nm in outer diameter', 'Microtubules are hollow tubes some 25 nm in diameter participating in the eukaryotic cytoskeleton.', 'Microtubule assembly is accompanied by hydrolysis of GTP associated with beta-tubulin so that microtubules consist principally of "GDP-tubulin" stabilized by a short "GTP cap." Microtubules are polar, cylindrical structures some 25 nm in diameter.', 'They are hollow cylindrical shells with a ∼ 25\xa0nm outer diameter and are tens of microns long', 'Microtubule assembly is accompanied by hydrolysis of GTP associated with beta-tubulin so that microtubules consist principally of "GDP-tubulin" stabilized by a short "GTP cap." Microtubules are polar, cylindrical structures some 25 nm in diameter', 'Microtubules are hollow tubes some 25 nm in diameter participating in the eukaryotic cytoskeleton']

['Microtubules are highly anisotropic structures built from tubulin heterodimers. They are hollow cylindrical shells with a ∼ 25 nm (24nm - 25nm) outer diameter.']

['24nm - 25 nm']

Which metabolite activates AtxA?

['Here we report that bioinformatic analyses suggested the presence in AtxA of two PTS (phosphenolpyruvate : sugar phosphotransferase system) regulation domains (PRD) generally regulated by phosphorylation/dephosphorylation at conserved histidine residues.', 'Our results link virulence factor production in B. anthracis to carbohydrate metabolism and, for the first time, provide a mechanistic explanation for AtxA transcriptional activity.', 'Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer.', 'The 475 amino acid sequence of AtxA reveals DNA binding motifs and regions similar to proteins associated with the phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS). ', 'cultures grown with elevated CO(2) /bicarbonate exhibited increased AtxA dimer/monomer ratios and increased AtxA activity, relative to cultures grown without added CO(2) /bicarbonate, suggesting that this host-associated signal enhances AtxA function by shifting the dimer/monomer equilibrium towards the dimeric state.', 'Transcription of the major Bacillus anthracis virulence genes is triggered by CO2, a signal mimicking the host environment. ', 'Furthermore, in vitro in presence of CO2 and in vivo, AtxA is part of the sap and eag regulatory network. ', 'Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis.', ' In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. ', 'Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. ', 'The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2', 'CO2-enhanced toxin gene transcription is not observed in atx4-null mutants.', 'Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. ', 'Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. ', 'data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.', 'Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate.', 'The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis.', 'Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism', 'Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. ', 'Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism.', 'Expression of the toxin genes by B. anthracis is enhanced during growth under elevated levels of CO2.', 'This CO2 effect is observed only in the presence of another pXO1 gene, atxA, which encodes a transactivator of anthrax toxin synthesis.', 'Here we show that transcription of atxA does not appear to differ in cells grown in 5% CO2 compared with cells grown in air.', 'Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site.', 'We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate.', 'Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate.', 'Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis.', 'The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis.']

['Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer. Cultures grown with elevated CO(2) /bicarbonate exhibited increased AtxA dimer/monomer ratios and increased AtxA activity, relative to cultures grown without added CO(2) /bicarbonate, suggesting that this host-associated signal enhances AtxA function by shifting the dimer/monomer equilibrium towards the dimeric state. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Overall data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.', 'Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. All mutants multimerized, but one mutation, C402S, prevented cross-linking.']

['CO2', 'bicarbonate']

What is the main role of Ctf4 in dna replication?

