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Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?

['Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex', 'We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity', 'FANCA was demonstrated to associate with the endogenous SWI/SNF complex', 'FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair', 'Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.', 'We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product.', 'Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1.', 'We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product', 'Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1']

['The Fanconi anemia protein FANCA has been shown to interact with the brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity.', 'FANCA was demonstrated to associate with the endogenous SWI/SNF complexFANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair']

['BRG1']

What is the synonym of the lubag disease?

['IMPORTANCE: Despite recessive inheritance, X-linked dystonia-parkinsonism (Lubag disease) has also been described in women presenting with a late-onset isolated parkinsonian syndrome.', 'Anesthesia for deep brain stimulation in a patient with X-linked dystonia-parkinsonism/Lubag disease.', 'Lubag disease is a genetic X-linked dystonia-parkinsonism syndrome afflicting Filipino men. ', 'X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism.', "X-chromosomal dystonia parkinsonism syndrome (XDP, 'lubag') is associated with sequence changes within the TAF1/DYT3 multiple transcript system. ", 'The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag").', 'Sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag") is an adult-onset, progressive, debilitating movement disorder first described in Filipino males from Panay Islands in 1975. ', "We cover dopa-responsive dystonia, Wilson's disease, Parkin-, PINK1-, and DJ-1-associated parkinsonism (PARK2, 6, and 7), x-linked dystonia-parkinsonism/Lubag (DYT3), rapid-onset dystonia-parkinsonism (DYT12) and DYT16 dystonia, the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) including pantothenate kinase (PANK2)- and PLA2G6 (PARK14)-associated neurodegeneration, neuroferritinopathy, Kufor-Rakeb disease (PARK9) and the recently described SENDA syndrome; FBXO7-associated neurodegeneration (PARK15), autosomal-recessive spastic paraplegia with a thin corpus callosum (SPG11), and dystonia parkinsonism due to mutations in the SLC6A3 gene encoding the dopamine transporter.", 'Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease.', 'X-Linked Dystonia-Parkinsonism (XDP or "Lubag") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines.', 'First case of X-linked dystonia-parkinsonism ("Lubag") to demonstrate a response to bilateral pallidal stimulation.', '"Lubag" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men.', "First case report of X linked dystonia parkinsonism (XDP) or 'lubag' in Australia.", "PURPOSE: To present the first genetically supported case of X linked dystonia parkinsonism (XDP) or 'lubag' reported in an Australian hospital. ", 'Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ("lubag") in women.', 'BACKGROUND: X-linked dystonia-parkinsonism (XDP) or "lubag" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. ', "Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study.", "We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. ", 'Three affected siblings were found to share an identical haplotype at the X-linked dystonia-parkinsonism locus (XDP; Lubag; OMIM*314250).', "These neuropathological findings differed from those of Parkinson's disease or juvenile parkinsonism, but mimic to those of X-linked dystonia parkinsonism (Lubag).", 'Phenomenology of "Lubag" or X-linked dystonia-parkinsonism.', 'X-linked dystonia-parkinsonism (XDP), or Lubag syndrome, is known to cause progressive dystonia, with or without parkinsonism, among Filipino male adults with maternal roots from the Philippine island of Panay. ', 'Adductor laryngeal breathing dystonia in a patient with lubag (X-linked dystonia-Parkinsonism syndrome).', 'We report a patient with Lubag (X-linked dystonia-parkinsonism) who presented with severe respiratory stridor from adductor laryngeal breathing dystonia. ', 'Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women.', 'Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. ', 'Regional and global metabolic rates for glucose (rCMRGlc and GMR) were estimated using [18F]fluorodeoxyglucose and positron emission tomography in 3 patients with Filipino X-linked dystonia-parkinsonism (lubag). ', 'Neuropathology of lubag (x-linked dystonia parkinsonism).', 'Lubag is an x-linked recessive dystonia parkinsonism that affects Filipino men originating principally from the Panay Island.', 'Genetic mapping of "Lubag" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome.', '"Lubag" is an X-linked disorder causing dystonia and parkinsonism that has only been described in families from the Philippines, principally from the island of Panay. ', 'X-Linked Dystonia-Parkinsonism (XDP or "Lubag") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines', 'Lubag disease is a genetic X-linked dystonia-parkinsonism syndrome afflicting Filipino men', "These neuropathological findings differed from those of Parkinson's disease or juvenile parkinsonism, but mimic to those of X-linked dystonia parkinsonism (Lubag)"]

['Lubag disease is also known as X-linked dystonia-parkinsonism (XDP). This disease is characterized by dystonia and parkinsonism, and afflicts Filipino men, and rarely, women originating principally from the Panay Island.']

['X-linked dystonia-parkinsonism']

Does helicobacter pylori infection increase risk for ischemic stroke?

["Helicobacter pylori (H. pylori) infection is reported to be associated with many extragastrointestinal manifestations, such as hematological diseases [idiopathic thrombocytopenic purpura (ITP) and unexplained iron deficiency anemia (IDA)], cardiovascular diseases (ischemic heart diseases), neurological disorders (stroke, Parkinson's disease, Alzheimer's disease), obesity and skin disorders.", 'Helicobacter pylori infection contributes to high risk of ischemic stroke: evidence from a meta-analysis.', 'This meta-analysis indicated that chronic H. pylori infection was significantly associated with an increased risk of IS, especially for non-cardioembolic IS. ', 'In the last years, a considerable number of studies have been performed on the relationship between infection from Helicobacter Pylori and atherosclerotic diseases, like stroke and ischemic heart disease. ', 'However, there are conflicting results on the relevance of chronic infection by Helicobacter pylori as a risk factor for ischemic stroke.', 'CONCLUSIONS: This case-control study does not reveal any strong association between chronic Helicobacter pylori infection and ischemic stroke. ', 'Case-control and prospective studies indicate that chronic infections, such as periodontitis, chronic bronchitis and infection with Helicobacter pylori, Chlamydia pneumoniae or Cytomegalovirus, might increase stroke risk, although considerable variation exists in the results of these studies, and methodological issues regarding serological results remain unresolved.', 'Chronic infections, presently discussed as stroke risk factors mainly include periodontitis and infections with Helicobacter pylori (Hp) and Chlamydia pneumoniae (Cp). ', 'CONCLUSION: H. Pylori gastritis is not independently associated with increased risk for stroke. ', 'CONCLUSIONS: Our results support the hypothesis that CagA-seropositive strains infection is significantly associated with susceptibility to ischemic strokes and coronary heart diseases. ', 'BACKGROUND: Previous studies suggested an association between CagA-positive H. pylori strains and ischemic stroke. ', 'CONCLUSIONS: Our findings suggest that CagA-positive strains of H. pylori are significantly associated to atherosclerotic stroke.', 'We concluded that H pylori infection is common in DM and seems to be linked to the presence of atherosclerosis and ischemic cerebrovascular stroke. ', 'Interesting results show that H. pylori infection affects atherosclerosis and is weakly associated with ischemic heart disease and stroke. Moreover, CagA-positive H. pylori strains may play a role in the natural history of atherosclerotic stroke.', 'Interestingly, the majority of the extradigestive-related literature is focused on two vascular manifestations: stroke and ischemic heart disease. ', 'Chronic infectious diseases that may increase the risk of stroke include periodontitis, chronic bronchitis and infections with microbial antigens, such as Helicobacter pylori and Chlamydia pneumoniae. ', 'CONCLUSIONS: These results suggest that H. pylori infection is a risk factor for ischemic stroke and that CD14 polymorphism is not.', ' CONCLUSIONS: Our case-control study provides evidence of an association between the immune response to H. pylori , a marker of prior infection with this organism and noncardioembolic ischemic stroke.', 'Case-control studies and a few prospective studies have indicated that chronic infections may add to the risk of stroke and that acute infections may act as trigger factors for stroke. Such chronic infections include periodontal disease, infection with Chlamydia pneumoniae or Helicobacter pylori, and chronic bronchitis', 'Chronic H. pylori infection still showed an overall association with ischemic stroke (odds ratio for all subtypes combined: 2.57; 95% CI: 1.09-6.08) after adjusting for major cardiovascular risk factors. These results suggest that chronic H. pylori infection may be a triggering factor that increases the risk of acute ischemic stroke.', 'BACKGROUND AND PURPOSE: Studies on Helicobacter pylori infection and risk of ischemic stroke yielded variable results. ', 'CONCLUSIONS: Our results support the hypothesis of an association between infection with CagA-positive H. pylori strains and acute cerebral ischemia.', ' Chronic infections (eg, infection with Chlamydia pneumoniae or Helicobacter pylori) were found to increase the risk of stroke; however, study results are at variance, residual confounding is not excluded, and causality is not established at present. ', 'CONCLUSIONS: Infection with Helicobacter pylori is associated with an increased risk of stroke and increased fibrinogen levels but these findings can be attributed to a confounding effect of socio-economic status.', ' CONCLUSIONS: Hp infection represents risk factor of ischemic stoke via an interaction of Hp cytotoxins or cytokines with atherosclerotic plaques in carotic arteries.', 'CONCLUSIONS: The association between H pylori and acute cerebrovascular disease seems to be due to a higher prevalence of more virulent H pylori strains in patients with atherosclerotic stroke.', 'CONCLUSIONS: H. pylori infection appears to be significantly more frequent in middle-aged patients with acute ischemic stroke than in controls.', 'Chronic H pylori infection was associated with a higher risk of stroke caused by small-artery occlusion (adjusted odds ratio, 3.31; 95% CI, 1.15 to 9.56) and a lower risk of cardioembolic stroke (adjusted odds ratio, 0.21; 95% CI, 0.06 to 0.71). Overall, elevated H pylori as well as elevated C pneumoniae antibodies were not associated with ischemic stroke.', 'Presently, it is insufficiently established whether Helicobacter pylori infection represents a risk factor for ischemic stroke.', ' H. pylori seropositivity may be an independent risk factor for stroke of atherothrombotic origin.', 'Appropriately randomized studies employing an antibiotic treatment for patients affected by ischemic vascular disease will answer the question of whether H. pylori has a causal role in the pathogenesis of acute myocardial infarction and ischemic stroke.', 'Results on the association between this bacterium and acute myocardial infarction or stroke are controversial, due to the degree of studies heterogeneity. ', 'Interventional randomized studies employing an antibiotic treatment for patients affected by ischemic vascular diseases will rapidly answer the question of wheather Helicobacter pylori has a causal role in the pathogenesis of acute myocardial infarction and ischemic stroke.', ' CONCLUSION: Chronic H pylori infection is an independent risk factor for ischaemic cerebrovascular disease and may act, at least in part, by increasing atherosclerosis.', 'Presently, it is insufficiently established whether Helicobacter pylori infection represents a risk factor for ischemic stroke.', 'This case-control study does not reveal any strong association between chronic Helicobacter pylori infection and ischemic stroke.', 'However, there are conflicting results on the relevance of chronic infection by Helicobacter pylori as a risk factor for ischemic stroke.', 'Chronic infections (eg, infection with Chlamydia pneumoniae or Helicobacter pylori) were found to increase the risk of stroke; however, study results are at variance, residual confounding is not excluded, and causality is not established at present.', 'BACKGROUND AND PURPOSE: Studies on Helicobacter pylori infection and risk of ischemic stroke yielded variable results.', 'This case-control study does not reveal any strong association between chronic Helicobacter pylori infection and ischemic stroke.', 'Presently, it is insufficiently established whether Helicobacter pylori infection represents a risk factor for ischemic stroke', 'Chronic infectious diseases that may increase the risk of stroke include periodontitis, chronic bronchitis and infections with microbial antigens, such as Helicobacter pylori and Chlamydia pneumoniae', 'Studies on Helicobacter pylori infection and risk of ischemic stroke yielded variable results', 'Presently, it is insufficiently established whether Helicobacter pylori infection represents a risk factor for ischemic stroke', 'However, there are conflicting results on the relevance of chronic infection by Helicobacter pylori as a risk factor for ischemic stroke']

['Findings regarding association between helicobacter pylori infection and ischemic stroke risk are conflicting. There is evidence to suggest that helicobacter pylori infection is associated with increased risk for ischemic stroke and should be considered stroke risk factors. However, some studies reported no association between helicobacter pylori infection and stroke.']

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Mutations in which gene and which protein are associated with Netherton syndrome?

['NS is due to loss-of-function mutations in the SPINK5 gene and to the consequent lack of expression of its encoded protein LEKTI in the skin and all stratified epithelial tissues.', 'Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome.', 'Netherton syndrome (NS) is a rare, life-threatening ichthyosiform syndrome caused by recessive loss-of-function mutations in SPINK5 gene encoding lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor expressed in the most differentiated epidermal layers and crucial for skin barrier function.', 'Netherton syndrome (NS) is a debilitating congenital skin disorder caused by mutations in the SPINK5 gene encoding the lymphoepithelial Kazal-type-related inhibitor (LEKTI).', 'Loss-of-function mutations in the Kazal-type serine protease inhibitor, LEKTI, encoded by the SPINK5 gene cause the rare autosomal recessive skin disease Netherton syndrome (NS).', 'SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases.', "Netherton's syndrome is a rare autosomal recessive disorder caused by mutations of the SPINK5 gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI) protein.", "We observed microstructural changes and detected LEKTI activity and SPINK5 gene mutation in three Chinese patients with Netherton's syndrome.", 'Several skin diseases and atopic disorders including Netherton syndrome and atopic dermatitis have been associated with mutations and deviations of expression of SPINK5, the gene encoding the human 15-domain serine proteinase inhibitor LEKTI', 'Loss-of-function mutations in the Kazal-type serine protease inhibitor, LEKTI, encoded by the SPINK5 gene cause the rare autosomal recessive skin disease Netherton syndrome (NS)', 'Mutations in the serine protease inhibitor Kazal type 5 (SPINK5) gene leading to lymphoepithelial Kazal-type-related inhibitor (LEKTI) deficiency cause NS. ', ' Netherton syndrome is a severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome.', 'Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing.', 'Mutation of the SPINK5 gene has been identified as disease-causing in Netherton syndrome, but the pathophysiology still remains unclear. Almost all SPINK5 mutations result in the absence of the serine-protease inhibitor LEKTI protein in both keratinocytes and lymphocytes.', 'Several skin diseases and atopic disorders including Netherton syndrome and atopic dermatitis have been associated with mutations and deviations of expression of SPINK5, the gene encoding the human 15-domain serine proteinase inhibitor LEKTI.', 'Netherton's syndrome is a rare autosomal recessive disorder caused by mutations of the SPINK5 gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI) protein. We observed microstructural changes and detected LEKTI activity and SPINK5 gene mutation in three Chinese patients with Netherton's syndrome.', 'NS is due to loss-of-function mutations in the SPINK5 gene and to the consequent lack of expression of its encoded protein LEKTI in the skin and all stratified epithelial tissues. Following the identification of the NS causative gene and protein, specific diagnostic tools have been developed, thus breaking up the challenge of distinguishing NS from other congenital ichthyoses with overlapping features, and from severe, early-onset forms of atopic dermatitis or psoriasis.', 'Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome.']

['NS is due to loss-of-function mutations in the SPINK5 gene and to the consequent lack of expression of its encoded protein LEKTI in the skin and all stratified epithelial tissues.']

['SPINK5 gene', 'LEKTI protein']

What is Prudent Diet?

['Long-term diet was assessed by using FFQs every 4 y since 1986. Prudent (high in vegetables) and Western (high in meats) patterns were identified by using a principal component analysis.', 'The Prudent dietary pattern was characterised by high intakes of vegetables, fruits, whole grain products and low intakes of refined grain products and the Western dietary pattern, by high intakes of refined grain products, desserts, sweets and processed meats.', 'aerobic exercise combined with diet recommendations (saturated/trans fat intake less than 10% of total calories and cholesterol less than 300 mg/day and/or fiber intake ≥ 25 g/day in women and ≥ 35 grams per day in men', ' a prudent pattern (high in fish, peas, honey, nuts, juice, dry fruits, vegetable oil, liver and organic meat, and coconuts and low in hydrogenated fat and non-leafy vegetables)', ' The prudent pattern was characterized by higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains, while the Western pattern was characterized by higher intakes of red and processed meats, sweets and desserts, french fries, and refined grains.']

['The Prudent dietary pattern is characterised by high intakes of vegetables, fruits, whole grain products and low intakes of refined grain products, legumes, fish, poultry. Generally recommendations are to use saturated/trans fat intake less than 10% of total calories and cholesterol less than 300 mg/day and/or fiber intake ≥ 25 g/day in women and ≥ 35 grams per day in men.']

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Is dexamethasone recommended for treatment of intracerebral hemorrhage?

['Dexamethasone and other glucocorticoids should be avoided. ', 'During the third interim analysis, the death rate at the 21st day was identical in the two groups (dexamethasone vs. placebo, 21 of 46 vs. 21 of 47; chi-square = 0.01, P = 0.93). In contrast, the rate of complications (mostly infections and complications of diabetes) was much higher in the dexamethasone group (chi-square = 10.89, P less than 0.001), leading to early termination of the study. In the light of the absence of a demonstrable beneficial effect and the presence of a significant harmful effect, current practices of using dexamethasone for treatment of primary supratentorial hemorrhage should be reconsidered.', 'In the light of the absence of a demonstrable beneficial effect and the presence of a significant harmful effect, current practices of using dexamethasone for treatment of primary supratentorial hemorrhage should be reconsidered.']

['No. Dexamethasone and other glucocorticoids should be avoided for treatment of intracerebral hemorrhage because they do not improve patient outcome and are associated with increased risk of side effects.']

['no']

Are CD44 variants (CD44v) associated with poor prognosis of metastasis?

['CD44 variants and prognosis', 'The CD44 variant (CD44v) isoforms have been noted as markers for tumour metastasis and prognosis in several adenocarcinomas.', 'Positive CD44v3 expression was associated with more advanced pathological stage and poorer prognosis than negative CD44v3 expression', 'CD44v6 expression in the adenocarcinoma component may directly affect the behavior of carcinoma and the prognosis of patients', 'D44 variant 6 in endometrioid carcinoma of the uterus: its expression in the adenocarcinoma component is an independent prognostic marker', 'CD44v5 expression is independently positively correlated with the aggressiveness of thymic epithelial tumors. The expression of CD44v5 may be a potential trigger of tumor invasion in thymomas', 'analysis of CD44v expression provides indications of biological and clinical relevance also in low grade lymphoproliferative disorders', 'clinical relevance of CD44 variant isoform expression on B-cell chronic lymphocytic leukemia', 'CD44 variants and its association with survival in pancreatic cancer', 'CD44 variant 6(v6) molecule has been noted as a marker for tumor metastasis and prognosis in several tumors', 'CD44v2 and CD44v6 may be useful markers for poor prognosis in curatively resected primary pancreatic cancer', 'CD44v8-10 may play an important role in the adhesion of tumor cells to the capillaries of distant organs in the metastatic process, and that immunohistochemical detection of CD44v8-10 may be a biologic marker of prognostic significance.', 'combined expression of CD44v8-10 and SLX may be a biologic marker of prognostic significance', 'variant isoforms (CD44v) are expressed on different malignant cells and tissues. Their upregulation has been implicated, in the progression and metastasis of malignomas.', 'expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer', 'a number of variant forms of CD44 are frequently expressed, although these variants are infrequently expressed in normal lung tissue, and that the expression of CD44v6 is particularly associated with lymph node metastasis in NSCLC', 'Expression of CD44v6 may suggest an increased risk for local lymph node metastasis in NSCLCs', 'different CD44 isoforms are found in human skin cancers and are modulated during carcinogenesis', 'D44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer', "Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma", 'Certain splice variants (CD44v) can promote the metastatic behaviour of cancer cells. In human colon and breast cancer the presence of epitopes encoded by exon v6 on primary resected tumour material indicates poor prognosis', 'In human mammary carcinomas and colorectal carcinomas, the expression of CD44v has also been correlated with more progressed tumor stages.']

['Yes, several isoforms (obtained by by usage of ten variant exons in various combinations) have been causally related to metastasis.']

['yes']

Which enzyme is inhibited by a drug fostamatinib?

['It outlines preclinical and early clinical experiences with the Syk inhibitor fostamatinib disodium (R788) and discusses various options for further clinical development of this compound. ', 'To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies. ', 'The mTOR inhibitors temsirolimus and everolimus have demonstrated antitumor activity in all types of lymphoma, the Syk inhibitor fostamatinib has activity in diffuse large B-cell lymphoma and chronic lymphocytic leukemia, and the PKC-β inhibitor enzastaurin is being used as consolidation therapy after remission in diffuse large B-cell lymphoma. ', 'Fostamatinib, a Syk-kinase inhibitor, does not affect methotrexate pharmacokinetics in patients with rheumatoid arthritis.', 'The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy.', 'The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling.', 'We have now investigated whether inhibition of BCR signaling with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop in the Eμ-TCL1 transgenic mouse model of CLL.', 'We show that conditional ablation of the syk gene in dendritic cells (DCs) abrogates FcgammaR-mediated cross priming of diabetogenic T cells in RIP-mOVA mice, a situation phenocopied in wild-type RIP-mOVA mice treated with the selective Syk inhibitor R788.', 'We investigated the ability of a small drug Syk inhibitor, R788, to protect mice against mesenteric ischemia-reperfusion (I/R)-induced local (intestine) and remote lung injury.', 'The spleen tyrosine kinase (Syk) inhibitor R406 is orally administered as the prodrug R788. ', 'Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia.', 'These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). ', 'We examined the effect of R788 (fostamatinib disodium), an oral prodrug of the selective Syk inhibitor R406, in nephrotoxic nephritis in Wistar-Kyoto rats.', 'Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases.', 'Rigel Pharmaceuticals Inc is developing fostamatinib, a prodrug of the spleen tyrosine kinase (Syk) inhibitor R-406, for the potential treatment of autoimmune diseases such as rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and B-cell lymphomas.', 'In developmental toxicity studies with the Syk kinase inhibitor R788, a spectrum of findings, including renal agenesis, were observed.', 'R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). ', 'In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. ', 'Fostamatinib (R788) inhibits spleen tyrosine kinase (Syk) and has been in clinical trials involving both MTX inadequate responders (MTX-IRs) and biologic inadequate responders. ', 'The compounds that are currently investigated in patients with CLL include ibrutinib -inhibitor of Btk, fostamatinib-inhibitor of Syk and idelalisib (GS-1101) -a specific isoform of the PI3K (PI3K) inhibitor. ', 'TK inhibitors including spleen TK (fostamatinib) and Janus kinases (tofacitinib) inhibitors are two novel oral therapies that have demonstrated short-term good clinical responses in active rheumatoid arthritis patients with and inadequate responses to methotrexate or other traditional (non-biologic) disease-modifying antirheumatic drugs (DMARDs). ', 'Progress is also being made with orally active Syk inhibitors. One such inhibitor (fostamatinib) is currently in large-scale phase 3 trials, and there are others in clinical development.', "We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro.", 'Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-related quality of life in patients with active rheumatoid arthritis: analyses of patient-reported outcomes from a randomized, double-blind, placebo-controlled trial.', 'Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies.', 'Fostamatinib (R788) is an orally dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis.', 'Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK.', 'Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects.', 'Fostamatinib (R788) is a prodrug rapidly converted to its active metabolite on oral administration. This (known as R406) is a potent inhibitor of spleen tyrosine kinase, required for the expression of a number of proinflammatory cytokines. ', 'The Syk inhibitor, fostamatinib, proved superior to placebo in Phase II trials and is currently under Phase III investigation. T', "More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). ", 'Because inhibitors of SYK activity, such as fostamatinib, are in advanced clinical trials for rheumatoid arthritis and other autoimmune diseases, understanding the role of SYK in signalling via TLR4 is of immediate importance. ', "The search terms used were Bruton's tyrosine kinase (Btk) inhibitors, PCI-32765, GDC-0834, LFM-A13, AVL-101, AVL-292, spleen tyrosine kinase (Syk) inhibitors, R343, R406, R112, R788, fostamatinib, BAY-61-3606, C-61, piceatannol, Lyn, imatinib, nilotinib, bafetinib, dasatinib, GDC-0834, PP2, SU6656 in conjunction with lymphoid malignancy, NHL, CLL, autoimmune disease, allergic disease, asthma, and rheumatoid arthritis.", 'Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury.', 'Recently, Syk inhibitor fostamatinib has exerted potent therapeutic efficacy against autoimmune and allergic diseases such as rheumatoid arthritis (RA), bronchial asthma and thrombocytopenic purpura (ITP).', 'In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor.', 'In vivo expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity.', 'Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion.', 'No oral biologic agents are available at this time but promising data is emerging for two drugs, tofacitinib and fostamatinib, inhibitors of JAK and Syk kinases, respectively. ', 'Fostamatinib (R-788) is an orally bioavailable small molecule. It is the prodrug of R406, which is a potent Syk inhibitor. ', 'The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice.', 'Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. ']

['Fostamatinib (R788) acts by inhibiting spleen tyrosine kinase. Fostamatinib (R788) is a prodrug rapidly converted to its active metabolite on oral administration. This (known as R406) is a potent inhibitor of spleen tyrosine kinase that is required for the expression of a number of proinflammatory cytokines. Fostamatinib has been shown to be effective in patients with rheumatoid arthritis, leukemia, lymphoma, bronchial asthma and thrombocytopenic purpura.']

['spleen tyrosine kinase']

Is pesticide exposure associated with polyneuropathy?

