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What fruit causes Jamaican vomiting sickness?
['The aril of the unripe fruit has high concentrations of HGA, the cause of Jamaican vomiting sickness, which is very often fatal.', 'In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. ', 'Ackee apple fruit is a native fruit to Jamaica and some parts of west Africa. Its toxicity known as "Jamaican vomiting sickness" dates back to the nineteenth century.', 'Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks.', 'An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated.', 'Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks.', 'The aril of the unripe fruit has high concentrations of HGA, the cause of Jamaican vomiting sickness, which is very often fatal.', 'In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit.', 'Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome.', 'Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks', 'An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated', 'Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome', 'Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome. ', 'An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated. ', 'In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit.']
['Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks.']
['Ackee fruit']
Which properties of the mRNA does N6-methyladenosine (m6A) affect?
['N(6)-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate.', 'm(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. ', 'Recent discoveries of reversible N(6)-methyladenosine (m(6)A) methylation on messenger RNA (mRNA) and mapping of m(6)A methylomes in mammals and yeast have revealed potential regulatory functions of this RNA modification', 'Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps and their classification into WTAP-dependent and -independent sites. WTAP-dependent sites are located at internal positions in transcripts, topologically static across a variety of systems we surveyed, and inversely correlated with mRNA stability, consistent with a role in establishing "basal" degradation rates.', 'Methylations of adenosine residues (m6A) in pre-mRNA are important for formation of late simian virus 40 mRNAs', 'The data argues for a role of internal m6A moieties in modulating the processing-linked transport of mRNA from the nucleus to the cytoplasm of nontransformed cells. ', 'N6-Methyladenosine (m6A) residues, which are found internally in viral and cellular mRNA populations at the sequences Apm6ApC and Gpm6ApC, have been proposed to play a role in mRNA processing and transport.', 'The role of Fat Mass and Obesity-associated protein (FTO) and its substrate N6-methyladenosine (m6A) in mRNA processing and adipogenesis remains largely unknown.', 'N6-methyladenosine (m6A) is a common modification of mRNA with potential roles in fine-tuning the RNA life cycle.', 'The results of that study and of experiments using inhibitors of methylation suggest that m6A might be involved in mRNA processing events. ', 'Previous studies suggested that m6A affects the efficiency of mRNA processing or transport, although the mechanism by which this occurs is not known. ', ' The methylation of internal adenosine residues in eukaryotic mRNA, forming N6-methyladenosine (m6A), is catalyzed by a complex multicomponent enzyme. Previous studies suggested that m6A affects the efficiency of mRNA processing or transport, although the mechanism by which this occurs is not known.', 'Previous studies suggested that m6A affects the efficiency of mRNA processing or transport, although the mechanism by which this occurs is not known. As a step toward better understanding the mechanism and function of this ubiquitous posttranscriptional modification, we have shown that HeLa mRNA (N6-adenosine)-methyltransferase requires at least two separate protein factors, MT-A and MT-B, and MT-A contains the AdoMet binding site on a 70-kDa subunit (MT-A70).', 'The methylation of internal adenosine residues in eukaryotic mRNA, forming N6-methyladenosine (m6A), is catalyzed by a complex multicomponent enzyme. Previous studies suggested that m6A affects the efficiency of mRNA processing or transport, although the mechanism by which this occurs is not known.']
['N(6)-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate. m6A predominantly and directly reduces mRNA stability.']
['mRNA stability']
Is selumetinib effective in thyroid cancer?
['A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours.', 'BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor).', 'Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of>6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma.', 'CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.', 'MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro.', 'Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC.', 'The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). ', 'BACKGROUND AND AIM: Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer.', 'CONCLUSIONS: Compared with current chemotherapy, selumetinib has modest clinical activity as monotherapy in patients with advanced cancer, but combinations of selumetinib with cytotoxic agents in patients with BRAF or KRAS mutations hold great promise for cancer treatment.', 'Selumetinib may be an effective redifferentiating agent and could be used within several years.', 'Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.', 'METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. ', 'Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations).', 'CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. ', 'ECENT FINDINGS: For patients with advanced differentiated thyroid cancers, sorafenib, selumetinib, pazopanib and sunitinib have been investigated with promising results. ', 'Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer.', 'Selumetinib may be an effective redifferentiating agent and could be used within several years.', 'Here, selumetinib targets the mitogen-activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the (V600E)BRAF mutation.', 'CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. ']
['Yes, selumetinib was shown to be effective treatment for thyroid cancer. Selumetinib may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer. Clinical efficacy of selumetinib was also investigated in other solid tumors.']
['yes']
Is cocaine use associated with increased risk for intracerebral hemorrhage?
['Stroke in crack-cocaine abusers is increasingly recognized.', 'There were significant differences between crack-cocaine cases and controls in age (48.7 years vs. 55 years) (P = 0.0001), male gender (65.6% vs. 40.9%) (odds ratios, OR = 1.64, 95% CI 1.22-2.21), arterial hypertension (61.1% vs. 83.9%) (OR = 0.30, 95% CI 0.15-0.60), hypercholesterolemia (18.7% vs. 68.5%) (OR = 0.10, 95% CI 0.05-0.21), diabetes (20.9% vs. 41.9%) (OR = 0.36, 95% CI 0.19-0.70), cigarette smoking (70.6% vs. 29%) (OR = 5.86, 95% CI 3.07-11.20), ischemic stroke (61.3% vs. 79.6%) (OR = 0.40, 95% CI 0.21-0.78), and intracerebral hemorrhage (33.3% vs. 17.2%) (OR = 3.03, 95% CI 1.53-6.00).', 'Intracerebral hemorrhage (ICH) is a well-recognized complication of recreational cocaine use.', 'ICH is more common in those currently using cocaine perhaps because of acute spikes in blood pressure.', 'Intracerebral hemorrhage in cocaine users.', 'Cocaine is a cause of intracerebral hemorrhage (ICH), but there are no large studies that have characterized the location, pathology, and outcome of patients with cocaine-associated ICH', 'Aneurysmal SAH may be largely a preventable disease among the young and middle-aged because several prevalent risk factors can be modified by medication (eg, hypertension) or behavioral change (eg, cigarette smoking, cocaine use).', 'Cocaine use and hypertension are major risk factors for intracerebral hemorrhage in young African Americans.', 'Cocaine use (OR 6.1, 95% CI 3.3-11.8), hypertension (OR 5.2, 95% CI 3.2-8.7) and alcohol use (OR 1.9, 95% CI 1.1-3.3) were independently associated with increased risk for ICH', 'Cocaine use has been temporally associated with neurovascular complications, including the rupture of intracerebral aneurysms.', 'Chronic cocaine use appears to predispose patients who harbor incidental neurovascular anomalies to present at an earlier point in their natural history than similar non-cocaine users.', 'Acute intoxication with either cocaine or methamphetamine may contribute to formation and rupture of a berry aneurysm by causing transient hypertension and tachycardia.', 'Although the exact mechanism by which berry aneurysms form remains undetermined, research indicates that propagation and rupture of the aneurysm are aggravated by hypertension and tachycardia, both of which are pharmacologic side effects of cocaine and methamphetamine', 'The high frequency of hypertension, hypertensive intracerebral hemorrhage, and lacunar infarction among young black patients with stroke suggests accelerated hypertensive arteriolar damage, possibly due to poor control of hypertension.', 'Cocaine induced intracerebral hemorrhage: analysis of predisposing factors and mechanisms causing hemorrhagic strokes.', 'hypertensive cardiovascular disease (HCVD) was significantly higher in persons with intracerebral hemorrhage than in those with aneurysm rupture. Our findings suggest that HCVD predisposes to cocaine induced intracerebral hemorrhage', 'Intracerebral hemorrhage associated with cocaine abuse.', 'n view of the present epidemic of cocaine abuse, cocaine toxicity should be considered in the differential diagnosis of intracerebral hemorrhage', 'An increase in cocaine abuse by pregnant women has been associated with a range of maternal/fetal cardiovascular complications. Intracerebral hemorrhage has been reported as a cocaine-related complication,', '13 patients were identified with neurologic deficits attributable to the use of cocaine. Ischemic manifestations were the most frequent, occurring in seven (54%) patients, with a mean age of 34.2 years. Three (23%) patients had subarachnoid hemorrhage, and three (23%) had intracerebral hemorrhage.', 'OBJECTIVE: An association between cocaine use and stroke has been reported, but few studies have examined cocaine-related neurovascular disease using modern stroke diagnostic techniques.', 'OBJECTIVE: Cocaine is a cause of intracerebral hemorrhage (ICH), but there are no large studies that have characterized the location, pathology, and outcome of patients with cocaine-associated ICH.', 'Because cocaine and ecstasy abuse has been reported to be a risk factor for ischemic stroke and fatal brain hemorrhage, thromboaspiration may be an alternative therapy to thrombolysis.', 'CONCLUSIONS: Aneurysmal SAH may be largely a preventable disease among the young and middle-aged because several prevalent risk factors can be modified by medication (eg, hypertension) or behavioral change (eg, cigarette smoking, cocaine use).', 'OBJECTIVE: The use of cocaine has been increasingly associated with cerebrovascular disease specially in young adults.', 'Cocaine hydrochloride causes mainly intracerebral and subarachnoidal bleeding, while crack (freebase) causes intracranial hemorrhage and ischemic infarctions with equal frequency.', 'CONCLUSIONS: These findings implicate cocaine use as a significant risk factor for fatal brain hemorrhage and may explain, in part, the increased incidence of hemorrhagic stroke in some drug-using cohorts.', 'Abuse of amphetamine, cocaine and related compounds has become an important risk factor for intracerebral haemorrhage in young adults.', 'Strokes occurred within 3 h of cocaine use in 15 patients with infarcts and 17 with hemorrhages.', 'We present three cases of intracerebral hemorrhage which occurred after cocaine consumption (intranasal route in two cases and intravenous route in one case).']
['Cocaine use is associated with increased incidence of intracranial hemorrhages most likely due to pressure increases.']
['yes']
What is the name for anorexia in gymnasts?
['Elite Rhythmic Gymnasts (RGs) constitute a unique metabolic model and they are prone to developing Anorexia Athletica.', 'We studied 13 female juvenile elite gymnasts with anorexia athletica (AA']
['Anorexia athletica']
['Anorexia Athletica']
How are CRM (cis-regulatory modules) defined?
['Eukaryotic genes are often regulated by several transcription factors whose binding sites are tightly clustered and form cis-regulatory modules.', 'In many species, especially higher eukaryotes, transcription factor binding sites tend to occur as homotypic or heterotypic clusters, also known as cis-regulatory modules', 'This conserved sequence has therefore been proposed to act as a long-range, cis-acting regulator of limb-specific Shh expression. ', 'The conserved upstream sequence can activate gene expression from basal promoters in the brain vesicle, although it requires additional cis-regulatory sequences to fully activate the CNS-specific gene expression.', 'The genomic instructions used to regulate development are encoded within a set of functional DNA elements called cis-regulatory modules ', 'Several tools allow to detect significant co-occurrences of closely located binding sites (cis-regulatory modules, CRMs). ', 'However, studies on the cis-regulatory sequences mediating the synergistic effects of these transcription factors are complicated by the limited knowledge of notochord genes and cis-regulatory modules (CRMs) that are directly targeted by both.', 'The identification of transcription factor binding sites (TFBSs) and cis-regulatory modules (CRMs) is a crucial step in studying gene expression, but the computational method attempting to distinguish CRMs from NCNRs still remains a challenging problem due to the limited knowledge of specific interactions involved.', 'In eukaryotes, transcriptional regulation is usually mediated by interactions of multiple transcription factors (TFs) with their respective specific cis-regulatory elements (CREs) in the so-called cis-regulatory modules (CRMs) in DNA.', 'The transcriptional regulation of a metazoan gene depends on the cooperative action of multiple transcription factors that bind to cis-regulatory modules (CRMs) located in the neighborhood of the gene.', 'Dynamic in vivo binding of transcription factors to cis-regulatory modules of cer and gsc in the stepwise formation of the Spemann-Mangold organizer.', 'We also identified potential cis-regulatory modules (CRMs) defined as clusters of conserved TFBSs in the entire mouse genome.']
['Eukaryotic genes are often regulated by several transcription factors whose binding sites are tightly clustered and form cis-regulatory modules.', 'In many species, especially higher eukaryotes, transcription factor binding sites tend to occur as homotypic or heterotypic clusters, also known as cis-regulatory modules. Several tools allow to detect significant co-occurrences of closely located binding sites (cis-regulatory modules, CRMs).', 'Several tools allow to detect significant co-occurrences of closely located binding sites (cis-regulatory modules, CRMs). ', 'CisMiner can be queried for the results presented in this work and can also perform a customized cis-regulatory module prediction on a query set of transcription factor binding sites provided by the user. In many species, especially higher eukaryotes, transcription factor binding sites tend to occur as homotypic or heterotypic clusters, also known as cis-regulatory modules. Eukaryotic genes are often regulated by several transcription factors whose binding sites are tightly clustered and form cis-regulatory modules. Our web server is available at http://creme.dcode.org.']
[]
Where is the histone variant CENPA preferentially localized?
['centromere protein A (CENPA),', 'Centromere activity of the alphoid YAC was suppressed at ectopic locations on the host chromosome, as indicated by the absent or reduced assembly of CENP-A and -C.', 'Heterozygous and homozygous Cenpa-GFP fusion-protein mouse mutants, generated through targeted insertion of the green fluorescent protein (GFP) gene into the mouse Cenpa gene locus, show specific localized fluorescence at all the centromeres.', 'Co-immunoprecipitation assay demonstrates interaction between PARP-2 and its functional homolog PARP-1, constitutive centromere proteins Cenpa and Cenpb, and spindle checkpoint protein Bub3, but not with a third constitutive centromere protein Cenpc.', 'Here we investigated the interaction of this protein with, and poly(ADP-ribosyl)ation of, three constitutive centromere proteins, Cenpa, Cenpb, and Cenpc, and a spindle checkpoint protein, Bub3', 'The evidence is consistent with the proposal of a critical epigenetic function for CENP-A in marking a chromosomal region for centromere formation', 'CENPA is a member of the histone H3-like proteins and is thought to replace histone H3 in centromeric nucleosomes. CENPC is a DNA-binding protein that is located at the inner kinetochore plate of active mammalian centromeres.', 'ENPA/Cse4 assembles centromeric chromatin on diverse DNA', 'constitutive kinetochore proteins such as CENPA', 'A specific histone H3 variant, CENPA, replaces conventional histone H3 and together with centromere-specific-DNA-binding factors directs the assembly of active kinetochores']
['Centromere protein A (Cenpa for mouse, CENP-A for other species) is an essential histone H3-like protein that localizes to the centromeric region of eukaryotic chromosomes, where it replaces conventional histone H3 and together with centromere-specific-DNA-binding factors directs the assembly of active kinetochores.', 'THe histone variant CENPA is preferentially located at Centromeric chromatin']
['Centromeres', 'CENPA is preferentially localized in eukaryotic centromeres']
What molecule is targeted by brodalumab?
['BACKGROUND: Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis.', 'METHODS: We reviewed the results of the phase II clinical trials for the anti-IL-17 agents secukinumab, ixekizumab and brodalumab in order to assess the efficacy and safety profile of each agent.', 'These include the IL-17 antagonists, secukinumab, brodalumab and ixekizumab; the IL-23 antagonists, guselkumab and tildrakizumab; and the oral small molecule therapies, tofacitinib and apremilast. ', 'RECENT FINDINGS: New drugs that are designed to inhibit steps in this pathway, the IL12/IL23 inhibitor, ustekinumab, the IL17A inhibitors secukinumab and ixekizumab, the IL17A receptor inhibitor, brodalumab, and the IL23 inhibitors guselkumab and tildrakizumab, have demonstrated significant effectiveness in treating these diseases, particularly psoriasis, psoriatic arthritis and ankylosing spondylitis.', 'Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.', 'Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.', 'Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma.', 'Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody.', 'The three new therapies with biologic drugs - brodalumab, secukinumab, and ixekizumab - all target the IL-17 signaling pathway. Secukinumab and ixekizumab neutralize IL-17A, while brodalumab blocks its receptor.', 'Brodalumab is a human monoclonal antibody that targets IL-17 receptor A,']
['Interleukin-17. Brodalumab is anti interleukin-17 monoclonal antibody.']
['Interleukin-17']
List the classical symptoms of the Moschcowitz syndrome (Thrombotic thrombocytopenic purpura).
['The combination of neurological symptoms, thrombocytopenia, fever, renal failure and hemolytic anemia in a patient taking ticlopidine points to a diagnosis of TTP.', 'In addition to the typical manifestations of thrombotic-thrombocytopenic purpura like thrombocytopenia, haemolysis, fever, coma and renal failure, signs of a beginning DIC could be seen in a patient after abdominal surgery. ', 'Moschcowitz syndrome or thrombotic thrombocytopenic purpura is a rare disorder with a poor prognosis. This syndrome is characterized by a microangiopathic hemolytic anemia with thrombocytopenia, neurologic symptoms and renal disease. ', "Moschcowitz's syndrome is a rare condition with poor prognosis. It is characterized by a microangiopathic haemolytic anaemia associated with thrombocytopenia, neurological symptoms and renal involvement.", 'Thrombotic thrombocytopenic purpura (TTP), in 1924 first described by Moschcowitz, is a clinically heterogeneous syndrome associated with thrombocytopenia, Coombs-negative hemolytic anemia, neurologic changes, renal impairment, and fever.', 'Thrombotic thrombocytopenic purpura (TTP), in 1924 first described by Moschcowitz, is a clinically heterogeneous syndrome associated with thrombocytopenia, Coombs-negative hemolytic anemia, neurologic changes, renal impairment, and fever', 'Thrombotic thrombocytopenic purpura (TTP, Moschcowitz disease) is characterized by thrombotic microangiopathy leading to microvascular occlusion and ischemic dysfunction of various organs including the brain', 'Severe deficiency of von Willebrand factor-cleaving protease (ADAMTS-13) activity (<5% of normal) is specific for classical thrombotic thrombocytopenic purpura (TTP), a disorder presenting with thrombocytopenia, microangiopathic haemolytic anaemia and often with organ dysfunction such as neurological symptoms, renal failure, and fever.', "In a 57-year-old female patient, who was admitted with fluctuating central neurological abnormalities and generalized purpura, was made the diagnosis of a thrombotic thrombocytopenic purpura (TTP, Moschcowitz' syndrome).", 'Thrombotic thrombocytopenic purpura (TTP) is a syndrome that occurs mainly in adults with multiorgan microvascular thrombosis consisting of thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal involvement, and fever.']
['The typical manifestations of Moschocowitz syndrome (Thrombotic-thrombocytopenic purpura) are:\n1) thrombocytopenia, \n2) haemolysis, \n3) fever, \n4) coma and \n5) renal failure.']
['thrombocytopenia', 'thrombotic microangiopathy', 'haemolysis', 'hemolytic anemia', 'fever', 'coma', 'neurological symptoms', 'renal failure']
Which software package is available for the analysis of conserved genomic loci?
['PHYLUCE is a software package for the analysis of conserved genomic loci', 'Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci.', 'PHYLUCE is a software package for the analysis of conserved genomic loci.']
['PHYLUCE is a software package for the analysis of conserved genomic loci. It identifies targeted, enriched loci from the off-target background data; aligns enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci', 'PHYLUCE is a software package for the analysis of conserved genomic loci']
['PHYLUCE']
Which is the prognostic meaning of delayed enhancement documented in patients hypertrophic cardiomyopathy?
[' It is possible to conclude that there is a high prevalence of myocardial fibrosis in hypertrophic cardiomyopathy patients with high-risk or recovered from cardiac sudden death, like those with clinical indication to implantable cardioverter -defibrillator. ', 'AF in HCM is related with myocardial fibrosis detected by DE-CMR and dilatation of the LA. ', 'Over the follow-up period, the annualized adverse cardiovascular event rate in patients with DE exceeded that in patients without DE but did not achieve statistical significance (5.5% versus 3.3%; P=0.5). ', 'Late gadolinium enhancement by CMR has prognostic value in predicting adverse cardiovascular events among HCM patients. There are significant relationships between LGE and cardiovascular mortality, heart failure death, and all-cause mortality in HCM. Additionally, LGE and SCD/aborted SCD displayed a trend toward significance. ', 'The hyperenhanced apical myocardium had a lower percentage of systolic myocardial thickening, and was associated with serious symptoms (e.g. syncope) and ventricular arrhythmias. ', 'A semi-quantitative index of DCE is a significant multivariable predictor of both clinical VT/VF and of risk for SCD and may contribute to risk assessment in borderline or controversial cases.', 'Myocardial scar imaged by CE-CMR is common in patients with HCM, and is predictive of VT. ']
['Delayed enhancement by CMR has prognostic value in predicting adverse cardiovascular events among HCM patients, and is associated with cardiovascular mortality, heart failure death, and all-cause mortality in HCM.']
['Delayed enhancement by CMR has prognostic value in predicting adverse cardiovascular events among HCM patients.']
Which is the subcellular localization of the protein angiogenin?
['Under growth conditions, ANG is located in nucleolus where it promotes ribosomal RNA (rRNA) transcription thereby stimulating cell growth. In adverse conditions, ANG is relocated to cytoplasm to promote damage repairs and cell survival. ', 'Under growth conditions, ANG undergoes nuclear translocation and accumulates in the nucleolus where it stimulates rRNA transcription', 'Under growth conditions, ANG is located in the nucleus ', 'Under stress conditions, ANG is localized to the cytoplasm and is concentrated in stress granules', 'Silencing ANG or inhibiting its nuclear translocation resulted in decreased nuclear LANA-1 and ANG levels,', ' results in loss of nuclear translocation activity in ANG mutants', 'Immunofluorescence staining was applied to investigate co-localization and nuclear translocation.', 'Recombinant angiogenin was found to mainly concentrate in the pars granulosa of the nucleus, where the protein accumulates to form ribonucleoprotein particles.', 'Identification of the nucleolar targeting signal of human angiogenin.', 'Angiogenin is endocytosed by subconfluent endothelial cells, translocated to the nucleus and accumulates in the nucleolus. ', 'Nuclear translocation of human angiogenin in cultured human umbilical artery endothelial cells is microtubule and lysosome independent.', 'Exogenous angiogenin undergoes rapid nuclear translocation in cultured human umbilical artery endothelial cells at 37 degrees C but not at 4 degrees ', 'the nuclear localization of angiogenin in proliferating endothelial cells ']
['Under growth conditions, ANG is located in nucleolus where it promotes ribosomal RNA (rRNA) transcription thereby stimulating cell growth. In adverse conditions, ANG is relocated to cytoplasm to promote damage repairs and cell survival.']