['In this report, interactions between human Ctf4 (hCtf4) and the replicative helicase containing the cell division cycle 45 (Cdc45)/minichromosome maintenance 2-7 (Mcm2-7)/Go, Ichi, Nii, and San (GINS) (CMG) proteins [human CMG (hCMG) complex] were examined', 'We demonstrate that the hCtf4-CMG complex contains a homodimeric hCtf4 and a monomeric hCMG complex and suggest that the homodimeric hCtf4 acts as a platform linking polymerase α to the hCMG complex', 'Drosophila Ctf4 is essential for efficient DNA replication and normal cell cycle progression', 'The Ctf4 protein has been shown to be a central member of the replication fork and links the replicative MCM helicase and DNA polymerase α primase', ' it has been implicated as a member of a complex that promotes replication fork stability, the Fork Protection Complex (FPC), and as being important for sister chromatid cohesion', 'Drosophila Ctf4 is a conserved protein that interacts with members of the GINS complex, Mcm2, and Polymerase α primase', 'Ctf4 remains a central player in DNA replication', 'These data indicate that Ctf4p facilitates Mcm10p to promote the DNA replication', ' hCtf4 plays an essential role in DNA replication and its ability to stimulate the replicative DNA polymerases ', 'Our data indicate that a complex of the GINS and Ctf4 components of the RPC is crucial to couple MCM2-7 to DNA polymerase alpha', 'coupling MCM2-7 to replicative polymerases is an important feature of the regulation of chromosome replication in eukaryotes, and highlight a key role for Ctf4 in this process', 'Ctf4 coordinates the progression of helicase and DNA polymerase alpha', 'Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication', 'We show that And-1/Ctf4 (Chromosome transmission fidelity 4) interacts with Mcm10, which associates with MCM2-7, and with the p180 subunit of DNA pol alpha', 'And-1/Ctf4 is therefore a new replication initiation factor that brings together the MCM2-7 helicase and the DNA pol alpha-primase complex, analogous to the linker between helicase and primase or helicase and polymerase that is seen in the bacterial replication machinery', 'Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication.', 'Ctf4 remains a central player in DNA replication.', 'Drosophila Ctf4 is essential for efficient DNA replication and normal cell cycle progression.', 'Influence of the human cohesion establishment factor Ctf4/AND-1 on DNA replication.', 'Ctf4/AND-1 is a highly conserved gene product required for both DNA replication and the establishment of sister chromatid cohesion.', 'In this report, we examined the mechanism of action of human Ctf4 (hCtf4) in DNA replication both in vitro and in vivo.', 'And-1/Ctf4 is therefore a new replication initiation factor that brings together the MCM2-7 helicase and the DNA pol alpha-primase complex, analogous to the linker between helicase and primase or helicase and polymerase that is seen in the bacterial replication machinery.', 'We show that cells lacking both Ctf4 and Mrc1 experience chronic activation of the DNA damage checkpoint during chromosome replication and do not complete the cell cycle.', 'Using in vivo RNAi knockdown of CTF4 in Drosophila we show that Ctf4 is required for viability, S phase progression, sister chromatid cohesion, endoreplication, and coping with replication stress.', 'We show that Ctf4 function is conserved and that Drosophila can be effectively used as a model to further probe the precise function of Ctf4 as a member of the replication fork and possible roles in development.', 'Chromosome transmission fidelity 4 (Ctf4) is a conserved protein required for DNA replication.', 'Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks.', 'A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryotic replisome.']

['coupling MCM2-7 to replicative polymerases is an important feature of the regulation of chromosome replication in eukaryotes, and highlight a key role for Ctf4 in this processAnd-1/Ctf4 is therefore a new replication initiation factor that brings together the MCM2-7 helicase and the DNA pol alpha-primase complex, analogous to the linker between helicase and primase or helicase and polymerase that is seen in the bacterial replication machinery', 'Ctf4 coordinates the progression of helicase and DNA polymerase alpha. Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication. And-1/Ctf4 is therefore a new replication initiation factor that brings together the MCM2-7 helicase and the DNA pol alpha-primase complex, analogous to the linker between helicase and primase or helicase and polymerase that is seen in the bacterial replication machinery.']

['Coordination of the progression of helicase and DNA polymerase alpha at the eukaryotic replication fork.']

What role does the SHH-Gli pathway play in brain growth and medulloblastoma, in relation to WNT signaling and potential therapy with cyclopamine?