["As the syndrome occurred after the acute cholinergic syndrome but before organophosphate-induced delayed polyneuropathy, the syndrome was called 'intermediate syndrome'.", 'The characteristic features of the IMS are weakness of the muscles of respiration (diaphragm, intercostal muscles and accessory muscles including neck muscles) and of proximal limb muscles. Accompanying features often include weakness of muscles innervated by some cranial nerves. It is now emerging that the degree and extent of muscle weakness may vary following the onset of the IMS. ', "Electrophysiological studies following OP poisoning have revealed three characteristic phenomena: (i) repetitive firing following a single stimulus; (ii) gradual reduction in twitch height or compound muscle action potential followed by an increase with repetitive stimulation (the 'decrement-increment response'); and (iii) continued reduction in twitch height or compound muscle action potential with repetitive simulation ('decrementing response'). ", 'Organophosphate-induced delayed polyneuropathy is a sensory-motor distal axonopathy which usually occurs after exposure of certain OP insecticides. Neuropathies due to ingestion of OPs have rarely been reported in the literature.', 'We report a patient with serious organophosphorus-induced delayed neuropathy due to malathion injection. The patient was a 32-year-old female who self-injected undetermined amounts of malathion over the median nerve trace on the forearm crease in a suicide attempt which resulted in peripheral neuropathy.', ' Acutely, these patients present with cholinergic crisis; intermediate syndrome and delayed polyneuropathy are other sequel of this form of poisoning.', 'There was no strong evidence of irreversible peripheral nerve damage following acute OP poisoning, however further studies are required.', 'Particular interactions are also addressed, such as those of pesticides acting as endocrine disruptors, the cumulative toxicity of organophosphates and organochlorines resulting in estrogenic effects and the promotion of organophosphate-induced delayed polyneuropathy.', "The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. ", 'These compounds cause four important neurotoxic effects in humans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP) and chronic organophosphate-induced neuropsychiatric disorder (COPIND). ', 'An 18-year-old woman and a 22-year-old man were admitted to the hospital with weakness, paresthesia, and gait disturbances at 35 and 22 days, respectively, after ingesting dimethyl-2,2-dichloro vinyl phosphate (DDVP). Neurological examination revealed weakness, vibration sense loss, bilateral dropped foot, brisk deep tendon reflexes, and bilaterally positive Babinski sign. Electroneurography demonstrated distal motor polyneuropathy with segmental demyelination associated with axonal degeneration prominent in the distal parts of both lower extremities.', 'Sensory complaints and electrodiagnostic findings consistent with polyneuropathy were found in a minority (3/7) of subjects 28 years after an acute toxic arsenic exposure.', 'Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. ', 'Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity.', 'Several studies have reported the occurrence of sensory neuropathy with exposure to chlorpyrifos and other organophosphorus insecticides, at levels not associated with overt toxicity. ', 'We found no evidence of sensory neuropathy or isolated peripheral abnormalities among subjects with long-term chlorpyrifos exposure at levels known to be associated with the manufacturing process.', 'Persistent, mainly motor, impairment of the peripheral nervous system was found in men two years after OP poisoning, in particular in severe occupational and intentional poisonings with neuropathic OPs. This finding is possibly due to remaining organophosphate induced delayed polyneuropathy.', 'Besides the well known acute cholinergic toxicity, these compounds may cause late-onset distal polyneuropathy occurring two to three weeks after the acute exposure. ', 'Electromyography demonstrated motor weighed sensory-motor polyneuropathy with axonal degeneration significant in the distal parts of bilateral lower extremities. ', 'The two cases are presented here since organophosphate poisonings are common in our country, and since late-onset polyneuropathy is not a well known clinical presentation as acute toxicity.', 'The course of organophosphate-induced delayed polyneuropathy (OPIDP) in humans has not been quantitatively measured in epidemiologic studies.', 'The persistence of deficits in motor strength in all severely poisoned patients regardless of pesticide type was unexpected, and may reflect persistent cholinergic blockade or intermediate syndrome, neuropathy, or a combination of these.', 'The findings showed a strong association between exposure to OP concentrate and neurological symptoms, but a less consistent association with sensory thresholds. ', 'Following accidental or suicidal exposure, these anticholinesterases lead to three well defined neurological syndromes i.e. initial life threatening acute cholinergic crisis which often requires management in intensive care unit, intermediate syndrome in which cranial nerve palsies, proximal muscle weakness and respiratory muscle weakness are common and patients often require respiratory support and delayed organophosphate induced polyneuropathy.', '[Late onset polyneuropathy due to exposure to organophosphates].', ' Less often a polyneuropathic syndrome of late onset may occur.', "On electromyography there was sensomotor peripheral polyneuropathy, which was primarily axonal and predominantly motor and distal. Peripheral nerve biopsy confirmed the presence of 'dying back' type axonopathy. ", 'Agricultural workers chronically exposed to organophosphate insecticides, without adequate protection, have an increased risk of developing late onset neuropathy due to organophosphates. ', "Epidemiologic studies on pesticides have found associations with long-term effects on health mainly in three fields: cancer (especially hematological cancer), neurotoxic effects (polyneuropathy, neuro-behavioral hazards, Parkinson's disease), and reproductive disorders (infertility, birth defects, adverse pregnancy outcomes, perinatal mortality). ", 'EMG studies showed evidence of partial denervation of the anterior tibial group of muscles and flexor digiti minimi in 2 of the 30 workers (6.7%) who underwent EMG examination.', 'Neurological symptoms consist in cerebro-organic disfunctions, locomotory disorders reminiscent of multiple sclerosis or M. Parkinson, and sensory, motoric and vegetative polyneuropathy, leading, for instance, to cardiovascular regulatory disorder like sympathicotonia or, orthostatic hypotonia. ', 'Thirty percent of patients had definite or possible exposure to organophosphate pesticides, and the peak use coincides with the peak incidence of Guillain-Barré syndrome.', 'These results suggest that previously reported cases of organophosphate-induced delayed polyneuropathy may represent only the worst disease in a spectrum of impairment, a sequela of exposure that may be much more common than previously thought.', 'It is suggested that the main cause of nervous lesions in these cases was the complex effect of pesticides.', 'Delayed polyneuropathy develops within 1 to 3 weeks and abates after 6 to 12 months. ', 'Isolated case reports have circumstantially linked the use of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) to polyneuropathy.', 'Thus, the weight of evidence indicates that 2,4-D is an unlikely cause of polyneuropathy.', 'A patient is reported presenting a cerebellar disorder developing about 5 weeks after acute exposure to an organophosphate insecticide. ', 'Less well known, but more complex and idiosyncratic, is the potential for some agents to produce a delayed and progressive polyneuropathy--Organophosphorus Induced Delayed Neurotox-icity (OPIDN).', ' It is also quite probable that human neurotoxicity may be a potential hazard from exposure to more than the handful of organophosphorus pesticides that have been described in the literature.', 'In the present study the electroencephalograms of 3 of a group 10 workmen, who had been continually exposed to hexachlorcyclohexane, show pathological findings. The electromyograms of 8 of these 10 workman demonstrate a disturbance of the peripherical motoneuron. All probands, who exhibit o pathological EEG, also show a polyneuropathy.', 'Many organophosphorus compounds, including the organophosphate insecticides, may cause polyneuropathy of delayed onset.', 'Nevertheless, we describe a patient with delayed polyneuropathy after suicidal ingestion of parathion.', 'Following acute organophosphorus (OP) poisoning patients complain of numbness without objective sensory abnormalities or other features of OP induced delayed polyneuropathy. ']

['Yes, it is associated with peripheral neuropathy.', "Yes, pesticide exposure is associated with delayed polyneuropathy. Electrophysiological studies have revealed three characteristic phenomena: (i) repetitive firing following a single stimulus; (ii) gradual reduction in twitch height or compound muscle action potential followed by an increase with repetitive stimulation (the 'decrement-increment response'); and (iii) continued reduction in twitch height or compound muscle action potential with repetitive simulation ('decrementing response'). Pesticide exposure was also implicated in Alzheimer's disease, suicide attempts and affective disorders."]

['yes']

Is there a crystal structure of Greek Goat Encephalitis?

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['Based on results no crustal structure of Greek Goat Encephalitis found.']

['no']

How are triple negative gliomas characterized?

['According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis.', 'Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. ', 'Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations', 'Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance', 'Few data are available in the literature regarding the relationship between IDH mutations and HIF expression in low-grade gliomas (LGGs), especially in a recently described aggressive molecular subtype: "triple negative" (IDH non mutated, 1p 19q non codeleted, p53 expression negative) gliomas.', 'Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas.', 'Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance.', 'Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas', 'Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas.', 'Few data are available in the literature regarding the relationship between IDH mutations and HIF expression in low-grade gliomas (LGGs), especially in a recently described aggressive molecular subtype: "triple negative" (IDH non mutated, 1p 19q non codeleted, p53 expression negative) gliomas.']

['of these markers - 1p/19q deletions , mgmt methylation status , and mutations in the idh1 gene - are so potent that a new brain tumor subtype , the "triple negative" glioma (1p/19q intact , mgmt unmethylated , idh1 non-mutated) has entered common parlance . ', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis.', 'Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. ', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. (Funded by the National Institutes of Health and others. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance.', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. ', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative (IDH-/p53-/1p19q-), this last subgroup having the worst prognosis.', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. ', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations', 'According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance']

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What is the endemic neurological disease in Northeast Siberia known as Viliuisk encephalomyelitis?

['["BACKGROUND: Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.", "Communicating hydrocephalus following eosinophilic meningitis is pathogenic for chronic Viliuisk encephalomyelitis in Northeastern Siberia.", "Epidemiology of Viliuisk encephalomyelitis in Eastern Siberia.", ". An epidemic of this disease has been spreading throughout the Yakut Republic of the Russian Federation.", "METHODS: Detailed clinical, pathologic, laboratory, and epidemiologic studies have identified 414 patients with definite Viliuisk encephalomyelitis in 15 of 33 administrative regions of the Yakut Republic between 1940 and 1999.", "Viliuisk encephalomyelitis in Eastern Siberia - analysis of 390 cases.", "Viliuisk encephalomyelitis (VE) is a unique disease occurring in the Yakut (Sakha) population of Eastern Siberia. ", "Viliuisk encephalomyelitis in Northeastern Siberia is not caused by Borrelia burgdorferi infection.", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin. ", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin.", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.", "Viliuisk encephalomyelitis in the Iakut people of Siberia.", "Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.", "Viliuisk encephalomyelitis (VE) is an unique neurological disease occurring in the Iakut (Sakha) people of Siberia.", "Viliuisk encephalomyelitis (VEM) appears to be endemic disease, affecting native population in Yakutia (Yakut, Even, Evenk).", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006", "Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease", "Viliuisk encephalomyelitis (VE) is a unique disease occurring in the Yakut (Sakha) population of Eastern Siberia", "Viliuisk encephalomyelitis in Northeastern Siberia is not caused by Borrelia burgdorferi infection", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin", "Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006.", "IgG antibodies to HTLV-I were measured in the sera and/or cerebrospinal fluid from 82 Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia, 164 Guamanian normal controls, 10 patients with kuru from']

Viliuisk encephalomyelitis

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What is known about the Digit Ratio (2D:4D) cancer?

['RESULTS: Right 2D:4D was not associated with TGCT [odds ratio (OR) for a one-standard deviation (SD) increase in right-hand 2D:4D: 1.12, 95% confidence interval (CI): 0.93-1.34]. The results were consistent when evaluating the association based on the left hand. The difference between right and left-hand 2D:4D was also not associated with TGCT risk [OR for a one-SD increase in ΔR-L: 1.03, 95% CI: 0.87-1.23]. ', 'Digit ratio (2D:4D) is associated with gastric cancer.', 'RESULTS: GCA group presented significantly higher left 2D:4D, but significantly lower R-L in comparison to healthy controls, particularly so for males. Digit ratio did not correlate to clinical staging or TNM staging.', 'The 2D:4D pattern found for gastric cancer parallels that earlier described for breast cancer.', 'Higher second fourth digit ratio predicts higher incidence of prostate cancer in prostate biopsy.', '2D/4D ratio >0,95 (OR (CI 95%) 4,4 (1,491-13,107) was related to neoplasia. ', 'CONCLUSION: High digit ratio predicts PCa in men undergoing prostate biopsy. Digit ratio >0,95 has 4-fold risk of PCa compared to men with digit ratio ≤0.95.', 'RESULTS: African-American men with prostate cancer are 3.70 times more likely to have a low 2D:4D digit ratio than Caucasian men with prostate cancer (95% confidence interval: 1.98, 6.92; P < 0.0001). There were no statistically significant differences in the presence of metastasis, Gleason score, family history or age at diagnosis by digit ratio. CONCLUSION: 2D:4D ratio shows strong differences between African-Americans and Caucasians; however, it does not correlate with disease severity in men already diagnosed with prostate cancer. ', 'RESULTS: We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk. Among breast cancer cases, both right 2D:4D and Δ(r-l) were inversely associated with age at diagnosis.', 'CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer.', 'Recent studies have reported a strong association between 2D:4D and risk of prostate cancer. ', 'RESULTS: No association was observed between 2D:4D and prostate cancer risk overall (HRs 1.00; 95% CIs, 0.92-1.08 for right, 0.93-1.08 for left). ', 'CONCLUSION: Our results are not consistent with an association between 2D:4D and overall prostate cancer risk, but we cannot exclude a weak inverse association between 2D:4D and early onset prostate cancer risk.', 'Males in the OSCC group presented significantly higher digit ratio (P = 0.03) in comparison with males with OPLs and individuals without oral lesions. CONCLUSIONS: According to the results, males with the higher digit ratio seem to be more prone to undergo malignization of lesions in the oral cavity. ', 'Compared with index finger shorter than ring finger (low 2D\u2009:\u20094D), men with index finger longer than ring finger (high 2D\u2009:\u20094D) showed a negative association, suggesting a protective effect with a 33% risk reduction (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.57-0.80). Risk reduction was even greater (87%) in age group <60 (OR 0.13, 95% CI 0.09-0.21). CONCLUSION: Pattern of finger lengths may be a simple marker of prostate cancer risk, with length of 2D greater than 4D suggestive of lower risk.', 'In the case-control analysis (n = 263), after controlling for ethnicity, women who developed CIN were significantly more likely to have a higher 2D:4D compared with HPV-negative women. A similar, nonsignificant trend was observed among women with a persistent HPV infection. CONCLUSION: Lower fetal androgen exposure may predispose to persistent HPV and increased risk of CIN.', 'Low numbers of CAG repeats and low 2D:4D are both associated with high sperm numbers and protection against breast cancer. ', 'Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer.', 'A lower digit ratio is related to an increased detection rate of prostate cancer, a high percentage of core cancer volume and a high Gleason score.', ' Digit ratio could act as a possible marker for cancer predisposition.', 'Right hand digit ratio (2D:4D) is associated with oral cancer.', 'CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer.', 'Second to fourth digit ratio: a predictor of prostate-specific antigen level and the presence of prostate cancer.', 'CONCLUSIONS: Patients with a lower digit ratio have higher risks of prostate biopsy and prostate cancer.', 'Second and fourth digit ratio has also found to be correlated with sexual orientation, left hand preference autism and some adult onset diseases such as breast cancer and myocardial infarction.', 'Low numbers of CAG repeats and low 2D:4D are both associated with high sperm numbers and protection against breast cancer.', 'Findings from AR studies predict that low 2D:4D will be associated with prostate and hepatocellular cancer, urolithiasis, ADHD, ankylosing spondylitis, spontaneous abortion, and polycystic ovaries, while high 2D:4D will be associated with motor neuron diseases and endometrial cancer.', 'We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk', 'Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer', 'The 2D:4D pattern found for gastric cancer parallels that earlier described for breast cancer']

['Digit ratio (2D:4D) is associated with gastric cancer, prostate cancer, breast cancer, cervical intraepithelial neoplasia and oral squamous cell carcinoma. 2D:4D was found to be higher in patients diagnosed with gastric cancer and prostate cancer patients relative to controls. Among prostate cancer patients, 2D:4D shows strong differences between African-Americans and Caucasians; however, it does not correlate with disease severity in men already diagnosed with prostate cancer. However, other authors did not find an association between 2D:4D and prostate cancer risk.\n 2D:4D is not associated with testicular germ cell tumors.']

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What is ISMARA?

['ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs.', 'We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis). Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles. These include predicted activities of the regulators across the samples, their genome-wide targets, enriched gene categories among the targets, and direct interactions between the regulators. Applying ISMARA to data sets from well-studied systems, we show that it consistently identifies known key regulators ab initio. We also present a number of novel predictions including regulatory interactions in innate immunity, a master regulator of mucociliary differentiation, TFs consistently disregulated in cancer, and TFs that mediate specific chromatin modifications', 'Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles.', 'We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis).', 'Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles. These include predicted activities of the regulators across the samples, their genome-wide targets, enriched gene categories among the targets, and direct interactions between the regulators. Applying ISMARA to data sets from well-studied systems, we show that it consistently identifies known key regulators ab initio. ', 'Although gene expression and chromatin state dynamics are ultimately encoded by constellations of binding sites recognized by regulators such as transcriptions factors (TFs) and microRNAs (miRNAs), our understanding of this regulatory code and its context-dependent read-out remains very limited. Given that there are thousands of potential regulators in mammals, it is not practical to use direct experimentation to identify which of these play a key role for a particular system of interest. We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis). ', 'We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis). Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles.', 'Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles. These include predicted activities of the regulators across the samples, their genome-wide targets, enriched gene categories among the targets, and direct interactions between the regulators.', 'Given that there are thousands of potential regulators in mammals, it is not practical to use direct experimentation to identify which of these play a key role for a particular system of interest. We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis).']

['ISMARA (Integrated System for Motif Activity Response Analysis) is a web-based tool that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites. Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles. These include predicted activities of the regulators across the samples, their genome-wide targets, enriched gene categories among the targets, and direct interactions between the regulators.']

[]

List processes which are under the control of the YAP protein.

['in which YAP appears to regulate cell proliferation ', 'YAP and TAZ oncoproteins confer malignancy and drug resistance to various cancer types. ', 'Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control and cancer development', 'YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. ', 'The Hippo signaling pathway converges on YAP to regulate growth, differentiation, and regeneration.', 'Yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. ', 'Intracellular molecules Yap, Akt, mTOR, and Erk are signaling pathway members that regulate the proliferation of tumor cells']

['Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control, cell poliferation and cancer development and tissue homeostasis and differentiation.']

['cell proliferation', 'organ size control', 'cancer development', 'tissue homeostasis', 'cell differentiation']

What is the role of invadopodia in EMT?

['FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT.', 'Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT.', 'Invadopodia are considered to be crucial structures that allow cancer cells to penetrate across the extracellular matrix (ECM) by using matrix metalloproteinases (MMPs).', 'Previously, we isolated a highly invasive A431-III subline from parental A431 cells by Boyden chamber assay. The A431-III cells possess higher invasive and migratory abilities, elevated levels of MMP-9 and an enhanced epithelial-mesenchymal transition (EMT) phenotype. In this study, we discovered that A431-III cells had an increased potential to form invadopodia and an improved capacity to degrade ECM compared with the original A431 cells.', 'Activated Twist upregulates N-cadherin and downregulates E-cadherin, which are the hallmarks of EMT. Moreover, Twist plays an important role in some physiological processes involved in metastasis, like angiogenesis, invadopodia, extravasation, and chromosomal instability.', 'Transforming growth factor β (TGF-β)-stimulated epithelial-mesenchymal transition (EMT) is an important developmental process that has also been implicated in increased cell invasion and metastatic potential of cancer cells.', 'Herein, we demonstrate that TGF-β-induced Hic-5 up-regulation or ectopic expression of Hic-5 in normal MCF10A cells promoted increased extracellular matrix degradation and invasion through the formation of invadopodia.', 'These data identify Hic-5 as a critical mediator of TGF-β-stimulated invadopodia formation, cell migration, and invasion.', 'Recently, invadopodia have been increasingly recognized as important drivers of local invasion in metastasis. Invadopodia are basally-localized, actin-rich structures that concentrate protease activity to areas of the cell in contact with the extracellular matrix. We recently found that the transcription factor Twist1, a central regulator of the epithelial-mesenchymal transition (EMT), promotes invadopodia formation via upregulation of platelet-derived growth factor receptor (PDGFR) expression and activity.', 'Twist1-induced invadopodia formation promotes tumor metastasis', 'The Twist1 transcription factor is known to promote tumor metastasis and induce Epithelial-Mesenchymal Transition (EMT). Here, we report that Twist1 is capable of promoting the formation of invadopodia, specialized membrane protrusions for extracellular matrix degradation.', 'Twist1 induces PDGFRα expression, which in turn activates Src, to promote invadopodia formation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation in response to various EMT-inducing signals.', 'Podosome-like structures of non-invasive carcinoma cells are replaced in epithelial-mesenchymal transition by actin comet-embedded invadopodia', 'Podosomes and invadopodia are actin-based structures at the ventral cell membrane, which have a role in cell adhesion, migration and invasion.', 'In conclusion, EMT affects the invasion machinery of oral squamous carcinoma cells. Non-invasive squamous carcinoma cells constitutively organize podosomes, whereas invasive cells form invadopodia. The club-ended cell extensions, or externalized invadopodia, are involved in ECM degradation and maintenance of contact to adhesion substrate and surrounding cells during invasion.', 'In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization.']

['In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. An important type of such membrane protrusions are the invadopodia, which have been increasingly recognized as important drivers of local invasion in metastasis. They are basally-localized, actin-rich structures that concentrate protease activity to areas of the cell in contact with the extracellular matrix.']

[]

What is the major adverse effect of adriamycin(doxorubicin)?

['It remains to be seen whether inhibition by adriamycin of these systems is related to the severe cardiotoxicity, the major adverse effect of the drug that limits its clinical usefulness.', 'Leukocytopenia was the major adverse effect among patients undergoing systemic THP administration', 'The major adverse effect was bone-marrow suppression;', 'The major adverse effect was bone marrow suppression;', 'Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic;', 'chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy', 'Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently', 'In spite of the routine use of this drug its major adverse effect, the dose-dependent cardiotoxicity, cannot be prevented yet', 'The major adverse effect was myelosuppression', 'Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy', 'Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity', 'The major adverse effect of DOX treatment in cancer patients is the onset of cardiomyopathy and heart failure']

['Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy ', 'Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy. In spite of the routine use of this drug its major adverse effect, the dose-dependent cardiotoxicity, cannot be prevented yet. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic.']

['Cardiotoxicity', 'Cardiac toxicity']

What is the triple screening test performed during pregnancy measuring?

['AFP--1.18 MoM and estriol--1.29 MoM and significantly higher mean median value for the free beta-hCG', 'alpha-fetoprotein (AFP), 1.02 for human chorionic gonadotropin (hCG) and 1.01 for unconjugated estriol (uE3', 'alpha fetoprotein (AFP), beta human chorionic gonadotropin (beta-hCG), and unconjugated estriol (uE3) ', 'alpha-fetoprotein (AFP), intact HCG and unconjugated estriol (uE3)', 'lpha-fetoprotein (AFP), total beta human chorionic gonadotrophin (hCG) and estriol (uE(3)', 'alpha feto-protein, HCG and unconjugated estriol', 'maternal serum alpha-fetoprotein, human chorionic gonadotropin and unconjugated oestriol ', 'maternal serum alpha fetoprotein, unconjugated oestriol and human chorionic gonadotrophin']

['Alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and unconjugated estriol (uE3)']

['AFP', 'Estriol', 'hCG']

Approximately how many recombination hotspots have been found in the yeast genome?

['In the fission yeast genome DSBs are located within 194 prominent peaks separated on average by 65-kbp intervals of DNA that are largely free of DSBs', 'Most meiotic recombination is positioned at hotspots, but knowledge of the mechanisms is nebulous', 'meiotic recombination is initiated by double-strand DNA breaks (DSBs) which occur at relatively high frequencies in some genomic regions (hotspots) and relatively low frequencies in others (coldspots)']

['In the fission yeast genome DSBs are located within 194 prominent peaks separated on average by 65-kbp intervals of DNA that are largely free of DSBs.']

['Approximately 200', '200', '~200']

Is there a difference in the rate between gene fusion and gene fission?

['we illustrate arrangement diversity within closely related organisms, estimate arrangement turnover frequency and establish, for the first time, branch-specific rate estimates for fusion, fission, domain addition and terminal loss.', 'Rate and polarity of gene fusion and fission in Oryza sativa and Arabidopsis thaliana', 'We have identified all differentially composite or split genes in 2 fully sequenced plant genomes, Oryza sativa and Arabidopsis thaliana', 'Polarizing these events by outgroup comparison revealed differences in the rate of gene fission but not of gene fusion in the rice and Arabidopsis lineages. Gene fission occurred at a higher rate than gene fusion in the O. sativa lineage and was furthermore more common in rice than in Arabidopsis.', 'Gene fusion and fission are thus rare and slow processes in higher plant genomes; they should be of utility to address deeper evolutionary relationships among plants--and the relationship of plants to other eukaryotic lineages--where sequence-based phylogenies provide equivocal or conflicting results.', 'Primary factors correlating with fusion rates are the presence of transmembrane helices in HKs and the presence of DNA-binding domains in RRs, features that require correct (and separate) spatial location. In the absence of such features, there is a relative abundance of fused genes.', 'We show that indels are the most frequent elementary events and that they occur in most cases at either the N- or C-terminus of the proteins. As revealed by the genomic neighbourhood/context of the corresponding genes, we show that a substantial number of these terminal indels are the consequence of gene fusions/fissions. We provide evidence showing that the contribution of gene fusion/fission to the evolution of multi-domain bacterial proteins is lower-bounded by 27% and upper-bounded by 64%. We conclude that gene fusion/fission is a major contributor to the evolution of multi-domain bacterial proteins.', 'We found that fusion events are approximately four times more common than fission events, and we established that, in most cases, any particular fusion or fission event only occurred once during the course of evolution.', 'Analyzing the most parsimonious pathways, we find 87% of architectures to gain complexity over time through simple changes, among which fusion events account for 5.6 times as many architectures as fission.', 'These trees defined timelines of architectural discovery and revealed remarkable evolutionary patterns, including the explosive appearance of domain combinations during the rise of organismal lineages, the dominance of domain fusion processes throughout evolution, and the late appearance of a new class of multifunctional modules in Eukarya by fission of domain combinations', 'We searched for examples which have arisen by one of the three postulated mechanisms: independent fusion/fission, "duplication/deletion," and plasmid-mediated "cut and paste." We conclude that all three mechanisms can be observed, with the independent fusion/fission being the most frequent.']

['Yes. Several studies have estimated that gene fusion and fission are relatively rare events and the gene fusion/fission rate is approximately between 2 and 6. A conflicting case has been discovered in an analysis of plant genomes, where in Oryza sativa the opposite trend was observed.']

['yes']

Are there focused databases from which you can retrieve gene expression data on renal disease?

['Proteomics database in chronic kidney disease', 'Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease']

['Biological databases are used to store and edit large amount of data, created from genomics data. In the most of the cases the data are stored according to their type but there are cases of focused databases that store database on a specific disease. In the case of renal disease there are plenty of databases, for example KUPKB a collection of omics datasets, Nephromine a renal genome-wide gene expression dataset based in transcriptomics, CDKD and Proteomics Database in Chronic Kidney Disease.']

['yes']

Are ultraconserved elements depleted among copy number variants (CNVs)?

['We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison. Here, we report that nonexonic UCEs are also depleted among 10 of 11 recent genomewide data sets of human CNVs, including 3 obtained with strategies permitting greater precision in determining the extents of CNVs', 'Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs)', 'We propose that these elements may be interpreted as hallmarks for dose-sensitive genes, particularly for those genes whose gain or loss may be directly implied in neurodevelopmental disorders. Therefore, their presence in genomic imbalances of unknown effect might be suggestive of a clinically relevant condition', 'Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants.', 'Ultraconserved elements (UCEs) are strongly depleted from segmental duplications and copy number variations (CNVs) in the human genome, suggesting that deletion or duplication of a UCE can be deleterious to the mammalian cell.', 'Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs).', 'We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison.', 'We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison', 'Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs)', 'Here, we show that UCEs are significantly depleted among segmental duplications and copy number variants', 'The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as cancer']

['Yes. Interestingly, human ultraconserved elements (UCEs) have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs). These elements may be interpreted as hallmarks for dose-sensitive genes, particularly for those genes whose gain or loss may be directly implied in neurodevelopmental disorders. Therefore, their presence in genomic imbalances of unknown effect might be suggestive of a clinically relevant condition']

['yes']

Is MammaPrint cleared by the United States Food and Drug Administration?

['Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel.']

['Yes. MammaPrint is cleared by the FDA for breast cancer recurrence.']

['yes']

Is amoxicillin used for treatment of malnutrition in children?