['Both nucleolar and cytoplasmic']
Does strenuous physical activity affect thyroid hormone metabolism?
['The results of the present study in a unique experimental human model of maximal exposure to altitude and physical exercise demonstrate that extreme HA and strenuous physical exercise are coupled with specific endocrine adaptations. These include increased activity of the GH/IGF-I axis and a low T(3) syndrome', "3,5,3'-triiodothyronine (T3) and T4 levels increase during strenuous exercise, and, at the end of the exercise bout, a decrease of T3 and T4 levels, with an increase in TSH during the following 4-5 days, is seen.", 'the obtained results indicate that in intense exercise, causing the rapid development of fatigue, rapid increases in serum levels of hormones of the pituitary-adrenocortical, pituitary-gonadal and pituitary-thyroid systems occur.', 'Mean levels of fasting plasma estradiol, luteinizing hormone, follicle-stimulating hormone, free thyroxine and triiodothyronine were significantly lower in AR compared to ER and SE.', "Reductions in plasma T4, T3 and T3/T4 ratio are probably due to inhibition of T4 secretion and 5'-monodeiodination with possible conversion of T4 to reverse T3 (rT3). These processes may represent a mechanism for regulation of thyroid hormone metabolism during strenuous and extended flight.", 'Strenuous endurance training seems to have minor changes on the function of the thyroid gland. Depressed T4 levels in runners may rather be due to lowered TBG levels than due to direct effect of training.', 'brief strenuous swimming or moderate bicycle exercise had minor or no effect on thyroid hormone concentrations when consideration was given to the attendant hemoconcentration.', 'thyroxine were determined in 26 men participating in a 90-km cross-country ski race, before, immediately after, and on the following days', 'Total thyroxine and free thyroxine in serum were significantly increased at the end of the race, but had returned to the pre-raced levels during the rest of the observation period.', 'There are controversial results concerning thyroid hormone metabolism during strenuous exercise in adult athletes and only scant data concerning the impact of strenuous exercise on thyroid hormone metabolism in children and adolescents.']
['YES']
['yes']
What is the role of the Ada O6-alkylguanine alkyltransferase in bacteria?
['multifunctional 39 kDa Escherichia coli Ada protein (O6-methylguanine-DNA methyltransferase) (EC 2.1.1.63), product of the ada gene', 'The Ada protein accepts stoichiometrically the alkyl group from O6-alkylguanine in DNA at the Cys-321 residue and from alkyl phosphotriester at the Cys-69 residue. This protein functions in DNA repair by direct dealkylation of mutagenic O6-alkylguanine. The protein methylated at Cys-69 becomes a transcriptional activator of the genes in the ada regulon, including its own. ', 'O6-Alkylguanine DNA-alkyltransferase (ATase) repairs toxic, mutagenic and carcinogenic O6-alkylguanine (O6-alkG) lesions in DNA', 'O6-Methylguanine is removed from DNA via the transfer of the methyl group to a cysteine acceptor site present in the DNA repair protein O6-alkylguanine-DNA alkyltransferase.', 'DNA repair by O6-alkylguanine-DNA alkyltransferases plays a major role in removing lesions responsible for GC-->AT transitions induced by CCNU, influencing their ultimate distribution with respect to sequence context.', 'alkyltransferase (ATase)', 'the ada ATase induced by exposure to low doses of a methylating agent.', 'The Escherichia coli Ada and Ogt DNA methyltransferases (MTases) are known to transfer simple alkyl groups from O6-alkylguanine and O4-alkylthymine, directly restoring these alkylated DNA lesions to guanine and thymine.', 'During exponential growth, the spontaneous rate of G:C to A:T transitions and G:C to C:G transversions was elevated about fourfold in ada ogt double mutant versus wild-type E. coli.', 'compared with the wild type, stationary populations of the MTase-deficient E. coli (under lactose selection) displayed increased G:C to A:T and A:T to G:C transitions (10- and 3-fold, respectively) and increased G:C to C:G, A:T to C:G, and A:T to T:A transversions (10-, 2.5-, and 1.7-fold, respectively).', 'ATases are able to repair O6-alkylguanine (O6-AlkG) and O4-alkylthymine (O4-AlkT) ', 'The inducible resistance to alkylation mutagenesis and killing in Escherichia coli (the adaptive response) is controlled by the ada gene.', 'The Ada protein acts both as a positive regulator of the response and as a DNA repair enzyme, correcting premutagenic O6-alkylguanine in DNA by suicidal transfer of the alkyl group to one of its own cysteine residues.', 'Forward mutations induced by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in the lacl gene of Escherichia coli were recovered from bacteria proficient (Ogt+ Ada+) and deficient (Ogt- Ada-) in O6-alkylguanine-DNA alkyltransferase activity.', 'Spontaneous mutagenesis in O6-alkylguanine-DNA alkyltransferase-proficient and -deficient (ada ogt mutants) Escherichia coli was studied in two ways: in bacteria growing in nonselective liquid medium and in bacteria resting on selective agar plates.', 'We now show by Southern analysis that the mutation involves a gross deletion covering at least the ogt and fnr genes and that no O6-alkylguanine-DNA-alkyltransferase activity is present in cell-free extracts of an ada::Tn10 derivative of these bacteria.', 'O6-Alkylguanine DNA-alkyltransferase (ATase) repairs toxic, mutagenic and carcinogenic O6-alkylguanine (O6-alkG) lesions in DNA by a highly conserved reaction involving the stoichiometric transfer of the alkyl group to the active centre cysteine residue of the ATase protein.', 'Although the human O6-alkylguanine-DNA alkyltransferase (AGT) is very sensitive to inactivation by O6-benzylguanine (BG) or 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine (5-nitroso-BP), the equivalent protein formed by the carboxyl terminal domain of the product of the Escherichia coli ada gene (Ada-C) is unaffected by these inhibitors.', 'A mutant of Bacillus subtilis defective in the constitutive activity of O6-alkylguanine-DNA alkyltransferase was isolated from a strain (ada-1) deficient in the adaptive response to DNA alkylation.', 'Mutations in the Ada O6-alkylguanine-DNA alkyltransferase conferring sensitivity to inactivation by O6-benzylguanine and 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine.', 'The protein O 6-alkylguanine-DNA alkyltransferase(alkyltransferase) is involved in the repair of O 6-alkylguanine and O 4-alkylthymine in DNA and plays an important role in most organisms in attenuating the cytotoxic and mutagenic effects of certain classes of alkylating agents.', 'O6-Alkylguanine-DNA alkyltransferase (EC 2.1.1.63) repairs O6-alkylguanine lesions in DNA.', 'Spontaneous mutagenesis in O6-alkylguanine-DNA alkyltransferase-proficient and -deficient (ada ogt mutants) Escherichia coli was studied in two ways: in bacteria growing in nonselective liquid medium and in bacteria resting on selective agar plates', 'The protein O 6-alkylguanine-DNA alkyltransferase(alkyltransferase) is involved in the repair of O 6-alkylguanine and O 4-alkylthymine in DNA and plays an important role in most organisms in attenuating the cytotoxic and mutagenic effects of certain classes of alkylating agents', 'In summary, this paper presents for the first time evidence that DNA repair by O6-alkylguanine-DNA alkyltransferases plays a major role in removing lesions responsible for GC-->AT transitions induced by CCNU, influencing their ultimate distribution with respect to sequence context.', 'Forward mutations induced by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in the lacl gene of Escherichia coli were recovered from bacteria proficient (Ogt+ Ada+) and deficient (Ogt- Ada-) in O6-alkylguanine-DNA alkyltransferase activity', 'Repair of O6-benzylguanine by the Escherichia coli Ada and Ogt and the human O6-alkylguanine-DNA alkyltransferases.', 'O6-Alkylguanine DNA-alkyltransferase (ATase) repairs toxic, mutagenic and carcinogenic O6-alkylguanine (O6-alkG) lesions in DNA by a highly conserved reaction involving the stoichiometric transfer of the alkyl group to the active centre cysteine residue of the ATase protein', 'O6-Alkylguanine-DNA alkyltransferase (EC 2.1.1.63) repairs O6-alkylguanine lesions in DNA']
['The Ada O6-methylguanine-DNA methyltransferase is a multifunctional protein, product of the ada gene. Ada functions in DNA repair by direct dealkylation of alkylated DNA lesions, such as the toxic, mutagenic and carcinogenic O6-alkylguanine (O6-AlkG) and O4-alkylthymine (O4-AlkT) which are restored to guanine and thymine. Ada accepts stoichiometrically the alkyl group from O6-alkylguanine in DNA at the Cys-321 residue and from alkyl phosphotriester at the Cys-69 residue. When methylated at Cys-69, Ada becomes a transcriptional activator of the genes in the ada regulon, including its own. The ada gene controls the inducible resistance to alkylation mutagenesis and killing (the adaptive response). Ada alkyltransferase (ATase) is induced by exposure to low doses of methylating agents. During exponential growth, Ada removes lesions responsible for G:C to A:T transitions and G:C to C:G transversions, while in stationary populations it removes lesions causing G:C to A:T and A:T to G:C transitions, and G:C to C:G, A:T to C:G, and A:T to T:A transversions. Thus, Ada protein acts both as a positive regulator of the ada response and as a DNA repair enzyme.']
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What are the reported adverse effects of topical minoxidil?
['Hypertrichosis is a well-recognized adverse effect of therapy with either oral or topical minoxidil.', 'reported increase of adverse events (additional hair growth on areas other than the scalp) with minoxidil (5%) twice daily. ', 'a case of central serous chorioretinopathy after application of topical minoxidil solution.', 'One month after the drug was discontinued, normal findings were found upon reexamination', 'The incidence of adverse effects such as pruritus or local irritation was similar in the 5% minoxidil group', 'The patients tolerated treatment with 1% topical minoxidil well without significant adverse effects.', 'An increased occurrence of pruritus, local irritation, and hypertrichosis was observed with 5% topical minoxidil versus 2% topical minoxidil and placebo.', 'Allergic contact dermatitis to topical minoxidil solution: etiology and treatment.', 'However, some patients present with complaints of pruritus and scaling of the scalp. The most common causes of these symptoms include irritant contact dermatitis, allergic contact dermatitis, or an exacerbation of seborrheic dermatitis. Patients suffering from allergic contact dermatitis may benefit from patch testing to determine the causative allergen. Among the patients we patch tested, propylene glycol was found to be the contactant in a majority of cases, not the minoxidil itself. ', 'A case of acute myocardial infarction associated with topical use of minoxidil (RiUP) for treatment of baldness.', 'A 45-year-old Japanese man with paroxysmal atrial fibrillation (AF) developed acute anteroseptal myocardial infarction (MI). He had used 1% topical minoxidil (RiUP) once a day for 4 months before the onset of MI for treatment of baldness.', 'Diffuse hypertrichosis during treatment with 5% topical minoxidil.', 'Five women affected by androgenetic alopecia developed severe hypertrichosis of the face and limbs after 2-3 months of treatment with 5% topical minoxidil. Minoxidil was discontinued and in all patients the hypertrichosis disappeared from the face and arms after 1-3 months, and from legs after 4-5 months', 'Generalized hypertrichosis after treatment with topical minoxidil.', 'hypertrichosis is uncommon after treatment with topical minoxidil for alopecia, and normally only occurs in areas close to the site of application. A 16-year-old girl is presented who developed generalized hypertrichosis 3 months after applying topical minoxidil for treatment of diffuse alopecia in doses greater than that prescribed', 'Two of our patients developed smoking intolerance during treatment with topical minoxidil for androgenital alopecia.', 'The relation between treatment with minoxidil and smoking intolerance was emphasized by stopping treatment and the disappearance of the smoking intolerance, and then by rechallenge in both patients. ', 'We observed an as yet unreported "polymyalgia syndrome" in four otherwise healthy males whose sole medication was topically applied minoxidil. They experienced fatigue, weight loss and severe pain in the shoulders and pelvic girdle, suggesting connective tissue disease. Three patients had a transient rise in liver enzymes, while other laboratory analyses remained normal. Tritanomaly was detected in two patients who underwent systematic color vision testing. All symptoms disappeared after withdrawal of minoxidil. Rechallenge was positive once in one patient and twice in another. ', 'During 6 months of follow-up, blood pressure did not change, whereas minoxidil increased heart rate by 3-5 beats min-1. Compared with placebo, topical minoxidil caused significant increases in LV end-diastolic volume, in cardiac output (by 0.751 min-1) and in LV mass (by 5 g m-2). We conclude that in healthy subjects short-term use of topical minoxidil is likely not to be detrimental. However, safety needs to be established regarding ischaemic symptoms in patients with coronary artery disease as well as for the possible development of LV hypertrophy in healthy subjects during years of therapy.', 'The most frequently reported adverse reactions are mild scalp dryness and irritation and, rarely, allergic contact dermatitis.', 'Eight deaths that occurred during Upjohn-sponsored clinical trials of topical minoxidil and two deaths in subjects who used extemporaneous formulations of the drug are summarized. Of the eight patients in clinical trials, five had cardiovascular abnormalities and two had acquired immunodeficiency syndrome-related pneumonia. One patient died of a self-inflicted gunshot wound. One of the subjects who was using extemporaneous topical minoxidil had hypertension and arteriosclerotic disease and the other died of a myocardial infarction. There is little likelihood of significant adverse effects attributable to topical minoxidil because of its low systemic absorption. The evidence suggests that these deaths were the result of causes other than use of the drug.', 'Only 2% of prescribers reported complications other than local irritation that they associated with topical minoxidil therapy, but underreporting of noncutaneous side effects in this survey of dermatologists cannot be excluded.', 'Typical side effects of this topical treatment include irritative dermatitis going along with pruritus, erythema, scaling and dryness, which occur especially at the onset of the therapy. In some cases, allergic contact dermatitis or exacerbation of seborrheic dermatitis has been reported. While most of the patients with allergic contact dermatitis described in the literature showed a positive sensitization to the vehicle substance propylene glycol evaluated by patch testing, reactions to the active ingredient minoxidil are rare']
['Typical side effects of this topical treatment include irritative dermatitis going along with pruritus, erythema, scaling and dryness, which occur especially at the onset of the therapy. In some cases, allergic contact dermatitis or exacerbation of seborrheic dermatitis has been reported.\nHypertrichosis is a well-recognized adverse effect of therapy with either oral or topical minoxidil.\nWe observed an as yet unreported "polymyalgia syndrome" in four otherwise healthy males whose sole medication was topically applied minoxidil. They experienced fatigue, weight loss and severe pain in the shoulders and pelvic girdle, suggesting connective tissue disease. Three patients had a transient rise in liver enzymes, while other laboratory analyses remained normal. Tritanomaly was detected in two patients who underwent systematic color vision testing.\nA case of central serous chorioretinopathy after application of topical minoxidil solution.\nA case of acute myocardial infarction associated with topical use of minoxidil (RiUP) for treatment of baldness.\nCompared with placebo, topical minoxidil caused significant increases in LV end-diastolic volume, in cardiac output (by 0.751 min-1) and in LV mass (by 5 g m-2).\nTwo of our patients developed smoking intolerance during treatment with topical minoxidil for androgenital alopecia.']
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Which is the mass-tag that reveal the ubiquitination of a lysine residue?
['antibodies that recognize the Lys-ɛ-Gly-Gly (K-ɛ-GG) remnant produced by trypsin digestion of proteins having ubiquitinated lysine side chains have markedly improved the ability to enrich and detect endogenous ubiquitination sites by mass spectrometry (MS). ', 'Recent publications have also highlighted the use of peptide-level immunoaffinity enrichment of K-GG modified peptides from whole cell lysates for global characterization of ubiquitination sites. ', 'In this work, levels of lysine ubiquitination were quantitated using a structurally homologous label that is chemically similar to the diglycine (GlyGly) tag, which is left at the ubiquitination site upon trypsinolysis', 'Tandem mass spectrometry (LC-MS/MS) analysis of immunoprecipitated proteins resulted in the identification of five peptides containing ubiquitin (diglycine) modifications on eIF2Bε']
['Lys-ɛ-Gly-Gly (K-ɛ-GG) is the remnant produced by trypsin digestion of proteins having ubiquitinated lysine side chains.']
['Lys-ɛ-Gly-Gly (K-ɛ-GG) is the remnant produced by trypsin digestion of proteins having ubiquitinated lysine side chains.']
List components of the CRSP/Med complex.
[' Here we describe a new human factor, CRSP, that is required together with the TAF(II)s for transcriptional activation by Sp1. Purification of CRSP identifies a complex of approximate relative molecular mass 700,000 (M(r) approximately 700K) that contains nine subunits with M(r) values ranging from 33K to 200K. Cloning of genes encoding CRSP subunits reveals that CRSP33 is a homologue of the yeast mediator subunit Med7, whereas CRSP150 contains a domain conserved in yeast mediator subunit Rgr1. CRSP p200 is identical to the nuclear hormone-receptor co-activator subunit TRIP2/PBP. CRSPs 34, 77 and 130 are new proteins, but the amino terminus of CRSP70 is homologous to elongation factor TFIIS.', 'CRSP contains unique subunits as well as polypeptides that are shared with other cofactor complexes.', 'The multi-subunit, human CRSP coactivator-also known as Mediator (Med)-regulates transcription by mediating signals between enhancer-bound factors (activators) and the core transcriptional machinery. Interestingly, different activators are known to bind distinct subunits within the CRSP/Med complex. We have isolated a stable, endogenous CRSP/Med complex (CRSP/Med2) that specifically lacks both the Med220 and the Med70 subunits. ']
['Mediator of RNA polymerase II transcription subunit 7\nMediator of RNA polymerase II transcription subunit 14\nMediator of RNA polymerase II transcription subunit 17\nMediator of RNA polymerase II transcription subunit 23\nMediator of RNA polymerase II transcription subunit 24\nMediator of RNA polymerase II transcription subunit 26\nMediator of RNA polymerase II transcription subunit 27']
['Mediator of RNA polymerase II transcription subunit 7', 'Mediator of RNA polymerase II transcription subunit 14', 'Mediator of RNA polymerase II transcription subunit 17', 'Mediator of RNA polymerase II transcription subunit 23', 'Mediator of RNA polymerase II transcription subunit 26', 'Mediator of RNA polymerase II transcription subunit 27', 'Mediator of RNA polymerase II transcription subunit 24']
Which is the molecular function of the protein CCDC40?
['Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia.', 'Primary ciliary dyskinesia (PCD) is a rare genetic disorder leading to recurrent respiratory tract infections.', 'Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia.', 'Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.', 'Human cilia were once thought merely to be important in respiratory mucociliary clearance, with primary ciliary dyskinesia (PCD) the sole manifestation of ciliary dysfunction. ', 'The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.', 'CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation.']
['The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation and mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.']
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Do statins cause diabetes?
['Statin use has been associated with increased risk of developing type 2 diabetes (T2DM), and with impaired glycemic control in T2DM patients', 'The relationship between T2DM and statins is further complicated since these drugs can cause new onset diabetes (NOD) although there is an overall benefit in terms of preventing vascular events ', 'It has been repeatedly reported that statins may cause new-onset diabetes mellitus (DM).', 'However, a small, but significant risk of new-onset diabetes has been reported in patients treated with statins.', 'The National Lipid Association (NLA) Statin Diabetes Safety Task Force concluded that the cardiovascular benefit of statin therapy outweighs the risk for developing diabetes', 'It has been repeatedly reported that statins may cause new-onset diabetes mellitus (DM)', 'It has been repeatedly reported that statins may cause new-onset diabetes mellitus (DM). However, limited evidence exists from direct head to head comparisons of statins on whether the risk of DM differs among statins.', 'Short-term statin exposure is associated with reduced all-cause mortality in persons with diabetes.', 'Despite the fact that higher statin doses are more likely to lead to new-onset diabetes, for every case of diabetes caused, there are approximately three cardiovascular events reduced with high dose versus moderate dose statin therapy.', 'It has been repeatedly reported that statins may cause new-onset diabetes mellitus (DM).', ' Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes', ' Compared with pravastatin, treatment with higher potency statins, especially atorvastatin and simvastatin, might be associated with an increased risk of new onset diabetes', ' statins are associated with a small increase in incidence of diabetes in patients predisposed to glycemic alteration', ' Higher potency statin use is associated with a moderate increase in the risk of new onset diabetes compared with lower potency statins in patients treated for secondary prevention of cardiovascular disease', 'An increased risk of new onset treated diabetes was found in those treated with statins showing significant duration and dose effect', 'Although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control', 'Statin therapy can slightly increase risk of incident diabetes in subjects with hypercholesterolemia.']
['The relationship between T2DM and statins is further complicated since these drugs can cause new onset diabetes (NOD) although there is an overall benefit in terms of preventing vascular events.', 'Statin use has been associated with increased risk of developing type 2 diabetes (T2DM), and with impaired glycemic control in T2DM patients']
['yes']
What is the life expectancy of professional athletes in respect to the general population?
['In conclusion, while regular physical activity increases life expectancy, it remains unclear if high-intensity sports activities further increase life expectancy.', 'Competitive exercise does not induce cardiac damage in individuals with healthy hearts, but does induce physiological functional and structural cardiac adaptations which have positive effects on life expectancy.', 'It appears that elite endurance (aerobic) athletes and mixed-sports (aerobic and anaerobic) athletes survive longer than the general population, as indicated by lower mortality and higher longevity. Lower cardiovascular disease mortality is likely the primary reason for their better survival rates. On the other hand, there are inconsistent results among studies of power (anaerobic) athletes.']
['Elite endurance (aerobic) athletes and mixed-sports (aerobic and anaerobic) athletes show higher longevity than the general population, but results about power (anaerobic) athletes are inconsistent.', 'It remains unclear if high-intensity sports activities further increase life expectancy.\nCompetitive exercise does not induce cardiac damage in individuals with healthy hearts, but does induce physiological functional and structural cardiac adaptations which have positive effects on life expectancy\nIt appears that elite endurance (aerobic) athletes and mixed-sports (aerobic and anaerobic) athletes survive longer than the general population, as indicated by lower mortality and higher longevity.']
['longer than the general population', 'No clear results indicating improved life expectancy in professional athletes']
Which molecule is targeted by a monoclonal antibody Secukinumab?