['148a having potential tumor/metastasis suppressive activity were found to be overexpressed in the WNT signaling associated medulloblastomas", "The requirement for SHH-Gli signaling in the growth of the mouse brain, together with the ability of inappropriate pathway activation in the cerebellum to cause medulloblastomas, and the inhibition of the growth of a number of brain tumors with cyclopamine, a SHH signaling inhibitor, underscores the critical role of the SHH-GLI pathway in brain growth and tumor formation", "Aberrant activation of the Hedgehog (Hh) and Wnt developmental pathways is associated with medulloblastoma, but deregulation of other molecular pathways, including insulin-like growth factor (IGF) signaling, has also been implicated in the pathogenesis of the tumor", "Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway."]', '148a having potential tumor/metastasis suppressive activity were found to be overexpressed in the WNT signaling associated medulloblastomas", "The requirement for SHH-Gli signaling in the growth of the mouse brain, together with the ability of inappropriate pathway activation in the cerebellum to cause medulloblastomas, and the inhibition of the growth of a number of brain tumors with cyclopamine, a SHH signaling inhibitor, underscores the critical role of the SHH-GLI pathway in brain growth and tumor formation", "Aberrant activation of the Hedgehog (Hh) and Wnt developmental pathways is associated with medulloblastoma, but deregulation of other molecular pathways, including insulin-like growth factor (IGF) signaling, has also been implicated in the pathogenesis of the tumor", "Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway."]']

The SHH-Gli pathway plays a critical role in brain growth and tumor formation, particularly in medulloblastomas associated with WNT signaling. Inappropriate pathway activation in the cerebellum can lead to medulloblastomas, and the growth of brain tumors can be inhibited with cyclopamine, a SHH signaling inhibitor.

[]

Which NGS alignment software implement the Burrows-Wheeler Transform?

['For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches.', 'We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows-Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.', 'SOAP2 is a significantly improved version of the short oligonucleotide alignment program that both reduces computer memory usage and increases alignment speed at an unprecedented rate. We used a Burrows Wheeler Transformation (BWT) compression index to substitute the seed strategy for indexing the reference sequence in the main memory.', "We designed and implemented a new algorithm, Burrows-Wheeler Aligner's Smith-Waterman Alignment (BWA-SW), to align long sequences up to 1 Mb against a large sequence database (e.g. the human genome) with a few gigabytes of memory.", 'Here, we propose a new base-calling algorithm, TotalReCaller, to achieve improved performance. A linear error model for the raw intensity data and Burrows-Wheeler transform (BWT) based alignment are combined utilizing a Bayesian score function, which is then globally optimized over all possible genomic locations using an efficient branch-and-bound approach.', 'To tackle this problem, a new alignment tool BWBBLE is introduced in this article. We (i) introduce a new compressed representation of a collection of genomes, which explicitly tackles the genomic variation observed at every position, and (ii) design a new alignment algorithm based on the Burrows-Wheeler transform that maps short reads from a newly sequenced genome to an arbitrary collection of two or more (up to millions of) genomes with high accuracy and no inherent bias to one specific genome.', 'Seed-based algorithms are generally slow but robust, while Burrows-Wheeler Transform (BWT) based algorithms are fast but less robust. To have both advantages, we developed an algorithm FANSe2 with iterative mapping strategy based on the statistics of real-world sequencing error distribution to substantially accelerate the mapping without compromising the accuracy.', "Therefore, in this paper, we introduce Burrows-Wheeler Aligner's Smith-Waterman Alignment on Parallel MapReduce (BWASW-PMR) cloud platform for long sequence alignment.", 'In this paper, we propose a BWA-MT tool, evolved from BWA but supporting multi-thread computation, designed to fully utilize the underlying multi-core architecture of computing resources. By using multi-thread computation, BWA-MT can significantly shorten the time needed to generate an alignment for single-end read sequences.', 'The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals.We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows-Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps', 'Although the Burrows-Wheeler Aligner (BWA) tool is one of the most widely used open-source software tools to align read sequences, it is still limited in that it does not fully support multi-thread mechanisms during the alignment steps', 'We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows-Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.', "We designed and implemented a new algorithm, Burrows-Wheeler Aligner's Smith-Waterman Alignment (BWA-SW), to align long sequences up to 1 Mb against a large sequence database (e.g.", 'Although the Burrows-Wheeler Aligner (BWA) tool is one of the most widely used open-source software tools to align read sequences, it is still limited in that it does not fully support multi-thread mechanisms during the alignment steps.']

['The most widely used software belong to the family of the Burrows-Wheeler Aligner (BWA) and its variants for local alignment BWASW, map reduce BWASW-PMR and multi-threaded implementation BWA-MT. Other approaches include Bowtie, SOAP2, BWBBLE, SOAP2 and FANSe2.']