[' Another RCT did not show superiority of ceftriaxone over amoxicilllin for these same outcomes, but adressed SAM children with and without complications (p\u200a=\u200a0.27). Another RCT showed no difference between amoxicillin and cotrimoxazole efficacies for pneumonia in underweight, but not SAM. Our meta-analysis of 12 pooled susceptibility-studies for all types of bacterial isolates, including 2767 stricly SAM children, favoured amoxicillin over cotrimoxazole for susceptibility medians: 42% (IQR 27-55%) vs 22% (IQR 17-23%) and population-weighted-means 52.9% (range 23-57%) vs 35.4% (range 6.7-42%).', ' Susceptibility-studies favour amoxicillin over cotrimoxazole. ', 'Oral amoxicillin for 5\xa0days was as effective as intramuscular ceftriaxone for 2\xa0days (1 RCT). For uncomplicated SAM, amoxicillin showed no benefit over placebo (1 retrospective study). ', "Children who took amoxicillin and de-worming had 95% (HR\u200a=\u200a1.95, 95%-CI\u200a=\u200a1.17, 3.23) and 74% (HR\u200a=\u200a1.74, 95%-CI\u200a=\u200a1.07, 2.83) more probability to recover from SAM as compared to those who didn't take them.", 'METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned Malawian children, 6 to 59 months of age, with severe acute malnutrition to receive amoxicillin, cefdinir, or placebo for 7 days in addition to ready-to-use therapeutic food for the outpatient treatment of uncomplicated severe acute malnutrition. ', 'In the amoxicillin, cefdinir, and placebo groups, 88.7%, 90.9%, and 85.1% of the children recovered, respectively (relative risk of treatment failure with placebo vs. amoxicillin, 1.32; 95% confidence interval [CI], 1.04 to 1.68; relative risk with placebo vs. cefdinir, 1.64; 95% CI, 1.27 to 2.11). The mortality rates for the three groups were 4.8%, 4.1%, and 7.4%, respectively (relative risk of death with placebo vs. amoxicillin, 1.55; 95% CI, 1.07 to 2.24; relative risk with placebo vs. cefdinir, 1.80; 95% CI, 1.22 to 2.64).', 'Evaluation of the routine use of amoxicillin as part of the home-based treatment of severe acute malnutrition.', 'OBJECTIVE: To determine whether the inclusion of amoxicillin correlates with better recovery rates in the home-based treatment of severe acute malnutrition with ready-to-use therapeutic food.', 'The standard protocol group received a 7-day course of amoxicillin at the onset of treatment.', 'RESULTS: Four hundred and ninety-eight children were treated according to the standard protocol with amoxicillin, and 1955 were treated under the alternate protocol without antibiotics. ', 'The recovery rate for children who received amoxicillin was worse at 4 weeks (40%vs. 71%) but similar after up to 12 weeks of therapy (84%vs. 86%), compared to the children treated without antibiotics.', 'CONCLUSIONS: This review of two therapeutic feeding programmes suggests that children with severe acute malnutrition who were treated without amoxicillin did not have an inferior rate of recovery.', 'Treatment of severe malnutrition with 2-day intramuscular ceftriaxone vs 5-day amoxicillin.', 'To determine whether the inclusion of amoxicillin correlates with better recovery rates in the home-based treatment of severe acute malnutrition with ready-to-use therapeutic food.', 'Evaluation of the routine use of amoxicillin as part of the home-based treatment of severe acute malnutrition', 'OBJECTIVE: To determine whether the inclusion of amoxicillin correlates with better recovery rates in the home-based treatment of severe acute malnutrition with ready-to-use therapeutic food. METHODS: This retrospective cohort study compared data from the treatment of two groups of children in Malawi aged 6-59 months with uncomplicated severe acute malnutrition. ', 'The recovery rate for children who received amoxicillin was worse at 4 weeks (40%vs. 71%) but similar after up to 12 weeks of therapy (84%vs. 86%), compared to the children treated without antibiotics. Regression modelling indicated that this difference at 4 weeks was most strongly associated with the receipt of amoxicillin. CONCLUSIONS: This review of two therapeutic feeding programmes suggests that children with severe acute malnutrition who were treated without amoxicillin did not have an inferior rate of recovery. ', 'CONCLUSIONS: This review of two therapeutic feeding programmes suggests that children with severe acute malnutrition who were treated without amoxicillin did not have an inferior rate of recovery. ']

['Yes, amoxicillin is used for treatment of malnutrition in children.']

['yes']

Which are the common symptoms of Cushing's syndrome?

['Cushing syndrome is the constellation of signs and symptoms caused by protracted exposure to glucocorticoids. The most common cause of Cushing syndrome in children and adolescents is exogenous administration of glucocorticoids. Presenting features commonly include weight gain, growth retardation, hirsutism, obesity, striae, acne and hypertension', "This is a rare syndrome and its main endocrine manifestation, primary pigmented nodular adrenal disease (PPNAD), is an uncommon cause of adrenocorticotropic hormone-independent Cushing's syndrome.We report the case of a 20-year-old patient with a history of weight gain, hirsutism, acne, secondary amenorrhea and facial lentiginosis."]

['Cushing syndrome is the constellation of signs and symptoms caused by protracted exposure to glucocorticoids. Presenting features commonly include weight gain, growth retardation, hirsutism, obesity, striae, acne and hypertension.']

['weight gain', 'growth retardation', 'hirsutism', 'obesity', 'striae', 'acne', 'hypertension']

What is apelin?

['Apelin, a small regulatory peptide, is the endogenous ligand for the apelin receptor (APJ) receptor.', 'Apelin is an adipocyte-derived hormone that plays important roles in energy metabolism.', 'Apelin, as the endogenous ligand of G protein-coupled receptor APJ, participates in a number of physiological and pathological processes. ', 'Apelin is a novel bioactive peptide as the endogenous ligand for APJ.', 'adipokine apelin ', 'Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor family.', 'To date four adipokines (leptin, visfatin, apelin and ghrelin) have been investigated and all affect myometrial contractility, but some more potently than others.', 'The adipocytokine apelin is a peptide, Apelin and its receptor are abundantly expressed in the nervous and cardiovascular systems.', 'The aim of this study was to determine the levels of regulatory peptides apelin', 'Apelin is a vaso-dilatory peptide that also has a modulatory role in pain processing. ']

['Apelin, a small regulatory peptide, is the endogenous ligand for the apelin receptor (APJ) receptor.']

['Apelin, a small regulatory peptide, is the endogenous ligand for the apelin receptor (APJ) receptor.']

Has the fungus Ashbya gossypii got many nuclei that share cytoplasm?

['multinucleated Ashbya gossypii cells.', 'multinucleated Ashbya gossypii fungal cells', 'Nuclei in the filamentous, multinucleated fungus Ashbya gossypii divide asynchronously. ', 'multinucleated Ashbya gossypii cells', 'We analyzed a unique asynchronous nuclear division cycle in a multinucleated filamentous fungus, Ashbya gossypii.', ' multinucleated hyphae in Ashbya gossypii.', 'We have followed the migration of GFP-labelled nuclei in multinucleate hyphae of Ashbya gossypii', 'multinucleate fungus Ashbya gossypii', 'Ashbya gossypii grows as multinucleated and constantly elongating hyphae', 'multinucleated hyphae of Ashbya gossypii.', 'We report the mechanistic basis guiding the migration pattern of multiple nuclei in hyphae of Ashbya gossypii. ', 'multinucleate fungal cells', 'multinucleate Ashbya gossypii cells relies on a minimal network of genes', 'Clustering of nuclei in multinucleated hyphae is prevented by dynein-driven bidirectional nuclear movements and microtubule growth control in Ashbya gossypii.', 'In the multinucleate fungus Ashbya gossypii, cytoplasmic microtubules (cMTs) emerge from the spindle pole body outer plaque (OP) in perpendicular and tangential directions.', 'multinucleated hyphae of Ashbya gossypii.', 'multiple nuclei in Ashbya gossypii hyphae', 'Ashbya gossypii has a budding yeast-like genome but grows exclusively as multinucleated hyphae.']

['Yes, Ashbya gossypii has a budding yeast-like genome but grows exclusively as multinucleated hyphae.']

['yes']

Could transcription factors act as cell-cell signalling molecules?

['Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short-range cell-cell signalling molecules, hormones and structural proteins', 'Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities']

['Yes. Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities.', 'Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short-range cell-cell signalling molecules, hormones and structural proteins']

['yes']

Do plant genomes contain CpG islands?

['This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants', "In plant genomes, there exist discrete regions rich in CpG dinucleotides, namely CpG clusters. In rice, most of these CpG clusters are associated with genes. Rice genes are grouped into one of the five classes according to the position of an associated CpG cluster. Among them, class 1 genes, which harbor a CpG cluster at the 5'-terminus, share similarities with human genes having CpG islands", 'Segmental distribution of genes harboring a CpG island-like region on rice chromosomes', 'Highly-expressed Arabidopsis genes had overall a more marked GC-skew in the TSS compared to genes with low expression levels. We therefore propose that the GC-skew around the TSS in some plants and fungi is related to transcription. It might be caused by mutations during transcription initiation or the frequent use of transcription factor-biding sites having a strand preference. In addition, GC-skew is a good candidate index for TSS prediction in plant genomes, where there is a lack of correlation among CpG islands and genes', 'Preliminary analysis shows that promoter location based on the detection of potential CpG/CpNpG islands in the Arabidopsis genome is not straightforward. Nevertheless, because the landscape of CpG/CpNpG islands differs considerably between promoters and introns on the one side and exons (whether coding or not) on the other, more sophisticated approaches can probably be developed for the successful detection of "putative" CpG and CpNpG islands in plants', 'This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants.', 'These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands.', 'CONCLUSIONS: This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants.', 'In plant genomes, there exist discrete regions rich in CpG dinucleotides, namely CpG clusters.', 'These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands.', 'Unmethylated CpG islands associated with genes in higher plant DNA.', 'This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants.', 'These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands', 'We screened plant genome sequences, primarily from rice and Arabidopsis thaliana, for CpG islands, and identified DNA segments rich in CpG dinucleotides within these sequences']

['In plant genomes, there exist discrete regions rich in CpG dinucleotides, namely CpG clusters. In rice, most of these CpG clusters are associated with genes. Rice genes are grouped into one of the five classes according to the position of an associated CpG cluster. Among them, class 1 genes, which harbor a CpG cluster at the 5 -terminus, share similarities with human genes having CpG islands ', 'Yes. In plant genomes, there exist discrete regions rich in CpG dinucleotides, namely CpG clusters. In rice, most of these CpG clusters are associated with genes. Rice genes are grouped into one of the five classes according to the position of an associated CpG cluster.']

['yes']

Which ones are the ESKAPE organisms?

['The aim of this study was to test in the clinic whether antimicrobial diversity affects resistance of Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogens in ventilator-associated pneumonia (VAP).', 'Despite important geographical variations, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species (ESKAPE) pathogens constitute more than 80% of ventilator-associated pneumonia (VAP) episodes. ', "Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals.", 'Patients recovering from traumatic injuries or surgery often require weeks to months of hospitalization, increasing the risk for wound and surgical site infections caused by ESKAPE pathogens, which include A. baumannii (the ESKAPE pathogens are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).', "'ESKAPE' (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acintobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens play a major role in the rapidly changing scenario of antimicrobial resistance in the 21st century.", 'Although bacteremias caused by the 6 ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have recently been highlighted as a serious complication in solid organ transplant (SOT), more information is urgently needed. ', "Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.", "Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals. "]

['The 6 ESKAPE pathogens are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.']

['Enterococcus faecium', 'Staphylococcus aureus', 'Klebsiella pneumoniae', 'Acinetobacter baumannii', 'Pseudomonas aeruginosa', 'Enterobacter species']

Have the promoter regions of the genes implicated in Rett Syndrome been characterized with CAGE?

['CAGE-defined promoter regions of the genes implicated in Rett Syndrome.', 'Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes.RESULTS: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum.CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome.', 'CAGE-defined promoter regions of the genes implicated in Rett Syndrome', 'CAGE-defined promoter regions of the genes implicated in Rett Syndrome.']

['Yes. Promoter regions of the genes implicated in Rett Syndrome have been characterized using CAGE.']

['yes']

Which syndrome is NHE6 associated with?

['A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES)', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia.', 'Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.', 'Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6).', 'Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.', 'Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6).', 'A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES).', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. ', 'OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). ', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia.', 'encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome,']

['Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia.']

['Christianson syndrome']

Which is the most common gene signature in Rheumatoid Arthritis patients?

['A five gene type I IFN signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type I IFN pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the WB with clinical measurements.R', 'Baseline disease activity measurements correlated with a type I IFN gene signature in the WB of subjects with SLE, PM and SSc, as did various serum autoantibody levels in subjects with SLE and DM. This signature was also well correlated between disease-affected tissue and WB in subjects with SLE, DM, PM and SSc.', 'We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a).', 'A CD4 T cell gene signature for early rheumatoid arthritis implicates interleukin 6-mediated STAT3 signalling, particularly in anti-citrullinated peptide antibody-negative disease', "A 12-gene transcriptional 'signature' identified RA patients in the training cohort and predicted the subsequent development of RA among UA patients in the validation cohort (sensitivity 68%, specificity 70%). ", 'The involvement of HIF isoforms in generating the angiogenic signature of RA FLS stimulated with hypoxia and/or cytokines was investigated using a DNA-binding assay and RNA interference.', 'The objective of our study was to characterise the angiogenic gene signature of RA fibroblast-like synoviocytes (FLS) in response to hypoxia, as well as Th1 and T-helper cell 2 (Th2) cytokines, and in particular to dissect out effects of combined hypoxia and cytokines on hypoxia inducible transcription factors (HIFs) and angiogenesis.', 'Multiple folate metabolism-related genes were consistently and significantly altered between the 3 groups in both cohorts. Concurrent with evidence of an immune-activation gene signature in MTX-naive RA patients, significant up-regulation of the folate-metabolizing enzymes γ-glutamyl hydrolase and dihydrofolate reductase, as well as the MTX/folate efflux transporters ABCC2 and ABCC5, was observed in the MTX-naive RA group compared to healthy controls.', 'We used microarray profiling of peripheral blood mononuclear cells (PBMCs) in 30 RA patients to assess the effect of different biologic agent (biologics) treatments and to quantify the degree of a type-I interferon (IFN) signature in these patients. ', 'The 256 genes identified were used to derive a gene signature score by averaging their log expression within each patient.', ' IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. ', 'We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). ', 'Flow cytometry and gene profiling indicated that RA-SF macrophages express pro-inflammatory polarization markers (MMP12, EGLN3, CCR2), lack expression of markers associated with homeostatic and anti-inflammatory polarization (IGF1, HTR2B) and exhibit a transcriptomic profile that resembles the activin A-dependent gene signature of pro-inflammatory in vitro-generated macrophages.', 'Gene expression analyses showed a greater prevalence of significantly upregulated genes in HCs with negative ANA values than in those with significant ANA positivity. Genes upregulated in high ANA HCs included a celiac disease autoantigen and some components of the Type I interferon (IFN) gene signature.', 'We therefore initiated this study to identify signatures that would be of utility in studying rheumatoid arthritis (RA).We used microarray profiling of peripheral blood mononuclear cells (PBMCs) in 30 RA patients to assess the effect of different biologic agent (biologics) treatments and to quantify the degree of a type-I interferon (IFN) signature in these patients', 'Gene expression analysis of peripheral blood cells from patients with rheumatoid arthritis and multiple sclerosis demonstrate an interferon signature similar to but less intense than that seen in patients with lupus.', 'To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients.Twenty RA patients were treated with rituximab (cohort 1).', 'To validate the presence and demonstrate the clinical value of the type I interferon (IFN)-signature during arthritis development.In 115 seropositive arthralgia patients who were followed for the development of arthritis (Amsterdam Reade cohort), and 25 presymptomatic individuals who developed rheumatoid arthritis (RA) later, and 45 population-based controls (Northern Sweden cohort), the expression levels of 7 type I IFN response genes were determined with multiplex qPCR and an IFN-score was calculated.', "Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature.", 'More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus).', 'Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients.', 'Importance of correlation between gene expression levels: application to the type I interferon signature in rheumatoid arthritis.', 'To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients.']

['A five gene type I IFN signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type I IFN pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the WB with clinical measurements.R Baseline disease activity measurements correlated with a type I IFN gene signature in the WB of subjects with SLE, PM and SSc, as did various serum autoantibody levels in subjects with SLE and DM.', 'Baseline disease activity measurements correlated with a type I IFN gene signature in the WB of subjects. The type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA.', 'a five gene type i ifn signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type i ifn pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the wb with clinical measurements.', 'A five gene type I IFN signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type I IFN pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the WB with clinical measurements.R']

['Interferon signature', 'IFN signature']

Which are the state-of-the-art computational tools for the prediction of gene fusion events?

['MosaicFinder: Identification of fused gene families in sequence similarity networks', 'This leads to an efficient formulation of previous methods of fused gene identification, which we implemented in the Python program FusedTriplets.', 'We implemented this method in the C++ program MosaicFinder, which additionally uses local alignments to discard false positive candidates and indicates potential fusion points.', 'Inference of gene function based on gene fusion events: the rosetta-stone method.', 'The basic idea is based on the principle of "guilt by association." It is assumed that two proteins, which are found to be transcribed by a single transcript in one (or several) genomes are likely to be functionally linked, for example by acting in a same metabolic pathway or by forming a multiprotein complex. This method is of particular interest for studying genes that exhibit no, or only remote, homologies with already well-characterized proteins', 'This chapter uses the FusionDB database (http://www.igs.cnrs-mrs.fr/FusionDB/) as source of information. FusionDB provides a characterization of a large number of gene fusion events at hand of multiple sequence alignments.', 'PLEX can be searched iteratively and also enables searches for chromosomal gene neighbors and Rosetta Stone linkages.', 'While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships.', 'Functional links between proteins can often be inferred from genomic associations between the genes that encode them: groups of genes that are required for the same function tend to show similar species coverage, are often located in close proximity on the genome (in prokaryotes), and tend to be involved in gene-fusion events. The database STRING is a precomputed global resource for the exploration and analysis of these associations.', 'Protein interaction maps for complete genomes based on gene fusion events', 'Here we present a method that identifies gene-fusion events in complete genomes, solely based on sequence comparison.', 'Gene fusions have been suggested to be useful characters for identifying evolutionary relationships because they constitute synapomorphies or cladistic characters. To investigate the fidelity of gene-fusion characters, we developed an approach for identifying differentially distributed gene fusions among whole-genome datasets: fdfBLAST.', 'Genome-scale comparative analysis of gene fusions, gene fissions', 'Here we present Predictome, a database of predicted links between the proteins of 44 genomes based on the implementation of three computational methods--chromosomal proximity, phylogenetic profiling and domain fusion', 'Pairs of genes that function together in a pathway or cellular system can sometimes be found fused together in another organism as a Rosetta Stone protein--a fusion protein whose separate domains are homologous to the two functionally-related proteins.', 'Using the Rosetta Stone method and this scoring scheme, we find all significant functional linkages for proteins of E. coli, P. horikshii and S. cerevisiae, and measure the extent of the resulting protein networks.']

["Gene fusion detection - also known as the 'Rosetta Stone' method - involves the identification of fused composite genes in a set of reference genomes, which indicates potential interactions between its un-fused counterpart genes in query genomes. A few methods/tools and computational pipelines for the detection of gene fusion events have been introduced. The basic steps followed in these approaches consist of (i) all-against-all sequence comparison, (ii) detection of non-overlapping similarities of two genes/proteins (components) to a single gene/protein (composite), and optionally (iii) elimination of putative spurious hits (e.g. due to promiscuous domains) achieves via clustering based on sequence similarity and examining dense regions of the resulting graph or by querying the PFAM database. An advantage of gene fusion analysis is that functional associations can be predicted even in cases of genes of unknown function. Due to the computationally intense nature of these approaches, precompiled data of this type are often organized in specialized databases. Tools and databases developed for this purpose include (in alphabetical order): fdfBLAST, FusionDB, InPrePPI, (Integrated method for Prediction of Protein-Protein Interactions), MosaicFinder, Phydbac2, PLEX, Predictome, Rosetta Stone method, STRING."]

['fdfBLAST', 'FusionDB', 'InPrePPI', 'Integrated method for Prediction of Protein-Protein Interactions', 'MosaicFinder', 'Phydbac2', 'PLEX', 'Predictome', 'Rosetta Stone method', 'STRING']

What is the gold standard treatment for Iatrogenic male incontinence?

['The initial treatment for SUI that persists after 12 months consists of conservative measures such as pelvic floor muscle exercises and behavioral therapy. Properly selected and informed patients can also be treated efficiently with minimally invasive procedures such as the implantation of a male suburethral sling, although the experience with such devices is not extensive. However, the implantation of artificial urinary sphincter is the gold standard therapy.', 'treatments such as periurethral injection of bulking agents, artificial urinary sphincter (AUS) implantation, and sub-urethral sling positioning. The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options.', 'Today, three different sling procedures are commonly performed: bone-anchored, readjustable, and trans-obturator slings systems.', 'The bone anchored suburethral synthetic sling is a simple and attractive procedure that can produce immediate good results with low morbidity, especially when strictly selected patients are treated. ', 'BAUS implantation is a safe, effective, minimally invasive option for iatrogenic male incontinence due to ISD. It compares favourably with AUS.']

['The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options.']

['Artificial urethral sphincter', 'AUS']

What is the incidence of sudden cardiac death among young athletes?

['Sudden cardiac death is the leading cause of mortality among young athletes with an incidence of 1-2 per 100,000 athletes per annum.', 'The incidence of SCD is expected at one case for each 200,000 young athletes per year.', 'The incidence of sudden cardiac death (SCD) among young athletes is estimated to be 1-3 per 100,000 person years, and may be underestimated. ', 'Sudden cardiac death in a young athlete is a tragic and marking event, even though the media attention it gets is more important than its incidence (1-2/100000 per year). ', 'The sudden death of athletes under 35 years engaged in competitive sports is a well-known occurrence; the incidence is higher in athletes (approximately 2/100,000 per year) than in non-athletes (2.5 : 1), and the cause is cardiovascular in over 90%.']

['the incidence of sudden cardiac death among young athletes ranges from 0.5 to 3 per 100,000 athletes per year .']

['0.5 to 3 per 100,000 athletes per year']

Is statin use associated with improved outcomes after aneurysmal subarachnoid hemorrhage?

['Statins have been shown in two recent small phase I/II trials to be associated with a marked reduction in clinical and transcranial Doppler (TCD) evidence of vasospasm after aneurysmal subarachnoid haemorrhage (SAH). ', 'Statins did not result in reduced TCD velocities, clinical or angiographic vasospasm, or improvements in global outcome at the time of hospital discharge. ', 'There remains significant uncertainty as to the role of statins in preventing vasospasm after SAH.', 'Although the results of 2 randomized clinical trials demonstrated that statin decreases the incidence of symptomatic cerebral vasospasm after aSAH, retrospective studies have failed to confirm this.', 'There were no differences in the incidence of symptomatic vasospasm (25.3 vs 30.5%; p = 0.277), in-hospital mortality rate (18 vs 15%; p = 0.468), length of hospitalization (21 +/- 15 vs 19 +/- 12 days; p = 0.281), or poor outcome at discharge (Glasgow Outcome Scale Scores 1-2: 21.7 vs 18.2%; p = 0.416) between the simvastatin and nonstatin cohorts. ', 'The uniform introduction of simvastatin did not reduce the incidence of symptomatic cerebral vasospasm, death, or poor outcome in patients with aSAH. Simvastatin was well tolerated, but its benefit may be less than has been previously reported.', 'Cholesterol-reducing agents might improve unfavourable outcomes.', 'We cannot draw any conclusions about the effectiveness and safety of lowering cholesterol in aneurysmal SAH because of insufficient reliable evidence from only one small trial.', 'Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage.', 'There was an improvement in the functional outcome in the simvastatin group at 1, 3 or 6 months in the follow-up; however, this difference was not statistically significant.', ' There was benefit of simvastatin in terms of reduction in clinical vasospasm, mortality or improved functional outcome, however, this was not statistically significant.', 'Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA.', 'Atorvastatin decreases computed tomography and S100-assessed brain ischemia after subarachnoid aneurysmal hemorrhage: a comparative study.', 'In the overall population, cerebral vasospasm was significantly less common in the statin-treated group. Severity of vasospasm, as assessed on the most severe angiogram, was lowered with statin. Statins significantly reduced volume of ischemia in patients with vasospasm and an uncomplicated coiling procedure. S100B levels were significantly lower in statin-treated patients, and the decrease was greatest among high-grade patients (World Federation of Neurological Surgeons 3-5). No differences were found between statin-treated and untreated groups regarding rescue therapy intensity or 1-yr clinical outcomes.', 'Atorvastatin reduces the incidence, the severity and the ischemic consequences of vasospasm as assessed on computed tomography. In high-grade World Federation of Neurological Surgeons patients, atorvastatin decreases serum levels of S100B, a biomarker of brain ischemia. Despite these positive effects on biomarkers, no improvement of outcome was seen in the overall population, although there was a tendency for a better clinical outcome in high-grade patients.', '3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved clinical outcomes after ischemic stroke and subarachnoid hemorrhage, but with an increased risk of incidental spontaneous intracerebral hemorrhage (ICH).', 'Statins are known to have pleiotropic vascular effects, some of which may interrupt the pathogenesis of DNDs. Based on promising preliminary reports, many clinicians routinely administer statins to prevent DNDs.', 'However, observational studies have not revealed an association between statin-use and reduced DNDs or improved neurological outcomes. Results of RCTs have been inconsistent and limited by small sample size, but together suggest that statins may reduce DNDs, with no clear impact on mortality or neurological recovery.', 'the role of statins in the management of patients with SAH remains unclear. Although promising, statins should not, at this time, be considered standard care.', 'In patients with SAH, they may decrease the incidence of symptomatic vasospasm, although the effects on overall outcome are less clear.', 'Statins treatment may have potential clinical impact in vascular disease beyond cholesterol lowering. Its benefits have been documented in cerebral ischaemia and in subarachnoid haemorrhage.', 'A recent meta-analysis investigating the efficacy of statin treatment in patients with aneurysmal subarachnoid hemorrhage reported a reduced incidence of vasospasm, delayed cerebral ischemia, and mortality in statin-treated patients.', 'The results of the present systematic review do not lend statistically significant support to the finding of a beneficial effect of statins in patients with aneurysmal subarachnoid hemorrhage as reported in a previous meta-analysis.', 'Pre-treatment with cholesterol lowering drugs of the statin family may exert protective effects in patients with ischaemic stroke and subarachnoid haemorrhage but their effects are not clear in patients with intracerebral haemorrhage (ICH). ', 'Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality.', 'We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH.', 'Novel uses of their anti-inflammatory properties in sepsis and vasomotor properties in subarachnoid haemorrhage are being further investigated by randomised trials.', 'A trend towards a lower mortality within 14 days in patients receiving solely simvastatin and those receiving statin and magnesium as compared with the control group was found. ', 'Initiation of statin therapy after aneurysmal SAH significantly reduces the incidence of vasospasm, delayed ischemic deficits, and mortality.', 'The addition of statins to standard care was not associated with any reduction in the development of vasospasm or improvement in outcomes after aneurysmal subarachnoid hemorrhage. ', 'We have previously demonstrated that acute pravastatin therapy after aneurysmal subarachnoid hemorrhage ameliorates vasospasm-related delayed ischemic deficits.', ' This trial demonstrates that acute statin treatment reduces traditional rescue therapy for vasospasm after aneurysmal subarachnoid hemorrhage. Improvement in early outcome has proved robust at 6 months, particularly in relation to physical and psychosocial (Short Form 36) outcome.', 'The authors previously have demonstrated that acute treatment with pravastatin after aneurysmal subarachnoid hemorrhage (SAH) can ameliorate vasospasm-related delayed ischemic neurological deficits (DINDs).', 'The neuroprotective effects of acute treatment with pravastatin following aneurysmal SAH are associated with enhancement of autoregulation', 'Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial.', 'The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit.', 'Acute treatment with pravastatin after aSAH is safe and ameliorates cerebral vasospasm, improves cerebral autoregulation, and reduces vasospasm-related DID.', ' SAH statin users demonstrated significant improvement in 14-day functional outcome, a significantly lower incidence of DCI and cerebral infarctions of any type, as well as prevention of TCD highest mean velocity elevation. However, we did not find a significant statin impact on mortality or global outcome (Modified Rankin Scale) in this small sample. ']

['Statin use after subarachnoid hemorrhage has been shown be associated with improved outcomes by some prospective clinical trials. It has been reported that statin use after subarachnoid hemorrhage reduced rates of vasospasm, delayed cerebral ischemia, and mortality. However, other authors have failed to find beneficial effect of statin use in subarachnoid hemorrhage patients.']