['We identified 3 distinct clonotypes that efficiently neutralized IL17A in a cell-based in vitro assay. Their potencies were comparable to those of known neutralizing antibodies, including 2, AIN457 (secukinumab) and ixekizumab that are currently in clinical development for the treatment of various inflammatory disorders. ', 'Secukinumab, a fully human anti-IL-17A monoclonal antibody, neutralizes IL-17A, a key cytokine in the pathogenesis of psoriasis.', 'BACKGROUND: Secukinumab is a fully human anti-interleukin-17A monoclonal antibody.', 'BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. ', 'We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. ', 'Ustekinumab (a monoclonal antibody directed against the common p40 subunit of IL-23 and IL-12), secukinumab, ixekizumab (both monoclonal antibodies directed against IL-17A), and brodalumab a monoclonal antibody against the IL-17RA receptor) have been recently used in proof-of-concept and randomized trials in the ankylosing spondylitis and/or psoriatic arthritis subforms of SpA, with overall very promising clinical efficacy.', 'The selective anti-IL17A monoclonal antibody secukinumab (AIN457) attenuates IL17A-induced levels of IL6 in human astrocytes.', 'The family of interleukin 17 receptors (IL17Rs), subtypes IL17RA-IL17RE, is targeted by the group of pro-inflammatory IL17 cytokines (IL17A-F) and moreover the newly developed anti-IL17A antibody secukinumab (AIN457) has shown promise in Phase II trials in multiple sclerosis. ', ' Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are currently being tested for efficacy and safety in the treatment of plaque psoriasis and PsA. Secukinumab is a fully human IgG1 monoclonal antibody that selectively binds and neutralizes IL-17A whose efficacy in the therapy of chronic plaque psoriasis has been demonstrated in different phase II clinical trial. ', 'Associations between IGA 0/1 responder rates and PASI scores were evaluated using data from two phase 2 studies with the anti-interleukin (IL)-17A monoclonal antibody secukinumab (AIN457) that utilized a similar 6-point IGA.', ' Several IL-17A inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibodies, secukinumab and ixekizumab, and the anti-17RA monoclonal antibody brodalumab.', 'Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.', 'We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. ', "In a proof-of-concept study for the treatment of patients with Crohn's disease, secukinumab, a monoclonal antibody directed against IL-17A, was ineffective and associated with more adverse events than placebo.", 'Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. ', 'Further studies are needed to clarify whether the therapeutic blockade of IL-17A through the anti-IL-17A monoclonal antibody secukinumab is able to counteract the fibrogenic process in CD.', 'Th-17A antagonism has been investigated by a randomized controlled trial in PsA patients with secukinumab, a fully human, high-affinity, monoclonal antibody in a cohort of patients with active PsA. ', 'Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial.', 'OBJECTIVE: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). ', 'PURPOSE: To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis.', 'Effect of IL-17A blockade with secukinumab in autoimmune diseases.', 'Early clinical data are now available on secukinumab (AIN457), a recombinant, highly selective, fully human monoclonal anti-IL-17A antibody of the IgG1/κ isotype, enabling a preliminary assessment of the effects of IL-17A inhibition in multiple autoimmune diseases.', 'In conjunction with studies using the humanised anti-IL-17A monoclonal antibody (mAb) ixekizumab (LY2439821) and the fully human anti-IL-17RA mAb brodalumab (AMG 827), the findings on secukinumab provide evidence for the role of IL-17A in the pathophysiology of autoimmune disease and suggest the potential value of targeting this cytokine.', 'OBJECTIVES: To assess the efficacy and safety of different doses of secukinumab, a fully human anti-IL-17A IgG1κ monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. ', 'Treatment with the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of influenza and meningococcal vaccinations in healthy subjects: results of an open-label, parallel-group, randomized single-center study.', 'Our objective was to evaluate the efficacy of influenza and meningococcal vaccinations in healthy subjects exposed to the anti-interleukin-17A (IL-17A) monoclonal antibody (MAb) secukinumab.', 'Blockade of IL-17A by secukinumab does not appear to interfere with efficacy of influenza and meningococcal vaccinations, as assessed by the achievement of protective antibody levels.', "Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.", "OBJECTIVE: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. ", 'Secukinumab is an IL-17A monoclonal antibody that is under development and preliminary results have suggested its efficacy in inflammatory mediated diseases such as psoriasis and ankylosing spondylitis. ', 'Promising recent Phase II results on the anti-IL-17A antibody secukinumab (AIN457) are outlined and a short update on tabalumab (LY2127399) is given', 'Several IL-17A inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibodies, secukinumab and ixekizumab, and the anti-17RA monoclonal antibody brodalumab', 'Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials']
['Secukinumab (AIN457) is a fully human anti-interleukin-17A monoclonal antibody that neutralizes interleukin-17A.']
['interleukin-17A']
Does Jarid2 play a role in early embryo development?
['Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development', 'Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2(-/-) ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered β-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2(-/-) with wild-type ESCs restores variable Nanog expression and β-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development.', 'Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development.', 'Consistent with an essential role for PcG proteins in early development, we demonstrate that JARID2 is required for the differentiation of mouse embryonic stem cells.', 'Jumonij (JMJ)/Jarid2 plays important roles in embryonic development and functions as a transcriptional repressor.', 'Thus, these results demonstrate that JARID2 is essential for the binding of PcG proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development.', 'JARID2 is an accessory component of Polycomb repressive complex-2 (PRC2) required for the differentiation of embryonic stem cells (ESCs).', 'Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development.', 'These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development..']
['Yes. Jarid2 coordinates Nanog expression and PCP/Wnt signaling required for efficient ESC differentiation and early embryo development.']
['yes']
What is the incidence of Edwards syndrom in the european population?
["dwards syndrome (trisomy 18) occurs in 1: 8000 live births and is closely related to the mother's age", 'Mean incidence was 390.06 (449.08 in boys and 327.93 in girls) per 10 000 live births', 'The incidence of Edwards syndrome is 1:5000 of live-born', 'The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26)', 'The live birth prevalence in the absence of prenatal screening and selective termination in England and Wales from 1997 to 2004 was 1.4 (95% CI: 1.2-1.6) per 10 000 births for trisomy 13 and 2.3 (95% CI: 2.1-2.5) for trisomy 18', 'During the period under the study, following total numbers, mean relative incidences (per 10,000 live births, in brackets) and mean prenatal diagnostics efficiency (in %) were found in following chromosomal syndromes: Down syndrome 2,244 (16.58) and 63.37%, Edwards syndrome 521 (3.85) and 79.93%, Patau syndrome 201 (1.49) and 68.87%, Turner syndrome 380 (2.81) and 79.89%, 47,XXX syndrome 61 (0.45) and 59.74%, Klinefelter syndrome 163 (1.20) and 73.65% and 47,XYY syndrome 22 (0.16) and 54.76%', 'There was evidence of space-time clustering for Down syndrome (fixed threshold of close in space: P = 0.01, NN threshold: P = 0.02), but little or no clustering for Patau (P = 0.57, P = 0.19) or Edwards (P = 0.37, P = 0.06) syndromes. ', "Of the 49,806 pregnant women between 15 and 23 weeks' gestational age who received prenatal serum screening with a cut-off value (a risk of 1:270 for Down and 1:100 for Edwards syndrome), 2,116 (4.2%) and 196 (0.4%) were screen positive for Down syndrome and for Edwards syndrome, respectively.", '26,803 of the 27,313 women (98%) were screened. The average was 25.1, and 1.7% of them were over 35. Serum screening showed that 1,244 (5%) were Down syndrome positive and 105 (0.4%) were Edwards syndrome positive.', '235 pregnancies of women delivered in units in the North West Thames region over a two-year period (1990-91) whose babies or fetuses were diagnosed as having Down, Edwards or Patau syndrome. RESULTS: 33% of Down syndrome, 68% of Edwards syndrome and 52% of Patau syndrome were diagnosed prenatally (before 28 weeks) in the region without the use of serum screening. ']
['Between 0.125 and 39 in every 1000 live births. Most probably 1:5000 of live-born.']
['1:5000']
What is known about the effectiveness of electronic food diaries ?
['Electronic dietary records were better than food diaries in terms of fat percentage reduction in our trials, indicating that teledietetics increases healthy-eating awareness.', 'Nutrition monitoring is a relevant method to gain an overview of factors influencing health. However, keeping a food diary often constitutes a challenge for a patient, and developing a user-friendly and useful electronic food diary is not straightforward', 'The analyzed apps reflected a variety of approaches to recording food intake and nutrition using different terminals--mostly mobile phones (35%), followed by PCs (29%) and PDAs (23%) for older studies, designed mainly for users with obesity (45%), diabetes mellitus (42%) and overweight (32%), or people who want to stay healthy (10%). The majority of the reviewed applications (67%) offered only input of food type and quantity. All approaches (n=31), except for two, relied on manual input of data, either by typing or by selecting a food type from a database. The exceptions (n=2) used a barcode scanning function. Users of mobile phone applications were not limited to data recording, but could view their data on the screen and send it via email. The tested web applications offered similar functionalities for recording food intake.', 'electronic food diary on a mobile phone that includes an energy balance visualization and computes and displays the difference between energy intake from food entries and energy expenditure from a multiple-sensor device that provides objective estimates of energy expenditure in real time']
['Electronic dietary records were better than food diaries in terms of fat percentage reduction in our trials, indicating that teledietetics increases healthy-eating awareness.']
[]
List functions that are evaluated with the Full Outline of Unresponsiveness score?
['The Full Outline of UnResponsiveness (FOUR) Score is a coma scale that consists of four components (eye and motor response, brainstem reflexes, and respiration). ', 'Recently, the full outline of unresponsiveness (FOUR) score was introduced, which is composed of four clinically distinct categories of evaluation: eye reaction, motor function, brainstem reflexes and respiratory pattern. ', 'The FOUR (Full Outline of UnResponsiveness) score, a new coma scale, evaluates 4 components: eye and motor responses, brainstem reflexes and respiration. ', 'The FOUR (Full Outline of UnResponsiveness) score, a new coma scale, evaluates 4 components: eye and motor responses, brainstem reflexes and respiration.', 'To evaluate the validity of the FOUR (Full Outline of UnResponsiveness) score (ranging from 0 to 16), a new coma scale consisting of 4 components (eye response, motor response, brainstem reflexes, and respiration pattern), when used by the staff members of a medical intensive care unit (ICU).', 'To evaluate the validity of the FOUR (Full Outline of UnResponsiveness) score (ranging from 0 to 16), a new coma scale consisting of 4 components (eye response, motor response, brainstem reflexes, and respiration pattern), when used by the staff members of a medical intensive care unit (ICU).', 'Recently, the full outline of unresponsiveness (FOUR) score was introduced, which is composed of four clinically distinct categories of evaluation: eye reaction, motor function, brainstem reflexes and respiratory pattern.', 'The FOUR (Full Outline of UnResponsiveness) score, a new coma scale, evaluates 4 components: eye and motor responses, brainstem reflexes and respiration.']
['The FOUR (Full Outline of UnResponsiveness) score, a new coma scale, evaluates 4 components: eye and motor responses, brainstem reflexes and respiration.']
['eye responses', 'motor responses', 'brainstem reflexes', 'respiration']
Which disorder is rated by Palmini classification?
['This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias.', 'Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. ', 'Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB).', 'MCD were classified following the existing classification schemes (Barkovich et al., 2012. Brain. 135, 1348-1369; Palmini et al., 2004. Neurology. 62, S2-S8) and the ILAE classification for FCD recently proposed by Blümcke in 2011. ', 'DISCUSSION: This short review provides an overview of the issues which account for the varied historical approaches to FCD classification and descriptions of gross pathologic findings associated with FCD and an overview of two more recently developed and widely used schema, the Palmini et al. (Neurology 62: S2-8, 2004) and the International League Against Epilepsy (ILAE) classifications Blumcke et al. Epilepsia 52: 158-174, 2011. ', ' In contrast to the former FCD classification by Palmini, which considered only histologic features, the novel ILAE classification also relies on magnetic resonance imaging (MRI) findings and presumed pathogenesis.', 'Rates of high frequency oscillations in patients with pathologically confirmed focal cortical dysplasia of Palmini type 1a and b were compared with those in type 2a and b.', 'Tuberous sclerosis complex (TSC) and severe cortical dysplasia (CD), or CD type II according to Palmini classification, share histopathologic similarities, specifically the presence of cytomegalic neurons and balloon cells.', 'This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias.', 'Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA.', 'Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB.', 'Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB).', 'Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency.', "Since early 2000, the definition of FCD has gradually been given a broader interpretation than the case described by Taylor et al., as shown in Palmini's classification (2004) or the newest classification (2011) proposed by the Neuropathology Task Force of the International League Against Epilepsy (ILAE).", "Palmini's classification proposed in 2004 is now widely used to categorize FCD.", "According to Palmini's classification system, these lesions were categorized as focal cortical dysplasia (FCD) type II.", 'In contrast to the former FCD classification by Palmini, which considered only histologic features, the novel ILAE classification also relies on magnetic resonance imaging (MRI) findings and presumed pathogenesis.', "According to Palmini's classification system, these lesions were categorized as focal cortical dysplasia (FCD) type II. ", "According to Palmini's classification system, the following pathologic subgroups were identified: FCD type IA (3/38), FCD type IB (20/38), FCD type IIA (5/38) and FCD type IIB (5/38). ", "In addition, severe pathologic features (Palmini's classification, FCD type II) (p = 0.025) showed significant correlation with a better surgical outcome. ", 'Tuberous sclerosis complex (TSC) and severe cortical dysplasia (CD), or CD type II according to Palmini classification, share histopathologic similarities, specifically the presence of cytomegalic neurons and balloon cells. ', "In detail, according to Palmini's classification, mild malformations of cortical development (mMCDs) were disclosed in three patients, focal cortical dysplasia (FCD) type Ia in three patients, and FCD type Ib in five patients. ", 'These results showed considerable improvement compared to a previous study evaluating the 2004 Palmini FCD classification. ', 'In contrast to the former FCD classification by Palmini, which considered only histologic features, the novel ILAE classification also relies on magnetic resonance imaging (MRI) findings and presumed pathogenesis. ', 'Rates of high frequency oscillations in patients with pathologically confirmed focal cortical dysplasia of Palmini type 1a and b were compared with those in type 2a and b. ', 'Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA. ', 'Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed - from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011.', 'Tuberous sclerosis complex (TSC) and severe cortical dysplasia (CD), or CD type II according to Palmini classification, share histopathologic similarities, specifically the presence of cytomegalic neurons and balloon cells.', 'in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe.Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children.', 'In contrast to the former FCD classification by Palmini, which considered only histologic features, the novel ILAE classification also relies on magnetic resonance imaging (MRI) findings and presumed pathogenesis.', 'Since early 2000, the definition of FCD has gradually been given a broader interpretation than the case described by Taylor et al., as shown in Palmini&apos;s classification (2004) or the newest classification (2011) proposed by the Neuropathology Task Force of the International League Against Epilepsy (ILAE). The ILAE classification describes 3 types of disease: Type I, Type II, and Type III.', 'in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.']
['Palmini classification system is used for classification of focal cortical dysplasia.']
['focal cortical dysplasia']
Which drugs are utilized to treat eosinophilic esophagitis?
['Current therapeutic options include use of proton-pump inhibitors, immunosuppressive drugs, elimination diets, and esophageal dilatation.', 'Aerosolized, swallowed fluticasone leads to a histologic but not a symptomatic response in adults with EoE', 'OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE.']
['Therapeutic options of eosinophilic esophagitis include use of proton-pump inhibitors, immunosuppressive drugs, elimination diets, and esophageal dilatation.\nOral viscous budesonide (OVB) is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features.']
['proton pump inhibitors', 'immunosoppressive drugs', 'budesonide']
Which virus type causes Molluscum contagiosum?
['Molluscum contagiosum virus (MCV), a poxvirus pathogenic for humans, replicates well in human skin in vivo, but not in vitro in standard monolayer cell cultures.', 'Molluscum contagiosum virus (MCV) is a poxvirus that causes tumor-like skin lesions. ', 'Molluscum contagiosum poxvirus (MCV) type 1 and type 2 encode two chemokine-like proteins MC148R1 and MC148R2. I', 'Molluscum contagiosum virus (MCV) is a common, human poxvirus that causes small papular skin lesions that persist for long periods without signs of inflammation. ', 'All poxviruses studied encode a type 1B topoisomerase that introduces transient nicks into DNA and thereby relaxes DNA supercoils. Here we present a study of the protein domains of the topoisomerase of the poxvirus molluscum contagiosum (MCV), which allows us to specify DNA contacts made by different domains. ', 'Molluscum contagiosum virus (MCV) causes molluscum contagiosum (MC) in both children and adults.', 'MC54L, the IL-18 binding protein of the human poxvirus that causes molluscum contagiosum, is unique in having a C-terminal tail of nearly 100 amino acids that is dispensable for IL-18 binding.', 'Molluscum contagiosum is a common superficial skin infection caused by the poxvirus, Molluscum Contagiosum virus.', 'Molluscum contagiosum is a common skin and mucosal disease of viral origin, caused by molluscum contagiosum virus (MCV) virus of poxvirus family.', 'Molluscum contagiosum is a benign contagious disease caused by a poxvirus.', 'Molluscum contagiosum is a common superficial skin infection caused by the poxvirus, Molluscum Contagiosum virus', 'Molluscum contagiosum is a common skin and mucosal disease of viral origin, caused by molluscum contagiosum virus (MCV) virus of poxvirus family', 'Molluscum contagiosum is a viral infection of the skin and mucous membranes that is caused by infection with the molluscum contagiosum virus', 'Molluscum contagiosum (MC) is a very common benign self-limiting cutaneous viral infection caused by molluscum contagiosum virus', 'Molluscum contagiosum is caused by the molluscum contagiosum virus (MCV) and is a very common skin disorder mainly involving young children Cryotherapy, curettage or some topical therapies have been applied for MC, but all of these treatments need several sessions, can be somewhat ineffective, and very painful', 'Molluscum contagiosum virus (MCV) causes an innocuous yet persistent skin infection in immunocompetent individuals and is spread by contact with lesions', 'Molluscum contagiosum virus (MCV) is a poxvirus that causes localized papules in healthy persons', 'Molluscum contagiosum is a virus that causes characteristic pearly lesions on the surface of the skin', 'Molluscum contagiosum virus (MCV) is a poxvirus that causes tumor-like skin lesions', 'Molluscum contagiosum virus is a human and animal dermatotropic pathogen, which causes a severe disease in immunocompromised individuals', 'Given that human diseases caused by poxviruses can be as lethal as smallpox or as benign as Molluscum contagiosum, and that vaccinia virus, the prototypic member of the pox family, persists as a mainstay of vaccine design and has potential as an oncolytic virus for tumor therapy, further research in this area remains important.', 'These cases support earlier evidence that the molluscum contagiosum virus may act as cases support earlier evidence that the molluscum contagiosum virus may act as an opportunistic pathogen.', 'Molluscum contagiosum is a viral infection of the skin and mucous membranes that is caused by infection with the molluscum contagiosum virus.']
['Molluscum contagiosum virus (MCV) is a human poxvirus that causes tumor-like skin lesions.']
['human poxvirus']
What is a mitochondrial nucleoid?
['A naked mtDNA molecule is longer than a typical mitochondrion and is therefore compacted in vivo to form a nucleoprotein complex, denoted the mitochondrial nucleoid.', 'The packaging of mitochondrial DNA (mtDNA) into DNA-protein assemblies called nucleoids provides an efficient segregating unit of mtDNA,', 'Mitochondrial DNA (mtDNA) is organized in nucleoids in complex with accessory proteins, proteins of mtDNA replication and gene expression machinery.', 'The independent mitochondrial genetic information is organized in so-called mitochondrial nucleoids', ' packaging of mitochondrial DNA (mtDNA) into protein-DNA assemblies called nucleoids confers higher-order organization to the mitochondrial genome.', 'mitochondrial DNA is packaged into macromolecular assemblies called nucleoids, composed of one or more copies of mitochondrial DNA and associated proteins. ', 'human mitochondrial DNA (mtDNA) had long been believed to be rather naked because mitochondria lack histone']
['A naked mtDNA molecule is longer than a typical mitochondrion and is therefore compacted in vivo to form a nucleoprotein complex, denoted the mitochondrial nucleoid.']
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Is Mammaprint approved by the United States Food and Drug Administration?
['an FDA-cleared 70-gene signature of MammaPrint panel ', 'on MammaPrint, the first and only assay for breast cancer management that has been cleared by the FDA.', 'The MammaPrint assay has the advantages of a 510(k) clearance by the US Food and Drug Administration, a larger gene number which may enhance further utility, and the potentially wider patient eligibility including lymph node-positive, ER-negative, ', 'The MammaPrint assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node-positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). ']
['Yes, Mammaprint has been approved by the US Food and Drug Administration.']
['yes']
What is the mechanism of action of onartuzumab?
[' In this study, e-training was used to train board-certified pathologists to evaluate non-small cell lung carcinoma for eligibility for treatment with onartuzumab, a MET-inhibiting agent.', 'A Randomized Phase II Study of FOLFOX With or Without the MET Inhibitor Onartuzumab in Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction.', 'MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined.', 'CONCLUSION: The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population.IMPLICATIONS FOR PRACTICE: The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry.', ' The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. ', 'We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC.', 'Conclusion Onartuzumab plus erlotinib did not improve clinical outcomes, with shorter OS in the onartuzumab arm, compared with erlotinib in patients with MET-positive non-small-cell lung cancer.', 'A recent example of a failed trial is the Phase III MetLung trial that compared the effects of the c-MET monovalent antibody onartuzumab with erlotinib versus erlotinib alone in late-stage non-small-cell lung cancer. ', 'Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent.', 'Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy.', 'Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab.', 'Onartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF).', 'Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent', 'Nonclinical evaluation of the serum pharmacodynamic biomarkers HGF and shed MET following dosing with the anti-MET monovalent monoclonal antibody onartuzumab.', 'Onartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors.', 'Successful therapeutic targeting of the MET/HGF pathway has been achieved using monoclonal antibodies against the MET receptor and its ligand HGF in addition to MET-specific and multitargeted small-molecule tyrosine-kinase inhibitors with several drugs in late-phase clinical trials including onartuzumab, rilotumumab, tivantinib, and cabozantinib.', 'Grade 3-5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively.The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population.The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry.', 'Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent.']