['Bowtie', 'Burrows-Wheeler Alignment Tool', 'BWA', 'SOAP2', "Burrows-Wheeler Aligner's Smith-Waterman Alignment", 'BWA-SW', 'TotalReCaller', 'BWBBLE', 'FANSe2', "Burrows-Wheeler Aligner's Smith-Waterman Alignment Map Reduce", 'BWASW-PMR', 'Burrows-Wheeler Aligner Multi-Thread', 'BWA-MT']

What is the most likely age of diagnosis of Crohn's disease (CD)?

['Eighteen, 17, and 12 patients were diagnosed at ages<40, 40-59, and ≥60 years, respectively', "Crohn's disease (CD) diagnosed in pediatric patients has been reported to have a more aggressive phenotype and course, with a greater prevalence of upper gastrointestinal involvement, than in adults.", 'There was a significant association between body mass index and bone mineral density (P = 0.004) and a significant difference in the T scores of patients according to age at diagnosis (Montreal Classification: P = 0.0006) with patients diagnosed<17 years (n = 13) having lower T scores than those diagnosed at older age groups (n = 70).', 'Increasing age of diagnosis was negatively associated with complicated disease and positively associated with colonic disease. As age of diagnosis increased, disease duration (P<0.001), family history of Inflammatory bowel disease (IBD) (P = 0.015) and perianal disease decreased (P<0.0015). ', "Crohn's disease incidence rates in the 10-19-year age category increased by 71%, from 6.5 (1988-1990) to 11.1 (2006-2007)", "Consequently, studies on Crohn's disease risk factors should focus on the population under 20 years of age.", "For those with biologic use, average age at time of diagnosis of Crohn's disease was 32.3 ± 12.2 years, compared with 43.7 ± 16.3 years for those who had not received biologics (P = 0.005).", 'Sixty one patients (50.4%) were 20-39 years old and 43 patients (35.5%) were 40 years and older. Colonic involvement was significantly more common (46,5%) in the 40 years and older group compared with 20-39 years group (24.6%) (p = 0.01)', "When the age-related incidence of Crohn's disease was plotted for all countries from which such data were available, the peaks of greatest case frequency occurred at ages 15 to 25 years and paralleled a similar peak representing the number of Peyer's patches as a function of age", "Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals. ", 'Current therapy for CD in the UK is less likely than previously to involve the use of long-term glucocorticoids.WHAT THIS STUDY ADDS: Despite advances in therapy, short stature and slow growth continue to be encountered in children with CD. There is a need for simple and consistent definitions of growth that can identify poor growth in children with chronic disease.METHODS: The anthropometric and treatment details of 116 children (68 male) with a mean (range) age at diagnosis of 10.8 years (4.9-15.5) and a mean age at maximum follow-up (MF) of 15.4 years (9.4-19.3) were studied retrospectively at diagnosis (T0), at 1 (T1), 2 (T2) and 3 years (T3) after diagnosis and at MF.RESULTS: At T0, mean height SD score (HtSDS) was -0.5 (-3.3 to 2.6) compared to a mid-parental HtSDS of 0.2 (-2.0 to 01.4) (p=0.002). ', 'White patients were significantly more likely to have ileal disease, whereas African American patients were significantly more likely to have ileocolonic and colonic disease. Age at diagnosis younger than 40 years (odds ratio [OR] 4.', 'Both age at diagnosis and site of CD involvement were independently associated with expression of ASCA and anti-CBir1.Compared to children 8-15 years of age at diagnosis, those 0-7 years are more likely to express anti-CBir1 but only half as likely to express ASCA.']

["Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals. When the age-related incidence of Crohn's disease was plotted for all countries from which such data were available, the peaks of greatest case frequency occurred at ages 15 to 25 years and paralleled a similar peak representing the number of Peyer's patches as a function of age. For those with biologic use, average age at time of diagnosis of Crohn's disease was 32.3 ± 12.2 years, compared with 43.7 ± 16.3 years for those who had not received biologics (P = 0.005)."]

["Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals."]

Which is the neurodevelopmental disorder associated to mutations in the X- linked gene mecp2?

['Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2).', 'Rett syndrome is one of the most common causes of complex disability in girls. It is characterized by early neurological regression that severely affects motor, cognitive and communication skills, by autonomic dysfunction and often a seizure disorder. It is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2.', 'Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed.', 'Out of the 365 cases, 315 had MECP2 gene mutations and 3 had de novo CDKL5 gene mutations. No patients had FOXG1 mutation.', 'Mutations were detected in ≈ 70% of classic and ≈ 21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations.', 'Mutations in the MECP2 gene were detected in 13 of the 20 (65 percent) RS patients.', 'This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations', 'Mutation screening revealed 31 different mutations in 68 patients and 12 non-pathogenic polymorphisms.', 'In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients.', 'Mutations in MECP2 were found in about 55%', 'We identified mutations in the MECP2 gene and documented the clinical manifestations in 65 Rett syndrome patients to characterize the genotype-phenotype spectrum.', 'We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females. Following our previous report of mutations in two families and eight sporadic cases, we here present 18 additional mutations.', 'The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences.', 'Mutations were identified in 44/55 (80%) unrelated classical sporadic and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT', 'Collectively, we tested 228 unrelated female patients with a diagnosis of possible (209) or classic (19) RTT and found MECP2 mutations in 83 (40%) of 209 and 16 (84%) of 19 of the patients, respectively. Thirty-two different mutations were identified (8 missense, 9 nonsense, 1 splice site, and 14 frameshifts), of which 12 are novel and 9 recurrent in unrelated patients.', 'Mutations in MECP2 were identified from most of the patients with classical and variant RTT (25 of 27 cases)', 'In our series, 19 different de novo MECP2 mutations, eight of which were previously unreported, were found in 35 out of 50 Rett girls (70%)', 'Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25).', 'We have identified 15 different MECP2 mutations in 26 of 30 Danish RTT patients.']

['The neurodevelopmental disorder named Rett syndrome, originally termed as cerebroatrophic hyperammonemia. Although most exclusively affects females, has also been found in male patients.']

['Rett syndrome']

Can RNAPolII function as an RNA-dependent RNA-polymerase?

['RNA polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA', 'RNA polymerase II (Pol II) is a well-characterized DNA-dependent RNA polymerase, which has also been reported to have RNA-dependent RNA polymerase (RdRP) activity.', ". Our studies provide compelling evidence that mammalian Pol II acts as an RdRP to control the stability of a cellular RNA by extending its 3'-end.", 'here is, however, evidence that Pol II also possesses RNA-dependent RNA polymerase (RdRP) activity. Pol II can use a homopolymeric RNA template, can extend RNA by several nucleotides in the absence of DNA, and has been implicated in the replication of the RNA genomes of hepatitis delta virus (HDV) and plant viroids.', 'The RdRP activity of Pol II provides a missing link in molecular evolution, because it suggests that Pol II evolved from an ancient replicase that duplicated RNA genomes.', 'The present findings provide a framework for further studies to elucidate the mechanistic principles of transcription by a viral RNA polymerase and have implications for the regulation of Pol II activities in infected cells.', 'Influenza A virus transcribes its segmented negative sense RNA genome in the nuclei of infected cells in a process long known to require host RNA polymerase II (RNAP-II).', 'We conclude that influenza A virus replication requires RNAP-II activity not just to provide capped mRNA substrates but also to facilitate nuclear export of selected viral mRNAs.', "Thus, influenza virus specifically interferes with Pol II elongation, but not Pol II initiation. We propose that influenza virus RNA polymerase, by binding to the CTD of initiating Pol II and subsequent cleavage of the capped 5' end of the nascent transcript, triggers premature Pol II termination.", 'We show that RNA polymerase II (RNAPolII) preinitiation complex recruitment and H3 Lys 4 (H3-K4) methylation at the Xist promoter form the basis of the Xist expression profiles that drives both imprinted and random XCI.', 'Identification of these ENL-associated proteins (EAPs) by mass spectrometry revealed enzymes with a known role in transcriptional elongation (RNA polymerase II C-terminal domain kinase [RNAPolII CTD] positive transcription elongation factor b [pTEFb]), and in chromatin modification (histone-H3 methyltransferase DOT1L) as well as other frequent MLL partners (AF4, AF5q31, and LAF4), and polycomb group members (RING1, CBX8, and BCoR).', 'RNA polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA.', 'Association of the influenza A virus RNA-dependent RNA polymerase with cellular RNA polymerase II.', 'It is also well established that viral RNA-dependent RNA polymerase (vRNP) associates with cellular RNA polymerase II (Pol II), on which viral replication depends. ', 'RNA polymerase II (Pol II) is a well-characterized DNA-dependent RNA polymerase, which has also been reported to have RNA-dependent RNA polymerase (RdRP) activity. Natural cellular RNA substrates of mammalian Pol II, however, have not been identified and the cellular function of the Pol II RdRP activity is unknown.', 'RNA polymerase II (Pol II) is a well-characterized DNA-dependent RNA polymerase, which has also been reported to have RNA-dependent RNA polymerase (RdRP) activity.', 'RNA polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA.']