['yes']

What is the role of Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) in development?

['Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism.', ' We show that HPL-2 regulates the expression of germline genes, extracellular matrix components and genes involved in lipid metabolism. Comparison of our expression data with HPL-2 ChIP-on-chip profiles reveals that a significant number of genes up- and down-regulated in the absence of HPL-2 are bound by HPL-2. Germline genes are specifically up-regulated in hpl-2 mutants, consistent with the function of HPL-2 as a repressor of ectopic germ cell fate. ', 'HPL-2 regulates the dauer developmental decision, a striking example of phenotypic plasticity in which environmental conditions determine developmental fate.', 'Our results suggest that the worm HP1 homologue HPL-2 may coordinately regulate dauer diapause, longevity and lipid metabolism, three processes dependent on developmental input and environmental conditions.', 'Interestingly, lin-61 genetically interacts with two other synMuvB genes, hpl-2, an HP1 homologous H3K9me2/3 binding factor, and met-2, a SETDB1 homologous H3K9 methyl transferase (H3K9MT), in determining C. elegans vulva development and fertility.', 'We have specifically characterized the intranuclear positioning of in vivo fluorescence of the Caenorhabditis elegans HP1 homologue HPL-2 as a marker for heterochromatin domains in developing embryos. ', 'While HPL-2 functions in vulval and germline development, no function has so far been attributed to HPL-1. Here we report the characterization of an hpl-1 null allele. We show that while the absence of hpl-1 alone results in no obvious phenotype, hpl-1;hpl-2 double mutants show synthetic, temperature sensitive phenotypes including larval lethality and severe defects in the development of the somatic gonad. Furthermore, we find that hpl-1 has an unexpected role in vulval development by acting redundantly with hpl-2, but not other genes previously implicated in vulval development. Localization studies show that like HPL-2, HPL-1 is a ubiquitously expressed nuclear protein. However, HPL-1 and HPL-2 localization does not completely overlap. Our results show that HPL-1 and HPL-2 play both unique and redundant functions in post-embryonic development.', 'We show that one of the homologues, HPL-2, is required for the formation of a functional germline and for the development of the vulva by acting in an Rb-related pathway. ', 'A heterochromatin protein 1 homologue in Caenorhabditis elegans acts in germline and vulval development.', 'We have specifically characterized the intranuclear positioning of in vivo fluorescence of the Caenorhabditis elegans HP1 homologue HPL-2 as a marker for heterochromatin domains in developing embryos.', 'Germline genes are specifically up-regulated in hpl-2 mutants, consistent with the function of HPL-2 as a repressor of ectopic germ cell fate.']

['Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism. HPL-2 regulates the expression of germline genes, extracellular matrix components and genes involved in lipid metabolism. In addition, HPL-2 regulates the dauer developmental decision, a striking example of phenotypic plasticity in which environmental conditions determine developmental fate. Furthermore, it is required for the formation of a functional germline and for the development of the vulva by acting in an Rb-related pathway.']

[]

Which is the protein encoded by the human gene GRIK?

['GRIK\u2009=\u2009glutamate receptor, ionotropic, kainate', ' To this end, the effects of chronic ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA) subunit variant and kainate (GRIK)']

['Glutamate Receptor Ionotropic Kainate']

['glutamate receptor ionotropic kainate']

Which are the inhibitors of histone methyltransferases?

['However, in general, HMTs have no widely accepted high-throughput screening (HTS) assay format, and reference inhibitors are not available for many of the enzymes.', 'Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum.', 'We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC(50) values of ~100 nM, values at least 22-fold more potent than their apparent IC(50) toward two human cell lines and one mouse cell line.', 'Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death.', 'Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L.', 'A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM.', 'Several new reagents and assays were developed to aid in the identification of EZH2 inhibitors, and these were used to execute two high-throughput screening campaigns.', 'Of the five histone methyltransferases known to mediate methylation of the lysine 9 residue of histone H3 (H3K9), euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) has been shown to be a primary mediator of H3K9 dimethylation; BIX-01294 has been shown to be a specific inhibitor of EHMT2', 'We hypothesised that inhibition of EHMT2 by BIX-01294 would result in reduced levels of H3K9 dimethylation and compromised embryo development.', 'We also demonstrate that peptides that mimic SET1 family Win motif sequences inhibit H3K4 dimethylation by the MLL1 core complex with varying degrees of efficiency.', 'Studies of H3K4me3 demethylation by KDM5B/Jarid1B/PLU1 reveals strong substrate recognition in vitro and identifies 2,4-pyridine-dicarboxylic acid as an in vitro and in cell inhibitor.', 'Inhibition studies of ccKDM5B showed both in vitro and in cell inhibition of ccKDM5B by 2,4-pyridinedicarboxylic acid (2,4-PDCA) with a potency similar to that reported for the HDM KDM4C.', 'Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji cells when in combination with an HDAC inhibitor, trichostatin A (TSA).', 'All assays allowed profiling of known SET7/9 and LSD1 inhibitors. The results demonstrate that the optimized LANCE Ultra and AlphaLISA assay formats provide a relevant biochemical screening approach toward the identification of small-molecule inhibitors of HMTs and HDMs that could lead to novel epigenetic therapies.', 'Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies.', 'We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM.', 'Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer.', 'Short hairpin RNAs were used to inhibit several histone methyltransferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene expression.', 'DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knockdown.', 'Recent evidence shows that S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors (AHI) such as 3-deazaneplanocin A (DZNep) modulate chromatin through indirect inhibition of histone methyltransferases including EZH2. We investigated the biological effects of AdoHcy hydrolase inhibition using DZNep and its structural analogues 3-deazaadenosine (DZA) and neplanocin A (Nep A) in breast cancer cells.', 'A chemiluminescence-based method for identification of histone lysine methyltransferase inhibitors.', 'The method is particularly well suited for detection of inhibitors acting by the desired histone peptide competitive mechanism and is applicable to testing other HMTs, demonstrated here with the G9a homolog EHMT1, also known as GLP.', 'This study reports the pharmacokinetics and tissue distribution of a novel histone deacetylase and DNA methyltransferase inhibitor, psammaplin A (PsA), in mice.', 'Human diet contains many histone deacetylase (HDAC) inhibitors, such as the bioactive component sulforaphane (SFN), whose epigenetic effects on MSTN gene in satellite cells are unknown.', "We found that DNA methyltransferase inhibitor (5-Aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) reduced leptin receptor expression.", 'However, histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate (NaBt) significantly increased Wnt5a mRNA expression in SW620.']

['In general, histone methyltransferases (HMTs) have no widely approved high-throughput screening assay format, and therefore reference inhibitors are not available for many of the HMTs. However, there are several selective HMT inhibitors: Trichostatin A (TSA), BIX-01294 and its derivative TM2-115, 2,4-pyridinedicarboxylic acid (2,4-PDCA), 3-deazaneplanocin A (DZNep), Psammaplin A (PsA) and Sulforaphane (SFN).']

['BIX-01294', 'TM2-115', '2,4-pyridinedicarboxylic acid', '2,4-PDCA', '3-deazaneplanocin A', 'DZNep', 'Trichostatin A', 'TSA', 'Psammaplin A', 'PsA', 'Sulforaphane', 'SFN']

Are CTCF and BORIS involved in genome regulation and cancer?

['CTCF is ubiquitously expressed and plays diverse roles in gene regulation, imprinting, insulation, intra/interchromosomal interactions, nuclear compartmentalisation, and alternative splicing. CTCF has a single paralogue, the testes-specific CTCF-like gene (CTCFL)/BORIS. CTCF and BORIS can be deregulated in cancer. The tumour suppressor gene CTCF can be mutated or deleted in cancer, or CTCF DNA binding can be altered by epigenetic changes. BORIS is aberrantly expressed frequently in cancer, leading some to propose a pro-tumourigenic role for BORIS. However, BORIS can inhibit cell proliferation, and is mutated in cancer similarly to CTCF suggesting BORIS activation in cancer may be due to global genetic or epigenetic changes typical of malignant transformation', ' The investigation of the molecular mechanisms engaged by CTCF to modulate tumor-related genes emphasizes the cell-type dependency of its tumor suppressor role. Indeed, the ability of CTCF to bind their promoters strictly depends by cell-type features as DNA methylation, BORIS-binding and post-translational modifications as PARYlation', 'Moreover, reduction of CTCF in normally BORIS-negative human fibroblasts resulted in derepression of BORIS promoters. These results provide a mechanistic basis for understanding cancer-related associations between haploinsufficiency of CTCF and BORIS derepression, and between the lack of functional p53 and aberrant activation of BORIS', 'CTCF and BORIS in genome regulation and cancer.', 'The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer.', 'Collectively, these data indicate that reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter mediates epigenetic regulation of this CT gene in lung cancer cells, and suggest that induction of BORIS may be a novel strategy to augment immunogenicity of pulmonary carcinomas.', 'BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation.', 'However, BORIS can inhibit cell proliferation, and is mutated in cancer similarly to CTCF suggesting BORIS activation in cancer may be due to global genetic or epigenetic changes typical of malignant transformation.', 'We suggest that BORIS is likely tethering epigenetic machinery to a novel class of CTCF/BORIS 11ZF target sequences that mediate induction of cancer-testis genes.', 'Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a "cancer-testis" antigen.']

['Yes. CTCF is ubiquitously expressed and plays diverse roles in gene regulation, imprinting, insulation, intra/interchromosomal interactions, nuclear compartmentalisation, and alternative splicing. CTCF has a single paralogue, the testes-specific CTCF-like gene (CTCFL)/BORIS. CTCF and BORIS can be deregulated in cancer. The tumour suppressor gene CTCF can be mutated or deleted in cancer, or CTCF DNA binding can be altered by epigenetic changes. BORIS is aberrantly expressed frequently in cancer, leading some to propose a pro-tumourigenic role for BORIS. However, BORIS can inhibit cell proliferation, and is mutated in cancer similarly to CTCF suggesting BORIS activation in cancer may be due to global genetic or epigenetic changes typical of malignant transformation.']

['yes']

What is the role of the RUNX1-MYEF2 complex?

['A novel complex, RUNX1-MYEF2, represses hematopoietic genes in erythroid cells.', 'Functional analysis shows that a subset of the target genes is suppressed by RUNX1 via the newly identified partner MYEF2. Knockdown of Myef2 expression in developing zebrafish results in a reduced number of HSC.', 'Functional analysis shows that a subset of the target genes is suppressed by RUNX1 via the newly identified partner MYEF2. Knockdown of Myef2 expression in developing zebrafish results in a reduced number of HSC.', 'Chromatin immunoprecipitation followed by sequencing (ChIP-seq) and microarray expression analysis were used to show that RUNX1 binds approximately 9,000 target sites in erythroid cells and is primarily active in the undifferentiated state. Functional analysis shows that a subset of the target genes is suppressed by RUNX1 via the newly identified partner MYEF2.']

['A novel complex, RUNX1-MYEF2, represses hematopoietic genes in erythroid cells.']

['The repression of hematopoietic genes in erythroid cells.']

Are thyroid hormone receptor alpha1 mutations implicated in thyroid hormone resistance syndrome?

['Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis.', 'Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor']

['thyroid hormone receptor alpha1 mutations are implicated in thyroid hormone resistance syndrome']

['yes']

Do all archaea possess multiple origins of DNA replication?

['Origins differ in number and structure across the three domains of life and their properties determine the dynamics of chromosome replication. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins.', 'Replication starts at a single Ori site in bacteria, but in eukaryotes multiple Ori sites are used for fast copying across all chromosomes. The situation becomes complex in archaea, where some groups have single and others have multiple origins of replication.', 'Results from this in silico analysis show that the Themococcales have a single origin of replication.', 'Until recently, the only archaeon for which a bona fide origin of replication was reported was Pyrococcus abyssi, where a single origin was identified. Although several in silico analyses have suggested that some archaeal species might contain more than one origin, this has only been demonstrated recently.', 'In bacteria and eukaryotes, replication initiates from single and multiple origins, respectively, while archaea can adopt either of the two modes.', 'Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins.', 'Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins']

['Origins of DNA replication differ in number and structure across the three domains of life and their properties determine the dynamics of chromosome replication. Though most archaea replicate their chromosomes using multiple origins, there are also certain archaea that possess a single origin of DNA replication (such as Pyrococcus abyssi and some archaea belonging in the hyperthermophilic order of Themococcales).']

['no']

What is known about depression in caregivers of brain tumor patients?

["Data suggest that patients with primary or metastatic brain tumours often have a high symptom burden and unmet needs for palliative care, and symptoms are hard to diagnose; patients suffer often and early from cognitive impairment but are rarely appropriately prepared concerning end-of-life wishes. This reflects on their caregivers' burden as well", 'Reports of caregiver depressive symptoms and anxiety were lower when paired with higher reports of spirituality.', "Fifty-nine percent did not receive any financial aid for home care, 33% had increased risk for psychosomatic problems, 45% had anxiety, and 33% increased depression levels. The caregiver's quality of life was most strongly affected by the burden of care (p < .001) and the patient's mental state (p < .03).", 'Depressive symptoms are common in cancer patients and their family caregivers (FCs). ', "The psychological burden induced by brain tumor is profound both for the sick person and for their own family. This particular tumor not only impacts patients' quality of life, but also reduces seriously the caregivers' quality of life. ", 'Most caregivers experienced more depressive and anxiety symptoms, as compared with patients. ', "Therefore, it is necessary to monitor and treat, if necessary, caregivers' anxious or depressive symptomatology that impacts their quality of life, making them more helpless, frustrated and less able to handle the situation of disease and caregiving situation. ", 'Group-based trajectory modeling identified high-decreasing (51.1 % of caregivers) and consistently low (48.9 %) depressive symptom trajectories, high-decreasing (75.5 %) and low-decreasing (24.5 %) anxiety trajectories, and high (37.5 %), moderate (40.9 %), and low-decreasing (21.6 %) caregiver burden trajectories. High depressive symptoms were associated with high trajectories for both anxiety and burden, lower caregivers age, income, and social support, and lower care recipient functioning.', 'Studies suggest rates of depression and anxiety up to 48% in patients and up to 40% in caregivers, with many unmet needs and dissatisfaction with health care provider communication and information. ', 'Caregivers try to react to the illness of their relatives by mobilizing their physical reaction and growing their self-esteem, but they live with a clinically significant impairment of their quality of life, and experience a deep level of anxiety and depression.', ' There was a trend for economic hardship to predict CG depressive symptoms at 4 months (P = 0.09), but not at diagnosis.', 'Although previous research has documented the stress, depression, anxiety, and burden associated with caregiving, when these conditions occur is not known.', 'Among patients, 30% reported anxious mood and 17% depressed mood on the HADS, while corresponding numbers for carers were 40% and 10%, respectively. ', "Among patients and carers, 30% and 40%, respectively, reported anxious moods and 17% and 10%, respectively, reported depressed moods on the HADS. Significant correlations were observed between the FACT-G and HADS subscales, particularly emotional well-being and anxiety, as well as physical and functional well-being and depression, and between patients' and their carers' quality of life. ", "Findings showed a link between care recipients' problem behaviors and caregivers' depressive symptoms, a relationship that has not been well established in oncology. ", "Care recipients' neuropsychiatric status consistently affected caregivers' depressive symptoms and burden, and assisting with activities of daily living affected burden related to caregivers' schedules and health. "]

["Depression is common affecting up to 40% of caregivers of brain tumor patients. Depression is associated with poor quality of life of caregivers of brain tumor patients. Greater anxiety, patients’ emotional distress, economic hardship, lower caregivers’ age, lower income, less social support and lower patient functioning were associated with more caregivers’ depressive symptoms. Reports of caregiver depressive symptoms were lower when paired with higher reports of spirituality. It is important to monitor and treat caregiver's depression."]

[]

Which G protein is essential in the formation and function of lamellipodia?

['We specifically identified that the Spa homology domain (aa 250-420) of GIT1 is required for GIT1-cortactin complex localization to the leading edge. The mechanisms involved extracellular signal-regulated kinases 1 and 2-mediated Cortactin-S405 phosphorylation and activation of Rac1/Cdc42.', 'We demonstrated the utility of this system with LAD constructs that can recruit the small G-protein Rac1 to the plasma membrane and induce the local formation of lamellipodia in response to focal illumination.', 'We found that fibroblasts from EDG-1 null embryos did not migrate toward PDGF or SPP, and inhibition of motility correlated with defective activation of the small guanosine triphosphatase Rac, which is required for lamellipodia formation and directional locomotion', 'Deletion of edg-1 or inhibition of sphingosine kinase suppressed chemotaxis toward PDGF and also activation of the small guanosine triphosphatase Rac, which is essential for protrusion of lamellipodia and forward movement.', 'Evidence from these models indicates that migration is a highly complex process, which is likely to involve the tightly controlled spatial and temporal interaction of multiple factors:', '(v) molecules which regulate cytoskeletal function (e.g. Rac), which allows the formation of specialized cellular processes termed lamellipodia.']

['Recruitment of the small G-protein Rac1 to the plasma membrane is essential in inducing the local formation of specialized cellular processes termed lamellipodia.']

['Rac1']

Which protein is affected by dusp8 activation?

["Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.", 'Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase.', 'These results suggest that JNK activation by H(2)O(2) plus PDTC resulted from the down-regulation of JNK phosphatases.', 'M3/6 is a dual-specificity phosphatase selective for JNK', 'Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite.', 'Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK', 'Both anisomycin and arsenite activate the JNK pathway and, in addition, inactivate the M3/6 phosphatase.', 'M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins.', '. We suggest that reduction of HSP70 by expanded polyglutamine is implicated in aggregation and inhibition of M3/6 and in activation of JNK and AP-1.']

['dusp8 (M3/6) is a dual-specificity phosphatase selective for JNK.']

['JNK']

Which are the genes responsible for Dyskeratosis Congenita?

['Studies over the last 15 years have led to significant advances, with 8 DC genes (DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, and TCAB1) having been characterized', 'Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2)', 'Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure syndrome with seven disease-causing genes identified to date, six of which are linked to telomere maintenance. Mutations in one of these genes (TINF2), which encodes a component of the shelterin complex, are associated with particularly short telomeres', 'Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome characterized by reticulated hyperpigmentation, dystrophic nails and oral leukoplakia', 'Four genes, namely DKC1 (codes for dyskerin), TERC and TERT (code for telomerase) and NOP10, have been implicated in the pathogenesis', 'To date, CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10, and WRAP53 are the genes in which mutations are known to cause DC and result in very short telomeres', 'The mode of inheritance of DC varies by gene: DKC1 (X-linked), TERC and TINF2 (autosomal dominant), TERT (autosomal dominant or autosomal recessive), CTC1, WRAP53, NHP2, and NOP10 (autosomal recessive)', 'Six genes have been identified, defects in which cause different genetic subtypes (X-linked recessive, autosomal dominant, autosomal recessive) of DC. The products of these genes encode components that are critical for telomere maintenance; either because they are core constituents of telomerase (dyskerin, TERC, TERT, NOP10 and NHP2) or are part of the shelterin complex that protects the telomeric end (TIN2)', 'BACKGROUND: Telomerase complex genes mutations (DKC1, TERC, TERT, and NOP10) lead to premature telomere shortening and are responsible for different forms of dyskeratosis congenita.', 'Mutations in DKC1 gene encoding dyskerin are responsible for the X-linked dyskeratosis congenita.', 'The DC1 gene responsible for the X linked form (MIM 305000) of dyskeratosis congenita has been mapped to Xq28.', 'The DC1 gene responsible for the X linked form (MIM 305000) of dyskeratosis congenita has been mapped to Xq28', 'Mutations in DKC1 gene encoding dyskerin are responsible for the X-linked dyskeratosis congenita', 'Mutations in the DKC1 gene are responsible for causing X-linked recessive dyskeratosis congenita (DKC) and a more severe allelic variant of the disease, Hoyeraal-Hreidarsson syndrome', 'Telomerase complex genes mutations (DKC1, TERC, TERT, and NOP10) lead to premature telomere shortening and are responsible for different forms of dyskeratosis congenita', 'Linkage analysis in multiplex families confirmed that the DKC1 gene, responsible for the X-linked form of DC, is located within Xq28 and facilitated its positional cloning', 'DKC1 has been identified as the gene responsible for X-linked DC, and genetic analyses have been performed in a worldwide study']

['To date, 8 genes have been associated with Dyskeratosis Congenita development. These are DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, and TCAB1. Seven of these are important in telomere maintenance, because either they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2).', 'To date, CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10, and WRAP53 are the genes in which mutations are known to cause DC and result in very short telomeres Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2) ']

['DKC1', 'TERC', 'TERT', 'NOP10', 'NHP2', 'TIN2', 'C16orf57', 'TCAB1']

Which syndrome is caused by deletion of Pds5b in mice?

['Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome.', 'Pds5B mutant mice have developmental abnormalities resembling CdLS', 'Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome', 'Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown.', 'Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown.', 'Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome.']

['mice lacking sister chromatid cohesion protein pds5b exhibit developmental abnormalities reminiscent of cornelia de lange syndrome.', 'Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. ', 'Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome.', 'Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome', 'Mice lacking sister chromatid cohesion protein Pds5b exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome.']

['Cornelia de Lange syndrome.']

Name the factors required for selenoprotein synthesis in eukaryotes

['The process requires the Sec insertion sequence (SECIS) element, tRNASec, and protein factors including the SECIS binding protein 2 (SBP2)', 'Taken together, these data establish the role of SECp43 and SLA in selenoprotein biosynthesis through interaction with tRNA([Ser]Sec) in a multiprotein complex.', 'Selenophosphate synthetase (SelD) generates the selenium donor for selenocysteine biosynthesis in eubacteria. One homologue of SelD in eukaryotes is SPS1 (selenophosphate synthetase 1) and a second one, SPS2, was identified as a selenoprotein in mammals.', 'These in vivo studies indicate that SPS2 is essential for generating the selenium donor for selenocysteine biosynthesis in mammals, whereas SPS1 probably has a more specialized, non-essential role in selenoprotein metabolism.']

['eFSec, SBP2, SECp43, PSTK, Sec synthase (Sec S, SLA/LP), SPS2 (SelD), tRNASec, SECIS element, (L30), SPS1']

['eFSec', 'SBP2', 'SECp43', 'PSTK', 'Sec synthase', 'Sec S', 'SLA/LP', 'SPS2', 'SelD', 'tRNASec', 'SECIS element', '(L30)', 'SPS1']

Which diseases can be treated with Afamelanotide?

['Afamelanotide for Erythropoietic Protoporphyria.', 'CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria.', 'Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial.', 'CONCLUSIONS AND RELEVANCE: A combination of afamelanotide implant and NB-UV-B phototherapy resulted in clinically apparent, statistically significant superior and faster repigmentation compared with NB-UV-B monotherapy.', 'UNLABELLED: Afamelanotide is an α-melanocyte-stimulating hormone (α-MSH) agonist with proven efficacy in photodermatoses such as erythropoietic protoporphyria (EPP). ', 'Afamelanotide (CUV1647) in dermal phototoxicity of erythropoietic protoporphyria.', 'CONCLUSIONS: Afamelanotide is effective for the treatment of skin lesions in HHD.', 'CONCLUSIONS: Afamelanotide appears to have anti-inflammatory effects in patients with mild-to-moderate acne vulgaris.', 'In a recent trial, afamelanotide administered as controlled release implants protected erythropoietic protoporphyria (EPP) patients from sunlight induced phototoxic skin reactions.', 'CONCLUSIONS: We propose that afamelanotide represents a novel and potentially effective treatment for vitiligo.', 'Afamelanotide is currently undergoing phase II and III trials in Europe and the US for skin diseases including vitiligo, erythropoietic protoporphyria, polymorphic light eruption and prevention of actinic keratoses in organ transplant recipients. ', 'Currently, afamelanotide is already on the market in Italy and Switzerland for patients with erythropoietic protoporphyria. ', 'Agents that are showing promising results in early phases of clinical trials include betulinic acid; hedgehog signaling pathway inhibitors, such as cyclopamine and GDC-0449; alpha-melanocyte-stimulating hormone analogs, such as afamelanotide; epidermal growth factor receptor inhibitors, such as gefitinib and erlotinib; anti-epidermal growth factor receptor monoclonal antibodies, such as cetuximab and panitumumab; and the 5-fluorouracil prodrug capecitabine.', 'Meanwhile, the regulated α-MSH analogue afamelanotide (Clinuvel Pharmaceuticals Ltd, Melbourne, Australia) is showing promise for its photoprotective potential, and is undergoing phase II and III clinical trials in people with photosensitivity disorders and those prone to nonmelanoma skin cancer.', 'CONCLUSIONS: Among the six models proposed to assess the effectiveness of therapeutic interventions in PP the ETFP model demonstrates the highest sensitivity using the existing data from a clinical trial of afamelanotide in PP.', 'Afamelanotide, an agonistic analog of α-melanocyte-stimulating hormone, in dermal phototoxicity of erythropoietic protoporphyria.', 'IMPORTANCE OF THE FIELD: Afamelanotide, an α-melanocyte stimulating hormone (MSH) agonistic analog is a first-in-class therapeutic. Its application to protoporphyria (PP), a disease associated with absolute sunlight-intolerance is discussed.', 'TAKE HOME MESSAGE: Although early, results of the first trials of afamelanotide for PP are promising and the risk-safety profile appears favorable today.', 'This study examines the efficacy of afamelanotide in preventing symptoms in patients with EPP.', 'The findings demonstrate beneficial effects of afamelanotide in patients with EPP.', 'Afamelanotide is currently undergoing phase II and III trials in Europe and the US for skin diseases including vitiligo, erythropoietic protoporphyria, polymorphic light eruption and prevention of actinic keratoses in organ transplant recipients.', 'The application of afamelanotide, an α-melanocyte stimulating hormone agonistic analogue to protoporphyria, a disease with absolute sunlight-intolerance is discussed.', 'UNLABELLED: Afamelanotide is an �-melanocyte-stimulating hormone (�-MSH) agonist with proven efficacy in photodermatoses such as erythropoietic protoporphyria (EPP). This peptide drug, repeatedly administered over prolonged time, may induce anti-drug antibodies (ADA). ', 'Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug.CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).']

['Afamelanotide was ivestigated for treatment of erythropoietic protoporphyria, vitiligo, Hailey-Hailey disease, acne vulgaris, polymorphic light eruption, prevention of actinic keratoses in organ transplant recipients and nonmelanoma skin cancer.']

['erythropoietic protoporphyria', 'vitiligo', 'Hailey-Hailey disease', 'acne vulgaris', 'polymorphic light eruption', 'ctinic keratoses', 'nonmelanoma skin cancer']

What is a Caveolae?