['Onartuzumab is monoclonal antibody targeting MET. It works by inhibiting MET. Onartuzumab was tested for treatment of non-small cell lung carcinoma, adenocarcinoma of the stomach and gastroesophageal Junction, and recurrent glioblastoma.']
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What is the term for synapsin as a conserved presynaptic phosphoprotein?
['["Synapsin is an evolutionarily conserved presynaptic phosphoprotein.", "Synapsins as a family of presynaptic terminal phosphoprotein participates in neuronal development", "Synapsin III (SynIII) is a phosphoprotein", "The neuronal phosphoprotein synapsin III", "Synapsin II is a member of the neuronal phosphoprotein family.", "phosphoprotein synapsin"]', '["Synapsin is an evolutionarily conserved presynaptic phosphoprotein.", "Synapsins as a family of presynaptic terminal phosphoprotein participates in neuronal development", "Synapsin III (SynIII) is a phosphoprotein", "The neuronal phosphoprotein synapsin III", "Synapsin II is a member of the neuronal phosphoprotein family.", "phosphoprotein synapsin"]']
Synapsin
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Which components of the stress granules are known to be related to motor neuron degeneration in Amyotrophic Lateral Sclerosis?
['Here, we demonstrate that C-terminal ALS mutations disrupt the nuclear localizing signal (NLS) of FUS resulting in cytoplasmic accumulation in transfected cells and patient fibroblasts. FUS mislocalization is rescued by the addition of the wild-type FUS NLS to mutant proteins. We also show that oxidative stress recruits mutant FUS to cytoplasmic stress granules where it is able to bind and sequester wild-type FUS.', 'Recently, TDP-43 has been identified as a key protein in the pathogenesis of some cases of ALS. Although the role of TDP-43 in motor neuron degeneration is not yet known, TDP-43 has been shown to accumulate in RNA stress granules (SGs) in cell models and in spinal cord tissue from ALS patients. ', 'in response to oxidative stress or heat shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wild-type FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. These findings demonstrate a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS.', 'both stress granules (TIA-1 immunoreactive) and processing bodies (P-bodies; XRN-1 immunoreactive) were more prevalent in ALS motor neurons than in controls and demonstrated strong co-localization with TDP-43.', 'These data suggest that NFL mRNA processing is fundamentally altered in ALS spinal motor neurons to favour compartmentalization within both stress granules and P-bodies, and that TDP-43 plays a fundamental role in this process.', 'Transactive response DNA-binding protein 43 (TDP-43) forms abnormal ubiquitinated and phosphorylated inclusions in brain tissues from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. TDP-43 is a DNA/RNA-binding protein involved in RNA processing, such as transcription, pre-mRNA splicing, mRNA stabilization and transport to dendrites. We found that in response to oxidative stress and to environmental insults of different types TDP-43 is capable to assemble into stress granules (SGs), ribonucleoprotein complexes where protein synthesis is temporarily arrested. ', 'Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS.', 'Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal neurodegenerative disease that causes progressive muscular weakness and has overlapping clinical and pathologic characteristics with frontotemporal lobar degeneration.', 'Our results indicate that mutant-FUS alters the dynamic properties of stress granules, which is consistent with a gain-of-toxic mechanism for mutant-FUS in stress granule assembly and cellular stress response.', 'Expression of ALS-linked FUS mutations resulted in their assembly into cytoplasmic stress granules (SGs), cellular structures that package mRNA and RNA-binding proteins during cell stress.', 'TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) that is known to regulate the splicing, transport, and storage of specific mRNAs into stress granules', 'Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP-43 has been identified as a component of ubiquitin-immunoreactive inclusions of motor neurons in ALS.', 'SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)', 'PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions.']
['Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS.', 'TDP-43 and FUS have been identified as key proteins in the pathogenesis of some cases of ALS. Although their role in motor neuron degeneration is not yet known, TDP-43 and FUS have been shown to accumulate in RNA stress granules (SGs) in cell models and in spinal cord tissue from Amyotrophic Lateral Sclerosis (ALS) patients.']
['TDP-43', 'FUS']
What are the symptoms of abacavir hypersensitivity?
['patients receiving abacavir develop a hypersensitivity reaction, characterized by rash, fever and, occasionally, multisystemic involvement', 'The predictors included any one of several specific symptoms commonly found with this reaction, a claims diagnosis of adverse effect of drug, anaphylactic shock or unspecified allergy, and a discontinuation in abacavir prior to completing a 90-day course of therapy.', 'patients who receive abacavir develop an idiosyncratic hypersensitivity reaction. The most common symptoms are fever, skin rash and gastrointestinal disorders. Respiratory symptoms occurred in approximately 20% of patients who have hypersensitivity reaction. We describe the first case, to our knowledge, of hypesensitivity reaction characterized by enanthema and fever without skin rash promptly resolved after discontinuation of abacavir', 'Abacavir is associated with an infrequent but potentially serious hypersensitivity reaction (HSR) that can include a wide range of signs and symptoms.', 'Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P = 0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P = 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal symptoms was also predictive of hypersensitivity reaction (', 'the number of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P = 0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly associated with gastrointestinal (GI) symptoms.']
['Patients receiving abacavir develop an idiosyncratic hypersensitivity reaction that can include a wide range of symptoms. The most common are: fever, enathema, skin rash, nausea, vomiting, diarrhoea, cough, gastrointestinal disorders, anaphylactic shock, respiratory symptoms.']
['fever', 'enathema', 'skin rash', 'nausea', 'vomiting', 'diarrhea', 'cough', 'gastrointestinal disorders', 'anaphylactic shock', 'respiratory symptoms']
Are there currently applications of deep learning in genomics?
['Deep learning of the tissue-regulated splicing code.', 'Using a deep neural network, we developed a model inferred from mouse RNA-Seq data that can predict splicing patterns in individual tissues and differences in splicing patterns across tissues. Our architecture uses hidden variables that jointly represent features in genomic sequences and tissue types when making predictions. A graphics processing unit was used to greatly reduce the training time of our models with millions of parameters.', 'We show that the deep architecture surpasses the performance of the previous Bayesian method for predicting AS patterns. With the proper optimization procedure and selection of hyperparameters, we demonstrate that deep architectures can be beneficial, even with a moderately sparse dataset. An analysis of what the model has learned in terms of the genomic features is presented.', 'Machine learning applications in genetics and genomics']
['Yes. Deep learning has been used so far in genomics for predicting splicing patterns in individual tissues and differences in splicing patterns across tissues. The deep architecture surpasses the performance of the previous Bayesian method for predicting alternative splicing (AS) patterns.']
['yes']
is intense physical activity associated with longevity ?
['We found a very significant increase in average longevity (17%) of the cyclists when compared with the general population. The age at which 50% of the general population died was 73.5 vs. 81.5 years in Tour de France participants. Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners.', 'Competitive exercise does not induce cardiac damage in individuals with healthy hearts, but does induce physiological functional and structural cardiac adaptations which have positive effects on life expectancy.', 'Medallists lived an average of 2.8 years longer than controls. Medallists in eight of the nine country groups had a significant survival advantage compared with controls. Gold, silver, and bronze medallists each enjoyed similar sized survival advantages. Medallists in endurance sports and mixed sports had a larger survival advantage over controls at 30 years (1.13, 1.09 to 1.17; 1.11, 1.09 to 1.13) than that of medallists in power sports (1.05, 1.01 to 1.08). CONCLUSIONS: Olympic medallists live longer than the general population, irrespective of country, medal, or sport. This study was not designed to explain this effect, but possible explanations include genetic factors, physical activity, healthy lifestyle, and the wealth and status that come with international sporting glory.', 'Long-term endurance training induces in elderly subjects an increased HRV and a higher exercise working capacity, which are well-established predictors of cardiovascular and overall mortality.', 'Sports activity in adolescents and young adults was associated with an increased risk of SD, both in males and females. Sports, per se, was not a cause of the enhanced mortality, but it triggered SD in those athletes who were affected by cardiovascular conditions predisposing to life-threatening ventricular arrhythmias during physical exercise.']
['Several survival studies showed that professional athletes has higher longevity than general population. These epidemiological data matches the evidences that long-term endurance training induces in elderly subjects an increased HRV and a higher exercise working capacity, which are well-established predictors of cardiovascular and overall mortality, and also telomere length.']
['yes']
Are seizures among the neurological symptoms of incontinentia pigmenti?
['High-dose glucocorticoid therapy in the management of seizures in neonatal incontinentia pigmenti', 'Incontinentia pigmenti is an X-linked dominant disorder resulting from a mutation of IKBKG. This disorder has a classic dermatologic presentation, but neurologic involvement, with seizures and cortical infarction, can arise shortly after birth', 'Some children with incontinentia pigmenti exhibit encephalopathic features with severe seizures and disturbed consciousness, from the neonatal through the early infantile period', 'Incontinentia pigmenti (IP) is a rare X-linked dominant neurocutaneous disorder affecting ectodermal tissue: skin, eyes, central nervous system, hair, nails, and teeth. It is usually lethal for males in utero. The involved gene is NEMO, an essential component of the nuclear factor-kappa B (NF-κB) signaling pathway. Skin lesions are highly diagnostic, occurring in neonates, with a particular distribution on Blaschko lines. The severity of the disease is related to ocular and neurological impairment. The hallmark of ocular IP is retinal vasculopathy including peripheral retinal vascular nonperfusion, macular infarction and neovascularization, and preretinal neovascularization. CNS involvement consists of seizures, mental retardation, hemiparesis, spasticity, microcephaly, cerebellar ataxia, and coma', 'Incontinentia Pigmenti is a rare X-linked multisystem disorder with well described and pathognomonic skin manifestations. Neurological manifestations are found in 30% of IP patients, forming one of the major causes of morbidity and mortality of the condition. In this review, clinical and brain imaging data of 45 IP patients with a neurological phenotype are reviewed. Several clinical presentations could be identified, comprising seizures, infantile encephalopathy, acute disseminated encephalomyelitis and ischemic stroke', 'Incontinentia pigmenti presenting as seizures.', 'Neonatal seizures in two sisters with incontinentia pigmenti.', 'High-dose glucocorticoid therapy in the management of seizures in neonatal incontinentia pigmenti: a case report.', 'Incontinentia Pigmenti is an X-linked dominant neurocutaneous disorder with central nervous system manifestations in 30% of cases, including seizures and mental retardation.', 'Neonatal seizures in two sisters with incontinentia pigmenti', 'A rare cause of neonatal seizure: incontinentia pigmenti.', 'Here, we describe the clinical, electrographic, and neuroradiologic effect of systemic glucocorticoid therapy in a neonate with incontinentia pigmenti manifesting an epileptic encephalopathy.', 'Incontinentia pigmenti presenting as seizures.', 'Neonatal seizures in two sisters with incontinentia pigmenti.']
['Incontinentia pigmenti is an X-linked dominant disorder resulting from a mutation of IKBKG. This disorder has a classic dermatologic presentation, but neurologic involvement, with seizures and cortical infarction, can arise shortly after birth.']
['yes']
Are there any urine biomarkers for bladder cancer diagnosis?
['CONCLUSIONS: Several gene-based urinary biomarkers have demonstrated promise in initial studies, which now need to be rigorously validated in the clinical setting for them to be translated into clinically useful tests in diagnosis, surveillance or risk-stratification of bladder cancer', ' Novel promising markers are in various stages of clinical testing, and a panel of biomarkers may serve in the future as a feasible alternative to urine cytology and cystoscopy for the screening, detection, and follow-up of non-muscle invasive bladder cancer.', 'RESULTS: Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer. The 7 biomarkers were assessed in a new model, which had an AUROC of 0.88 (95% CI 0.84-0.93), and 74% sensitivity and 90% specificity.', 'The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays.', 'The urinary concentrations of 14 biomarkers (IL-8, MMP-9, MMP-10, SDC1, CCL18, PAI-1, CD44, VEGF, ANG, CA9, A1AT, OPN, PTX3, and APOE) were assessed by enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of each biomarker and multivariate models were compared using receiver operating characteristic curves and the chi-square test. An 8-biomarker model achieved the most accurate BCa diagnosis (sensitivity 92%, specificity 97%), but a combination of 3 of the 8 biomarkers (IL-8, VEGF, and APOE) was also highly accurate (sensitivity 90%, specificity 97%). For comparison, the commercial BTA-Trak ELISA test achieved a sensitivity of 79% and a specificity of 83%, and voided urine cytology detected only 33% of BCa cases in the same cohort. These data show that a multivariate urine-based assay can markedly improve the accuracy of non-invasive BCa detection', ': Histopathological grading of papillary urothelial tumors (PUTs) of the urinary bladder is subjective and poorly reproducible. We investigated the relationship between the expression of frequently deregulated microRNAs (miRNAs) as well as their target genes (ZEB1/ZEB2) and bladder cancer histopathological grade in an attempt to find a miRNA that might allow more reliable grading of PUTs.', 'The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.', 'HYAL-1 and HAS1 expression predicted BCa metastasis, and HYAL-1 expression also predicted disease-specific survival. Furthermore, the combined HAS2-HYAL-1 biomarker detected BCa and significantly predicted its recurrence.', 'Cancer biomarkers are the backbone for the implementation of individualized approaches to bladder cancer (BCa). ', 'Through genomic and proteomic profiling of urine, we have identified a panel of biomarkers associated with the presence of BCa. In this study, we evaluated the utility of three of these biomarkers, interleukin 8 (IL-8), Matrix metallopeptidase 9 (MMP-9) and Syndecan in the diagnosis of BCa through urinalysis. METHODS: Voided urines from 127 subjects, cancer subjects (n = 64), non-cancer subjects (n = 63) were analyzed. The protein concentrations of IL-8, MMP-9, and Syndecan were assessed by enzyme-linked immunosorbent assay (ELISA).', '. There was an association between differences in individual biomarkers and differences in protein levels over time, particularly in control patients. Collectively, our findings identify caveats intrinsic to the common practice of protein standardization in biomarker discovery studies conducted on urine, particularly in patients with hematuria']
['Bladder cancer is any of several types of malignancy arising from the epithelial lining of the urinary bladder. Rarely the bladder is involved by non-epithelial cancers, such as lymphoma or sarcoma. It is a disease in which abnormal cells multiply without control in the bladder.The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis. The most common type of bladder cancer recapitulates the normal histology of the urothelium and is known as transitional cell carcinoma or more properly urothelial cell carcinoma. It is estimated that there are 383,000 cases of bladder cancer worldwide', 'Yes, there are. Urine biomarkers for bladder cancer diagnosis range from voided urine cytology and the UroVysion® cytogenetic test, to fluorescence in situ hybridisation (FISH), ImmunoCyt, NMP22, Bladder Tumor Antigen, BLCA-1, BLCA-4, hyaluronic acid, hyaluronidase, Lewis X antigen, microsatellite analysis, Quanticyt, soluble Fas, Survivin, telomerase, IL-8, MMP-9 and 10, PAI-1, VEGF, ANG, CA9 and APOE.']
['yes']
List bacterial species identified in the iceman tissues.
['Here, we report the molecular detection of the oral spirochete Treponema denticola in ancient human tissue biopsies of the Iceman, a 5,300-year-old Copper Age natural ice mummy. ', "The colon, on the other hand, contains several members of the fecal flora of humans, such as Clostridium perfringens, C. ghonii, C. sordellii, Eubacterium tenue, and Bacteroides sp. The Iceman's colon, however, was found to contain, rather unexpectedly, also some members of the genus Vibrio. ", ' while the untreated skin still bears the remains of large numbers of bacteria belonging to the genera Sphingomonas, Afipia, Curtobacterium, Microbacterium, Agromyces, and others.']
['Spirochete Treponema denticola\nClostridium perfringens\nClostridium ghonii\nClostridium sordellii\nEubacterium tenue\nBacteroides sp\nVibrio\nSphingomonas\nAfipia\nCurtobacterium\nMicrobacterium\nAgromyces']
['Spirochete Treponema denticola', 'Clostridium perfringens', 'Clostridium ghonii', 'Clostridium sordellii', 'Eubacterium tenue', 'Bacteroides sp', 'Vibrio', 'Sphingomonas', 'Afipia', 'Curtobacterium', 'Microbacterium', 'Agromyces']
What is the effect of resveratrol on mTOR activity?
['Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR', 'Here, we show that RSV inhibits insulin- and leucine-stimulated mTOR signaling in C2C12 fibroblasts via a Sirt1-independent mechanism', 'Treating C2C12 cells with RSV dramatically inhibited insulin-stimulated Akt, S6 kinase, and 4E-BP1 phosphorylation but had little effect on tyrosine phosphorylation of the insulin receptor and activation of the p44/42 MAPK signaling pathway', 'RSV treatment also partially blocked mTOR and S6 kinase phosphorylation in TSC1/2-deficient mouse embryonic fibroblasts, suggesting the presence of an inhibitory site downstream of TSC1/2', 'Taken together, our studies reveal that RSV inhibits leucine-stimulated mTORC1 activation by promoting mTOR/DEPTOR interaction and thus uncover a novel mechanism by which RSV negatively regulates mTOR activity', 'Recent studies suggest that modulation of the mTOR signalling pathway could play an important role in mediating the beneficial effects of RSV. ', 'Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells', 'esveratrol blocked the oxLDL-induced phosphorylation and activation of the PI3K/Akt/mTOR/p70S6K pathway and strongly inhibited both the DNA synthesis and proliferation of SMC', 'At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence', 'Here we demonstrated that, at cytostatic, near-toxic concentrations, resveratrol inhibited S6 phosphorylation and prevented the senescence morphology in human cells', 'Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells', 'On the other hand, RSV significantly increased the association between mTOR and its inhibitor, DEPTOR', 'Resveratrol inhibits mTOR signaling by targeting DEPTOR', 'Recent studies suggest that suppressing the signaling pathway mediated by mTOR, a well-known energy sensor that integrates various hormonal, nutrient and environmental signals to regulate cell growth, metabolism and survival, could play an important role in mediating the beneficial effect of RSV', 'Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain', 'Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity', 'Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway', 'Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling.', 'Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR.', 'Consistent with the in vitro findings, resveratrol intervention in the PTEN knockout mouse model was associated with reduction in the prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1.', 'Resveratrol inhibited the phosphorylation of PI3K, AKT and mTOR.', 'Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells.', 'Resveratrol also alleviated the PI3K/Akt/mTOR signaling by down-regulation of Akt phosphorylation and up-regulation of PTEN expression.', 'Resveratrol blocked the oxLDL-induced phosphorylation and activation of the PI3K/Akt/mTOR/p70S6K pathway and strongly inhibited both the DNA synthesis and proliferation of SMC.', 'Resveratrol reduced phosphorylation of ribosomal protein S6 and the mTOR inhibitor rapamycin further enhanced resveratrol-induced cell death.', 'Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells.', 'Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity.', 'The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner.', 'We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling.', 'RSV treatment has no effect on the expression levels of mTOR, raptor and DEPTOR, but greatly promotes the interaction between mTOR and its inhibitor DEPTOR.', 'Taken together, our studies reveal that RSV inhibits leucine-stimulated mTORC1 activation by promoting mTOR/DEPTOR interaction and thus uncover a novel mechanism by which RSV negatively regulates mTOR activity.', 'Furthermore, the inhibitory effect of RSV on leucine-stimulated mTOR signaling was greatly reduced in cells in which the expression levels of DEPTOR were suppressed by RNAi', 'Consistent with the in vitro findings, resveratrol intervention in the PTEN knockout mouse model was associated with reduction in the prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1', 'The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner', 'However, most frequently, RSV is found to inhibit the activity of the mTOR pathway proteins, and to activate AMPK and LKB1, which can suppress mTOR signalling', 'Over the past few years, numerous studies have suggested that suppressing the activity of mammalian target of rapamycin (mTOR), a critical regulator of cell metabolism, growth, and proliferation, may provide a key mechanism underlying the anticarcinogenic properties of resveratrol', 'Resveratrol blocks specifically this pathway, thereby inhibiting oxLDL-induced SMC proliferation. ', 'Resveratrol causes cell cycle arrest and induces apoptotic cell death in various types of cancer cells', 'Resveratrol decreased both the expression and phosphorylation of Akt', ' Modulation of the AMPK, Akt and mTOR pathways', 'RSV (2.5-5 μM) inhibited clonogenic survival of PC3 and 22RV1 cells but not of normal prostate PNT1A cells', 'RSV enhanced IR-activation of ATM and AMPK but inhibited basal and IR-induced phosphorylation of Akt', 'Our results suggest that RSV arrests cell cycle, promotes apoptosis and sensitizes PrCa cells to IR likely through a desirable dual action to activate the ATM-AMPK-p53-p21(cip1)/p27(kip1) and inhibit the Akt signalling pathways', 'Resveratrol pre-treatment reduces early inflammatory responses induced by status epilepticus via mTOR signaling', 'Over the past few years, numerous studies have suggested that suppressing the activity of mammalian target of rapamycin (mTOR), a critical regulator of cell metabolism, growth, and proliferation, may provide a key mechanism underlying the anticarcinogenic properties of resveratrol.', 'It has been found that resveratrol targets multiple components of the phosphatidylinositol 3- kinase(PI3K)/Akt and mTOR signaling pathways, including PI3K, Akt, PTEN, and DEPTOR, suggesting that this natural compound and its derivatives may offer a promising new cancer treatment. ', 'Autophagic cell death induced by resveratrol depends on the Ca(2+)/AMPK/mTOR pathway in A549 cells', 'In conclusion, we demonstrate that resveratrol-induced A549 cell death was mediated by the process of autophagic cell death via Ca(2+)/AMPK-mTOR signaling pathway.']
['Resveratrol (RSV) inhibits leucine-stimulated mTORC1 activation by promoting mTOR/DEPTOR.', 'Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human cells. It has been found that resveratrol targets multiple components of the phosphatidylinositol 3- kinase(PI3K)/Akt and mTOR signaling pathways, including PI3K, Akt, PTEN, and DEPTOR, suggesting that this natural compound and its derivatives may offer a promising new cancer treatment.']
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What is known about telomere length shortening and stress?
['A significant relationship between more perceived stress and shorter telomere length is consistent with theoretical frameworks positing that stress induces physiological changes that result in shortened telomeres. ', 'Psychological stress contributes to numerous diseases and may do so in part through damage to telomeres, protective non-coding segments on the ends of chromosomes.', 'Our results support the hypothesis that depression is associated with accelerated cell aging. Future studies are required to clarify whether the association is mediated through environmental stress, and whether effective treatment can halt cell aging.', 'Telomere length, a reliable predictor of disease pathogenesis, can be affected by genetics, chronic stress and health behaviors. Cross-sectionally, highly stressed postmenopausal women have shorter telomeres, but only if they are inactive. ']
['A significant relationship between more perceived stress and shorter telomere length is consistent with theoretical frameworks positing that stress induces physiological changes that result in shortened telomeres.']