['RNA polymerase II (Pol II) is a well-characterized DNA-dependent RNA polymerase, which has also been reported to have RNA-dependent RNA polymerase (RdRP) activity. Pol II can use a homopolymeric RNA template, can extend RNA by several nucleotides in the absence of DNA, and has been implicated in the replication of the RNA genomes of hepatitis delta virus (HDV) and plant viroids. The RdRP activity of Pol II provides a missing link in molecular evolution, because it suggests that Pol II evolved from an ancient replicase that duplicated RNA genomes.', 'There is, however, evidence that Pol II also possesses RNA-dependent RNA polymerase (RdRP) activity. Here we show the intrinsic RdRP activity of Pol II with only pure polymerase, an RNA template-product scaffold and nucleoside triphosphates (NTPs). RNA polymerase II (Pol II) is a well-characterized DNA-dependent RNA polymerase, which has also been reported to have RNA-dependent RNA polymerase (RdRP) activity. We conclude that influenza A virus replication requires RNAP-II activity not just to provide capped mRNA substrates but also to facilitate nuclear export of selected viral mRNAs.', 'RNA polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA']

['yes']

What is the target of tanezumab?

['Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model.', 'OBJECTIVE: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials.', ' Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against β-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones.', 'Areas covered: This manuscript is a review that examines both the pharmacological properties and clinical studies of tanezumab, the most widely studied antibody to NGF, for management of osteoarthritis (OA) and low back pain. ', 'OBJECTIVE: Evaluate efficacy and safety of tanezumab, a humanized monoclonal antibody against nerve growth factor, in neuropathic pain.', 'In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models.', 'Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions.', 'Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.', 'In this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain.Patients with interstitial cystitis received a single intravenous dose of 200 μg/kg tanezumab or placebo', 'Nerve safety of tanezumab, a nerve growth factor inhibitor for pain treatment.', 'In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models.', 'Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions.', 'Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system..']

['Tanezumab is a humanized monoclonal antibody against nerve growth factor.']

['nerve growth factor', 'NGF']

What is the effect of amitriptyline in the mdx mouse model of Duchenne muscular dystrophy?

['Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy', 'Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus', ' Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the forelimb flexors. Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment', 'Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy.', 'Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus.', 'Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor- and interleukin-6 in the forelimb flexors.', 'Positive effects of amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD.', 'Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment.', 'Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus.', 'Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the forelimb flexors.', 'Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment. Positive effects of amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD.', 'Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy.', 'Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment.', 'Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus.', 'Positive effects of amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD.']

['Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy', 'Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. On the other hand, inflammation in mdx skeletal muscle tissue was also reduced as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the forelimb flexors.', 'Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy ']

[]

Which currently known mitochondrial diseases have been attributed to POLG mutations?

['Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO)', 'Mutations in the gene encoding mitochondrial DNA polymerase gamma (POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease-autosomal dominant or recessive progressive external ophthalmoplegia-and multiple deletions of mtDNA.', 'About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes.', 'Nineteen exhibited a cluster of three or more predefined clinical manifestations suggestive of POLG-related disease: progressive external ophthalmoplegia, seizures and/or an abnormal electroencephalogram, neuropathy, ataxia, liver function abnormalities, migraine or dysphagia/dysarthria. ', 'Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.']

['Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO).', 'Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO)']

['childhood Myocerebrohepatopathy Spectrum disorders (MCHS)', 'Alpers syndrome', 'Ataxia Neuropathy Spectrum (ANS) disorders', 'Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA)', 'autosomal recessive Progressive External Ophthalmoplegia (arPEO)', 'autosomal dominant Progressive External Ophthalmoplegia (adPEO)']