['Caveolae are flask-shaped plasma membrane invaginations formed by constitutive caveolin proteins and regulatory cavin proteins. ', 'Caveolae are membrane subdomains that function as signaling platforms, endocytic carriers, sensors of membrane tension, and mechanical stress, as well as in lipid homeostasis', 'Caveolae are cholesterol-rich microdomains that form mechanically deformable invaginations of the sarcolemma.', 'Caveolae are specialized membrane lipid rafts coated with caveolin scaffolding proteins,', ' Caveolae are membrane microdomains where important signalling pathways are assembled and molecular effects transduced.', 'Caveolae, plasma membrane invaginations of 60-80nm in diameter, are a subset of lipid rafts enriched in cholesterol and sphingolipids.', 'The efficiency of youth is built upon cellular signaling scaffolds that provide tight and coordinated signaling. Lipid rafts are one such scaffold of which caveolae are a subset.', 'Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types', 'Caveolae are non-clathrin invaginations of the plasma membrane in most cell types', 'Caveolae are cholesterol and sphingolipids rich subcellular domains on plasma membrane.', 'Caveolae are an abundant feature of the plasma membrane of many mammalian cell types, ']

['Caveolae, plasma membrane invaginations of 60-80nm in diameter, are a subset of lipid rafts enriched in cholesterol and sphingolipids.']

[]

What is the link between HOT regions and RNA polymerase recruitment?

['Transcription-factor occupancy at HOT regions quantitatively predicts RNA polymerase recruitment in five human cell lines.', 'Most HOT regions co-localize with RNA polymerase II binding sites, but many are not near the promoters of annotated genes. At HOT promoters, TF occupancy is strongly predictive of transcription preinitiation complex recruitment and moderately predictive of initiating Pol II recruitment, but only weakly predictive of elongating Pol II and RNA transcript abundance.', 'CONCLUSIONS: Mammalian HOT regions are regulatory hubs that integrate the signals from diverse regulatory pathways to quantitatively tune the promoter for RNA polymerase II recruitment.', 'We identified HOT regions by a comprehensive analysis of ChIP-seq data from 96 DNA-associated proteins in 5 human cell lines. Most HOT regions co-localize with RNA polymerase II binding sites, but many are not near the promoters of annotated genes.', 'Most HOT regions co-localize with RNA polymerase II binding sites, but many are not near the promoters of annotated genes. At HOT promoters, TF occupancy is strongly predictive of transcription preinitiation complex recruitment and moderately predictive of initiating Pol II recruitment, but only weakly predictive of elongating Pol II and RNA transcript abundance.', 'At HOT promoters, TF occupancy is strongly predictive of transcription preinitiation complex recruitment and moderately predictive of initiating Pol II recruitment, but only weakly predictive of elongating Pol II and RNA transcript abundance. TF occupancy varies quantitatively within human HOT regions; we used this variation to discover novel associations between TFs.', 'Mammalian HOT regions are regulatory hubs that integrate the signals from diverse regulatory pathways to quantitatively tune the promoter for RNA polymerase II recruitment.', 'We identified HOT regions by a comprehensive analysis of ChIP-seq data from 96 DNA-associated proteins in 5 human cell lines. Most HOT regions co-localize with RNA polymerase II binding sites, but many are not near the promoters of annotated genes.', 'Mammalian HOT regions are regulatory hubs that integrate the signals from diverse regulatory pathways to quantitatively tune the promoter for RNA polymerase II recruitment.']

['Most HOT regions co-localize with RNA polymerase II binding sites, but many are not near the promoters of annotated genes. At HOT promoters, TF occupancy is strongly predictive of transcription preinitiation complex recruitment and moderately predictive of initiating Pol II recruitment, but only weakly predictive of elongating Pol II and RNA transcript abundance.']

['Transcription-factor occupancy at HOT regions quantitatively predicts RNA polymerase recruitment.']

Which is the major symptom of the Doose syndrome?

['KD is particularly effective in myoclonic astatic epilepsy (MAE; Doose Syndrome) and West syndrome with 100% and 81.25% of the patients having a greater than 50% seizure reduction, respectively. ', 'Myoclonic astatic epilepsy (Doose syndrome) - a lamotrigine responsive epilepsy?', 'PURPOSE: Myoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood.', 'Herman Doose first described the generalized childhood epilepsy syndrome of myoclonic astatic epilepsy (MAE) in 1970, attributing a genetic cause from this first description. ', 'RECENT FINDINGS: In the past several years, neurologists are finding new indications to use these dietary treatments, perhaps even as first-line therapy, including infantile spasms, myoclonic-astatic epilepsy (Doose syndrome), Dravet syndrome, and status epilepticus (including FIRES syndrome).', 'First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome).', 'INTRODUCTION: We evaluated the long-term efficacy and tolerability of the orphan drug rufinamide (RUF) in children with pharmacoresistant myoclonic-astatic epilepsy (MAE, Doose syndrome).', 'Mutations in SCN1A gene, encoding the voltage-gated sodium channel α1-subunit, are found to be associated with severe myoclonic epilepsy in infancy or Dravet syndrome (DS), but only rarely with the myoclonic astatic epilepsy (MAE, or Doose syndrome). ', 'The difficulty early in the course of Lennox-Gastaut syndrome is distinguishing this diagnosis from severe myoclonic epilepsy of infancy (Dravet syndrome) or from myoclonic-astatic epilepsy (Doose syndrome), as the seizure patterns in these three syndromes may overlap at the onset. ', 'Doose syndrome (myoclonic-astatic epilepsy): 40 years of progress.', 'Doose syndrome, otherwise traditionally known as myoclonic-astatic epilepsy, was first described as a unique epilepsy syndrome by Dr Hermann Doose in 1970.', 'Of 38 patients, 22 had Lennox-Gastaut syndrome (58%); 6 had myoclonic-astatic epilepsy of Doose (16%); 5 had symptomatic generalized epilepsy, not otherwise specified (13%); and 5 had symptomatic localization-related epilepsy (13%). ', 'With felbamate treatment, 6 patients (16%) became seizure free, including 4 of the 6 patients with myoclonic-astatic epilepsy of Doose; 24 patients (63%) had a greater than 50% reduction in seizure frequency.', 'Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures.', 'This includes syndromes with multiple etiologies, including Lennox-Gastaut syndrome and infantile spasms; developmental syndromes of unknown etiology, such as Landau-Kleffner syndrome; and idiopathic epilepsies, such as myoclonic-astatic (Doose) epilepsy. ', 'It should be considered early in the treatment of Dravet syndrome and myoclonic-astatic epilepsy (Doose syndrome). ', 'The purpose of this article is to present a short review of the natural history of myoclonic astatic epilepsy (MAE; Doose syndrome) and the Lennox-Gastaut syndrome (LGS). ', '[Clinical case of the month. Myoclonic-astatic epilepsy in a young child (MAE) or Doose syndrome].', 'His refractory epilepsy which started 7 years ago shares symptoms and signs of both epilepsy with myoclonic-astatic seizures (Doose Syndrome) and Lennox-Gastaut Syndrome.', 'PURPOSE: Before 1986, the spectrum of childhood epilepsies, including Lennox-Gastaut syndrome (LGS) and Doose syndrome (DS), known collectively as "epilepsia myoclonica astatica," was believed to represent a single disease. ', 'We reported a 7-year-old girl with myoclonic-astatic epilepsy of early childhood (Doose syndrome). ', "Other myoclonic epilepsy syndromes with onset in the first year of life (Aicardi's Neonatal (Early) Myoclonic Encephalopathy, West's Syndrome, Dravet's Severe Myoclonic Epilepsy, and Dravet's Benign Myoclonic Epilepsy of Infancy), in early childhood (Lennox-Gastaut-Dravet Syndrome, Myoclonic Variant of Lennox Gastaut Dravet Syndrome, Myoclonic-Astatic Epilepsy of Doose, Benign Myoclonic Epilepsies (BME), or even in late childhood (Childhood Absence Epilepsy with myoclonias, vs. Myoclonic Absence Epilepsy) are probably genetically complex diseases. ", 'A study of epileptic drop attacks (EDA) by simultaneous video-polygraphic recordings was carried out in one epileptic patient with myoclonic astatic seizures (Doose syndrome). ', 'A number of variants or atypical forms have been proposed. As a result, differential diagnosis presents a major challenge and includes specific generalized epilepsies, i.e., metabolic or inflammatory; secondarily generalized epilepsies, i.e., those arising from the frontal lobe; and severe forms of idiopathic generalized epilepsy, i.e., Doose syndrome.', 'Video-EEG analysis of drop seizures in myoclonic astatic epilepsy of early childhood (Doose syndrome).', ' The clinical and EEG pattern, the high familial incidence are shared by the Doose syndrome, of which the present series seems to be a subgroup, as are other well-defined syndromes: benign and severe myoclonic epilepsies of infancy.', 'The difficulty early in the course of Lennox-Gastaut syndrome is distinguishing this diagnosis from severe myoclonic epilepsy of infancy (Dravet syndrome) or from myoclonic-astatic epilepsy (Doose syndrome), as the seizure patterns in these three syndromes may overlap at the onset.', 'The difficulty early in the course of Lennox-Gastaut syndrome is distinguishing this diagnosis from severe myoclonic epilepsy of infancy (Dravet syndrome) or from myoclonic-astatic epilepsy (Doose syndrome), as the seizure patterns in these three syndromes may overlap at the onset', 'His refractory epilepsy which started 7 years ago shares symptoms and signs of both epilepsy with myoclonic-astatic seizures (Doose Syndrome) and Lennox-Gastaut Syndrome', 'Doose syndrome, otherwise traditionally known as myoclonic-astatic epilepsy, was first described as a unique epilepsy syndrome by Dr Hermann Doose in 1970']

['Myoclonic astatic epilepsy is the major symptom of the Doose syndrome, which is a difficult to treat idiopathic generalized epilepsy of early childhood.']

['myoclonic astatic epilepsy']

Which pituitary adenoma is common cause of infertility is women?

['Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility.', 'Examination of the tissue excised by transsphenoidal excision of the mass showed a pituitary adenoma that stained strongly for FSH. RESULTS: Regular menses resumed soon after excision of the gonadotroph adenoma, followed by a spontaneous pregnancy.', 'CONCLUSIONS: Gonadotroph adenoma should be suspected in a reproductive age woman with oligomenorrhea or amenorrhea, infertility, multiple preovulatory follicles, and a persistently elevated serum estradiol concentration.', 'Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis, occurring mostly in women and presenting most commonly with amenorrhea and galactorrhea. Causes of hyperprolactinemia include physiologic, pharmacologic and pathologic factors; pituitary adenoma is a common pathologic cause. Women may present with decreased libido, infertility, oligomenorrhea/amenorrhea and galactorrhea.', 'When specific treatable underlying causes have been eliminated and in cases of severe hyperprolactinemia, the most likely cause is a prolactin (PRL)-secreting pituitary adenoma. Microadenomas should be treated medically, with a dopamine agonist, if there is an indication for therapy (such as amenorrhea, infertility or bothersome galactorrhea).', 'Pregnancy in a woman with active acromegaly is very rare, because amenorrhea, due to hyperprolactinemia and disturbed pituitary gonadotropin secretion may cause infertility.', 'Of the remaining six patients who had been investigated for infertility, no demonstrable cause of infertility was found in three. Of the other three patients, one showed evidence of bilateral tubal occlusion secondary to pelvic inflammatory disease, one has had a right ectopic pregnancy followed by two abortions, and the third patient was found to have a pituitary adenoma.', 'Results in 136 hyperprolactinaemic women who presented with infertility, amenorrhoea, menstrual irregularities and/or galactorrhoea are reported. There was radiographic evidence of pituitary microadenoma in 21 (15.4%) patients and 5 (3.7%) had macroadenoma.', 'Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy.', 'There was no significant difference in the pregnancy rate between the patients with or without pituitary adenoma.', 'Two hyperprolactinemic infertile women, one with and one without a pituitary adenoma, who were resistant to bromocriptine treatment, were treated orally with Hachimijiogan, a Chinese herbal medicine.', 'Infertility caused by hyperprolactinemic amenorrhea may be complicated by pituitary adenoma.']

['Prolactinoma is a pituitary adenoma that is strongly associated with infertility in women mainly due to increased prolactin secretion causing hyperprolactinemia. Other pituitary lesions can also be associated with infertility.']

['prolactinoma']

What are the most frequent non-canonical sequence motifs at the donor and acceptor splice sites in vertebrates?

["About 1-2% of introns are non-canonical, with the most abundant subtype of non-canonical introns being characterized by GC and AG dinucleotides at their 5'- and 3'-termini, respectively.", 'Our results indicate that the incorporation of non-canonical splice site models yields dramatic improvements in annotating genes containing GC-AG and AT-AC non-canonical introns', 'If we assume that approximately the same situation is true for the whole set of annotated mammalian non-canonical splice sites, then the 99.24% of splice site pairs should be GT-AG, 0.69% GC-AG, 0.05% AT-AC and finally only 0.02% could consist of other types of non-canonical splice sites.']

['There are two major exceptions to the canonical GT-AG dinucleotides at donor and acceptor sites: the GG-AG splice site pairs, recognized through the typical U2 splicing machinery, and the AT-AC splice pairs recognized by the U12 splicing machinery.']

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What is the treatment of amiodarone-induced thyrotoxicosis?

['Prednisone remains the preferred treatment modality of AIT type 2, because perchlorate given alone or in combination with prednisone had no better outcomes.', 'Total thyroidectomy, by rapidly restoring euthyroidism, may improve cardiac function and reduce the risk of mortality in AIT patients with severe LV dysfunction.', 'Prednisone restores euthyroidism in most type 2 AIT patients, irrespective of amiodarone continuation or withdrawal. However, continuing amiodarone increases the recurrence rate of thyrotoxicosis, causing a delay in the stable restoration of euthyroidism and a longer exposure of the heart to thyroid hormone excess.', 'Steroid therapy should be started when findings indicate type II or mixed-type AIT. Beta blockers may prevent heart thyrotoxicosis and recurrence of primary arrhythmia if amiodarone is discontinued.', 'Glucocorticoids are the first-line treatment in type 2 AIT, whereas thionamides play no role in this destructive thyroiditis.', 'iopanoic can be used to rapidly lower FT(3) levels and to treat symptoms of thyrotoxicosis in a preoperative setting.', 'The patient responded to iopanoic acid with a rapid decrease in his FT(3) level and slight increase in his FT(4) level.', 'In patients with type-2 AIT, RAI treatment may be the therapy of choice for thyroid gland ablation.', 'In type 1 AIT thionamides represent the treatment of choice for North Americans as well as for Europeans,', 'Glucocorticoids are the selected treatment for type 2 AIT, alone (62%vs. 46% in Europe, P < 0.05) or in association with thionamides', 'After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 AIT less frequently by North Americans.']

['Treatment of amiodarone-induced thyrotoxicosis is complex and may include drugs such as antithyroid drugs, beta-blockers, corticosteroids lithium as well as iopanoic acid in preparation of thyroidectomy. Total thyroidectomy and radioiodine represent alternative treatment options']

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Which histone modifications have been associated to alternative splicing?

['We found that several types of histone modifications including H3K36me3 were associated with the inclusion or exclusion of alternative exons. Furthermore, we observed that the levels of H3K36me3 and H3K79me1 in the cell lines were well correlated with the differences in alternative splicing patterns between the cell lines.', 'Here we find that elevated levels of trimethylation of histone H3 on Lys9 (H3K9me3) are a characteristic of the alternative exons of several genes including CD44.', 'he first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene.', 'Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNA-mediated transcriptional gene silencing.', 'Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2, and H3K27me3 had evidently higher signals in internal exons than in the following introns and were clearly related to exon expression']

['H3K36m3 has been systematically associated to exon inclusion in almost all published studies. Other marks have been associated as well in specific studies to exon expression, but it can not be concluded that the effect of these marks in exon expression it is not a consequence of their effect in gene expression.']

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What is the function of the yeast protein Aft1?

['Using a scheme for selecting mutants of Saccharomyces cerevisiae with abnormalities of iron metabolism, we have identified a gene, AFT1, that mediates the control of iron uptake', 'AFT1 functions to activate transcription of target genes in response to iron deprivation and thereby plays a central role in iron homeostasis.', 'Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in yeast', 'Iron deprivation of Saccharomyces cerevisiae induces transcription of genes required for high-affinity iron uptake. AFT1 mediates this transcriptional control.', 'The AFT1 transcriptional factor is differentially required for expression of high-affinity iron uptake genes in Saccharomyces cerevisiae.', 'Aft1 displays phosphorylation modifications depending on the growth stage of the cells, and it might link induction of genes for iron uptake to other metabolically dominant requirement for cell growth.', 'an aft1 mutation in S. cerevisiae that makes cells dependent on iron for growth', 'Subcellular localization of Aft1 transcription factor responds to iron status in Saccharomyces cerevisiae.', 'The Aft1 transcription factor regulates the iron regulon in response to iron availability in Saccharomyces cerevisiae. Aft1 activates a battery of genes required for iron uptake under iron-starved conditions, whereas Aft1 function is inactivated under iron-replete conditions', 'the nuclear export of Aft1 is critical for ensuring iron-responsive transcriptional activation of the Aft1 regulon and that the nuclear import/export systems are involved in iron sensing by Aft1 in S. cerevisiae.', 'the Aft1 iron-responsive DNA-binding factor', 'Two transcriptional activators, Aft1 and Aft2, regulate iron homeostasis in Saccharomyces cerevisiae.', 'iron sensing by Aft1/Aft2 is not linked to the maturation of cytosolic/nuclear Fe-S proteins', 'The yeast Saccharomyces cerevisiae contains a pair of paralogous iron-responsive transcription activators, Aft1 and Aft2. Aft1 activates the cell surface iron uptake systems in iron depletion,', 'the absence of either Aft1 or Aft2 showed an iron-dependent increase in the amount of the remaining paralog', 'The transcription factors Aft1 and Aft2 from Saccharomyces cerevisiae regulate the expression of genes involved in iron homeostasis.', 'iron insufficiency-responsive transcription factor Aft1', 'The mRNA levels of 14 proteins involved in iron homeostasis were shown to be increased by cisplatin. Interestingly, the expression of all 14 genes is known to be regulated by Aft1, a transcription factor activated in response to iron insufficiency', 'Aft1 is a transcriptional activator in Saccharomyces cerevisiae that responds to iron availability and regulates the expression of genes in the iron regulon', 'we found that Aft1 physically interacts with the FOB (ferrioxamine B) transporter Arn3', 'These results suggest that Aft1 interacts with Arn3 and may regulate the ubiquitination of Arn3 in the cytosolic compartment', 'The Saccharomyces cerevisiae transcription factor Aft1 is activated in iron-deficient cells to induce the expression of iron regulon genes, which coordinate the increase of iron uptake and remodel cellular metabolism to survive low-iron conditions', 'Aft1 has been implicated in numerous cellular processes including cell-cycle progression and chromosome stability', 'We demonstrate that Aft1 works in parallel with the RIM101 pH pathway and the role of Aft1 in DNA damage repair is mediated by iron. In contrast, through both directed studies and microarray transcriptional profiling, we show that the role of Aft1 in chromosome maintenance and benomyl resistance is independent of its iron regulatory role, potentially through a nontranscriptional mechanism.', 'Aft1p is a major iron regulator in budding yeast Saccharomyces cerevisiae. It indirectly senses cytosolic Fe status and responds by activating or repressing iron regulon genes', 'Expression of components of the high-affinity system is controlled by the Aft1 transcriptional factor', 'Iron-responsive transcription factor Aft1 interacts with kinetochore protein Iml3 and promotes pericentromeric cohesin', 'The Saccharomyces cerevisiae iron-responsive transcription factor, Aft1, has a well established role in regulating iron homeostasis through the transcriptional induction of iron-regulon genes', 'recent studies have implicated Aft1 in other cellular processes independent of iron regulation such as chromosome stability', 'Aft1 interacts with and co-localizes with kinetochore proteins', 'Our work defines a new role for Aft1 in chromosome stability and transmission.', 'Our genetic network reveals that Aft1 affects a diverse range of cellular processes, including the RIM101 pH pathway, cell-wall stability, DNA damage, protein transport, chromosome stability, and mitochondrial function.']

['The Aft1 transcription factor regulates the iron regulon in response to iron availability in Saccharomyces cerevisiae. Aft1 activates a battery of genes required for iron uptake under iron-starved conditions, whereas Aft1 function is inactivated under iron-replete conditions. Aft1 interacts with the FOB (ferrioxamine B) transporter Arn3 and may regulate the ubiquitination of Arn3 in the cytosolic compartment. Aft1 has been implicated in numerous cellular processes including cell-cycle progression and chromosome stability. Aft1 has also been shown to affect a diverse range of cellular processes, including the RIM101 pH pathway, cell-wall stability, DNA damage, protein transport, chromosome stability, mitochondrial function, while it was recently shown to interact with the kinetochore protein Iml3 and to promote pericentromeric cohesin.']

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What is the purpose of HaploReg v4?

['HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.', 'Since first launching the website in 2011, we have greatly expanded HaploReg, increasing the number of chromatin state maps to 127 reference epigenomes from ENCODE 2012 and Roadmap Epigenomics, incorporating regulator binding data, expanding regulatory motif disruption annotations, and integrating expression quantitative trait locus (eQTL) variants and their tissue-specific target genes from GTEx, Geuvadis, and other recent studies. We present these updates as HaploReg v4, and illustrate a use case of HaploReg for attention deficit hyperactivity disorder (ADHD)-associated SNPs with putative brain regulatory mechanisms.', 'We present these updates as HaploReg v4, and illustrate a use case of HaploReg for attention deficit hyperactivity disorder (ADHD)-associated SNPs with putative brain regulatory mechanisms.', 'We present these updates as HaploReg v4, and illustrate a use case of HaploReg for attention deficit hyperactivity disorder (ADHD)-associated SNPs with putative brain regulatory mechanisms.', 'HaploReg V4.1 and Regulome DB were used to understand functional annotation on important SNV.', 'HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.']

['HaploReg v4 enables the systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.']

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What are the structures formed when keratin molecules come together?

[' Keratins form the intermediate filaments of the cytoskeleton and provide scaffold structures within cells.', 'keratin intermediate filaments', 'keratin intermediate filaments', 'keratin intermediate filament protein.', 'Keratin is a protein in the intermediate filament family ', 'Keratins are the intermediate filament (IF) proteins', 'squamous keratinocytes contain polymerized keratin intermediate filament bundles ', ' keratin filaments ', ' In this study, we have examined the distribution of four groups of IFs [cytokeratins (CKs), vimentin, desmin and lamins]', 'keratin filament network', 'An intact keratin 5/keratin 14 intermediate filament cytoskeleton is vital for the integrity of basal keratinocytes and for the development and maintenance of epidermal structures.', 'keratin intermediate filament cytoskeleton.', 'keratin filaments,', 'keratin filamentous network. ']

['Keratins form the intermediate filaments of the cytoskeleton and provide scaffold structures within cells.']

['Intermediate filaments']

Is STAT3 transcription factor regulated by mTORC1?

['Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity.', 'we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription', 'Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3).', 'Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process', 'Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas\xa0HIF-1α degradation remains unaffected', 'Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process. ', 'TSC1/TSC2 inactivation inhibits AKT through mTORC1-dependent up-regulation of STAT3-PTEN cascade.', 'Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). ', 'Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids.', 'Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARγ, PPARα, HIF1α, YY1–PGC1α and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts.']

['mTORC1 was found to regulate STAT3 activity in, at least, three ways: 1) after induction by IL6, 2) by direct phosphorylation during hypoxia, to promote HIF-1α mRNA transcription, and 3) after activation by excess amino acids, which then positively regulate Notch1 expression through STAT3 activation.']

['yes']

What is the function of the MTH1 enzyme in cancer cells?

['the glucose-responsive transcription factor Mth1', 'Human MTH1 (hMTH1) is an enzyme that hydrolyses several oxidized purine nucleoside triphosphates to their corresponding nucleoside monophosphates', ' We have recently shown that oncogenic RAS-induced DNA damage and attendant premature senescence can be prevented by overexpressing human MutT Homolog 1 (MTH1), the major mammalian detoxifier of the oxidized DNA precursor, 8-oxo-dGTP. ', 'Human Mut T Homolog 1 (MTH1): a roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS.', 'MutT homolog 1 (oxidized purine nucleoside triphosphatase, MTH1),', 'MTH1 cleaves 8-oxo-dGTP', 'MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. ', 'MutT-related proteins, including Escherichia coli MutT and the human MTH1 (NUDT1), degrade 8-oxo-7, 8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP) to 8-oxo-dGMP and thereby prevent mutations caused by the misincorporation of 8-oxoguanine into DNA.', 'MTH1 (or NUDT1) are also involved in the repair of 7,8-dihydro-8-oxoguanine (8-oxo-G), previous studies,', 'To counteract such deleterious effects of nucleotide pool damage, mammalian cells possess MutT homolog-1 (MTH1) with oxidized purine nucleoside triphosphatase and related enzymes, thus minimizing the accumulation of oxidized bases in cellular DNA', 'These results indicate that all three of the human MTH1, MTH2, and NUDT5 proteins act as a defense against the mutagenesis induced by oxidized dGTP.', 'Human MTH1, an oxidized purine nucleoside triphosphatase, hydrolyzes 8-oxo-dGTP thereby preventing its misincorporation into DNA. ', 'MTH1 is a mammalian ortholog of Escherichia coli MutT, which hydrolyzes 8-oxo-dGTP to its monophosphate form in nucleotide pools, thereby preventing incorporation of the mutagenic substrate into DNA. ', 'Several pathways are involved in the repair of DNA lesions caused by oxidative stress, such as the base excision repair system (BER), which repairs mutation involving 8-oxoguanine and comprises the MUTYH, OGG1 and MTH1 genes. ', 'The MTH1 protein catalyzes hydrolysis of oxidatively damaged purine nucleotides including 8-hydroxy-dGTP to the monophosphates. The MTH1 protein seems to act as an important defense system against mutagenesis, carcinogenesis, and cell death induced by oxidized purine nucleotides. ', 'In mammalian cells, MTH1 and NUDT5 proteins degrade 8-oxoGTP and 8-oxoGDP to 8-oxoGMP, which is an unusable form for RNA synthesis. In a search for proteins functioning at the RNA level, polynucleotide phosphorylase (PNP) protein has been suggested to be a good candidate for such a role. T', "Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria.", "In human and rodent cells, MTH1, an oxidized purine nucleoside triphosphatase, efficiently hydrolyzes oxidized dGTP, GTP, dATP and ATP such as 2'-deoxy-8-oxoguanosine triphosphate (8-oxo-dGTP) and 2'-deoxy-2-hydroxyadenosine triphosphate (2-OH-dATP) in nucleotide pools, thus avoiding their incorporation into DNA or RNA."]

['The MTH1 protein catalyzes hydrolysis of oxidatively damaged purine nucleotides including 8-hydroxy-dGTP to the monophosphates. The MTH1 protein seems to act as an important defense system against mutagenesis, carcinogenesis, and cell death induced by oxidized purine nucleotides.']