[]
What is a "chemobrain"?
['Frequency of chemotherapy-related cognitive impairment or "chemobrain" is mentioned to be significant in literature, although very little is known about the chemotherapy-caused chemobrain and its connection with metal homeostasis alteration.', "Cognitive decline or dementia is a debilitating problem of neurological disorders such as Alzheimer's and Parkinson's disease, including special conditions like chemobrain. ", 'Most cancer patients treated with systemic adjuvant chemotherapy endure long-lasting side effects including decrease in concentration, forgetfulness and slower thinking, which are globally termed "chemobrain." ', 'The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as "chemobrain," a condition that can persist long after the cessation of treatment in as many as 75% of survivors.', 'The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment. ']
['The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment.']
['The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment.']
What is clathrin?
['Clathrin-mediated endocytosis is a central and well-studied trafficking process in eukaryotic cells.', 'We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1).', 'Tubulobulbar complexes are elaborate clathrin/actin related structures that form at sites of intercellular attachment in the seminiferous epithelium of the mammalian testis.', ' Clathrin-coated vesicles (CCVs) are formed at the plasma membrane and act as vectors for endocytosis. They also assemble at the trans-Golgi network (TGN), but their exact function at this organelle is unclear. ', ' Clathrin immunohistochemistry and immunoblotting showed increased immunoreactivity of clathrin protein in the placental tissues of mice treated with 20- and 50-nm gold nanoparticles; clathrin immunopositivity was observed in syncytiotrophoblasts and fetal endothelial cells.']
['Clathrin helps build small vesicles in order to safely transport molecules within and between cells.']
[]
Are high-flow nasal cannulae effective for treatment of preterm infants?
['The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure (CPAP) for noninvasive respiratory support of very preterm infants (gestational age, <32 weeks) after extubation.', 'The use of high-flow nasal cannulae was noninferior to the use of nasal CPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the nasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk difference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). ', 'Although the result for the primary outcome was close to the margin of noninferiority, the efficacy of high-flow nasal cannulae was similar to that of CPAP as respiratory support for very preterm infants after extubation. ', "Recently high flow nasal cannula (HFNC) is emerging as an efficient, better tolerated form of NIV, allowing better access to the baby's face, which may improve nursing, feeding and bonding.", 'In conclusion, there is a growing evidence of the feasibility of HFNC as an alternative mode of NIV. ', 'HHHFNC and NCPAP produced similar rates of extubation failure.', 'The use of HFNC as a respiratory support modality is increasing in the infant, pediatric, and adult populations as an alternative to non-invasive positive pressure ventilation.', 'Current evidence suggests that HFNC is well tolerated and may be feasible in a subset of patients who require ventilatory support with non-invasive ventilation.', 'Heated, humidified, high-flow nasal cannula oxygen therapy (HHHFNC) has been used to improve ventilation in preterm infants. ', 'Increasing flow rates of HHHFNC therapy are associated with linear increases in NP pressures in bronchiolitis patients. ', 'An alternative to the use of nasal continuous positive airway pressure (NCPAP) as a non-invasive modality to support respiratory distress in premature infants has been the recent introduction of high flow nasal cannula (HFNC) devices in many neonatal units. There has been increased use of HFNC presumably because of anecdotal reports and experience that it is easy to use, and well tolerated by the infants, while experiencing decreased nasal septumerosion.', 'High-flow nasal cannulae (HFNC) are gaining in popularity as a form of non-invasive respiratory support for preterm infants in neonatal intensive care units around the world.', 'HFNC may be as effective as NCPAP at improving respiratory parameters such as tidal volume and work of breathing in preterm infants, but probably only at flow rates >2 litres/min. ', 'There is growing evidence of the feasibility of HFNC as an alternative to other forms of non-invasive ventilation in preterm infants. ', 'When used as primary respiratory support after birth, one trial found similar rates of treatment failure in infants treated with HFNC and nasal CPAP. Following extubation, one trial found that infants treated with HFNC had a significantly higher rate of reintubation than those treated with nasal CPAP. Another trial found similar rates of reintubation for humidified and non-humidified HFNC, and the fourth trial found no difference between two different models of equipment used to deliver humidified HFNC. ', 'When used following extubation, HFNC may be associated with a higher rate of reintubation than nasal CPAP. ', 'Early weaning from CPAP to high flow nasal cannula in preterm infants is associated with prolonged oxygen requirement: a randomized controlled trial.', 'After randomization, the no-NC group had fewer days on oxygen [median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p<0.001] and shorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, p=0.03]. There were no differences between groups regarding success of weaning from NCPAP. ', 'Weaning preterm infants from NCPAP to NC is associated with increased exposure to oxygen and longer duration of respiratory support.', 'A number of centers use high-flow nasal cannula (HFNC) in the management of AOP without measuring the positive distending pressure (PDP) generated.', 'HFNC is as effective as NCPAP in the management of AOP.']
['Yes. The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure for noninvasive respiratory support of preterm infants after extubation. However, the use of high-flow nasal cannulae in preterm infants was shown to be associated with a higher rate of reintubation, increased exposure to oxygen and longer duration of respiratory support. High-flow nasal cannulae are also effective for treatment of apnea of prematurity.']
['yes']
Tumors of which three organs are classically associated with the multiple endocrine neoplasia type 1 syndrome?
['Multiple endocrine neoplasia type 1 (MEN1; formerly known as Wermer syndrome) is a rare disorder characterized by the combined occurrence of two or more tumors involving parathyroid, pancreatic islets and anterior pituitary glands; some other tumors have also been described.', ' Hyperparathyroidism is the most common feature of MEN1 (95% of patients), pancreatic islet tumors or pancreatic NET (neuroendocrine tumor) occur in 40-70% and pituitary tumors in 30-40% of MEN 1 patients', ' In addition, other tumors, such as adrenal cortical tumors, carcinoid tumors, lipomas, angiofibromas, colagenomas and meningiomas may be present. ', 'the most important causes malignant pancreatic neuroendocrine tumors (NET) and thymic carcinoids. ', 'Multiple endocrine neoplasia type 1 (MEN1) is inherited in an autosomal dominant fashion and predisposes to the development of hyperplastic or neoplastic changes in the parathyroid and pituitary glands and the endocrine pancreas, along with numerous other characteristic tumors and features. ', 'Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid and adrenocortical tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. ', 'The pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary NETs are mostly prolactinomas and somatotrophinomas. ', 'We address the potential role of miRNAs in the endocrine pancreas, the pituitary gland, and the parathyroid glands-areas where MEN 1 shows high penetrance. ', 'Moreover, studies have provided evidence that dysregulation of miRNAs was responsible for endocrine carcinogenesis, including pancreatic, pituitary, and parathyroid tumors.', 'MEN1 and MEN2 are rare inherited cancer syndromes which express a variety of endocrine and nonendocrine tumors.', 'Multiple endocrine neoplasia Type 1 (MEN1) is a rare hereditary tumor syndrome predisposing to tumor development in several endocrine organs.', ' Its major manifestations include hyperparathyroidism, tumors of endocrine pancreas and pituitary. ', 'eside these three, several other endocrine (adrenocortical, foregut carcinoid) and nonendocrine (lipoma, angiofibroma, collagenoma, ependymoma, meningioma) tumors have been described to be associated with this syndrome', 'Both familial and sporadic forms of the disease are known. The diagnosis of MEN1 can be established if two of the three major manifestations are found in the same patient, whereas the diagnosis of familial MEN1 requires one MEN1 patient and a first degree relative with at least one MEN1 manifestation. ', 'Both benign (parathyroid, anterior pituitary) and malignant (gastrinoma, glucagonoma) lesions may develop in MEN1 patients', 'Multiple endocrine neoplasia type 1 (MEN1) is a classic hereditary tumor syndrome characterized by a genetic predisposition to develop a variety of neuroendocrine neoplasias and hormone excess syndromes.', 'Multiple endocrine neoplasia type 1 (MEN 1) is a familial syndrome characterized by parathyroid, enteropancreatic and pituitary tumors. ', 'Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited tumor syndrome characterized by the development of multiple endocrine tumors', 'Multiple facial angiofibromas were observed in 28 (88%) of the patients with MEN1, with 16 patients (50%) having 5 or more. Angiofibromas were clinically and histologically identical to those in individuals with tuberous sclerosis. Collagenomas were observed in 23 patients (72%). Also observed were cafe au lait macules in 12 patients (38%), lipomas in 11 patients (34%), confetti-like hypopigmented macules in 2 patients (6%), and multiple gingival papules in 2 patients (6%)', 'Multiple angiofibromas, collagenomas, lipomas, confetti-like hypopigmented macules and multiple gingival papules are cutaneous manifestations of MEN1 and should be looked for in both family members of patients with MEN1 and individuals with hyperparathyroidism of other MEN1-associated tumors. ', 'Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by nodular proliferation of the parathyroid glands and tumors of the anterior pituitary gland, the endocrine pancreas, and the neuroendocrine cell system of the gut.', 'We report here a genetic study of a female MEN1 patient with the association of nodular hyperplasia of two parathyroid glands, an insulinoma, multiple duodenal gastrinomas, a prolactinoma, and a gastric carcinoid.', 'Multiple endocrine neoplasia type 1 (MEN1) is defined clinically by the combined occurrence of multiple tumors, typically of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland.', 'In support of previous findings in islet tumors, we found down-regulation of the cell-cycle regulator, p18, in both the pancreatic islet and pituitary adenomas, suggesting that reduced p18 levels may be important for Men1-related tumorigenesis in multiple tissues. Surprisingly, we identified increased p16 transcript in pancreatic islet and pituitary tumors. ', ' The patient was studied and diagnosed with a multiple endocrine neoplasia type I (MEN I), familiar (mother with MEN I). A scintigraphic study with 99mTc-MIBI was performed in order to localize hyperfunctioning parathyroid glands because of biochemical diagnosis of primary hyperparathyroidism. ', 'The tumor was removed and histologically confirmed as a carcinoid within a thymus in a MEN type I syndrome. ', 'MEN I patients can benefit from the examination with this agent which can potentially localize not only parathyroid endocrine pathology but also unknown associated tumors.', 'Pancreatic endocrine tumors occur sporadically and as part of the multiple endocrine neoplasia type 1 (MEN 1) and von Hippel-Lindau (VHL) syndromes. ', 'We have analyzed 22 nonfamilial and 16 MEN 1-associated pancreatic endocrine tumors for loss of heterozygosity (LOH) at 3p, 11q13, and 18q. LOH at 3p was revealed in 45% and 36% of tumors from 31 patients with nonfamilial and MEN 1-associated disease, respectively.', 'The data indicate involvement of tumor suppressor genes on 3p and 18q, in addition to the MEN1 gene at 11q13, in the tumorigenesis of both nonfamilial and MEN 1-associated pancreatic endocrine tumors.', 'Multiple endocrine neoplasia type 1 (MEN1) is characterized by the development of endocrine tumors of the parathyroid and pituitary glands, pancreas, and duodenum. Less frequently occurring tumors associated with MEN1 include non-endocrine tumors such as lipomas and angiofibromas. ', 'An increased incidence of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 population. ', 'A germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene were consistently detected in multiple neuroendocrine tumors involving the parathyroid glands and the pancreas and a hepatic neuroendocrine tumor metastasis, as predicted by Knudson\'s "two hit" hypothesis.', "Two hits of the MEN1 gene were also detected in esophageal leiomyoma tissue, suggesting that tumorigenesis was directly related to the patient's underlying MEN1.", ' In contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal nodular hyperplasia, and adrenal cortical hyperplasia consistently showed retained heterozygosity of the MEN1 gene with flanking markers and an intragenic marker. Therefore, these tumors appear to develop along pathogenetic pathways that are different from classical MEN1-associated tumors.', 'Twelve unrelated (German MEN1 families and their associated tumors (5 parathyroid tumors, 1 vipoma, 1 gastrinoma, 1 insulinoma) were characterized for MEN1 gene mutations by single-strand conformational variant (SSCV) analysis and DNA sequence analysis as well as for loss of heterozygosity on chromosome 11q13. ', 'Multiple endocrine neoplasia type 1 (MEN1) consists of benign, and sometimes malignant, tumors (often multiple in a tissue) of the parathyroids, enteropancreatic neuroendocrine system, anterior pituitary, and other tissues. Skin angiofibromas and skin collagenomas are common. ']
['Multiple endocrine neoplasia type 1 syndrome is an inherited cancer syndrome defined by occurrence of multiple neuro-endocrine tumors and is classically associated with the combined occurrence of two or more tumors involving parathyroid gland, pancreas and pituitary gland. Other tumors, including but not limited to adrenal cortical tumor, carcinoid tumors lipoma, leiomyoma, duodenal gastrinoma, hepatic focal nodular hyperplasia, and renal angiomyolipoma, angiofibroma, colagenoma, thyroid tumor and meningioma, may also be present.']
['parathyroid gland', 'pancreas', 'pituitary gland']
How does stress affect telomere length?
['["A significant relationship between more perceived stress and shorter telomere length is consistent with theoretical frameworks positing that stress induces physiological changes that result in shortened telomeres. ", "Psychological stress contributes to numerous diseases and may do so in part through damage to telomeres, protective non-coding segments on the ends of chromosomes.", "Our results support the hypothesis that depression is associated with accelerated cell aging. Future studies are required to clarify whether the association is mediated through environmental stress, and whether effective treatment can halt cell aging.", "Telomere length, a reliable predictor of disease pathogenesis, can be affected by genetics, chronic stress and health behaviors. Cross-sectionally, highly stressed postmenopausal women have shorter telomeres, but only if they are inactive. "]']
Stress can lead to physiological changes that result in shortened telomeres. Psychological stress may contribute to diseases by damaging telomeres, which are protective segments on the ends of chromosomes. Highly stressed postmenopausal women have shorter telomeres, particularly if they are inactive.
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Which protein is causing Netherton syndrome?
['Netherton syndrome (NTS) is a rare genetic skin disease caused by mutations in the serine protease inhibitor Kazal-type 5 gene, which encodes the lympho-epithelial Kazal-type-related inhibitor.', 'Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 ', 'Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal type 5) which encodes for a serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor)', 'Mutations in the serine protease inhibitor Kazal type 5 (SPINK5) gene leading to lymphoepithelial Kazal-type-related inhibitor (LEKTI) deficiency cause NS.', '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.', 'syndrome and caused by a genetic mutation in SPINK5, may be a facilitating factor for the infection.', 'NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. ', 'Netherton syndrome, which arises due to mutations in serine protease inhibitor Kazal-type 5 (SPINK5)', 'Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is the defective protein of the ichthyosiform condition Netherton syndrome (NS).', 'Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome, which causes detachment of the stratum corneum and chronic inflammation. ']
['Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal type 5) which encodes for a serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor)']
['LEKTI', 'lymphoepithelial Kazal type-related inhibitor']
Selexipag is used for which disease?
['OBJECTIVE: Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension.', 'Selexipag for the treatment of pulmonary arterial hypertension.', 'This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH).', 'Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014).', 'Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.', 'OBJECTIVE: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects.', 'These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.', 'Our results encourage the further investigation of selexipag for the treatment of PAH.', 'Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension.', 'These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease', 'OBJECTIVE: Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. ', 'This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH).', 'Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014).', 'Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.', ' The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.', 'These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.', 'Selexipag for the treatment of pulmonary arterial hypertension.']
['Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension.']
['pulmonary arterial hypertension']
Which post-translational histone modifications are characteristic of constitutive heterochromatin?
['H3S10 phosphorylation marks constitutive heterochromatin during interphase in early mouse embryos until the 4-cell stage', 'We show here that the maternally inherited Snurf-Snrpn 3-Mb region, which is silenced by a potent transcription repressive mechanism, is uniformly enriched in histone methylation marks usually found in constitutive heterochromatin, such as H4K20me3, H3K9me3, and H3K79me3.', 'This result indicates that H3K36me3 is associated with both facultative and constitutive heterochromatin.', 'Classical histone modifications associated with heterochromatin, including H3K9me2, H3K27me1 and H3K27me2, were distributed throughout both A and B chromosomes.', 'In this review, available data will be evaluated concerning (1) the phylogenetic distribution of H3K9me as heterochromatin-specific histone modification and its evolutionary stability in relation to other epigenetic marks, (2) known families of H3K9 methyltransferases, (3) their responsibility for the formation of constitutive heterochromatin and (4) the evolution of Su(var)3-9-like and SUVH-like H3K9 methyltransferases', ' While these regions were furthermore largely devoid of the constitutive heterochromatin marker H3K9-me3, we observed rapid and widespread deposition of H3K27-me3 across latent KSHV genomes, a bivalent modification which is able to repress transcription in spite of the simultaneous presence of activating marks.', 'Histone modifications in Arabidopsis- high methylation of H3 lysine 9 is dispensable for constitutive heterochromatin', 'The recent discovery of the first histone Lys methyltransferase has allowed the identification of a molecular mechanism in which the specific methylation of histone H3 at Lys9 generates a binding site for heterochromatin-associated proteins.', 'At the SUMO-1 labelled areas, the presence of HP1alpha protein, as well as of trimethylated H3-K9 and H4-K20 histone modifications, supports a role for SUMO-1 in constitutive heterochromatin organization.', 'Surprisingly, the marsupial Xi was stably enriched for modifications associated with constitutive heterochromatin in all eukaryotes (H4K20me3, H3K9me3).', 'Constitutive heterochromatin during mouse oogenesis: the pattern of histone H3 modifications and localization of HP1alpha and HP1beta proteins.', 'In fission yeast, heterochromatin formation requires RNAi and the histone H3K9 methyltransferase complex CLRC, composed of Clr4, Raf1, Raf2, Cul4, and Rik1. ', 'Methylation of histone H3 at lysine 9 (H3-Lys9) by site-specific histone methyltransferases (Suv39h HMTases) marks constitutive heterochromatin. ', 'H3S10 phosphorylation marks constitutive heterochromatin during interphase in early mouse embryos until the 4-cell stage.', 'In placental mammals non-coding XIST RNA triggers silencing of one X (Xi) and recruits a characteristic suite of epigenetic modifications, including the histone mark H3K27me3.']
['H3K9me3 is the major marker of constitutive heterochromatin. Other histone methylation marks usually found in constitutive heterochromatin, are H4K20me3 and H3K79me3. Classical histone modifications associated with heterochromatin include H3K9me2, H3K27me1 and H3K27me2. Histone H3 trimethylation at lysine 36 is associated with constitutive and facultative heterochromatin. H3S10 phosphorylation marks constitutive heterochromatin during interphase in early mouse embryos until the 4-cell stage']
['H3S10p', 'H3K36me3', 'H4K20me3', 'H3K9me3', 'H3K79me3', 'H3K9me2', 'H3K27me1', 'H3K27me2', 'H3K27me3']
Is Stat4 a transcription factor?
['transcription factors T-bet and STAT4', 'STAT4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus. ', 'STAT4 is a latent cytosolic factor that encodes a transcription factor transmitting signals stimulated by cytokines. ', ' To investigate the role of signal transduction and activation of transcription 4 (STAT4) in the development and progression of human hepatocellular carcinoma (HCC)']
['Yes, Stat4 is a transcription factor.\nStat4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus.']
['yes']
What is the target of the drug Olaparib?
['We show that targeting PARP by the small molecule inhibitors, Olaparib ', 'Following treatment with the PARP1 inhibitor olaparib, ', 'the PARP inhibitor olaparib', 'Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors.', 'The poly(ADP-ribose) polymerase inhibitor olaparib', 'olaparib (poly(ADP ribose)polymerase inhibitor)', ' olaparib, a PARP inhibitor, ', 'Olaparib is an oral poly (ADP-ribose) polymerase inhibitor', 'olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. ', 'he poly (ADP-ribose) polymerase inhibitor olaparib ', ' PARP-inhibitor, Olaparib', 'Olaparib is a poly(ADP-ribose) polymerase inhibitor', 'olaparib, a specific PARP1 inhibitor.', 'PARP inhibitor olaparib ', 'We used two PARP inhibitors in clinical development, olaparib and rucaparib', ' the PARPi, olaparib, ']
['The drug Olaparib target the protein poly(ADP-ribose) polymerase.']
['poly(ADP-ribose) polymerase', 'PARP']
What is the main biological function of the CRISPR-CAS9 genome editing system?
['Mutagenesis and homologous recombination in Drosophila cell lines using CRISPR/Cas9.', 'We have applied the CRISPR/Cas9 system to Drosophila S2 cells to generate targeted genetic mutations in more than 85% of alleles. By targeting a constitutive exon of the AGO1 gene, we demonstrate homozygous mutation in up to 82% of cells, thereby allowing the study of genetic knockouts in a Drosophila cell line for the first time. We have shown that homologous gene targeting is possible at 1-4% efficiency using this system, allowing for the construction of defined insertions and deletions.', 'This technology enables controlled genetic manipulation in Drosophila cell lines, and its simplicity offers the opportunity to study cellular phenotypes genome-wide.', 'The prokaryotic CRISPR/Cas9 type II genome editing system has recently been applied in cell lines and vertebrates.', 'We now demonstrate that CRISPR/Cas9 mutagenesis in zebrafish is highly efficient, reaching up to 86.0%, and is heritable. The efficiency of the CRISPR/Cas9 system further facilitated the targeted knock-in of a protein tag provided by a donor oligonucleotide with knock-in efficiencies of 3.5-15.6%. ', 'The ease and efficiency of the CRISPR/Cas9 system with limited off-target effects make it a powerful genome engineering tool for in vivo studies.', 'Cas9/CRISPR has been reported to efficiently induce targeted gene disruption and homologous recombination in both prokaryotic and eukaryotic cells.', 'Sequence-specific nucleases like TALENs and the CRISPR/Cas9 system have greatly expanded the genome editing possibilities in model organisms such as zebrafish. Both systems have recently been used to create knock-out alleles with great efficiency, and TALENs have also been successfully employed in knock-in of DNA cassettes at defined loci via homologous recombination (HR). Here we report CRISPR/Cas9-mediated knock-in of DNA cassettes into the zebrafish genome at a very high rate by homology-independent double-strand break (DSB) repair pathways.', 'The type II CRISPR/Cas9 system (clustered regularly interspaced short palindromic repeats/CRISPR-associated) has recently emerged as an efficient and simple tool for site-specific engineering of eukaryotic genomes.', 'The CRISPR/Cas9 system has attracted significant attention for its potential to transform genome engineering. We and others have recently shown that the RNA-guided Cas9 nuclease can be employed to engineer the Drosophila genome, and that these modifications are efficiently transmitted through the germline.', 'Here we highlight the variety of genome modifications facilitated by the CRISPR/Cas9 system along with key considerations for starting your own CRISPR genome engineering project.', 'Here, we present a simple and highly efficient method for generating and detecting mutations of\xa0any gene in Drosophila melanogaster through the\xa0use of the CRISPR/Cas9 system (clustered regularly\xa0interspaced palindromic repeats/CRISPR-associated).', 'Recently the type II prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system has been adapted to serve as a targeted genome mutagenesis tool.', 'This CRISPR/Cas9 system represents a highly effective and scalable gene knockout method in zebrafish and has the potential for applications in other model organisms.', 'The CRISPR/Cas system has been adapted as an efficient gene-targeting technology with the potential for multiplexed genome editing.']