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Describe the mechanism of action of drisapersen

["Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. ", "UNLABELLED: Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration.", 'Currently, the most promising potential drugs are the exon-skipping agents eteplirsen and drisapersen.', 'Currently, the most promising potential drugs are the exon-skipping agents eteplirsen and drisapersen', "Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA", "Fast forward 25 years, and two phase 2b/3 trials have been carried out with agents designed to induce de novo dystrophin production in DMD patient's muscle; ataluren (stop codon read through) with 174 patients, and drisapersen (exon skipping) with 186 patients"]

["Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. It has potential for treatment of Duchenne muscular dystrophy."]

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Has Revlimid been approved by the US Food and Drug Administration?

['In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid).', 'In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin. ', 'In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin.', 'Thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade) are directed not only at MM cells but also at the BM milieu and have moved rapidly from the bench to the bedside and United States Food and Drug Administration approval to treat MM.', 'Lenalidomide (CC-5013, Revlimid; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy.', 'Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]', 'Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality', 'In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin.', 'lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma.', ' In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid).']

['Yes, Revlimid has been approved by the US Food and Drug Administration for treatment of multiple myeloma.']

['yes']

List the diseases for which there are point-of-care breath tests

['Additionally, we try to clarify controversial issues concerning possible experimental malpractice in the field, and propose ways to translate the basic science results as well as the mechanistic understanding to tools (sensors) that could serve as point-of-care diagnostics of cancer.', 'Point of care monitoring of hemodialysis patients with a breath ammonia measurement device based on printed polyaniline nanoparticle sensors.', ' Excellent intraindividual correlations were demonstrated between breath ammonia and BUN (0.86 to 0.96), which demonstrates the possibility of using low cost point of care breath ammonia systems as a noninvasive means of monitoring kidney dysfunction and treatment.', 'Recently, fractional exhaled nitric oxide (FeNO) has emerged as an important biomarker for the assessment and management of asthma.', 'Here we discuss the potential of adapting a technology from the electronics industry, surface acoustic wave (SAW) sensors, for diagnosis of multiple markers of sepsis in real time, using non-invasive assays of exhaled breath condensate. ', 'Together these data indicate that FeNO testing has an important role in the assessment and management of adult asthma. ', "Measurement of acetone in human breath samples has been previously shown to provide significant non-invasive diagnostic insight into the control of a patient's diabetic condition. ", ' Urea breath testing may provide a useful diagnostic and biomarker assay for tuberculosis and treatment response.', 'These animal model results suggest that exhaled breath can be used as a point-of-care tool for the diagnosis and monitoring of sepsis.', 'Point-of-care breath test for biomarkers of active pulmonary tuberculosis.', 'RATIONALE: Volatile organic compounds (VOCs) in breath provide biomarkers of tuberculosis (TB) because Mycobacterium tuberculosis manufactures VOC metabolites that are detectable in the breath of infected patients. ', 'CONCLUSIONS: A six-minute point-of-care breath test for volatile biomarkers accurately identified subjects with active pulmonary TB.', 'Selected ion flow tube-mass spectrometry (SIFT-MS) can measure volatile compounds in breath on-line in real time and has the potential to provide accurate breath tests for a number of inflammatory, infectious and metabolic diseases, including diabetes.', 'Breath analysis by SIFT-MS offers a rapid, reproducible and easily performed measurement of acetone concentration in ambulatory patients with type 2 diabetes. ', 'IGR is a new approach for non-invasive cardiac output measurement in mechanically ventilated individuals, but requires further investigation for clinical use.', 'The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. ', 'Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders.', '13[C]-urea breath test as a novel point-of-care biomarker for tuberculosis treatment and diagnosis.', 'CONCLUSIONS/SIGNIFICANCE: Urea breath testing may provide a useful diagnostic and biomarker assay for tuberculosis and for treatment response.', 'CONCLUSIONS: The non-invasive real-time BreathID GBT reliably assesses changes in liver glucose metabolism, and the degree of insulin resistance. ', 'DISCUSSION: The LiMAx test can validly determine liver function capacity and is feasible in every clinical situation.', 'A P(ET,CO(2)) of >or=36 mmHg may reliably exclude PE. Accuracy is augmented by combination with Wells score. P( ET,CO(2)) should be prospectively compared to D-dimer in accuracy and simplicity to exclude PE.', 'Point-of-care continuous (13)C-methacetin breath test improves decision making in acute liver disease: results of a pilot clinical trial.', 'CONCLUSION: The (13)C-MBT provides a rapid, non-invasive assessment of liver function in acute severe liver disease of diverse etiologies. ', 'CONCLUSION: The determination of CO by IGR and CWD revealed a good agreement and reproducibility with a low rate of impossible measurements, suggesting that IGR and CWD can be used interchangeably in the clinical setting.', 'BACKGROUND: Exhaled NO (FE(NO)) is a useful biomarker for the monitoring of asthma control and response to therapy. ', 'A high percentage of patients with different severities of asthma and regardless of their treatment with ICS and current smoking habit (current and/or ex-smokers) had highly elevated FE(NO) values, suggesting that their current therapy was possibly insufficient to control the underlying degree of airway inflammation and asthma symptoms.', 'H. pylori-positive status was defined by positivity on at least 2 tests: a commercial H. pylori stool antigen enzyme immunoassay, an immunoglobulin G antibody enzyme immunoassay, and the C-urea breath test', 'End-tidal carbon dioxide measurements in children with acute asthma.', 'CONCLUSIONS: Noninvasive bedside measurement of EtCO2 values among children with acute asthma is feasible. ', 'Review article: the assessment of liver function using breath tests.', 'The recent development of a real-time, point-of-care liver function breath test has made it straightforward to assess the metabolic function of the liver.', 'RESULTS: The (13)C-methacetin breath test enables accurate follow-up of patients with acute or chronic liver damage, where overall hepatic function is significantly suppressed by known causes of liver disorders, including acute, sub-acute or chronic conditions. ', 'CONCLUSIONS: Breath testing that provides continuous quantification of methacetin metabolism may be a sensitive tool for the diagnosis and follow-up of patients with liver disorders.', ' A multi-center study in a multi-ethnic population compared the RAPIRUN urine antibody test with the (13)C-urea breath test (C-UBT) and a traditional serologic test, the high-molecular-weight cell-associated protein enzyme immunoassay (HM-CAP EIA). ', 'CONCLUSION: EGA provided non-invasive, accurate, continuous, high-resolution COHb% measurements. Applying EGA to carboxyhaemoglobin dilution, we achieved RCV measurements with accuracy equivalent to that of CO-haemoximetry, with one-fifth of the COB infusion volume.', ' These results suggest that the IR device, which is small, light-weight, and rugged may enable the foreign gas uptake method to be used in clinical, field, and point-of-care settings for Q (T) measurement.', 'UNLABELLED: The 13C-urea breath test provides non-invasive testing for Helicobacter pylori infection with the possibility of analysis at the point of care. ', 'CONCLUSION: Fdlate, a variable of VCap, had a statistically better diagnostic performance in suspected PE than the PaCO(2)-EtCO(2) gradient. ', ' In conclusion, the investigated rebreathing system allows for a non-invasive determination of PBF at the bedside. ', 'Non-invasive measurement of pulmonary blood flow during prone positioning in patients with early acute respiratory distress syndrome.', 'The 13C-urea breath test provides accurate, noninvasive diagnosis of active Helicobacter pylori infection and can document posttherapy cure. ', 'A portable Fourier transform infrared (FT-IR) multicomponent point-of-care analyzer was tested for the diagnosis of methanol intoxications. Breath analysis with FT-IR was fast and easy, and no sample preparation was needed.', 'CONCLUSIONS: The Fd(late) is a valuable tool for bedside screening of PE in surgical patients.']

['Point of care breath tests are available for lung cancer, pulmonary embolism, respiratory distress syndrome, methanol intoxication, kidney diseases, liver diseases, Helicobacter pylori infection, asthma, sepsis, heart failure, diabetes and tuberculosis.']

['lung cancer', 'pulmonary embolism', 'respiratory distress syndrome', 'methanol intoxication', 'kidney diseases', 'liver diseases', 'Helicobacter pylori infection', 'asthma', 'sepsis', 'heart failure', 'diabetes', 'tuberculosis']

At which kind of individuals is pharmacological treatment of subclinical hypothyroidism effective in reducing cardiovascular events?

['sHT in older people should be not regarded as a unique condition, and moderately old patients (aged <70-75 y) could be considered clinically similar to the adult population, albeit with a higher optimal TSH target value. Conversely, the oldest old subjects should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment.', 'Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. An appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted.', 'SCH appears to influence the postoperative outcome for patients by increasing the development of postoperative atrial fibrillation. However, it is still unproven whether preoperative thyroxine replacement therapy for patients with SCH might prevent postoperative atrial fibrillation after CABG.', 'Sustained normalization of thyroid function during l-T(4) replacement therapy significantly decreases baPWV in female subclinical hypothyroid patients with autoimmune chronic thyroiditis, suggesting the improvement of arterial stiffening and, consequently, possible prevention of cardiovascular disease.', 'Our results suggest that L-T(4) replacement therapy may be especially beneficial in female subclinical hypothyroid patients with high baseline baPWV and pulse pressure. The beneficial effects of L-T(4) replacement therapy in decreasing arterial stiffening and thus preventing cardiovascular disease might be limited to this sub-population.', 'Although a consensus is still lacking, the strongest evidence for a beneficial effect of levothyroxine replacement on markers of cardiovascular risk is the substantial demonstration that restoration of euthyroidism can lower both total and low-density lipoprotein-cholesterol levels in most patients with subclinical hypothyroidism.', 'However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events remains to be elucidated.', 'Restoration of euthyroidism by levothyroxine (LT4) treatment may correct the lipid profile and cardiac abnormalities, especially in patients with an initially higher deviation from normality and higher serum TSH levels. Importantly, a strong association between SH and atherosclerotic cardiovascular disease, independent of the traditional risk factors, has been recently reported in a large cross-sectional survey (the Rotterdam Study). However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy.']

['Treatment of subclinical hypothyroidism is associated with fewer cardiovascular events in younger individuals, but this issue has not been resolved yet in elderly people.']

['effective in younger individuals']

How is myotonic dystrophy inherited?

['Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystem disorder caused by a CCTG tetranucleotide repeat expansion located in intron 1 of the zinc finger protein 9 gene (ZNF9 gene) on chromosome 3q 21.3.', 'Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder, caused by an expansion of a CTG triplet repeat in the DMPK gene.', "Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3.", 'proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9.', 'All patients have the DM2 (CCTG)(n) expansion.', 'Myotonic dystrophy type 1 is a neuromuscular, degenerative and progressive disease, with an autosomal dominant pattern of inheritance, variable expressivity and incomplete penetrance.', 'The worldwide intergenerational behavior of the DM1 mutation is similar in Costa Rica', 'Dystrophic myotonia is a sufficiently rare disease inherited mainly by the autosomal dominant type.']

['Myotonic dystrophy (DM) is a heterogeneous neuromuscular disease with an autosomal dominant pattern of inheritance.']

['autosomal dominant']

Which fusion protein is involved in the development of Ewing sarcoma?

['Ewing sarcoma is the second most common bone malignancy in children and young adults. It is driven by oncogenic fusion proteins (i.e. EWS/FLI1) acting as aberrant transcription factors that upregulate and downregulate target genes, leading to cellular transformation', 'EWS/FLI-1 oncoprotein subtypes impose different requirements for transformation and metastatic activity in a murine model', 'Ewing sarcoma/primitive neuroectodermal tumors (EWS/PNET) are characterized by specific chromosomal translocations most often generating a chimeric EWS/FLI-1 gene', 'The resulting EWS-FLI-1 fusion protein is believed to behave as an aberrant transcriptional activator that contributes to ESFT development by altering the expression of its target genes in a permissive cellular environment', 'Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor', 'The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors', 'The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1', 'The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression', 'Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor.', 'Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1.', 'EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES).', 'Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma.', 'Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene.', 'Blocking the road, stopping the engine or killing the driver? Advances in targeting EWS/FLI-1 fusion in Ewing sarcoma as novel therapy.', 'Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma.', 'Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewings sarcoma.', 'Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs).', 'Ewing sarcoma is primarily caused by a t(11;22) chromosomal translocation encoding the EWS-FLI1 fusion protein.', 'Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor.', "The EWS-ETS fusion is causative in the development of Ewing's tumour.", 'The resulting EWS-FLI-1 fusion protein is believed to behave as an aberrant transcriptional activator that contributes to ESFT development by altering the expression of its target genes in a permissive cellular environment.', "EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing's sarcoma family tumors (ESFT)", 'Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene', 'Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma', 'Together, our data reveal that EWSAT1 is a downstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes', "Thus, we developed a highly validated transcriptional profile for the EWS/FLI fusion protein and identified a critical target gene in Ewing's sarcoma development.", "Our understanding of Ewing's sarcoma development mediated by the EWS/FLI fusion protein has been limited by a lack of knowledge regarding the tumor cell of origin", "Ewing's sarcomas are characterized by recurrent chromosomal translocations expressing EWS-ETS fusion proteins, the most common of which is EWS-FLI.(1-5) EWS-FLI is an oncogenic transcription factor that regulates genes involved in tumorigenesis.(6,7) Because the Ewing's sarcoma cell of origin remains unknown, a variety of model systems have been developed to study EWS-FLI fusions,(8-14) and multiple microarray experiments describing potential EWS-FLI target genes have been reported.(8,10,11,13,15-21) Each model has potential benefits and drawbacks, but a large-scale comparison of these has not been reported", "Most cases of Ewing's sarcoma express the EWS/FLI fusion protein"]

['Ewing sarcoma is the second most common bone malignancy in children and young adults. In almost 95% of the cases, it is driven by oncogenic fusion protein EWS/FLI1, which acts as an aberrant transcription factor, that upregulates or downregulates target genes, leading to cellular transformation.']

['EWS/FLI1']

How were plasma levels of thyroid hormones affected by amiodarone and dronedarone treatment in Wistar rats?

['["Amiodarone resulted in increased T4, T4/T3 and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals.", "Fifty-five Wistar rats were randomly allocated to a 2-week oral treatment with either vehicle (n=18), amiodarone (30 mg/kg, n=20), or dronedarone (30 mg/kg, n=17).", "Thyroid function was similar in the 3 groups.", "Plasma levels of T3, T4, and rT3 were changed after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose-dependently increased by amiodarone treatment."]']

Amiodarone treatment resulted in increased T4, T4/T3, and rT3 levels in Wistar rats, while dronedarone did not alter the thyroid hormone profile in normal animals.

[]

Where in a protein can a signal sequence be found?

['A transmembrane domain (TMD) at the N-terminus of a membrane protein is a signal sequence that targets the protein to the endoplasmic reticulum (ER) membrane. ', ' an N-terminal signal sequence,', 'soluble AMO possesses an N-terminal signal sequence', 'n N-terminal "twin arginine" signal sequence suggested ', 'Proteins destined for the mitochondrial matrix space have leader sequences that are typically present at the most N-terminal end of the nuclear-encoded precursor protein. ', 'N-terminal signal sequence ', 'The predicted amino-acid sequence includes an N-terminal signal sequence ', 'These N-terminal sequences lack a typical signal sequence ', ' TAP can be bypassed by targeting peptides directly to the endoplasmic reticulum (ER) using NH2-terminal signal sequences. T', 'The amino terminal signal sequence, ', 'An amino-terminal domain containing a signal sequence', 'A nuclear localization signal (NLS) sequence was previously defined by point mutations in three short adjacent clusters of basic amino acids located in the amino-terminal region of the E1 protein. ', 'he human homologue also contains a putative N-terminal signal sequence']

['Proteins have signal sequences typically resent at the most N-terminal end.']

['N-terminally']

Is transcription-associated mutagenesis (TAM) related to gene expression levels?

['These mutations were frequent in plasmid-borne lacS expressed at a high level but not in single-copy lacS in the chromosome or at lower levels of expression in a plasmid.', 'The results suggest that important DNA repair or replication fidelity functions are impaired or overwhelmed in pJlacS, with results analogous to those of the "transcription-associated mutagenesis" seen in bacteria and eukaryotes.', 'the rate of point mutation in a gene increases with the expression level of the gene. Transcription induces mutagenesis on both DNA strands, indicating simultaneous actions of several TAM mechanisms.', 'High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM).', 'High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Here, we describe a pGAL-CAN1 forward mutation assay for studying transcription-associated mutagenesis (TAM) in yeast.', 'The acquisition of mutations was directly correlated to the level of transcription', 'Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels.', 'Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression', 'spontaneous mutation rate is directly proportional to the transcription level, suggesting that movement of RNA polymerase through the target initiates a mutagenic process(es)', 'High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM).', 'Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions.', 'Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication.', 'High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage.', 'Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions.', 'Using comparative genomics of related species as well as mutation accumulation lines, we show in yeast that the rate of point mutation in a gene increases with the expression level of the gene', 'High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM)', 'Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions', 'High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM)']

['Spontaneous point mutation rate in a gene increases with its transcription level, suggesting that movement of RNA polymerase through the target initiates a mutagenic process(es). This phenomenon is termed transcription-associated mutation (TAM). Transcription-associated mutagenesis is directly proportional to the level of gene expression.']

['yes']

Is Dupilumab used for treatment of atopic dermatitis?

['Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases.', 'Background Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.', 'Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.', 'Dupilumab is a biologic agent targeted at TH2 cytokines, but indirectly impacts IgE and is an important biologic agent for atopic disease.', 'Dupilumab for the treatment of atopic dermatitis: A clinical trial review.', 'Dupilumab is a novel monoclonal antibody that was recently studied in adult patients with moderate-to-severe AD.', 'Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity.', 'The robust effects of dupilumab on skin inflammation and pruritus confirm the pathogenic role of IL-4 and IL-13 signaling in adult AD, and further support the application of Th2 cytokine antagonists in the treatment of this disease.']

['Yes, patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity.']

['yes']

List 3 indications for Bupropion

[' For genotype, genes associated with nicotinic acetylcholine receptors (nAChRs) and related proteins have been found to predict response to first-line medications (e.g. nicotine replacement therapy [NRT], bupropion, or varenicline) or quitting over time without a controlled treatment trial. ', 'The approval of drug combinations, such as phentermine/topiramate and bupropion/naltrexone are also noteworthy, the components of which have been previously approved, but not necessarily for obesity as main indication.', 'Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. ', 'Bupropion SR is preferred to subjects with depression or smokers who have failed with the previous two agents, due to the many contra-indications and side effects of bupropion SR. With one of the 3 agents combined with follow-up visits with counselling, one can expect a 1-year quit rate around 20-25%.', 'In vitro intrinsic clearances were likewise different for bupropion enantiomers.CONCLUSIONS: Stereoselective bupropion hydroxylation may have implications for the therapeutic efficacy of bupropion as an antidepressant or smoking cessation therapy, and for the use of bupropion as an in vivo phenotypic probe for CYP2B6 activity.', 'PURPOSE: Hydroxylation of the antidepressant and smoking deterrent drug bupropion is a clinically important bioactivation and elimination pathway.', 'Although not U.S. Food and Drug Administration approved for these indications, bupropion has also been used as an adjunctive treatment to reverse antidepressant-induced sexual dysfunction and to augment anti-depressant efficacy in partial responders and non-responders to other agents.Bupropion has played and will continue to play an important role as a treatment for major depressive disorder in adults, as well as for other related disorders', 'Clinically, bupropion is used as a treatment for two indications, as an antidepressant, the indication for which it was developed, and as a tobacco use cessation agent', 'Sustained release bupropion (amfebutamone) is a non-nicotine agent that is indicated as an aid to smoking cessation. ', 'Bupropion was introduced for smoking cessation following a pivotal trial showing that it gave improved efficacy over the nicotine patch and also suggesting combination treatment was beneficial. ', 'Compared with a placebo control, bupropion approximately doubles smoking quit rates. ', 'Over the past decade, bupropion has become a major pharmacotherapy for smoking cessation in the Western world. Unlike other smoking cessation pharmacotherapies, bupropion is a non-nicotine treatment', 'Bupropion has been tested in over 40 controlled clinical trials and has been associated with higher rates of treatment discontinuation due to adverse events than NRTs. ', 'Bupropion SR is a useful oral and non-nicotine form of pharmacotherapy for smoking cessation.', 'everal new drugs for the treatment of obesity are either licensed in some parts of the world, submitted for registration, or completing phase III trials. These include combinations (at low dose) of existing drugs, e.g., bupropion + naltrexone (Contrave),']

['Bupropion is used to treat Obesity, for smoking cessation and for depression']

['weight loss in obesity', 'smoking cessation', 'depression']

Which major signaling pathways are regulated by RIP1?

['Major signaling pathways regulated by RIP1 include necroptosis, apoptosis, and pro-survival/inflammation NF-κB activation. ', 'receptor-interacting protein-1 (RIP1)-mediated necroptosis', 'TNF-induced apoptotic signaling pathways were assessed by monitoring levels of the anti-apoptotic protein, A20, and cleavage products of the caspase-8 substrate, RIP1.', 'Receptor-interacting protein (RIP) kinases promote the induction of necrotic cell death pathways. ', 'Together our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 inflammasome and establish a direct link between inflammation and cell-death signaling pathways.', 'Necroptosis exhibits a unique signaling pathway that requires the involvement of receptor interaction protein kinases 1 and 3 (RIP1 and RIP3),']

['necroptosis\napoptosis \npro-survival/inflammation NF-κB activation']

['necroptosis', 'apoptosis', 'pro-survival/inflammation NF-κB activation']

Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?

['The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer', 'he multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z.', 'Our results show that the Swr1-Z domain can deliver the H2A.Z-H2B dimer to the DNA-(H3-H4)2 tetrasome to form the nucleosome by a histone chaperone mechanism.', 'H2A.Z is deposited into chromatin by the SWR1 complex and is subject to acetylation of its four N-terminal tail lysine residues by the NuA4 and SAGA histone acetyltransferase complexes.', 'H2A.Z deposition is controlled by SWR-C chromatin remodeling enzymes that catalyze the nucleosomal exchange of canonical H2A with H2A.Z. ', 'Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z.', 'The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. ', 'We identified a complex containing 13 different polypeptides associated with a soluble pool of H2A.Z in Saccharomyces cerevisiae. This complex was designated SWR1-Com in reference to the Swr1p subunit, a Swi2/Snf2-paralog.', 'The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 in yeast) at specific chromatin regions.', 'In Saccharomyces cerevisiae, deposition of histone H2AZ is mediated by the multiprotein SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ.', 'In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by the fourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ.', 'This incorporation is mediated by the conserved SWR1 complex, which replaces histone H2A in canonical nucleosomes with H2A.Z in an ATP-dependent manner. ', 'Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. ', 'In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by the fourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. ', 'In Saccharomyces cerevisiae, deposition of histone H2AZ is mediated by the multiprotein SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. ', 'The Swc4p protein, encoded by an essential gene, is shared by two chromatin-remodeling complexes in Saccharomyces cerevisiae cells: NuA4 (nucleosome acetyltransferase of H4) and SWR1. ', 'The Saccharomyces cerevisiae protein Yaf9 is a subunit of both the essential histone acetyltransferase complex NuA4 and the ATP-dependent chromatin remodeling complex SWR1-C, which deposits histone variant H2A.Z into euchromatin.', 'Here, we identify and characterize SERRATED LEAVES AND EARLY FLOWERING (SEF), an Arabidopsis (Arabidopsis thaliana) homolog of the yeast SWC6 protein, a conserved subunit of the SWR1/SRCAP complex.', 'The SWR1/SRCAP complex is a chromatin-remodeling complex that has been shown to be involved in substitution of histone H2A by the histone variant H2A.Z in yeast (Saccharomyces cerevisiae) and animals.', 'The Swc4p protein, encoded by an essential gene, is shared by two chromatin-remodeling complexes in Saccharomyces cerevisiae cells: NuA4 (nucleosome acetyltransferase of H4) and SWR1.', 'The SWR1 complex (SWR1C) in yeast catalyzes the replacement of nucleosomal H2A with the H2AZ variant, which ensures full activation of underlying genes.', 'In addition, H2AZ, a substrate of SWR1C, interacts with both PIE1 and AtSWC2.', 'The incorporation of H2AZ into chromatin is dependent on the SWR1 complex, which catalyses the replacement of conventional histone H2A with H2AZ.', 'H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast.', 'They report that reversal of H2A.Z replacement is mediated by SWR1 and related INO80 on an H2A.Z nucleosome carrying H3K56Q.', 'The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer.', 'This incorporation is mediated by the conserved SWR1 complex, which replaces histone H2A in canonical nucleosomes with H2A.Z in an ATP-dependent manner.', 'Here, we show that the JmjC domain protein Msc1 is a novel component of the fission yeast Swr1 complex and is required for Swr1-mediated incorporation of H2A.Z into nucleosomes at gene promoters.']

['Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. We identified a complex containing 13 different polypeptides associated with a soluble pool of H2A.Z in Saccharomyces cerevisiae.', 'The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z. The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 in yeast) at specific chromatin regions.', 'The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z.', 'The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer', 'The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z.']

['SWR1']

Is Growth factor independence 1b (GFI1B) important for hematopoiesis?

['Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification', 'gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors,', 'gfi1b is required for definitive hematopoiesis', 'LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b', 'GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment', ' Taken together, our findings demonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the process leading to the generation of hematopoietic progenitors from hemogenic endothelium', 'A short Gfi-1B isoform controls erythroid differentiation', 'Gfi-1B is a transcriptional repressor essential for the regulation of erythropoiesis and megakaryopoiesis', 'Among the few down-regulated genes was Gfi1b, a known repressor of erythroid differentiation', 'This reversible modulation of endothelial-haematopoietic state is accomplished by targeting key haematopoietic transcription factors for downregulation, including Runx1, Gata1, Gfi1B, Ikaros, and PU.1', 'Gfi1 and Gfi1b: key regulators of hematopoiesis', 'we review how Gfi1 and its paralogue Gfi1b control the development of blood cells, discuss how changes in Gfi1 and Gfi1b function contribute to hematological disease and report on the molecular function of these proteins.', 'Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage', 'Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis', 'Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis', 'We here show that, in humans, Gfi-1B controls the development of erythrocytes and megakaryocytes by regulating the proliferation and differentiation of bipotent erythro-megakaryocytic progenitors', 'To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci)', 'Transcription factors play essential roles in both normal and malignant hematopoiesis. This is the case for the growth factor independent 1b (GFI1B) transcription factor, which is required for erythroid and megakaryocytic differentiation and over-expressed in leukemic patients and cell lines', 'We localized several conserved non-coding elements containing multiple erythroid specific transcription factor binding sites at the GFI1B locus. In GFI1B-expressing cells a subset of these conserved non-coding elements and the promoter adopt a close spatial conformation, localize with open chromatin sites, harbor chromatin modifications associated with gene activation and bind multiple transcription factors and co-repressors', 'Our findings indicate that GFI1B regulatory elements behave as activators and repressors', 'To investigate the molecular effects of growth factor independence 1B (Gfi-1B), a transcription factor essential for the development of hematopoietic cells and differentiation of erythroid and megakaryocytic lineages', 'Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations', 'Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse developmental contexts, including hematopoiesis and oncogenesis', 'Gfi1b:green fluorescent protein knock-in mice reveal a dynamic expression pattern of Gfi1b during hematopoiesis that is largely complementary to Gfi1', 'We found highly dynamic expression patterns of Gfi1b in erythroid cells, megakaryocytes, and their progenitor cells (MEPS) where Gfi1 is not detected. Vice versa, Gfi1b could not be found in granulocytes, activated macrophages, or their granulomonocytic precursors (GMPs) or in mature naive or activated lymphocytes where Gfi1 is expressed, suggesting a complementary regulation of both loci during hematopoiesis', 'Gfi1 and Gfi1b act equivalently in haematopoiesis', 'our findings show that an intact SNAG domain is essential for all functions of Gfi1 and that Gfi1b can replace Gfi1 functionally in haematopoiesis', 'Gfi-1 oncoproteins in hematopoiesis', 'Recent gene targeting experiments and mutational screening in humans have revealed an essential role for Gfi-1 and Gfi-1B in hematopoiesis', 'Gfi-1B disruption is embryonic lethal due to a block of erythropoiesis. Gfi-1B is required for both erythroid and megakaryocyte development', 'Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis', ' we identified that the expression of Gfi-1B (growth factor independence-1B) is highly restricted to hematopoietic stem cells, erythroblasts, and megakaryocytes', 'These findings establish Gfi-1B as a novel erythroid regulator and reveal its specific involvement in the regulation of erythroid cell growth through modulating erythroid-specific gene expression', 'The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages', 'we establish that Gfi-1b is required for the development of two related blood lineages, erythroid and megakaryocytic, in mice', 'Gfi-1b(-/-) embryonic stem cells fail to contribute to red cells of adult chimeras. Gfi-1b(-/-) embryos exhibit delayed maturation of primitive erythrocytes and subsequently die with failure to produce definitive enucleated erythrocytes', 'Gfi-1b is an essential transcriptional regulator of erythroid and megakaryocyte development', 'Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis.', 'Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis.', 'Gfi1b:green fluorescent protein knock-in mice reveal a dynamic expression pattern of Gfi1b during hematopoiesis that is largely complementary to Gfi1.', 'Gfi1 and Gfi1b: key regulators of hematopoiesis.', 'We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish.', 'Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis.', 'Growth factor independence 1b (gfi1b) is important for the maturation of erythroid cells and the regulation of embryonic globin expression.', 'Growth factor-independence 1b (Gfi1b) is a zinc finger transcription factor essential for erythroid and megakaryocytic development.', 'Gfi1b (growth factor independence 1b) is a zinc finger transcription factor essential for development of the erythroid and megakaryocytic lineages.', 'In fact, we demonstrate that VPA treatment is able to induce the expression of growth factor-independent protein 1B (GFI1B) and of mixed-lineage leukemia translocated to chromosome 3 protein (MLLT3), which are crucial regulators of erythrocyte and megakaryocyte differentiation, and that the up-regulation of these genes is mediated by the histone hyperacetylation at their promoter sites.', 'Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis.', 'Gfi-1B (growth factor independence-1B) gene is an erythroid-specific transcription factor, whose expression plays an essential role in erythropoiesis.', 'Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells.', 'We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood.', 'Growth factor-independence 1b (Gfi1b) is a zinc finger transcription factor essential for erythroid and megakaryocytic development', 'Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis.', 'Gfi-1B (growth factor independence-1B) gene is an erythroid-specific transcription factor, whose expression plays an essential role in erythropoiesis', 'Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations.', 'We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood']

['Yes. Gfi-1B is a transcriptional repressor essential for the regulation of erythropoiesis and megakaryopoiesis. Gfi-1b(-/-) embryonic stem cells fail to contribute to red cells of adult chimeras. Gfi-1b(-/-) embryos exhibit delayed maturation of primitive erythrocytes and subsequently die with failure to produce definitive enucleated erythrocytes.']

['yes']

Is there a role for gamma knife in treatment of Obsessive-Compulsive Disorder?

['OBJECTIVE Functional Gamma Knife radiosurgery (GKRS) procedures have been increasingly used for treating patients with tremor, trigeminal neuralgia (TN), and refractory obsessive-compulsive disorder.', 'METHODS The authors constructed a linear-quadratic model of BED in functional GKRS with a dose-protraction factor to correct for intrafraction DNA-damage repair and used standard single-fraction doses for trigeminal nerve ablation for TN (85 Gy), thalamotomy for tremor (130 Gy), and capsulotomy for obsessive-compulsive disorder (180 Gy). ', 'Gamma knife for obsessive compulsive disorder: can it be detrimental?', 'Gamma knife radiosurgery (GKRS) is also being practised to treat refractory obsessive- compulsive disorder (OCD).', 'Radio and neurosurgical procedures, including gamma knife radiation and deep brain stimulation, are reserved for severe, treatment-refractory disease that has not responded to multiple treatments, and some patients may benefit from transcranial magnetic stimulation.', ' We close with a discussion of gamma knife capsulotomy, a modality with deep historical roots.', 'Results following gamma knife radiosurgical anterior capsulotomies for obsessive compulsive disorder.', 'Gamma knife radiosurgery (GKRS) is also being practised to treat refractory obsessive- compulsive disorder (OCD).', 'Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere.', 'Neuropsychological outcome of ventral capsular/ventral striatal gamma capsulotomy for refractory obsessive-compulsive disorder: a pilot study', 'Gamma ventral capsulotomy for treatment of resistant obsessive-compulsive disorder: a structural MRI pilot prospective study', 'Results following gamma knife radiosurgical anterior capsulotomies for obsessive compulsive disorder', 'At 28 months, the third patient is living and working independently, and her YBOCS score is 18.CONCLUSION: Within a strict protocol, gamma knife radiosurgery provided improvement of OCD behavior with no adverse effects.', 'Gamma knife for obsessive compulsive disorder: can it be detrimental?']

['Yes. Gamma knife radiosurgery is being increasingly to treat refractory obsessive- compulsive disorder (OCD). It is reserved for severe, treatment-refractory disease that has not responded to multiple treatments.']

['yes']

Which genes are implicated in short QT syndrome?

['A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.', 'In this study, we identified a novel KCNJ2 gain-of-function mutation, M301K, associated with SQTS. ', 'A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1).', 'We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit. ', 'however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel.', 'In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS.', 'A novel mutation in the KCNH2 gene associated with short QT syndrome.', 'The altered function of T618I-HERG channels suggests that this mutation in the KCNH2 gene is responsible for the SQTS phenotype in this family. ', 'Gain of function mutations in three genes encoding K(+) channels have been identified, explaining the abbreviated repolarization seen in this condition: KCNH2 for I(kr) (SQT1), KCNQ1 for I(ks) (SQT2) and KCNJ2 for I(k1) (SQT3). ', 'To evaluate the possible diagnosis of SQTS, DNA sequencing of genes known to be associated with SQTS was performed and identified a novel mutation in the KCNH2 gene.', 'The mutation of genes (KCNH2, KCNQ1, and KCNJ2) encoding for cardiac potassium channels plays a central role in SQTS. ', 'To date, different mutations in genes encoding for cardiac ion channels (KCNH2, KCNQ1, and KCNJ2) have been identified to cause the short QT syndrome. ', 'Mutations in 3 different genes KCNQ1, KCNH2, and KCNJ2, all encoding cardiac ionic potassium channels have been identified in affected patients. ', 'Genetic analysis has, to date, identified three distinct forms of the condition, involving gain-of-function mutations to three different cardiac potassium channel genes: KCNH2 (SQT1), KCNQ1 (SQT2) and KCNJ2 (SQT3). ', 'Three different gain-of-function mutations in genes encoding for cardiac potassium channels (KCNH2, KCNQ1, and KCNJ2) have been identified up to now to cause short QT syndrome. ', 'To date, three different mutations in genes encoding cardiac ion channels (KCNH2, KCNQ1 and KCNJ2) have been identified as causing short QT syndrome.']

['The genes that are implicated in short QT syndrome are KCNJ2, KCNH2, CACNA2D1 and KCNQ1.']

['KCNJ2', 'inward rectifier potassium channel gene', 'HERG', 'KCNH2', 'CACNA2D1', 'KCNQ1', 'CACNB2b']

Borden classification is used for which disease?

['The locations of DAVFs were the transverse-sigmoid sinus in 11, tentorium in 10, cranial vault in 9, and superior sagittal sinus, jugular bulb, foramen magnum, and middle cranial fossa in 1 each. Borden classification was type I in 7, type II in 3, and type III in 24.', 'Transarterial glue embolization is highly effective for Borden type III DAVF with direct cortical venous drainage, but has limitations for Borden type I and II DAVFs in which the affected sinus is part of the normal venous circulation.', 'The results of subtype (Borden and Cognard classification), venous reflux and fistula sites were also accurately exhibited in 4D-CTA.', 'The commonly used Borden and Cognard classification systems for the prediction of clinical behavior of cranial dural arteriovenous shunts focus on the venous drainage, particularly the presence of leptomeningeal venous drainage, and on the direction of flow, particularly the presence of retrograde flow. ', 'The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively. ', 'The two most commonly used and clinically accepted DAVF classifications are the Merland-Cognard classification and the Borden classification, both based on the morphology of the venous drainage.', 'When analyzed according to the Borden classification, none (0%) of 55 Type I intracranial dural AVFs, two (11%) of 18 Type II, and 14 (48%) of 29 Type III intracranial dural AVFs presented with hemorrhage (p < 0.0001).', 'The configuration of venous anatomy as reflected by both the Cognard and Borden classifications strongly predicts intracranial dural AVFs that will present with ICH or nonhemorrhagic neurological deficit.', 'The two most commonly used and clinically accepted DAVF classifications are the Merland-Cognard classification and the Borden classification, both based on the morphology of the venous drainage', 'The commonly used Borden and Cognard classification systems for the prediction of clinical behavior of cranial dural arteriovenous shunts focus on the venous drainage, particularly the presence of leptomeningeal venous drainage, and on the direction of flow, particularly the presence of retrograde flow', 'When analyzed according to the Borden classification, none (0%) of 55 Type I intracranial dural AVFs, two (11%) of 18 Type II, and 14 (48%) of 29 Type III intracranial dural AVFs presented with hemorrhage (p &lt; 0.0001)', 'Borden classification showed Type III in 1 and Type II in 10 ncsDAVFs, and Type II in 4 and Type I in 6 csDAVFs', 'The recently proposed classification scheme of Borden, Wu, and Shucart (Borden(*)) should have the ability to identify those intracranial dural arteriovenous fistulae (ICDAVF) which will continue to behave in a benign fashion', 'The two most commonly used and clinically accepted DAVF classifications are the Merland-Cognard classification and the Borden classification, both based on the morphology of the venous drainage.', 'The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively.', 'A multivariate logistic regression model showed that intracranial hemorrhage in patients with DAVFs was correlated with higher Borden classification (OR 5.880; 95% CI, 3.370-10.257; p<0.001).', 'The configuration of venous anatomy as reflected by both the Cognard and Borden classifications strongly predicts intracranial dural AVFs that will present with ICH or nonhemorrhagic neurological deficit..', 'Borden classification showed Type III in 1 and Type II in 10 ncsDAVFs, and Type II in 4 and Type I in 6 csDAVFs.']

['Borden classification systems is used for the prediction of clinical behavior of cranial dural arteriovenous fistulas.']

['cranial dural arteriovenous fistula', 'DAVF']

Which are the different members/isoforms of the Ras oncogenes?

['The major Ras isoforms (K, H, and N) ', 'Mutations in Ras isoforms such as K-Ras, N-Ras, and H-Ras contribute to roughly 85, 15, and 1% of human cancers, respectively.', 'the Ras isoforms (H, N and K) ', 'The mutant forms of KRas, NRas and HRas', ' lipidated Ras isoforms (H-Ras and N-Ras)', ': H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors.', 'Human tumours frequently express Ras proteins (Ha-, Ki-, N-Ras) ', ' There are three major ras isoforms: H-, N- and K-Ras. ', 'All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras', 'hree closely related isoforms, HRAS, KRAS and NRAS, ', 'H-ras, N-ras, and K-ras are canonical ras gene family members frequently activated by point mutation in human cancers and coding for 4 different, highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B).', 'he 3 Ras isoforms-H-Ras, K-Ras, and N-Ras-', 'In this study, we compared the leukemogenic potential of activated NRAS, KRAS, and HRAS in the same bone marrow transduction/transplantation model system. ', 'H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors.', 'Ras proteins are small GTPase functioning as molecular switches that, in response to particular extracellular signalling, as growth factors, activate a diverse array of intracellular effector cascades regulating cell proliferation, differentiation and apoptosis. Human tumours frequently express Ras proteins (Ha-, Ki-, N-Ras) activated by point mutations which contribute to malignant phenotype, including invasiveness and angiogenesis.', 'Ras small GTPases function as transducers of extracellular signals regulating cell survival, growth and differentiation. There are three major ras isoforms: H-, N- and K-Ras. ', 'All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras, that promote oncogenesis when they are mutationally activated at codon 12, 13, or 61.', 'Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Three closely related isoforms, HRAS, KRAS and NRAS, are expressed in all cells and have overlapping but distinctive functions.', 'H-ras, N-ras, and K-ras are canonical ras gene family members frequently activated by point mutation in human cancers and coding for 4 different, highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B)']

['Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Three closely related isoforms, HRAS, KRAS and NRAS, are expressed in all cells and have overlapping but distinctive functions.', 'H-ras, N-ras, and K-ras are canonical ras gene family members frequently activated by point mutation in human cancers and coding for 4 different, highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B)']

['H-Ras', 'N-Ras', 'K-Ras4A', 'K-Ras4B']

What tissue is most affected in Ehlers-Danlos syndromes?

['The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. ', 'Ehlers-Danlos syndromes (EDSs) constitute a rare group of inherited connective tissue diseases, characterized by multisystemic manifestations and general tissue fragility.', 'Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility.', 'The Ehlers-Danlos syndromes (EDS) comprise a heterogenous group of heritable disorders of connective tissue, characterized by joint hypermobility, skin hyperextensibility and tissue fragility.', 'Ehlers-Danlos syndrome denotes a group of inherited connective tissue diseases comprising nine types.', 'The Ehlers-Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by articular hypermobility, skin extensibility, and tissue fragility.', 'Ehlers-Danlos syndrome is a heterogeneous group of heritable connective tissue disorders characterized by increased fragility of various non-ossified tissues', 'The Ehlers-Danlos Syndrome (EDS) is a rare connective tissue disorder characterised by fragility of the soft connective tissues and widespread manifestations in skin, ligaments, joints, blood vessels and internal organs', 'The Ehlers-Danlos syndromes (EDS) comprise a heterogenous group of heritable disorders of connective tissue, characterized by joint hypermobility, skin hyperextensibility and tissue fragility', 'Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders', 'The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders characterized by tissue fragility, hyperelasticity of the skin and joint hypermobility.', 'Ehlers-Danlos syndrome (EDS), a heterogeneous group of inheritable connective tissue disorders, is attributed to mutations in connective tissue genes.', 'Ehlers-Danlos syndrome is a heterogeneous group of heritable connective tissue disorders characterized by increased fragility of various non-ossified tissues.', 'The Ehlers-Danlos syndrome encompasses a group of hereditary disorders of the connective tissue, characterized by hyperextensible skin, joint hypermobility; and varying degrees of vessel and tissue fragility.', 'Ehlers-Danlos syndrome is an inherited connective tissue disorder.', 'The Ehlers-Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism.', 'The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders.', 'Ehlers-Danlos syndrome type 4, the vascular type, is a rare, life-threatening inherited disorder of the connective tissue.', 'The Ehlers-Danlos syndrome is characterized by abnormal connective tissue ', 'Ehlers-Danlos syndrome is a complex hereditary connective tissue disorder that is characterized by abnormalities of the skin and joints and visceral and neurological manifestation', 'The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility.', 'The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterised by joint hypermobility, involvement of skin and tissue fragility', 'Ehlers-Danlos syndrome (EDS), inherited disorder of connective tissue, frequently leads to impairment of various functional areas,', 'classic form of Ehlers-Danlos syndrome (cEDS) is an inherited connective tissue disorder, where mutations in type V collagen-encoding genes result in abnormal collagen fibrils. Thus the cEDS patients have pathological connective tissue morphology and low stiffness, but the rate of connective tissue protein turnover is unknown', 'Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility']

['the ehlers-danlos syndromes (eds) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility.', 'The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility.', 'The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. ']

['connective tissue']

What is the indication for Mirabegron?

['Mirabegron, the first β3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms.', 'The clinical indication for mirabegron is overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency and other storage symptoms in both men and women.', 'Mirabegron has been approved in Japan for the indication of urgency, urinary frequency and urge urinary incontinence associated with OAB, and was recently submitted for approval to U.S. and European authorities for the same indication.', 'Mirabegron was well tolerated.The early onset of action and good overall efficacy and tolerability balance that mirabegron offers may lead to high rates of persistence with mirabegron in the long-term treatment of OAB', 'Mirabegron, the selective β3-adrenoceptor agonist, heralds the latest development for the treatment of overactive bladder (OAB).To present the evidence available on the efficacy and tolerability of mirabegron and to discuss this treatments potential in our setting.We reviewed 11 studies conducted with mirabegron in patients with OAB (2 phase II, 9 phase III), all studies were compared to placebo with 6 studies also including tolterodine as an additional arm', 'More than 50% of patients had previously discontinued anticholinergics medication for OAB, thus allowing us to obtain data on the effectiveness of mirabegron in patients already treated with anticholinergics.Mirabegron is an efficacious drug which presents a statistically significant reduction in the number of incontinence episodes and in urinary frequency as of 4 weeks, with a higher percentage of dry patients and a higher percentage of patients with reduction ≥50% in the number of incontinence episodes than placebo', 'Mirabegron, a β(3)-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB).To assess the efficacy and tolerability of mirabegron versus placebo.Multicenter randomised double-blind, parallel-group placebo- and tolterodine-controlled phase 3 trial conducted in 27 countries in Europe and Australia in patients ≥ 18 yr of age with symptoms of OAB for ≥ 3 mo.After a 2-wk single-blind placebo run-in period, patients were randomised to receive placebo, mirabegron 50mg, mirabegron 100mg, or tolterodine extended release 4 mg orally once daily for 12 wk.Patients completed a micturition diary and quality-of-life (QoL) assessments.', 'Mirabegron is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder.The effects of mirabegron on primary bladder mechanosensitive single-unit afferent activities (SAAs) and bladder microcontractions were evaluated and compared with the effects of oxybutynin.Female Sprague-Dawley rats were anesthetized', 'Mirabegron exhibits a novel mode of action in targeting the β₃-AR for bladder relaxation, and the studies and trials conducted to date suggest mirabegron as a promising new treatment in the management of OAB symptoms, such as increased urinary urgency and frequency, and urgency incontinence', 'Mirabegron has been approved in Japan for the indication of urgency, urinary frequency and urge urinary incontinence associated with OAB, and was recently submitted for approval to U.S. and European authorities for the same indication', 'The clinical indication for mirabegron is overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency and other storage symptoms in both men and women.', "Mirabegron's efficacy on frequency, urgency, and urge incontinence was tested in several trials before its wide clinical introduction.", 'To discuss the pharmacotherapeutic aspects of Mirabegron which is a first-in class novel β3 receptor agonist drug recently approved by the food and drug administration (FDA) for the treatment of overactive bladder (OAB).We conducted a computerized search of the MEDLINE/PUBMED databases with the word Mirabegron, β3 receptor agonist and overactive bladder.Effect of Mirabegron on β3 adrenergic receptor purportedly releases nitric oxide(NO) by an increase in intracellular Ca2+ through accumulation of cyclic adenosine monophosphate (cAMP).', 'Mirabegron for the treatment of overactive bladder.', 'Mirabegron: a Beta-3 agonist for overactive bladder.', '[MIRABEGRON--A NEW DRUG FOR TREATMENT OF OVERACTIVE BLADDER].', 'Phase III clinical trials in patients with overactive bladder (OAB), mirabegron at daily doses of 25, 50, and 100\u2009mg demonstrated significant efficacy in treating the symptoms of OAB, including micturition frequency, urgency incontinence, and urgency.', 'To review the place in therapy of mirabegron, a new oral β3-adrenergic receptor agonist, for the treatment of overactive bladder (OAB', 'Mirabegron (YM178) is a β(3)-adrenoceptor agonist for the treatment of overactive bladder (OAB).', 'Two new therapies have emerged for treating overactive bladder (OAB): Mirabegron', ' OnabotulinumtoxinA and mirabegron have recently gained marketing authorisation to treat symptoms of overactive bladder (OAB).', 'irabegron (YM-178), currently in development by Astellas Pharma Inc, is an orally active β₃-adrenoceptor (AR) agonist for the potential symptomatic treatment of overactive bladder (OAB). ', 'To evaluate the efficacy and safety of the β3 -adrenoceptor agonist, mirabegron, compared with placebo in Japanese patients with overactive bladder (OAB).', 'Mirabegron is the first β3 -adrenoceptor agonist approved for treatment of overactive bladder syndrome. ', 'To examine the effects of mirabegron, a selective β3 -adrenoceptor agonist that has recently been approved for the treatment of overactive bladder (OAB', 'mirabegron is a β3-adrenoceptor agonist developed for the treatment of symptoms of overactive bladder (OAB).', 'mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder,', 'critically analyse available phase II and III randomised control trials (RCTs) reporting clinical data about the efficacy and tolerability of Mirabegron (a β₃-adrenoceptor agonist) in the treatment of overactive bladder (OAB) syndrome']

['Mirabegron, the first 尾3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms.', 'mirabegron, the first β3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (oab) syndrome symptoms.', 'Mirabegron, the first β3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms.', 'Mirabegron, the first �3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms.', 'Mirabegron, the first 3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms. ']

['OverActive Bladder syndrome']

What is the composition of the gamma-secretase complex?

['Gamma-secretase is a widely expressed multisubunit enzyme complex which is involved in the pathogenesis of Alzheimer disease and hematopoietic malignancies through its aberrant processing of the amyloid precursor protein (APP) and Notch1, respectively.', "Presenilin (PS1 or PS2) is the catalytic component of the gamma-secretase complex, which mediates the final proteolytic processing step leading to the Alzheimer's disease (AD)-characterizing amyloid beta-peptide. ", "gamma-Secretase is a membrane-embedded multi-protein complex that catalyzes the final cut of the Alzheimer's disease-related amyloid precursor protein (APP) to amyloid-beta peptides of variable length (37-43 amino acids) via an unusual intramembrane cleavage.", 'The gamma-secretase complex processes substrate proteins within membranes and consists of four proteins: presenilin (PS), nicastrin, Aph-1 and Pen-2. PS harbours the enzymatic activity of the complex, and there are two mammalian PS homologues: PS1 and PS2. ', 'gamma-Secretase is known to contain four major protein constituents: presenilin (PS), nicastrin, Aph-1, and Pen-2, all of which are integral membrane proteins. ', 'Here we describe the association of all four components of the gamma-secretase complex, namely presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons that fulfill the criteria of lipid rafts. ', 'In contrast, the authentic TMD of NCT is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex.', 'Active gamma-secretase is a tetrameric protein complex consisting of presenilin-1 (or -2), nicastrin, PEN-2, and Aph-1a (or -1b).', 'The gamma-secretase complex processes substrate proteins within membranes and consists of four proteins: presenilin (PS), nicastrin, Aph-1 and Pen-2.', 'Maturation of exogenous NCT, gamma-secretase complex formation and proteolytic function was then investigated.', 'gamma-Secretase complexes containing N- and C-terminal fragments of different presenilin origin retain normal gamma-secretase activity.', 'Co-overexpression of presenilin-1 or APH-1 abrogated gamma-secretase inhibition probably through prevention of the incorporation of CRB2 into the gamma-secretase complex', 'We conclude that a PS1/Pen2/Aph1a trimeric complex is an active enzyme, displaying biochemical properties similar to those of gamma-secretase and roughly 50% of its activity when normalized to PS1 N-terminal fragment levels', 'γ-Secretase is involved in the regulated intramembrane proteolysis of amyloid-β protein precursor (AβPP) and of many other important physiological substrates. γ-secretase is a multiproteic complex made of four main core components, namely presenilin 1 or 2, APH-1, PEN-2, and Nicastrin', 'Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging.', 'Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate.', 'Characterization of the reconstituted gamma-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin [correction of nacastrin], aph-1a, and pen-2.', 'p53-Dependent Aph-1 and Pen-2 anti-apoptotic phenotype requires the integrity of the gamma-secretase complex but is independent of its activity.', 'Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PS1 or PS2 support pathogenic Abeta(42) production. ', 'To characterize the functional similarity between complexes of various PS composition, we analysed PS1, PS2, and chimeric PS composed of the NTF from PS1 and CTF from PS2, or vice versa, in assembly and function of the gamma-secretase complex.', 'While beta-secretase is a classical aspartyl protease, gamma-secretase activity is associated with a high molecular weight complex. One of the complex components, which is critically required for gamma-secretase activity is nicastrin (NCT). Here we investigate the assembly of NCT into the gamma-secretase complex.', 'Maturation of exogenous NCT, gamma-secretase complex formation and proteolytic function was then investigated. This revealed that the cytoplasmic tail of NCT is dispensable for gamma-secretase complex assembly and function. In contrast, the authentic TMD of NCT is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex.', 'This revealed that the cytoplasmic tail of NCT is dispensable for gamma-secretase complex assembly and function. In contrast, the authentic TMD of NCT is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex.', 'While beta-secretase is a classical aspartyl protease, gamma-secretase activity is associated with a high molecular weight complex. One of the complex components, which is critically required for gamma-secretase activity is nicastrin (NCT).', 'This revealed that the cytoplasmic tail of NCT is dispensable for gamma-secretase complex assembly and function. In contrast, the authentic TMD of NCT is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. Neither soluble NCT lacking any membrane anchor nor NCT containing a heterologous TMD were inserted into the gamma-secretase complex.', 'In contrast, the authentic TMD of NCT is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. Neither soluble NCT lacking any membrane anchor nor NCT containing a heterologous TMD were inserted into the gamma-secretase complex.', 'Maturation of exogenous NCT, gamma-secretase complex formation and proteolytic function was then investigated. This revealed that the cytoplasmic tail of NCT is dispensable for gamma-secretase complex assembly and function.', 'Here we investigate the assembly of NCT into the gamma-secretase complex.', 'Co-overexpression of presenilin-1 or APH-1 abrogated gamma-secretase inhibition probably through prevention of the incorporation of CRB2 into the gamma-secretase complex.', 'This could be demonstrated also in cell-free assays, where in addition presenilin-1, the catalytic subunit of the gamma-secretase complex, was shifted out of lipid rafts.', 'In PS1(-/-)/PS2(-/-) and NCT(-/-) fibroblasts, gamma-secretase components that still remain fail to become detergent-resistant, suggesting that raft association requires gamma-secretase complex assembly.']

['Gamma-secretase is a multisubunit enzyme complex which is consists of four proteins: presenilin 1 (PS1) or presenilin 2 (PS2), nicastrin, Aph-1 and Pen-2.']

[]

Is protein M3/6 a dual specificity phosphatase?

['Involvement of the dual-specificity phosphatase M3/6 in c-Jun N-terminal kinase inactivation following cerebral ischemia in the rat hippocampus.', 'The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4\xa0h of reperfusion in rat hippocampi. ', 'This study examines the molecular mechanism underlying JNK dephosphorylation and inactivation evoked by dual-specificity phosphates following cerebral ischemia.', 'Phosphatases play a particularly important role in this respect, by tightly controlling MAPK phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins. ', 'Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK.', 'M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]. ', 'Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display highly specific inactivation of JNK/SAPK and p38 MAP kinases. ', 'We previously demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset of JNK (1).', 'the dual-specificity phosphatase M3/6', ' dual-specificity phosphatase M3/6 (DUSP8)', 'M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK ', 'the M3/6 dual-specificity phosphatase', 'M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK', 'M3/6 is a dual-specificity phosphatase selective for JNK', 'The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases.', 'Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite.', 'Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6.', 'Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters.', 'M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK.', 'M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]', 'M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK', 'Here we describe how diverse cellular stresses affect differently the stability and activity of a JNK-inactivating dual-specificity threonine-tyrosine phosphatase M3/6', 'M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]', 'Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. Analysis of a delta-like domain.', 'The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4\xa0h of reperfusion in rat hippocampi', 'Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6', 'Here we report that JIP-1 also binds the dual-specificity phosphatases MKP7 and M3/6 via a region independent of its JNK binding domain.', 'Differential regulation of M3/6 (DUSP8) signaling']

['M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs.', 'Yes. Phosphatases play a particularly important role in this respect, by tightly controlling MAPK phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins.', 'The protein M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK']

['yes']

What is the role of music therapy in coma patients.

['[Beneficial effect of preferred music on cognitive functions in minimally conscious state patients].', 'Several studies have shown that music can boost cognitive functions in normal and brain-damaged subjects. A few studies have suggested a beneficial effect of music in patients with a disorder of consciousness but it is difficult to conclude since they did not use quantified measures and a control condition/group. ', '. This new protocol suggests that preferred music has a beneficial effect on the cognitive abilities of MCS patients. ', 'This review presents an overview of the use of music therapy in neurological early rehabilitation of patients with coma and other disorders of consciousness (DOC) such as unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS). ', "The programs' content consisted of recreation and communication options, which involved activating music, videos, and basic requests, sending and receiving (listening to) text messages, and placing phone calls. ", 'Active music therapy in the rehabilitation of severe brain injured patients during coma recovery.', 'Active improvised music therapy may offer an adjuvant from of treatment in the early rehabilitation of severe brain-injured patients.', 'Our preliminary results show a significant improvement of the collaboration of the severe brain-injured patients and a reduction of undesired behaviours such as inertia (reduced psychomotor initiative) or psychomotor agitation.', "Hence, it is possible for music therapy to both establish contact with the seemingly non-responsive patient and re-stimulate the person's fundamental communication competencies and experience at the emotional, social and cognitive levels.", 'Six studies focused on the provision of multisensory stimulation or music therapy.']

['Several studies have shown that music can boost cognitive functions in patients with a disorder of consciousness but it is difficult to conclude since they did not use quantified measures and a control condition/group. Active improvised music therapy may offer an adjuvant form of treatment in the early rehabilitation of severe brain-injured patients.']

[]

Does triiodothyronine play a regulatory role in insulin secretion from pancreas?

['Our findings establish that p43 is an important regulator of glucose homeostasis and pancreatic β-cell function and provide evidence for the first time of a physiological role for a mitochondrial endocrine receptor.', 'The p43(-/-) mice had a major defect in insulin secretion both in vivo and in isolated pancreatic islets and a loss of glucose-stimulated insulin secretion.', 'We demonstrated that treatment of primary cultures of rat pancreatic islets with T3 results in augmented β-cell vitality with an increase of their functional properties.', 'Nonetheless, the insulin secretion is sensibly augmented after T3 stimulation.', 'Plasma glucose concentration of the fetal hypothyroid group during intravenous glucose tolerance test was significantly higher (p=0.003) at 5-20 min as compared to the control group, whereas plasma insulin concentration was significantly lower (p=0.012) at 5-20 min', 'Although adult offspring born from hypothyroid mothers were euthyroid, their glucose tolerance and glucose stimulated insulin secretion of islets were altered', 'hyroid hormones modulate the immune system and metabolism, influence insulin secretion', 'Only T(3) concentrations higher than 250 microM were able to decrease cell viability and proliferation rate, to increase the rate of apoptosis and to reduce glucose-induced insulin secretion.', 'Islets preincubated with glucose (3.3 mmol/l) and glucagon (1.4 mumol/l) plus theophylline (10 mmol/l), ACTH (0.11 nmol/l), bovine GH (0.46 mumol/l), prolactin (0.2 mumol/l) or tri-iodothyronine (1.0 nmol/l) have significantly lower Ca(2+)-ATPase activity than those preincubated with only 3.3 mmol glucose/l. All these hormones increased the release of insulin significantly.', 'T3 (0.2 nM) did not affect insulin secretion in the absence or presence of glucose or in the presence of secretagogues (potassium and glyceraldehyde).', "In the perfused rat pancreas, the addition of thyroxine (10 micrograms/dL) or 3,5,3'-triiodothyronine (150 ng/dL) to the perfusing medium did not affect insulin secretion.", 'The administration of thyroxine (40 micrograms/kg, s.c.) in vivo increased the plasma insulin level from 11 +/- 2 microUnits/mL (mean +/- SD) to 30 +/- 7 microUnits/mL', 'Addition of T3 to the incubation medium, significantly modified the insulin release, but its effect varied according to the glucose concentration in the medium, i.e. it enhanced the insulin release at a glucose concentration between 2 to 8 mmol/l; it has no effect at 12 mmol/glucose, and significantly inhibited the secretion of insulin in the presence of 16.6 mmol/l glucose.', 'Both T3 and T4 inhibited insulin secretion']

['YES']

['yes']

What is Contrave prescribed for?

['Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity', 'Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena.', 'Current antiobesity medications and pharmacological strategies will be reviewed.Two new antiobesity drugs - naltrexone/bupropion (Contrave) and liraglutide (Saxenda) - were approved by the US Food and Drug Administration in 2014 and join four other approved obesity medications, including phentermine/topiramate XR (Qsymia) and lorcaserin (Belviq), to form the largest number of medications available for the treatment of obesity.', 'The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants.Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA.', 'Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone.', 'Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity, and is used with lifestyle modification.', 'Naltrexone/bupropion: Contrave(R); naltrexone SR/bupropion SR.', 'Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity.', 'Naltrexone/bupropion ER (Contrave): newly approved treatment option for chronic weight management in obese adults.', ' The use of synergies of anti-obesity drugs with different mechanisms of action is an effective approach for developing new combined pharmaceutical compositions (Contrave®', 'Oral naltrexone extended-release/bupropion extended-release (naltrexone ER/bupropion ER; Contrave(®), Mysimba(™)) is available as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial body mass index (BMI) of ≥ 30 kg/m(2) (i.e. obese) or a BMI of ≥ 27 kg/m(2) (i.e. overweight) in the presence of at least one bodyweight-related comorbidity, such as type 2 diabetes mellitus, hypertension or dyslipidaemia. ', 'naltrexone/bupropion (NB32 or Contrave®)']

['Contrave(?) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity', 'Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity', 'Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity.']

['Obesity']

What is the clinical value of MammaPrint?

['In the intermediate-risk subgroup, the 70-gene signature could be useful to decide in elderly patients whether they may benefit from adjuvant chemotherapy or not.', 'Adjuvant assessment tools for prognosis and prediction of treatment benefit, including Adjuvant! Online, the St Gallen Consensus, Oncotype DX(®) and MammaPrint(®), aid clinical decision making', 'The 70-gene MammaPrint prognosis profile accurately identified Japanese breast cancer patients at low risk of developing recurrences. In fact, 100% of the individuals in the low-risk category remained metastasis-free for the duration of the observation period.', 'he probability of distant metastasis-free survival at five years was 100% for the low-risk group and 94% for the high-risk group.', 'The 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy.', 'The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions', 'A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy.', 'The EWG found adequate evidence to characterize the association of MammaPrint with future metastases, but inadequate evidence to assess the added value to standard risk stratification, and could not determine the population to which the test would best apply.', 'he EWG found no evidence regarding the clinical utility of the MammaPrint and Quest H:I Ratio tests, and inadequate evidence regarding Oncotype DX. These technologies have potential for both benefit and harm', 'MammaPrint, an oligonucleotide microassay performed on fresh-frozen tumor samples, analyzes the expression of 70 genes. Studies have found that MammaPrint allows young patients (<61 years) with early-stage breast cancer to be categorized as having a high or low risk of distant metastasis. High-risk patients may then be managed with more aggressive therapy.']

['MammaPrint has a prognostic value for distant metastasis and death, as well as predictive value for response to adjuvant chemotherapy in patients with breast cancer. However, the EGAPP Working Group found no evidence regarding the clinical utility of the MammaPrint.']

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What is the effect of nocodazole cell treatment?

['antimitotic SAC-inducing agents (i.e., nocodazole', 'spindle assembly checkpoint (SAC)', 'Cells can also be enriched in mitosis using nocodazole', ' escape of metaphase I arrest induced by nocodazole treatment ', ' the treatment of CD4+T-cells with nocodazole, which disrupts the microtubular network,', 'nocodazole-triggered mitotic arrest.']

['Nocodazole trigger mitotic arrest.']

['Mitotic arrest']

What colonoscopy findings have been reported in autism

['Autistic enterocolitis: fact or fiction?', 'There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls.', 'Intestinal mucosal pathology, characterized by ileo-colonic lymphoid nodular hyperplasia (LNH) and mild acute and chronic inflammation of the colorectum, small bowel and stomach, has been reported in children with autistic spectrum disorder (ASD)', 'One hundred and forty-eight consecutive children with ASD (median age 6 years; range 2-16; 127 male) with gastrointestinal symptoms were investigated by ileo-colonoscopy.', 'Ileo-colonic LNH is a characteristic pathological finding in children with ASD and gastrointestinal symptoms, and is associated with mucosal inflammation. Differences in age at colonoscopy and diet do not account for these changes. The data support the hypothesis that LNH is a significant pathological finding in ASD children.', 'Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms', 'Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.', " Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one)", 'A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.', 'Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%)']

['Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls.']

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Is invasion and metastasis one of the hallmarks of cancer?

['The pathogenesis of MM involves the accumulation of extensive cytogenetic changes, as well as cancer-related phenotypic alterations that facilitate tumor cell survival, invasion and metastasis. This review presents current knowledge regarding the biological characteristics of this disease that are linked to the so-called hallmarks of cancer.']

['Yes, invasion and metastasis are one of the so-called hallmarks of cancer.']

['yes']

Are integrins part of the extracellular matrix?

['Several constituents of the ECM provide adhesive cues, which serve as binding sites for cell trans-membrane receptors, such as integrins.', 'We also determined that blocking β1integrins, the major class of receptors for all ECM proteins tested,', 'Here, we elucidate a cross-scale mechanism for tissue assembly and ECM remodeling involving Cadherin 2, the ECM protein Fibronectin, and its receptor Integrin α5. ', 'due to the diverse functions and variable expression of proteoglycans, matrix proteins, and integrins, it is rather difficult to identify a comprehensive therapeutic target among ECM components.', 'Integrin-dependent cell-extracellular matrix (ECM) adhesion is a determinant of spindle orientation.', 'The extracellular matrix component periostin is a secreted protein that functions as both a cell attachment protein and an autocrine or paracrine factor that signals through the cell adhesion molecule integrins αvβ3 and αvβ5. ', 'Integrin receptors connect the extracellular matrix to the cell cytoskeleton to provide essential forces and signals. ', ' the integrin, talin, and actin filament form a linear complex of which both ends are typically anchored to the extracellular matrices via integrins.', 'Integrins, a central family of cellular ECM receptors, have been implicated in these processes but their specific role in ES cell self-renewal remains unclear.', 'Attachment to the extracellular matrix is mediated by a complex of adhesion proteins, including integrins, signaling molecules, actin and actin-binding proteins, and scaffolding proteins.', 'Beta 1 integrin binding plays a role in the constant traction force generation in response to varying stiffness for cells grown on mature cardiac extracellular matrix.']

['Yes, \tintegrins are a central family of extracellular matrix receptors.']

['yes']

Which are the known human transmembrane nucleoporins?

['We investigated the interplay between import receptors and the transmembrane nucleoporin Pom121', 'the transmembrane nucleoporin POM121 is critical for the incorporation of the Nup107/160 complex into new assembly sites specifically during interphase.', 'The transmembrane nucleoporin NDC1', 'NDC1 is a transmembrane nucleoporin that is required for NPC assembly and nucleocytoplasmic transport.', 'The only protein known to localize to and be important in the assembly of both of these yeast structures is the integral membrane protein, Ndc1p. However, no homologues of Ndc1p had been characterized in metazoa. Here, we identify and analyze NDC1 homologues that are conserved throughout evolution. We show that the overall topology of these homologues is conserved. Each contains six transmembrane segments in its N-terminal half and has a large soluble C-terminal half of approximately 300 amino acids.', 'Although it is not known whether vertebrate NDC1 protein localizes to nuclear pores like its yeast counterpart, the human homologue contains three FG repeats in the C-terminus, a feature of many nuclear pore proteins.', 'we bring together data from another study to demonstrate that the human homologue of NDC1 is the known inner nuclear membrane protein, NET3.', 'The conserved transmembrane nucleoporin NDC1', 'we characterize vertebrate NDC1--a transmembrane nucleoporin conserved between yeast and metazoans', 'gp210 is a major constituent of the nuclear pore complex (NPC) with possible structural and regulatory roles. It interacts with components of the NPC via its C-terminal domain (CTD), which follows a transmembrane domain and a massive ( approximately 200 kDa) N-terminal region that resides in the lumen of the perinuclear space.', 'The membrane-spanning glycoprotein gp210 is a major component of the nuclear pore complex. This nucleoporin contains a large cisternal N-terminal domain, a short C-terminal cytoplasmic tail, and a single transmembrane segment.', 'We propose that gp210 is organized into the pore membrane as a large array of gp210 dimers that may constitute a luminal submembranous protein skeleton.', 'Patients with primary biliary cirrhosis (PBC) frequently produce autoantibodies against gp210, an integral glycoprotein of the nuclear pores. this protein consists of three main domains: a large glycosylated lumenal domain, a single hydrophobic transmembrane segment and a short cytoplasmic tail.', 'Patients with primary biliary cirrhosis frequently develop autoantibodies directed to gp210, a major glycoprotein of the nuclear pore complex. This protein contains a large glycosylated cisternal domain, a single transmembrane segment, and a short cytoplasmic tail.', 'Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210', 'Patients with primary biliary cirrhosis (PBC) frequently have autoantibodies against a 210-kD integral glycoprotein of the nuclear envelope pore membrane. This protein, termed gp210, has a 1,783-amino acid amino-terminal domain located in the perinuclear space, a 20-amino acid transmembrane segment, and a 58-amino acid cytoplasmic carboxy-terminal tail.', 'We investigated the interplay between import receptors and the transmembrane nucleoporin Pom121.', 'Conversely, the transmembrane nucleoporin POM121 is critical for the incorporation of the Nup107/160 complex into new assembly sites specifically during interphase.', 'Here, we characterize vertebrate NDC1--a transmembrane nucleoporin conserved between yeast and metazoans.', 'Here, we report the solution structure of the human gp210 CTD as determined by various spectroscopic techniques.', 'Using human gp210 isolated from HeLa cells we found the lumenal domain as the major target.', 'This protein, termed gp210, has a 1,783-amino acid amino-terminal domain located in the perinuclear space, a 20-amino acid transmembrane segment, and a 58-amino acid cytoplasmic carboxy-terminal tail.', ' In vertebrate cells, GLYCOPROTEIN OF 210 kD (gp210), PORE MEMBRANE PROTEIN OF 121 kD (Pom121), and NUCLEAR DIVISION CYCLE1 (NDC1) have been identified as integral pore membrane proteins (Cronshaw et al., 2002). ']

['Transmembrane nucleoporins (NUPs) are integral membrane components of the eukaryotic nuclear pore, playing an important role in the Nuclear Pore Complex (NPC) assembly. Even though the NPC is a conserved feature of all eukaryotes, different lineages possess some distinct transmembrane NUP subunits. Currently, four human transmembrane NUPs have been characterized, namely: NDC1 (also known as TMEM48 or NET3 or hNDC1), POM121 (also known as Nup121), GP210 (also known as Nuclear pore membrane glycoprotein 210 or Nuclear envelope pore membrane protein POM 210, POM210 or Nup210) and TMEM33 (or DB83).']

['NDC1', 'TMEM48', 'NET3', 'hNDC1', 'POM121', 'Nup121', 'GP210', 'Nuclear pore membrane glycoprotein 210', 'Nuclear envelope pore membrane protein POM 210', 'POM210', 'Nup210', 'TMEM33', 'DB83']

Which antiepileptic drug is most strongly associated with spina bifida?

['The teratogenicity of antiepilepsy drug valproic acid (VPA) mostly is found in genetic and somatic levels, causing teratogenesis involving neurotubular defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta.', 'The summary odds ratio estimate for the association between valproic acid and spina bifida was 11.9 (95% uncertainty interval (UI): 4.0-21.2); for valproic acid and cleft palate 5.8 (95% UI: 3.3-9.5); for carbamazepine and spina bifida 3.6 (95% UI: 1.3-7.8); and for carbamazepine and cleft palate 2.4 (95% UI: 1.1-4.5) in the United States.', 'Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. ', 'Valproic acid, a drug commonly used to treat seizures and other psychiatric disorders, causes neural tube defects (NTDs) in exposed fetuses at a rate 20 times higher than in the general population. Failure of the neural tube to close during development results in exencephaly or anencephaly, as well as spina bifida.', 'Associations were found for spina bifida with valproic acid. ', 'Fetal exposure to valproic acid or carbamazepine increases the risk of neural tube defect (NTD)', 'Women with epilepsy giving birth during 1973 to 1991 were identified by record linkage of Swedish health registries. Among 3,625 identified infants, 9 had spina bifida. A nested case-control study was performed, comparing drugs used in early pregnancy in the 9 cases and in 18 controls, matched for year of delivery, maternal age, and parity. Six of the spina bifida mothers had used carbamazepine and two had used valproic acid. Among the controls, 5 women used carbamazepine and one valproic acid. There is an apparent excess risk for spina bifida after use of either of these two drugs, but it is not statistically significant when the analysis is restricted to drug-using women. T', 'A significant association was seen between maternal use of valproic acid and spina bifida, and a weaker, non-significant one between carbamazepine and spina bifida.', 'A statistically significant association between Spina Bifida and Valproic Acid (odds ratio 22.7; Fisher p value = 0.0364) was observed: no other anticonvulsant tested showed any association with any type of malformation.']

['Phenytoin is not used in pregnancy as it is associated with a severe fetal deformation. From the other anticonvulsants most studies report the higher association between use during pregnancy and spin bifida to occur with Valproate.']

['Valproate']

List Pentalogy of Fallot.

['Pentalogy of Fallot (POF) is a rare form of congenital heart disease characterized by the association of Tetralogy of Fallot (TOF) with an atrial septal defect (ASD).', 'Additionally, an atrial septal defect was found on necropsy, resulting in the final diagnosis of Tetralogy of Fallot with an atrial septal defect (a subclass of Pentalogy of Fallot).', 'Pentalogy of Fallot is a rare cyanotic congenital heart disease characterized by biventricular origin of the aorta above a large ventricular septal defect, obstruction of the pulmonary outflow, right ventricular hypertrophy (tetralogy of Fallot), and an atrial septal defect. ', "Postmortem examination of the ram's heart showed a pentalogy of Fallot, consisting of a pulmonic stenosis, a ventricular septal defect, an overriding aorta, a right ventricular hypertrophy and a patent foramen ovale.", 'Additionally, an atrial septal defect was found on necropsy, resulting in the final diagnosis of Tetralogy of Fallot with an atrial septal defect (a subclass of Pentalogy of Fallot).', 'Pentalogy of Fallot is a rare cyanotic congenital heart disease characterized by biventricular origin of the aorta above a large ventricular septal defect, obstruction of the pulmonary outflow, right ventricular hypertrophy (tetralogy of Fallot), and an atrial septal defect.', 'Based on these findings, the dog was diagnosed as a case of tetralogy of Fallot with atrial septal defect (pentalogy of Fallot).', 'the dog was diagnosed as a case of tetralogy of Fallot with atrial septal defect (pentalogy of Fallot).', 'In conclusion, whenever the diagnosis pentalogy of fallot is suspected, a multidisciplinary approach is essential. Pentalogy of fallot; Overriding Aorta; Ventricular Septal Defect; Atrial Septal Defect; Pulmonary Atresia; Doppler Echocardiography.', 'resulting in the final diagnosis of Tetralogy of Fallot with an atrial septal defect (a subclass of Pentalogy of Fallot).', 'Pentalogy of Fallot (POF) is a rare form of congenital heart disease characterized by the association of Tetralogy of Fallot (TOF) with an atrial septal defect (ASD).', 'In conclusion, whenever the diagnosis pentalogy of fallot is suspected, a multidisciplinary approach is essential.Pentalogy of fallot; Overriding Aorta; Ventricular Septal Defect; Atrial Septal Defect; Pulmonary Atresia; Doppler Echocardiography.']

['Pentalogy of Fallot consists of a pulmonic stenosis, a ventricular septal defect, an overriding aorta, a right ventricular hypertrophy and a patent foramen ovale.']

['pulmonic stenosis', 'ventricular septal defect', 'overriding aorta', 'right ventricular hypertrophy', 'patent foramen ovale']

How does cotranscriptional splicing impact the regulation of gene expression in eukaryotes?

['[", as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre-mRNA target sites but also on transcription-associated features such as protein recruitment to the transcribing machinery and elongation kinetics.", "recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms", "hese span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks.", "Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well", "Moreover, splicing was found to be necessary for the proper \'writing\' of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure.", "These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications.", "Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing.", "upporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns", "Moreover, the rate of transcription elongation has been linked to alternative splicing.", "ere we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide", "We recently showed that cotranscriptional splicing occurs efficiently in Drosophila,", "In recent years it became apparent that splicing is predominantly cotranscriptional", "To determine the prevalence of cotranscriptional splicing in Drosophila, we sequenced nascent RNA transcripts from Drosophila S2 cells as well as from Drosophila heads. Eighty-seven percent of the introns assayed manifest >50% cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced poorly or slowly, with \\u223c3% being almost completely retained in nascent pre-mRNA.", "We estimate that > or =90% of endogenous yeast splicing is posttranscriptional, consistent with an analysis of posttranscriptional snRNP-associated pre-mRNA.", "Notably, the topoisomerase I inhibitor camptothecin, which stalls elongating Pol II, increased cotranscriptional splicing factor accumulation and splicing in parallel. This provides direct evidence for a kinetic link between transcription, splicing factor recruitment and splicing catalysis.", "Recent evidence indicates that transcriptional elongation and splicing can be influenced reciprocally: Elongation rates control alternative splicing and splicing factors can, in turn, modulate pol II elongation.", "The presence of transcription factors in the spliceosome and the existence of proteins, such as the coactivator PGC-1, with dual activities in splicing and transcription can explain the links between both processes and add a new level of complexity to the regulation of gene expression in eukaryotes."]']

Cotranscriptional splicing impacts the regulation of gene expression in eukaryotes by influencing splicing factor recruitment, splicing catalysis, and the balance between transcription and splicing. It is a complex process that involves interactions between transcription-associated features, chromatin structure, and RNA polymerase II elongation rates, ultimately affecting the splicing decisions and patterns of gene expression.

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Is there evidence that tomato juice lowers cholesterol levels?

['The hypocholesterolemic effect of tomato juice has been investigated in an intervention study with rats, along with the possible inhibition effect of bioactive tomato compounds binding to the HMGCR enzyme.', 'The molecular modelling showed that components of tomato can bind to the active site of the enzyme and compete with the ligand HMGCoA. Lycopene, from tomato juice, accumulates in the liver and can inhibit the activity of the rate-limiting enzyme of cholesterol biosynthesis, HMGCR.', ' Juice consumption significantly improved resistance of LDL+VLDL-C to Cu(2+)-mediated oxidation (P = 0.039), HDL-C (47.3 ± 15.8 to 51.7 ± 14.8 mg/dL, P<0.001), and the ratio of total-C/HDL-C (4.25 ± 1.59 to 3.63 ± 1.16, P<0.001) at 8 wk.', 'RESULTS: Intervention with the enriched juice had no effect on the lipid profile, and serum levels of triglycerides and cholesterol (total, LDL, and HDL) remained unchanged. ', 'Women consuming ≥10 compared with<1.5 servings/wk of tomato-based food products had significant but clinically modest improvements in total cholesterol (TC) (5.38 vs. 5.51 mmol/L; P = 0.029), the TC:HDL cholesterol ratio (4.08 vs. 4.22; P = 0.046), and hemoglobin A1c (5.02 vs. 5.13%; P<0.001) in multivariable models. Considering clinical cutpoints, women consuming ≥10 compared with<1.5 servings/wk were 31% (95% CI = 6%, 50%), 40% (95% CI = 13%, 59%), and 66% (95% CI = 20%, 86%) less likely to have elevated TC (≥6.21 mmol/L), LDL cholesterol (≥4.14 mmol/L), and hemoglobin A1c (≥6%), respectively. ', 'In conclusion, women consuming ≥10 compared with<1.5 servings/wk of tomato-based food products had clinically modest but significant improvements in TC, the TC:HDL cholesterol ratio, and hemoglobin A1c but not other coronary biomarkers.', 'Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.', 'Total cholesterol concentration was reduced by 5.9 (sd 10) % (P = 0.002) and LDL cholesterol concentration by 12.9 (sd 17.0) % (P = 0.0002) with the high tomato diet compared to the low tomato diet.', 'In conclusion, a high dietary intake of tomato products had atheroprotective effects, it significantly reduced LDL cholesterol levels, and increased LDL resistance to oxidation in healthy normocholesterolaemic adults.', 'Total, LDL and HDL cholesterol were significantly lower in the intervention group after the intake of tomato juice', 'Total cholesterol concentration was reduced by 5.9 (sd 10) % (P = 0.002) and LDL cholesterol concentration by 12.9 (sd 17.0) % (P = 0.0002) with the high tomato diet compared to the low tomato diet. ']

['Yes, there is evidence to suggest that tomato juice (and other tomato products) can decrease cholesterol concentrations. It was shown that tomatoes inhibit cholesterol biosynthesis.']

['yes']

Is flibanserin effetive for Hypoactive Sexual Desire Disorder?

['Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder.', 'Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire.', 'Flibanserin is a novel, non-hormonal drug for the treatment of HSDD in pre- and postmenopausal women, although the application submitted to the U.S. Food and Drug Administration by Sprout Pharmaceuticals is only for premenopausal women.', 'CONCLUSIONS: In naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated.', 'INTRODUCTION: Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that has been developed for the treatment of hypoactive sexual desire disorder in women', 'BACKGROUND: Flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A) antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder (HSDD). ', 'Hypoactive sexual desire disorder (HSDD) is the most commonly described form of female sexual dysfunction. There is currently no pharmacological therapy approved to treat HSDD, and therefore, there is an unmet medical need for the development of efficacious treatment alternatives. Flibanserin is a novel, non-hormonal drug for the treatment of HSDD in pre- and postmenopausal women, although the application submitted to the U.S. ', 'Sexual function adverse events across flibanserin groups were generally comparable to placebo.Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.']

['Yes, flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A) antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder.']

['yes']

Which gene is mutated in the Karak syndrome?

['Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome', 'Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. ', 'BACKGROUND: PLA2G6 is the causative gene for infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome. ', 'PLA2G6 is the causative gene for infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome.', 'Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome.', 'Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment.', 'Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome.', 'We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome.', 'We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. ', 'Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. ', 'Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment.', 'Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome.', 'We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome.']

['PLA2G6 gene is mutated in the Karak syndrome.']

['PLA2G6']