['The CRISPR/Cas9 system (clustered regularly interspaced short palindromic repeats/CRISPR-associated) has recently emerged as an efficient and simple tool for site-specific engineering of eukaryotic genomes. The CRISPR/Cas9 system has attracted significant attention for its potential to transform genome engineering. It has been shown that the RNA-guided Cas9 nuclease can be employed to engineer the Drosophila genome, and that these modifications are efficiently transmitted through the germline. The CRISPR/Cas9 system has been reported to efficiently induce targeted gene disruption and homologous recombination in both prokaryotic and eukaryotic cells. The CRISPR/Cas9 system has been used to create knock-out alleles with great efficiency, and it has also been employed in knock-in of DNA cassettes at defined loci via homologous recombination (HR). The ease and efficiency of the CRISPR/Cas9 system with limited off-target effects make it a powerful genome engineering tool for in vivo studies.']
[]
Which is the E3 ubiquitin ligase of Hsp90?
['C-terminal Hsp-interacting protein (CHIP) is an HSP70 and HSP90 interacting co-chaperone and an E3 ubiquitin ligase. Previous studies have reported the role of CHIP in cancer progression by targeting protein degradation.', 'The U-box E3 ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins.', 'In vitro ubiquitination assays indicated that Ca(2+)/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1.', 'The E3 ubiquitin ligase CHIP (C-terminus of Hsc70-interacting protein) is believed to be a central player in the cellular triage decision, as it links the molecular chaperones Hsp70/Hsc70 and Hsp90 to the ubiquitin proteasomal degradation pathway.', 'We found that CHIP has a sixfold higher affinity for Hsp90 compared with Hsc70.', 'Carboxyl terminus of hsc70-interacting protein (CHIP) can remodel mature aryl hydrocarbon receptor (AhR) complexes and mediate ubiquitination of both the AhR and the 90 kDa heat-shock protein (hsp90) in vitro', 'The analysis of the sucrose-gradient-fractionated in vitro translated AhR complexes revealed that CHIP can mediate hsp90 ubiquitination while cooperating with unidentified factors to promote the ubiquitination of mature unliganded AhR complexes.']
['Carboxyl terminus of hsc70-interacting protein (CHIP) can mediate ubiquitination of the 90 kDa heat-shock protein (hsp90) in vitro, with subsequent proteasomal degradation of the chaperone.']
['Carboxyl terminus of hsc70-interacting protein (CHIP)']
List human proteins that are subject to a dimer-to-tetramer transition.
[' the ability of GAC to undergo the dimer-to-tetramer transition necessary for enzyme activation.', 'while SHMT2 undergoes a dimer-to-tetramer transition upon PLP binding.', 'AMPARs that is required for the critical dimer-to-tetramer transition.', 'We conclude that the human Orai1 and Orai3 channels undergo a dimer-to-tetramer transition to form a Ca(2+)-selective pore during store-operated activation and that Orai3 forms a dimeric nonselective cation pore upon activation by 2-APB.', 'the conformational requirement for the dimer-to-tetramer transition during the maturation of AMPA-Rs. ']
['GAC\nSHMT2\nAMPAR\nOrai1\nOrai3']
['GAC', 'SHMT2', 'AMPAR', 'Orai1', 'Orai3']
What is the characteristic domain of histone methyltransferases?
['C-terminal SET domain that catalyzes methylation of histone H3', 'not all members of the H3K4 methyltransferase family contain n-SET domains', 'protein methyltransferases (both protein arginine and lysine methyltransferases) and the relatedness of their catalytic domains. We identified 51 protein lysine methyltransferase proteins based on similarity to the canonical Drosophila Su(var)3-9, enhancer of zeste (E(z)), and trithorax (trx) domain', ' a SET domain histone methyltransferase ', 'A common feature of the mammalian MLL/SET1 complexes is the presence of three core components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain', 'catalytic histone methyltransferase SET-domain', 'SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues', 'The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain.', 'Polycomb repressive complex 2 (PRC2), which methylates lysine 27 of histone H3. Information on how PRC2 works is limited by lack of structural data on the catalytic subunit, Enhancer of zeste (E(Z)), and the paucity of E(z) mutant alleles that alter its SET domain.', 'histone modification is catalyzed by protein lysine methyltransferases (PKMTs). PKMTs contain a conserved SET domain', 'Set1A complex analogous to the yeast Set1/COMPASS histone H3-Lys4 methyltransferase complex ', 'Set1A protein shares 39% identity with an uncharacterized SET domain protein', 'multiple methylations catalyzed by SET domain protein methyltransferases', 'methyl group transfers by SET domain protein lysine methyltransferases.', 'SET domain protein functions as a histone methyltransferase', 'SUV39H1 impaired enzyme activity despite the presence of an intact catalytic SET domain', 'Meisetz (meiosis-induced factor containing a PR/SET domain and zinc-finger motif) is a histone methyltransferase', 'The fly complex contains a catalytic SET domain subuni', 'ESC-E(Z) complex of Drosophila melanogaster Polycomb group (PcG) repressors is a histone H3 methyltransferase (HMTase)', 'Murine G9a is a 1263 amino acid H3-K9 methyltransferase that possesses characteristic SET domain and ANK repeats', 'domains of SET proteins becoming ordered upon addition of AdoMet cofactor and develop a model for the catalytic cycle of these enzymes', 'SET domain, first identified within and named after proteins encoded by three Drosophila genes [Su(var)3-9, E(z), and Trithorax], is recognized as a signature motif for histone methyltransferases ', '(HMT)(1) class enzymes that methylate lysine residues of histones or proteins contain a conserved catalytic core termed the SET domain', 'ERG-associated protein with a SET domain, also called SETDB1) is a novel histone methyltransferase that catalyzes methylation of histone H3-lysine 9 (H3-K9)', 'SET domain histone methyltransferase', ' Unlike other histone methyltransferases, Dot1 does not contain a SET domain,', 'SET domain-containing HMTase ', 'SET (suppressor of variegation, enhancer of zest and trithorax) domain (ESET) that was found to have the activity of a histone H3-specific methyltransferase', 'SET domain contains the catalytic center of lysine methyltransferases that target the N-terminal tails of histones and regulate chromatin function', ' The evolutionarily conserved SET domain occurs in most proteins known to possess histone lysine methyltransferase activity', 'the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity']
['SET (suppressor of variegation, enhancer of zest and trithorax) domain']
['SET domain']
Which is the most known bacterium responsible for botulism (sausage-poisoning)?
['Botulism is a serious foodborne neuroparalytic disease, caused by botulinum neurotoxin (BoNT), produced by the anaerobic bacterium Clostridium botulinum.', 'Cattle botulism is a fatal intoxication caused by botulinum neurotoxins (BoNTs) produced by Clostridium botulinum serotypes C and D', 'Botulism in horses in the USA is attributed to Clostridium botulinum types A, B or C.', 'Clostridium botulinum is the etiological agent of botulism. Due to food-borne poisoning and the potential use of the extremely toxic botulinum neurotoxin (BoNT) from C. botulinum', 'Botulism is a serious neuroparalytic disease caused by toxins of Clostridium botulinum. Botulinum toxin is produced under anaerobic conditions and is one of the most dangerous toxin in the world.', 'Botulism is a neuroparalytic disease that can occur in all warm-blooded animals, birds, and fishes. The disease in animals is mainly caused by toxins produced by Clostridium botulinum strains belonging to group III, although outbreaks due to toxins produced by group I and II organisms have been recognized.', 'Botulism is a severe neuroparalytic disease that affects humans, all warm-blooded animals, and some fishes. The disease is caused by exposure to toxins produced by Clostridium botulinum and other botulinum toxin-producing clostridia.', 'The botulinum neurotoxins (BoNTs) produced by different strains of the bacterium Clostridium botulinum are responsible for the disease botulism and include a group of immunologically distinct serotypes (A, B, E, and F) that are considered to be the most lethal natural proteins known for humans.', 'Botulinumtoxin (BTX) is a neurotoxin produced from Clostridium botulinum under anaerobic conditions and is responsible for botulism, a notifiable, bacterial form of food poisoning.', 'Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum.', 'An epidemiological investigation and laboratory detection studies showed that sausage contaminated by type A Clostridium botulinum caused this outbreak of food poisoning.', 'Botulism is caused by botulinum neurotoxin produced by the bacterium Clostridium botulinum.', 'Botulinumtoxin (BTX) is a neurotoxin produced from Clostridium botulinum under anaerobic conditions and is responsible for botulism, a notifiable, bacterial form of food poisoning']
['Botulism is a severe neuroparalytic disease caused by botulinum neurotoxin (BoNT), and affects humans, all warm-blooded animals, birds, and some fishes. Botulinum toxin is produced under anaerobic conditions by the bacterium Clostridium botulinum, which is the most known etiological agent of the disease, and some other clostridia, and is one of the most dangerous toxin in the world.']
['Clostridium botulinum']
Explain the concept proteostasis.
['Protein homeostasis, or proteostasis, refers to a proper balance between synthesis, maturation, and degradation of cellular proteins.', 'Mechanisms that promote the homeostasis of the proteome, or proteostasis, can slow aging and decrease the incidence of age-related diseases.', 'The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states.', ' protein homeostasis (proteostasis) ', 'The folding biology common to all three kingdoms of life (Archaea, Bacteria, and Eukarya) is proteostasis. The proteostasis network (PN) functions as a “cloud” to generate, protect, and degrade the proteome.', 'Maintaining the dynamic proteome of a living cell in the face of an ever-changing environment depends on a fine-tuned balance of protein synthesis and protein degradation. Molecular chaperones exert key functions during protein homeostasis (proteostasis). ', 'This research highlighted the central importance of protein homeostasis, or proteostasis for short, defined as the cellular state in which the proteome is both stable and functional. It implicates an equilibrium between synthesis, folding, trafficking, aggregation, disaggregation and degradation.', 'Protein homeostasis, also called proteostasis, is critical for cellular health and its dysregulation is implicated in aging, cancer, metabolic disease, and neurodegenerative disorders.', ' protein homeostasis (proteostasis) ', ' Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases.', 'Protein homeostasis, proteostasis, is essential to understand cell function. Protein degradation is a crucial component of the proteostatic mechanisms of the cell.', 'Maintaining correct cellular function is a fundamental biological process for all forms of life. A critical aspect of this process is the maintenance of protein homeostasis (proteostasis) in the cell, which is largely performed by a group of proteins, referred to as the protein quality control (PQC) network. This network of proteins, comprised of chaperones and proteases, is critical for maintaining proteostasis not only during favourable growth conditions, but also in response to stress. ', 'All organisms--Bacteria, Archaea and Eukarya--have evolved a protein homeostasis, or proteostasis, network comprising chaperones and folding factors, degradation components, signalling pathways and specialized compartmentalized modules that manage protein folding in response to environmental stimuli and variation. ']
['Protein homeostasis, or proteostasis, refers to a proper balance between synthesis, maturation, and degradation of cellular proteins. Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases.']
[]
What is the application of the Bimolecular Fluorescence Complementation (BiFC) assay in Drosophila embryos?
['Bimolecular fluorescence complementation (BiFC) is a powerful method for studying protein-protein interactions in different cell types and organisms. This method was recently developed in the fruit fly Drosophila melanogaster, allowing analyzing protein interaction properties in a physiologically relevant developing context. Here we present a detailed protocol for performing BiFC with the Venus fluorescent protein in live Drosophila embryos, taking the Hox-PBC partnership as an illustrative test case. This protocol applies to any transcription factor and split fluorescent protein in general.', 'The understanding of developmental complexity will, therefore, require the characterization of protein interactions within their proper environment. The bimolecular fluorescence complementation (BiFC) technology offers this possibility as it enables the direct visualization of protein interactions in living cells.', 'Using a Hox protein partnership as a test case, we investigated the suitability of BiFC for the study of protein interactions in the living Drosophila embryo. Importantly, all BiFC parameters were established with constructs that were stably expressed under the control of endogenous promoters. Under these physiological conditions, we showed that BiFC is specific and sensitive enough to analyse dynamic protein interactions. We next used BiFC in a candidate interaction screen, which led to the identification of several Hox protein partners.', 'Using fluorescent proteins, we previously developed a bimolecular fluorescence complementation (BiFC) assay and a multicolor BiFC assay to visualize protein-protein interactions in living cells.', 'The bimolecular fluorescence complementation (BiFC) assay represents one of these imaging tools for direct visualization of PPIs in living cells.', 'The bimolecular fluorescence complementation (BiFC) assay provides an approach for the visualization of protein interactions and modifications in living cells.', 'The bimolecular fluorescence complementation (BiFC) assay provides a direct approach for the visualization of molecular interactions in living cells and organisms.', 'The purpose of this protocol is to calculate signal-to-noise (S/N) ratio in the bimolecular fluorescence complementation (BiFC) assay and to provide a semi-quantitative analysis of protein-protein interaction (PPI) in living cells.', 'Bimolecular fluorescence complementation (BiFC) analysis enables direct visualization of protein interactions in living cells.', 'The bimolecular fluorescence complementation (BiFC) assay has been widely accepted for studying in vivo detection of protein-protein interactions in several organisms.', 'Visualization of protein interactions in living Drosophila embryos by the bimolecular fluorescence complementation assay.', 'RESULTS: Using a Hox protein partnership as a test case, we investigated the suitability of BiFC for the study of protein interactions in the living Drosophila embryo. ', 'Design and implementation of bimolecular fluorescence complementation (BiFC) assays for the visualization of protein interactions in living cells.', 'However, its potential has rarely been applied in embryos of animal model organisms and was only performed under transient protein expression levels. RESULTS: Using a Hox protein partnership as a test case, we investigated the suitability of BiFC for the study of protein interactions in the living Drosophila embryo. ', 'However, its potential has rarely been applied in embryos of animal model organisms and was only performed under transient protein expression levels. Using a Hox protein partnership as a test case, we investigated the suitability of BiFC for the study of protein interactions in the living Drosophila embryo.', 'The bimolecular fluorescence complementation (BiFC) technology offers this possibility as it enables the direct visualization of protein interactions in living cells. However, its potential has rarely been applied in embryos of animal model organisms and was only performed under transient protein expression levels.', 'we previously developed a bimolecular fluorescence complementation (BiFC) assay and a multicolor BiFC assay to visualize protein-protein interactions in living cells.', 'Using a Hox protein partnership as a test case, we investigated the suitability of BiFC for the study of protein interactions in the living Drosophila embryo.', 'Using fluorescent proteins, we previously developed a bimolecular fluorescence complementation (BiFC) assay and a multicolor BiFC assay to visualize protein-protein interactions in living cells.']
['Bimolecular fluorescence complementation (BiFC) is a powerful method for studying protein-protein interactions in different cell types and organisms. This method was recently developed in the fruit fly Drosophila melanogaster, allowing analyzing protein interaction properties in a physiologically relevant developing context.']
['The study of protein-protein interactions in a physiologically relevant developing context.']
How is spastic diplegia diagnosed?
['Spastic diplegia is the most common form of cerebral palsy worldwide.', 'Hereditary spastic paraplegia (HSP) and spastic diplegia (SD) patients share a strong clinical resemblance. Thus, HSP patients are frequently misdiagnosed with a mild form of SD. Clinical gait analysis (CGA) has been highlighted as a possible tool to support the differential diagnosis of HSP and SD', 'The predominant clinical feature of patients with Hereditary Spastic Paraparesis (HSP) is gait disturbance owing to spasticity and weakness of the lower limbs; the spasticity in early-onset disease (infancy or childhood) often cannot be distinguished from mild form of spastic diplegia (SD)', 'The aim of this study was to quantify the gait strategy in HSP and SD children, focusing on the differences between groups as concerns functional limitation during gait. 9 HSP and 16 SD children were evaluated using Gait Analysis; kinematic and kinetic parameters and EMG pattern during walking were identified and calculated to compare the two gait strategies', 'In contrast to other urea cycle disorders, hyperammonemic encephalopathy is rarely observed in patients with argininemia. Rather, most exhibit an insidious onset and progression of neurologic manifestations, including spastic diplegia.', 'We conclude that argininemia should be considered more frequently in the differential diagnosis of a patient with slowly progressive neurologic manifestations, especially progressive spastic diplegia, even in a population where argininemia was previously unknown', 'To assess the reliability and validity of a newly described classification of sagittal plane alignment in spastic diplegic gait.', 'The objective of this prospective study was the application of proton magnetic resonance spectroscopy in children with spastic diplegia (SD) to determine the metabolite profile of SD children in the left basal ganglia, and to assess the relationship of this profile with motor and mental developmen', 'The aim of this study was to establish the reliability and validity of visual gait assessment in children with spastic diplegia, who were community or household ambulators, using a modified version of the Physicians Rating Scale, known as the Observational Gait Scale (OGS).', 'The aim of this study was to analyse quantitatively the gait of HSP and SD subjects in order to define the gait pattern in HSP and the differences between the two conditions', 'This study shows that GA complements traditional clinical evaluations, making it possible to distinguish, clearly, between motor ability in HSP and in SD patients; the duration of the knee hyperextension during midstance was found to discriminate between the two gait patterns.', "nstruct validity of the In-Hand Manipulation Test (IMT) by assessing the test's ability to discriminate between samples of children with and without known fine motor problems.METHOD: The IMT was administered to 55 children without known fine motor problems and 24 children with spastic diplegia who had mild to moderate fine motor problems.", 'A discriminant analysis indicated that IMT total score correctly classified 83.33% of the participants as having or not having fine motor problems.', 'Calcaneal gait or deformity can be a significant complication after heel cord lengthening. After heel cord lengthening, 20 children with spastic diplegia were evaluated by gait analysis to define calcaneal gait objectively and describe associated morbidity.', 'Significant differences were found in birth weight, birth head circumference, and the one-minute Apgar score', ' Intracranial hemorrhage and neonatal seizures occurred significantly more often in infants with SD', 'On the Movement Assessment of Infants at 4 months of age, the children with hemiplegia and quadriplegia showed significantly higher risk scores than the nonhandicapped group', 'At 1 year of age, however, the Bayley Motor Scale was extremely sensitive in picking up motor deficits in children with all three types of cerebral palsy.', 'Hip flexion combined with knee extension (leg elevation) and isolated knee movements were not seen in diplegic infants, but were seen in all control preterm infants with a good prognosis, after five and six months corrected age, respectively. The absence of these movements is a useful diagnostic item for spastic diplegia.', 'Full body gait analysis may improve diagnostic discrimination between hereditary spastic paraplegia and spastic diplegia', 'Clinical gait analysis (CGA) has been highlighted as a possible tool to support the differential diagnosis of HSP and SD. Previous analysis has focused on the lower-body but not the upper-body, where numerous compensations during walking occur. The aim of this study was to compare the full-body movements of HSP and SD groups and, in particular, the movement of the upper limbs', 'The study subjects were eight patients with spastic diplegia and eight normal children. Three-dimensional gait analysis was used for the survey. The measured gait variables were the joints of the lower extremity in the sagittal plane, frontal plane, and transverse planes and the maximum and minimum angles of their stance phase and swing phases', 'Relationships between spasticity, strength, gait, and the GMFM-66 in persons with spastic diplegia cerebral palsy.', '[Purpose] This study aimed to investigate the effects of Vojta therapy on spatiotemporal gait parameters in children with spastic diplegia. [Methods] The study population consisted of 3 children diagnosed with spastic diplegia.', 'The aim of this study was to explore the physical status and gait patterns of children with spastic diplegia secondary to human immunodeficiency virus encephalopathy (HIVE). A cross-sectional study was conducted on children diagnosed with HIVE and spastic diplegia.', 'The results demonstrated that HSP patients used more spine movement to compensate for lower limb movement alterations, whereas SD patients used their arms for compensation', 'To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia', 'To examine the validity and clinical utility of functional assessments (1-minute walk test, 10-meter walk test, Timed Up&Go [TUG] test, Timed Up and Down Stairs [TUDS]test, sit-to-stand [STS] test, and lateral step-up [LSU]test)', 'These functional assessments (1-minute walk, LSU, and 10-meter walk tests) are simple to administer, quick, low cost, and user-friendly. Although these assessments are not a substitute for the criterion standard (GMFM-88), they may be used for a quick assessment in adolescents with cerebral palsy (levels I-III) either at school or during rehabilitation, especially when time is limited', 'The aim of this study was to evaluate the effect of dynamic bilateral postural stability on balance control and gait parameters in children with cerebral palsy.DESIGN: Thirty children with spastic diplegia (8-10 yrs) were included in this study']
['Diagnosis of spastic diplegia is mainly carried out with through clinical gait analysis (CGA), with variations such as 1-minute walk, LSU, and 10-meter walk tests, or Gross Motor Function Measure-88 (GMFM-88). Other methods used for evaluation of patients include brain magnetic resonance imaging (MRI) and motor function, presence of epileptic episodes, and IQ or developmental quotient.', 'Clinical gait analysis (CGA) has been highlighted as a possible tool to support the differential diagnosis of Hereditary Spastic Paraplegia (HSP) and Spastic Diplegia (SD). Argininaimia should be considered more frequently in the differential diagnosis of a patient with slowly progressive neurologic manifestations, especially progressive spastic diplegia. Gait Analysis (GA) complements traditional clinical evaluations, making it possible to distinguish, clearly, between motor ability in HSP and in SD patients; the duration of the knee hyperextension during midstance was found to discriminate between the two gait patterns.']
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Intact macromolecular assemblies are analysed by advanced mass spectrometry. How large complexes (in molecular weight) have been studied?
['Here we show that the Orbitrap mass analyzer can be used to measure protein assemblies of molecular weights approaching one megadalton with sensitivity down to the detection of single ions.', 'Using this relationship we show that we can determine masses of both 30S subunits and intact 2.3 MDa 70S ribosomes from Thermus thermophilus.', 'We confirm the existence of these subpopulations using tandem mass spectrometry of intact 30S subunits. Overall, the results show that, rather than uniform particles, gas-phase ribosomes consist of a number of discrete populations. More generally, the results establish a rigorous procedure for accurate mass measurement and spectral analysis of heterogeneous macromolecular assemblies.']
['2.3 megadalton']
['2.3 megadalton']
What is targeted by monoclonal antibody Pembrolizumab?
['gents currently in active clinical development for lung cancer include ipilimumab, which modulates the cytotoxic T-lymphocyte-associated antigen 4 pathway, and multiple agents targeting the programmed death protein 1 (PD-1) pathway, both anti-PD-1 compounds (nivolumab, pembrolizumab [MK-3475]) and those that target programmed death ligand 1 (PD-L1), a key ligand for PD-1 (BMS-936559, MPDL3280A). ', 'Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways.', 'Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.', 'CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. ', 'METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency.', 'CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. ', 'The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab have been recently licensed by the Food and Drug Administration for the treatment of advanced melanoma. ', 'We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab. ', 'Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody and pembrolizumab, a monoclonal antibody targeting programmed death 1 receptor may be a feasible treatment option in patients with metastatic mucosal melanoma', 'Pembrolizumab, a humanized highly selective IgG4 anti-PD-1 monoclonal antibody, was recently approved for the treatment of advanced melanoma based on promising early-phase clinical data', 'Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.', 'Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. ', 'BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma.METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ?18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. ', 'Vemurafenib and dabrafenib are targeted agents for patients with BRAF mutation-positive melanoma. Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody and pembrolizumab, a monoclonal antibody targeting programmed death 1 receptor may be a feasible treatment option in patients with metastatic mucosal melanoma.', 'Pembrolizumab, a humanized highly selective IgG4 anti-PD-1 monoclonal antibody, was recently approved for the treatment of advanced melanoma based on promising early-phase clinical data. Encouraging results have also been seen in other malignancies, and PD-1-targeted therapies are likely to markedly change the treatment landscape.']
['Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. Pembrolizumab is approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways.']
['programmed cell death 1']
Is paramyxovirus involved in human subacute thyroiditis?
['Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus. Influenza immunization or infection may cause subacute thyroiditis.', 'Coxsackie virus has been reported to be one of the viruses associated with the disease.', 'The etiology of subacute granulomatous thyroiditis (SAT) is obscure, although it is postulated to be associated with viral infections and genetic factors.', 'The results suggest that SAT is not usually associated with acute infections', 'No evidence was obtained to support the proposed role of enteroviruses as an important etiologic agent of SAT.', 'The viral antibodies evaluated were those of Influenza A and B, Coxsackie A9, B1, B2, B3, B4, B5 and B6, Echo 3, 7, 11 and 12, Parainfluenza 1, 2, 3 and 4, and Adeno 8 virus. The following results were obtained: In class I HLA typing, the frequency of HLA-Bw35 in SAT was 67.4%, which was significantly (p less than 0.0001) higher than that in the control (14.1%). On the other hand, the frequency of Cw1 in SAT (14.6%) was significantly (p less than 0.01) lower than that of the control (32.1%), and that of Cw3 (65.2%) was significantly (p less than 0.01) higher than that of the control (46.5%).']
['There is no evidence that paramyxovirus are involved in etiology of subacute thyroiditis.']
['no']
Is c-myc subject to regulation by the circadian clock?
['The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1)', 'Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are involved in cell proliferation and apoptosis and hence may result in manifestation of CLL.', 'Loss of Bmal1 reduced the expression of per1, per2, per3, wee1 and p53. The expression of p21 and c-myc was also altered in certain cell lines.', 'In particular, the proto-oncogene c-Myc has been documented to be under circadian regulation.', 'The circadian expression of c-MYC is modulated by the histone deacetylase inhibitor trichostatin A in synchronized murine neuroblastoma cells.', 'Our results, using the murine neuroblastoma cell line N2A, show that Per1 and c-Myc steady-state mRNA levels oscillate with the same phase.', 'These experiments demonstrate for the first time that a significant decrease in c-Myc transcript and protein levels can be achieved after a short TSA treatment applied only at specific circadian times. This is also followed by a reduction in the proliferation rate of the cell population.', 'Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation.', 'Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice.', 'The results showed that over-expression of Per2 induced not only cell cycle arrest at G2/M phase but also an increase in apoptosis, which was confirmed by characteristic morphological changes, FCM and evident DNA fragmentation. Further experiments confirmed both up-regulation of P53 and down-regulation of CylinB1and C-myc.', 'On the other hand, while P53 was found to be down-regulated. CylinB1 and C-myc were up-regulated. after Per2 knockdown.', 'We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters.', 'Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control.', 'The expression of cell cycle genes such as Wee1, Cyclins, and c-Myc are under circadian control and could be directly under the regulation of the circadian transcriptional complex.', 'Overexpressed mPER2 also altered the expression of apoptosis-related genes. The mRNA and protein levels of c-Myc, Bcl-X(L) and Bcl-2 were downregulated,', 'Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2 and Gadd45alpha is deregulated in mPer2 mutant mice.', 'The temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2, and Gadd45alpha, is deregulated in mPer2 mutant mice.']
['Yes, the expression of c-myc is regulated by the circadian clock protein Per2.']
['yes']
Signaling of which pathways is inhibited by Dupilumab?
['This study reviewed all studies about any roles of IL-4 that can directly and indirectly be played in the development of pemphigus and IL-4 inhibition with interferons and dupilumab therapy were introduced as a novel pemphigus treatment for patients who are in relapse phase of the disease. Dupilumab was also introduced as a possible treatment for patients with severe pemphigus. It can directly inhibit IL-4 by targeting IL-4 α-chain receptor. ', 'OBJECTIVE: To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis.', 'BACKGROUND: Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. ', 'Anti-IL-4 and IL-13 agents (dupilumab, lebrikizumab, and tralokinumab) which block different Th-2 inflammatory pathways and agents targeting the Th-17 inflammatory pathway in severe refractory asthma are under development.', 'Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players.', '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. ', 'The world\'s first prospective controlled studies with the biologic human anti-IL4R antibody dupilumab for the indication "atopic dermatitis" were published in 2014.', 'An IL-4R antagonist, dupilumab, is the first drug that shows great promise in phase II trials. ', "Dupilumab, a humanized monoclonal antibody to the interteukin-4R is the first antibody (i.e. 'biological') with published efficacy shown in controlled prospective studies in atopic dermatitis. ", 'Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways.', 'Dupilumab inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling and was previously found to be effective in asthma.', 'Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways.', '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.', '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.', 'Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation.', 'Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways', 'In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor �, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized.OBJECTIVES: We sought to evaluate dupilumab modulation of the AD molecular signature.METHODS: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo.RESULTS: Exacerbation of the AD transcriptome was observed in placebo-treated patients. ', 'Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways.', 'Dupilumab inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling and was previously found to be effective in asthma.', '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.', 'In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor á, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized.OBJECTIVES: We sought to evaluate dupilumab modulation of the AD molecular signature.METHODS: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo.RESULTS: Exacerbation of the AD transcriptome was observed in placebo-treated patients.']
['Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling. It is used for treatment of atopic or allergic diseases.']
['interleukin-4', 'interleukin-13']
Which are the most widely used computational methods for the identification of CRMs (cis-regulatory modules)?
['Several tools allow to detect significant co-occurrences of closely located binding sites (cis-regulatory modules, CRMs). However, these tools present at least one of the following limitations: 1) scope limited to promoter or conserved regions of the genome; 2) do not allow to identify combinations involving more than two motifs; 3) require prior information about target motifs.', 'In this work we present CisMiner, a novel methodology to detect putative CRMs by means of a fuzzy itemset mining approach able to operate at genome-wide scale. CisMiner allows to perform a blind search of CRMs without any prior information about target CRMs nor limitation in the number of motifs. CisMiner tackles the combinatorial complexity of genome-wide cis-regulatory module extraction using a natural representation of motif combinations as itemsets and applying the Top-Down Fuzzy Frequent- Pattern Tree algorithm to identify significant itemsets.', "To be able to handle the large datasets, the query-based setting and other specificities proper to CRM detection on ChIP-Seq based data, we developed a novel powerful CRM detection method 'CPModule'", 'the optimal choice of method varies depending on species and composition of the sequences in question. When discriminating CRMs from non-coding regions, those methods considering evolutionary conservation have a stronger predictive power than methods designed to be run on a single genome. Different CRM representations and search strategies rely on different CRM properties, and different methods can complement one another. For example, some favour homotypical clusters of binding sites, while others perform best on short CRMs. Furthermore, most methods appear to be sensitive to the composition and structure of the genome to which they are applied. ', 'CisMiner: genome-wide in-silico cis-regulatory module prediction by fuzzy itemset mining', 'Additionally, we make a number of new predictions on combinatorial regulation of these five key TFs with other TFs documented in TRANSFAC.', 'Due to degeneracy of nucleotide content among binding site instances or motifs, and intricate &apos;grammatical organization&apos; of motifs within cis-regulatory modules (CRMs), extant pattern matching-based in silico motif search methods often suffer from impractically high false positive rates, especially in the context of analyzing large genomic datasets, and noisy position weight matrices which characterize binding sites', 'Genome-wide identification of cis-regulatory motifs and modules underlying gene coregulation using statistics and phylogeny.', 'We thus developed a new CRM identification method MOPAT (motif pair tree), which identifies CRMs through the identification of motif modules, groups of motifs co-occurring in multiple CRMs. It can identify &apos;orthologous&apos; CRMs without multiple alignments.', 'These methods are problematic when binding sites are not well aligned in multiple alignments or when the number of input known motifs is large. We thus developed a new CRM identification method MOPAT (motif pair tree), which identifies CRMs through the identification of motif modules, groups of motifs co-occurring in multiple CRMs.', 'We thus developed a new CRM identification method MOPAT (motif pair tree), which identifies CRMs through the identification of motif modules, groups of motifs co-occurring in multiple CRMs.']
['Computational methods attempting to identify instances of cis-regulatory modules (CRMs) in the genome face a challenging problem of searching for potentially interacting transcription factor binding sites while knowledge of the specific interactions involved remains limited. When discriminating CRMs from non-coding regions, those methods considering evolutionary conservation have a stronger predictive power than methods designed to be run on a single genome. Furthermore, most methods appear to be sensitive to the composition and structure of the genome to which they are applied. CisMiner allows to perform a blind search of CRMs without any prior information about target CRMs nor limitation in the number of motifs.', 'The optimal choice of method varies depending on species and composition of the sequences in question. When discriminating CRMs from non-coding regions, those methods considering evolutionary conservation have a stronger predictive power than methods designed to be run on a single genome. Different CRM representations and search strategies rely on different CRM properties, and different methods can complement one another. For example, some favour homotypical clusters of binding sites, while others perform best on short CRMs. Furthermore, most methods appear to be sensitive to the composition and structure of the genome to which they are applied. A statistical model to describe the underlying cluster structure as well as individual motif conservation has also been proposed, accompanied with a Monte Carlo motif screening strategy for predicting novel regulatory modules in upstream sequences of coregulated genes.']
['motif conservation', 'fuzzy itemset mining', 'combinatorial methods']
What is the main characteristic of Amyotrophic Lateral Sclerosis?
['Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration.', 'Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and lower motor neurons.', 'There are four main hypotheses about the cause of ALS: excitotoxicity linked to glutamate receptor overactivation; mutation of the superoxide dismutase gene; production of autoantibodies to calcium channels; neurofilament accumulation. The motoneuron degeneration characteristic of ALS could be caused by any one or a combination of these mechanisms.', 'Amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease and evidence from mice expressing amyotrophic lateral sclerosis-causing SOD1 mutations suggest that neurodegeneration is a non-cell autonomous process where microglial cells influence disease progression']
['Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and lower motor neurons. ', 'Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and lower motor neurons.']
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What role do septins play in cellular processes?
[' ", "The human genome codes for 13 members of a family of filament-forming GTP-binding proteins known as septins.", "Septins are evolutionary conserved cytoskeletal GTPases forming heteropolymer complexes involved in cytokinesis and other cellular processes", "Septins comprise a conserved family of GTPases important in cytokinesis.", "Septins are a highly conserved family of GTP-binding cytoskeletal proteins implicated in multiple cellular functions, including membrane transport, apoptosis, cell polarity, cell cycle regulation, cytokinesis, and oncogenesis"]']
Septins play a crucial role in cellular processes such as cytokinesis and other functions. They are evolutionary conserved cytoskeletal GTPases forming heteropolymer complexes involved in various cellular functions like membrane transport, apoptosis, cell polarity, cell cycle regulation, and oncogenesis.
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What is the role of histone variant H2A.W?
['The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis', 'The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing', 'In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization.', ' In non-flowering land plants, we identify a new class of H2A variants and propose their possible role in the emergence of the H2A.W variant class in flowering plants', 'Covalent histone modifications (e.g. ubiquitination, phosphorylation, methylation, acetylation) and H2A variants (H2A.Z, H2A.X and H2A.W) are also discussed in view of their crucial importance in modulating nucleosome organization and function.', 'The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis.', 'In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization. ', 'In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization.', 'The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis.', 'Similarities in conserved motifs between H2A.W and another H2A variant in metazoans suggest that plants and animals share common mechanisms for heterochromatin condensation..', 'In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif.']
['The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis. The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization. In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif. In non-flowering land plants, we identify a new class of H2A variants and propose their possible role in the emergence of the H2A.W variant class in flowering plants. ', 'The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization. In non-flowering land plants, we identify a new class of H2A variants and propose their possible role in the emergence of the H2A.W variant class in flowering plants Covalent histone modifications (e.g.', 'The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization. Histone chaperones escort histones, and play key functions during nucleosome assembly/disassembly and in nucleosome structure configuration. Here we focus on plant histone H2A/H2B chaperones, particularly members of the NUCLEOSOME ASSEMBLY PROTEIN-1 (NAP1) and FACILITATES CHROMATIN TRANSCRIPTION (FACT) families, discussing their molecular features, properties, regulation and function. We further discuss roles of NAP1 and FACT in chromatin-based processes, such as transcription, DNA replication and repair. Future major challenges remain in order to define in more detail the overlapping and specific roles of various members of the NAP1 family as well as differences and similarities between NAP1 and FACT family members, and to identify and characterize their partners as well as new families of chaperones to understand histone variant incorporation and chromatin target specificity.', ' In non-flowering land plants, we identify a new class of H2A variants and propose their possible role in the emergence of the H2A.W variant class in flowering plants In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization.', 'The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis', 'Histone variants play crucial roles in gene expression, genome integrity, and chromosome segregation. The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization. Histone chaperones escort histones, and play key functions during nucleosome assembly/disassembly and in nucleosome structure configuration. Covalent histone modifications (e.g. ubiquitination, phosphorylation, methylation, acetylation) and H2A variants (H2A.Z, H2A.X and H2A.W) are also discussed in view of their crucial importance in modulating nucleosome organization and function.', 'The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing. In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization.']
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Is there a package in R/bioconductor for classification of alternative splicing?
['spliceR: an R package for classification of alternative splicing and prediction of coding potential from RNA-seq data.', 'Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential.', 'spliceR uses the full-length transcript output from RNA-seq assemblers to detect single or multiple exon skipping, alternative donor and acceptor sites, intron retention, alternative first or last exon usage, and mutually exclusive exon events. For each of these events spliceR also annotates the genomic coordinates of the differentially spliced elements, facilitating downstream sequence analysis. For each transcript isoform fraction values are calculated to identify transcript switching between conditions. Lastly, spliceR predicts the coding potential, as well as the potential nonsense mediated decay (NMD) sensitivity of each transcript.', 'Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential.', 'Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential. ', 'Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential.']
['Yes. SpliceR is an R package for classification of alternative splicing and prediction of coding potential from RNA-seq data.']
['yes']
What are the main benefits of pharmacophore models?
['To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ(70) and the RNAP core enzyme.', 'the primary structural features required for estrogen receptor binding, the phenols, are not required for inhibiting parasitic growth. Significantly, the most active antileishmanial benzothiophenes lack the pharmacophore for estrogen receptor activity and therefore address potential concerns about the undesirable effects of using selective estrogen receptor modulators in women and children with leishmaniasis. ', 'series of novel diastereoisomeric σ ligands 3 was designed, synthesized and pharmacologically evaluated. The highly rigid [4.3.3]propellane scaffold was used to fix the three dimensional orientation of the pharmacophoric moieties required for σ affinity', 'This study was performed to identify natural iNOS inhibitors from traditional Chinese herbs through a combination of pharmacophore modeling, molecular docking and virtual screening. First, the pharmacophore models were generated though six known iNOS inhibitors and validated by a test database. The pharmacophore model_017 showed good performance in external validation and was employed to screen Traditional Chinese Medicine Database (Version 2009), which resulting in a hit list of 498 compounds with matching score (QFIT) above 40. Then, the hits were subjected to molecular docking for further refinement. An empirical scoring function was used to evaluate the affinity of the compounds and the target protein. Parts of compounds with high docking scores have been reported to have the related pharmacological activity from the literatures.', 'Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies']
['As researchers continue to search for new targets of therapeutic interest, transmembrane and G-protein coupled receptors are of ever-increasing importance. However, crystal structures for these targets may be impossible to resolve, posing great challenges in rational drug design. Structure-based virtual screening is not an option when the active site geometry is unknown, but assaying an entire library for hits is an inefficient and expensive proposition.\nPharmacophore modeling solves this problem by determining the spatial arrangement of chemical features that confer drug activity toward a target receptor. Having established the chemical space occupied by active ligands, pharmacophore modeling software allows researchers to create 3-D structure-activity relationships, screen databases, and generate hits without the benefit of a receptor structure.']
['They represent chemical functions valid not only for the existing bounds but also for unknown molecules.', 'Due their simplicity they are proper for large scale virtual screening', 'They are comprehensive and editable, so by changing chemical feature contains information can be easily trace back.']
How does miR-1 overexpression contribute to arrhythmias in cardiac conditions?
['["Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT).", "miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias.", "The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. ", "As miR-1 has been shown in animal models and clinical studies to contribute to arrhythmogenesis by regulating pacemaker channel genes, our finding of miR-1 up-regulation in patients with myocardial infarction indicates that it might be responsible for the higher risk for arrhythmias in these patients. ", "Lately, some highlight articles revealed that the altered expression of miRNAs such as miR-1, miR-133, miR-21, miR-208 etc in hearts also contributed to cardiovascular diseases, such as heart ischemia, cardiac hypertrophy, and arrhythmias.", "MicroRNA-1 (miR-1) reciprocally regulates inwardly rectifying potassium channel (Kir)2.1 expression in coronary disease, contributing to arrhythmogenesis. ", "miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased I(K1). Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.", "The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. ", "We conclude that the beta-adrenergic pathway can stimulate expression of arrhythmogenic miR-1, contributing to ischaemic arrhythmogenesis, and beta-blockers produce their beneficial effects partially by down-regulating miR-1, which might be a novel strategy for ischaemic cardioprotection.", "MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction.", "Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure.", "In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca(2+), events that occurred rarely in control myocytes under the same conditions.", "Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis.", " Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.", "MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction", "The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins", "Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure", "Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure"]']
miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias. The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction. Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure. In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca(2+), events that occurred rarely in control myocytes under the same conditions. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.
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What is the relationship between nucleosomes and exons?
['Nucleosomes preferentially are located at the ends of exons, thus protecting splice junctions, with the N9 positions of guanines of the GT and AG junctions oriented toward the histones.', 'Nucleosomes were found to be preferentially positioned within constitutive exons and/or constitutive portions of alternative exons, which was not associated with gene expression or states of cells but was based on sequence and positively related with the sequence conservation of splicing sites', 'Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons.', 'Here we show, by analysis of data sets from human sperm and T cells and medaka (Japanese killifish, Oryzias latipes) blastulae, that internal exons of genes are characterized by sharply elevated average nucleosome occupancy in comparison to flanking intronic sequences.', 'sing public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of Caenorhabditis elegans.', 'we have found stable nucleosome occupancy within human and Caenorhabditis elegans exons that is stronger in exons with weak splice sites.', 'This confirms previously reported findings about preferential positioning of splice junctions within the nucleosomes.']
['Nucleosomes are preferentially located within exons compared to nearby intronic sequences. Preferential positioning within the exons is indepedent of gene expression levels, stronger in exons with weak splice sites and conserved through metazoan evolution.']
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Which is the relation between sweating and anaerobic threshold?
['It is concluded that the sweating response during upright recovery is significantly modified by exercise intensity and may likely be influenced by the nonthermal baroreceptor reflex adjustments postexercise.', ' The purpose of this paper is to delineate the effects of training status, heat acclimation, environmental conditions and host factors on the sweating response to exercise.', 'These results would suggest that at a given exercise intensity in subjects with a higher aerobic capacity body temperature is maintained with a lower sweating rate than that in subjects with a lower aerobic capacity.']
['There is no clear evidence of the relationship between sweating and anaerobic threshold']
['There is no clear evidence of the relationship between sweating and anaerobic threshold']
What is the role of CRD-BP in stabilizing c-myc mRNA and protecting it from endonucleolytic cleavage?
['["CRD-BP shields c-myc and MDR-1 RNA from endonucleolytic attack by a mammalian endoribonuclease", "The c-myc mRNA coding region determinant-binding protein (CRD-BP) has high affinity for the coding region determinant (CRD) of c-myc mRNA. Such affinity is believed to protect c-myc CRD from endonucleolytic attack", " These results provide the first direct evidence that CRD-BP can indeed protect c-myc CRD cleavage initiated by an endoribonuclease", "CRD-BP: a c-Myc mRNA stabilizing protein with an oncofetal pattern of expression", "The Coding Region Determinant-Binding Protein (CRD-BP) is an RRM and KH-domain-containing protein that recognizes specifically at least three RNAs. It binds to one of the two c-myc mRNA instability elements", "CRD-BP has been assigned a role in stabilizing c-myc mRNA by preventing its endonucleolytic cleavage", "A 249-nucleotide coding region instability determinant (CRD) destabilizes c-myc mRNA. Previous experiments identified a CRD-binding protein (CRD-BP) that appears to protect the CRD from endonuclease cleavage", "These data suggest that c-myc mRNA is rapidly degraded unless it is (i) translated without pausing or (ii) protected by the CRD-BP when pausing occurs", "Here, we confirm that human CRD-BP/IMP-1 binds to c-myc mRNA", "The coding region determinant-binding protein (CRD-BP) binds in vitro to c-myc mRNA and is thought to stabilize the mRNA and increase c-Myc protein abundance", "Two regions within c- myc mRNA determine its short half-life. One is in the 3\'-untranslated region, the other is in the coding region. A cytoplasmic protein, the coding region determinant-binding protein (CRD-BP), binds in vitro to the c- myc coding region instability determinant. We have proposed that the CRD-BP, when bound to the mRNA, shields the mRNA from endonucleolytic attack and thereby prolongs the mRNA half-life", "Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c-myc mRNA in vitro", "We previously isolated and characterized a coding region determinant-binding protein (CRD-BP) that might regulate c-myc mRNA post-transcriptionally", "CRD-BP binds specifically to the coding region of c-myc mRNA and might stabilize c-myc mRNA in vitro by protecting it from endonucleolytic cleavage"]', '["CRD-BP shields c-myc and MDR-1 RNA from endonucleolytic attack by a mammalian endoribonuclease", "The c-myc mRNA coding region determinant-binding protein (CRD-BP) has high affinity for the coding region determinant (CRD) of c-myc mRNA. Such affinity is believed to protect c-myc CRD from endonucleolytic attack", " These results provide the first direct evidence that CRD-BP can indeed protect c-myc CRD cleavage initiated by an endoribonuclease", "CRD-BP: a c-Myc mRNA stabilizing protein with an oncofetal pattern of expression", "The Coding Region Determinant-Binding Protein (CRD-BP) is an RRM and KH-domain-containing protein that recognizes specifically at least three RNAs. It binds to one of the two c-myc mRNA instability elements", "CRD-BP has been assigned a role in stabilizing c-myc mRNA by preventing its endonucleolytic cleavage", "A 249-nucleotide coding region instability determinant (CRD) destabilizes c-myc mRNA. Previous experiments identified a CRD-binding protein (CRD-BP) that appears to protect the CRD from endonuclease cleavage", "These data suggest that c-myc mRNA is rapidly degraded unless it is (i) translated without pausing or (ii) protected by the CRD-BP when pausing occurs", "Here, we confirm that human CRD-BP/IMP-1 binds to c-myc mRNA", "The coding region determinant-binding protein (CRD-BP) binds in vitro to c-myc mRNA and is thought to stabilize the mRNA and increase c-Myc protein abundance", "Two regions within c- myc mRNA determine its short half-life. One is in the 3\'-untranslated region, the other is in the coding region. A cytoplasmic protein, the coding region determinant-binding protein (CRD-BP), binds in vitro to the c- myc coding region instability determinant. We have proposed that the CRD-BP, when bound to the mRNA, shields the mRNA from endonucleolytic attack and thereby prolongs the mRNA half-life", "Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c-myc mRNA in vitro", "We previously isolated and characterized a coding region determinant-binding protein (CRD-BP) that might regulate c-myc mRNA post-transcriptionally", "CRD-BP binds specifically to the coding region of c-myc mRNA and might stabilize c-myc mRNA in vitro by protecting it from endonucleolytic cleavage"]']
CRD-BP plays a role in stabilizing c-myc mRNA by preventing its endonucleolytic cleavage. It binds specifically to the coding region of c-myc mRNA and shields the mRNA from endonucleolytic attack, thereby prolonging the mRNA half-life.
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What do statins do?
['Statins are inhibitors of HMG-CoA reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid by NADPH', 'Statins, which specifically inhibit HMG Co-A reductase, the rate-limiting step of cholesterol biosynthesis, are widely prescribed to reduce serum cholesterol and cardiac risk,', 'OBJECTIVES: Statins are a lipid-lowering treatment, prescribed frequently to prevent cardiovascular events.', "The doctors' beliefs about statins' ability to prolong life were associated significantly with their willingness to initiate treatment.CONCLUSION: The overall results imply that doctors have varying and suboptimal understanding of the effect of statins.", 'However, the meta-regression analysis indicated that age of study participants modified the association between statin use and cancer risk (P = .003).CONCLUSION: Our findings do not support a protective effect of statins against cancer.', 'What is less well known is a phenomenon whereby statins may induce a myopathy, which persists or may progress after stopping the drug.', 'Statins can cause a necrotizing myopathy and hyperCKaemia which is reversible on cessation of the drug.', '* Our data do not show any beneficial effect of statins in reducing disease inflammation in RA patients.AIM: To investigate the possible anti-inflammatory effect of statins in a cohort of rheumatoid arthritis (RA) patients.METHODS: We conducted a cohort study consisting of all patients with at least one claim for RA using LifeLink, a health insurance claims database.', 'Statins are widely used in kidney transplant patients given their established benefits in the general population, however evidence favouring their use is lacking.To assess the benefits and harms of statin therapy on mortality and renal outcomes in kidney transplant recipients.We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and hand searched reference lists of articles and scientific proceedings.Randomised controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment or other statins in kidney transplant recipients.Two authors independently assessed study quality and extracted data', 'Thus, it is important to understand whether other signaling pathways that are involved in atherosclerosis could be targets of statins, and if so, whether individuals with "overactivity" of these pathways could benefit from statin therapy, regardless of serum cholesterol level.Statins inhibit the synthesis of isoprenoids, which are important for the function of the Rho/Rho-associated coiled-coil containing kinase (ROCK) pathway', 'Evidence for statins in people who have had a kidney transplant were sparse and lower quality due to imprecise effect estimates and provided limited systematic evaluation of treatment harm.Statins may reduce cardiovascular events in kidney transplant recipients, although treatment effects are imprecise', 'Statins decreased 24-hour urinary protein excretion (6 studies, 311 patients: MD -0.73 g/24 h, 95% CI -0.95 to -0.52), but there was no significant improvement in creatinine clearance - a surrogate marker of renal function (11 studies, 548 patients: MD 1.48 mL/min, 95% CI -2.32 to 5.28).The incidence of rhabdomyolysis, elevated liver enzymes and withdrawal rates due to adverse events (well known complications of statins use), were not significantly different between patients receiving statins and placebo.Statins significantly reduced the risk of all-cause and cardiovascular mortality in CKD patients who are not receiving renal replacement therapy.', 'Statins are less cost-effective when obtained at average retail prices, particularly in patients at lower CVD risk.Although statins reduce absolute CVD risk in patients with CKD, the increased risk of rhabdomyolysis, and competing risks associated with progressive CKD, partly offset these gains', 'In this review, we debate the relative effect of statins in driving insulin resistance and the impairment of insulin secretion.Narrative overview of the literature synthesizing the findings of literature was retrieved from searches of computerized databases, hand searches, and authoritative texts employing the key words "Statins", "Randomized Clinical Trial", "Insulin sensitivity", "Insulin resistance", "Insulin Secretion", "Diabetes Mellitus" alone and/or in combination.The weight of clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity.', 'This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs.We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNalpha production, and intracellular signaling.Statins inhibited IFNalpha production profoundly and tumor necrosis factor alpha production modestly in human PDCs in response to Toll-like receptor ligands', 'The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins', 'Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic activity.', 'Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.', 'HMG-CoA reductase inhibitors (statins) activate expression of PPARalpha/PPARgamma and ABCA1 in cultured gallbladder epithelial cells.', 'HMG-CoA reductase inhibitors (statins) might cause high elevations of creatine phosphokinase (CK) in patients with unnoticed hypothyroidism.', 'HMG-CoA reductase inhibitors (statins) reduce hypertrophic scar formation in a rabbit ear wounding model.', 'HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage.', 'The target for statins, HMG-CoA reductase, is expressed in ductal carcinoma-in situ and may predict patient response to radiotherapy.', 'Two meta-analyses have shown statins do not improve survival, whereas two others showed improved cardiac function and reduced inflammation in HF. It appears lipophilic statins produce better survival and other outcome benefits compared to hydrophilic statins.', 'Statins are the current basis of lipid-lowering therapy, despite which may have limitations on efficacy and safety. In high risk patients who do not achieve current lipid goals, in those intolerant to statins or those with atherogenic dyslipidemia, it is possible combine two or more lipid lowering drugs, including statins, ezetimibe, bile acid sequestrants, fibrates, niacin and prescription omega-3 fatty acids.', 'Statins are the current basis of lipid-lowering therapy, despite which may have limitations on efficacy and safety. In high risk patients who do not achieve current lipid goals, in those intolerant to statins or those with atherogenic dyslipidemia, it is possible combine two or more lipid lowering drugs, including statins, ezetimibe, bile acid sequestrants, fibrates, niacin and prescription omega-3 fatty acids. However, for most of these combination therapies pivotal data on clinical outcomes are still lacking.', 'Statins are the current basis of lipid-lowering therapy, despite which may have limitations on efficacy and safety.', 'However, the findings of two large RCTs do not support the evidence provided by previous studies and suggest statins lack beneficial effects in HF.', 'Subsequently, a number of nonrandomised studies have shown statins improve clinical outcomes in patients with heart failure (HF).', 'AND WHAT DOES THE STUDY ADD?: Statins have shown broad spectrum anti-cancer properties in laboratory studies.', 'Statin-induced myopathy is an important cause of statin intolerance and the most common cause of statin discontinuation.', 'These findings underscore the need to better define the pathophysiology of statin-induced myalgia and develop methodologies to guide treatment of statin-intolerant patients..']
['Statins lower high cholesterol', 'Statins, which specifically inhibit HMG Co-A reductase, the rate-limiting step of cholesterol biosynthesis, are widely prescribed to reduce serum cholesterol and cardiac risk,']
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Why do we use "N-terminal proteomics"?
['ChaFRADIC is a powerful and practicable tool for protease and peptidase research,', 'systematic identification of protease cleavage events by quantitative N-terminal proteomics,', ' identifying the largest set of protein protease substrates ever reported and gaining novel insight into substrate specificity differences of these cathepsins.', 'new insights into the structure-function relationship of protease targets and their validation from large-scale approaches.', 'revealed unknown cleavage specificities, uncharacterized extended specificity profiles, and macromolecular determinants in substrate selection that were confirmed by molecular modeling. ']
['N-terminal proteomics allows the systematic identification of protease/peptidase cleavage events revealing substrate cleavage specificities.']
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What is the genetic basis of Rubinstein-Taybi syndrome?
['The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features', 'Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16p13.3', 'these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-AMP-regulated gene expression', 'RTS was shown to be associated with disruption of the CREB-binding protein gene CBP (CREBBP), either by gross chromosomal rearrangements or by point mutations', 'Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease', 'A certain level of CREB-binding protein is essential for normal development, since inactivation of one allele causes Rubinstein-Taybi syndrome (RSTS)', 'In 92 patients, we were able to identify a total of 36 mutations in CBP', 'We extended the search for mutations to the EP300 gene and showed that mutations in EP300 also cause this disorder.', 'Mutations in the CREBBP (CREB-binding protein gene) cause Rubinstein-Taybi syndrome (RSTS).', 'Heterozygous CREBBP mutations were identified in 12 of the 21 patients: five frameshift mutations, three nonsense mutations, two splice-site mutations, and two missense mutations.', 'It could be possible that genetic heterogeneity is related with novel mutations in other genes.', 'identified a novel CREBBP missense mutation, c.2728A > G (predicting p.Thr910Ala)', 'The p.Thr910Ala variant is outside the crucial histone acetyltransferase domain, and this may explain the mild and variable phenotype', 'Rubinstein-Taybi syndrome (RSTS), a developmental disorder comprising abnormalities that include mental retardation, an unusual facial appearance, broad thumbs and big toes is frequently associated with molecular lesions in the CREB-binding protein gene, CREBBP', 'Direct sequencing of CREBBP performed in 13 RSTS patients identified the three zinc fingers (CH1, CH2, CH3) and HAT domain as mutational hotspots in which ten novel pathogenic mutations were localized']
['Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder (prevalence 1:125,000) characterised by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa and short stature. The known genetic causes are a microdeletion at 16p13.3 or mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) at 22q13 (5%). Direct sequencing of CREBBP performed in 13 RSTS patients identified the three zinc fingers (CH1, CH2, CH3) and HAT domain as mutational hotspots. Thus about 55% of patients have cytogenetic or molecular abnormalities in the Crebbp or E1A binding protein p300 (Ep300) gene, leaving the diagnosis in 45% of patients to rest on clinical features only.']
['Mutations or/and deletions in the genes of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) at 22q13 (5%).']
How do R-loops affect replication forks, and which enzyme helps?
[' detected in cancer cells.", "The multiple cleavage sites on the R-loop substrate match the priming sites observed in vivo, suggesting that RNase MRP alone is capable of generating virtually all of the leading-strand replication primers.", "Mechanisms of primer RNA synthesis and D-loop/R-loop-dependent DNA replication in Escherichia coli.", "Alternative oriC-independent modes of replication initiation are possible, one of which is constitutive stable DNA replication (cSDR) from transcription-associated RNA-DNA hybrids or R-loops.", "Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks.", "Critical role of R-loops in processing replication blocks.", "The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed.", "Competition between the RNA transcript and the nontemplate DNA strand during R-loop formation in vitro: a nick can serve as a strong R-loop initiation site.", "More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. ", "Consistent with this hypothesis, the 3\' ends of the mitochondrial R-loop formed by in vitro transcription are located close to the initiation sites of the mitochondrial DNA replication. ", "A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop.", "Previous studies have shown that the newly synthesized primers form a stable and persistent RNA-DNA hybrid, a R-loop, near the leading-strand origin of DNA replication. ", "Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI. "]', ' detected in cancer cells.", "The multiple cleavage sites on the R-loop substrate match the priming sites observed in vivo, suggesting that RNase MRP alone is capable of generating virtually all of the leading-strand replication primers.", "Mechanisms of primer RNA synthesis and D-loop/R-loop-dependent DNA replication in Escherichia coli.", "Alternative oriC-independent modes of replication initiation are possible, one of which is constitutive stable DNA replication (cSDR) from transcription-associated RNA-DNA hybrids or R-loops.", "Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks.", "Critical role of R-loops in processing replication blocks.", "The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed.", "Competition between the RNA transcript and the nontemplate DNA strand during R-loop formation in vitro: a nick can serve as a strong R-loop initiation site.", "More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. ", "Consistent with this hypothesis, the 3\' ends of the mitochondrial R-loop formed by in vitro transcription are located close to the initiation sites of the mitochondrial DNA replication. ", "A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop.", "Previous studies have shown that the newly synthesized primers form a stable and persistent RNA-DNA hybrid, a R-loop, near the leading-strand origin of DNA replication. ", "Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI. "]']
R-loop formation causes DNA replication fork stalling, and this underlies the effects of R loops on genomic stability. The enzyme Top1 helps by suppressing the formation of DNA-RNA hybrids during transcription, which are the R-loops interfering with the progression of replication forks.
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What is the function of gasdermin D?
['gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. ', 'Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria.']
['The gasdermin-N domains of the gasdermin proteins can bind membrane lipids, phosphoinositides and cardiolipin to produce membrane-disrupting cytotoxicity.']
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What is the most probable defect underlying triple negative breast cancer?
['We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction', 'BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy.', 'Sixty-six tumors (65%) had a BRCA1-like profile.']
['The most probable defect underlying triple negative breast cancer is BRCA1 dysfunction.']
['BRCA1 dysfunction']
Is Turcot syndrome associated with glioblastoma?
['Turcot syndrome is an autosomal recessive disorder clinically characterized by the occurrence of primary tumors of the central nervous system and adenomatous colonic polyps during the first or second decades of life, with a spectrum of clinical features such as "café-au-lait" spots, axillary freckling, and hyperpigmented spots. ', 'We present the case of a 20-year-old male with a clinical presentation of both glioblastoma multiforme and multiple adenomatous colonic polyps. ', 'Turcot syndrome (TS) is a rare hereditary disorder clinically characterized by the occurrence of primary tumors of the colon and the central nervous system (CNS). Here we present the case of an 11-year-old boy with a synchronous clinical presentation of both glioblastoma multiforme (GBM) and colonic adenocarcinoma.', 'Based on this case study, the synchronous presentation of glioblastoma multiforme and adenocarcinoma of the colon might suggest a shorter survival rate for patients with Turcot syndrome. ', "A 15-year-old boy was admitted with the diagnosis of colonic polyposis, and during a 2-year follow-up, he underwent operation for right parieto-occipital anaplastic astrocytoma, left-side colonic non-Hodgkin lymphoma (NHL) and cerebella glioblastoma which were all confirmed by histology. Although cases of Turcot's syndrome (TS) (colonic polyposis and primary brain tumour occurring in the same patient) have been previously described, association with haematological malignancy is rare. We hereby report such a case with TS.", 'Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome.', ' Biallelic mutations of MMR genes are associated with pediatric cancers, including glial tumors, in Turcot syndrome type 1 (TS1).', 'Glioblastomas with giant cell and sarcomatous features in patients with Turcot syndrome type 1: a clinicopathological study of 3 cases.', 'Turcot syndrome (TS) is a rare genetic disorder of DNA mismatch repair predisposing to glioblastoma (GBM) in the type 1 variant. ', 'We report the clinicopathological and genetic features of 3 gliomas in TS type 1 patients.', 'We conclude that 1) the giant cell variant of GBM is overrepresented in TS; 2) gliosarcomas may also be encountered; and 3) survival is often favorable, despite histological anaplasia and exuberant proliferation.', 'Malignant transformation of high-grade astrocytoma associated with neurocysticercosis in a patient with Turcot syndrome.', 'A 45-year-old woman with anaplastic astrocytoma was clinically diagnosed with Turcot syndrome, and subsequently developed simultaneous neurocysticercosis and malignant transformation to glioblastoma. ', 'Familial glioblastoma multiforme is a rather uncommon entity, being in most cases associated to known genetic disorders (as Turcot syndrome, Li-Fraumeni syndrome, neurofibromatosis, etc.). ', 'Turcot syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder.', 'We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. ', 'Of the 21 patients, 12 have died (10 after relapse, with a median time to progression for the whole series of 14 months; one with intratumoral bleeding at 40 months after diagnosis; and one affected by Turcot syndrome for duodenal cancer relapse).', '[Glioblastoma multiforme as a manifestation of Turcot syndrome].', "In the present case, a 60-year-old patient with glioblastoma multiforme and a history of hereditary malignomas is described as an example of a HNPCC-associated Turcot's syndrome.", 'Computed tomography brain scan and computed tomography-guided biopsy revealed a left frontoparietal glioblastoma multiforme. This case illustrates the rare presentation of Turcot syndrome-a hereditary colorectal polyposis syndrome-in an older adult.', 'Turcot syndrome is the association of colorectal polyposis with primary neuroepithelial tumors of the central nervous system such as glioblastoma and medulloblastoma. ', 'Brain tumor is mainly diagnosed as glioblastoma or astrocytoma and mismatch repair genes might be involved. ', 'Patients with Turcot syndrome (TS) are predisposed to colon tumors and primary brain tumors, typically glioblastomas or medulloblastomas. The authors describe a patient with TS featuring a known germline mutation of exon 5 of the hPMS2 mismatch repair gene who developed two metachronous glioblastomas, both with distinct oligodendroglial features.', 'Because this patient had an unusual underlying condition and his tumor had a unique histological appearance for TS, it was hypothesized that this genetic defect may predispose to malignant gliomas with oligodendroglial features. ', 'Turcot Syndrome caused by APC gene develops medulloblastoma and Turcot Syndrome caused by mismatch repair gene develops glioblastoma. ', 'It is characterized by central nervous system (CNS) neoplasms and gastrointestinal polyposis.', "Seven months after resection of this Dukes' C2 adenocarcinoma, she presented with a second primary CNS tumor, a glioblastoma multiforme.", 'The Turcot syndrome has been defined as the simultaneous presence of multiple polyposis of the colon and a malignant brain tumor.', 'The case of a 47-year-old man submitted to a right hemicolectomy for cancer and polyposis, following a series of endoscopic polypectomies and, finally, removal of left temporal glioma is here presented.', ' Two of 13 showed microsatellite instability, one of which in a patient with Turcot syndrome, the other in gliomatosis cerebri.', 'The Turcot syndrome (TS) is a rare, probably autosomal recessive, disorder characterized by development of primary neuroepithelial tumors of the central nervous system (CNS) and numerous adenomatous colorectal polyps. ', 'However, no somatic mutations in APC were found among 91 neuroepithelial tumors (medulloblastoma, glioblastoma, astrocytoma, and oligodendroglioma), whether sporadic or associated with TS. ', 'Such syndromes include neurofibromatosis type 2, neurofibromatosis type 1, Li-Fraumeni syndrome, as well as von Hippel-Lindau disease, tuberous sclerosis, and Turcot syndrome. ', "This patient's case deals with the association between a glioblastoma, anaplastic glioma (WHO Grade III) and colonic adenocarcinoma based on familial polyposis coli. ", "The authors describe two patients with the association of polyposis-coli and central nervous system tumor (Turcot's syndrome). ", "We report a case of Turcot's syndrome in a 20-year old man with multiple adenomatous polyps of the colon and glioblastoma multiforme. ", 'Another unusual autopsy case of the Turcot syndrome is reported in a 23-year-old woman with polyposis coli, who developed primary carcinoma of the jejunum and glioblastoma multiforme of the left frontal lobe. ', 'Turcot syndrome represents the unique and discrete occurrence of polyposis coli with glioblastoma multiforme, medulloblastoma, or both.']
['Yes, Turcot syndrome is associated with glioblastoma. Turcot syndrome is an autosomal recessive disorder clinically characterized by the occurrence of primary glial tumors of the central nervous system, including glioblastoma, and adenomatous colonic polyps during the first or second decades of life, with a spectrum of clinical features such as "café-au-lait" spots, axillary freckling, and hyperpigmented spots.']
['yes']
Is acid alpha-glucosidase the enzyme that causes Pompe disease when mutant?
['Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA))', 'Pompe disease is a systemic metabolic disorder characterized by lack of acid-alpha glucosidase (GAA) resulting in ubiquitous lysosomal glycogen accumulation', 'Pompe disease is an autosomal recessive myopathic disorder caused by the deficiency of lysosomal acid α-glucosidase (GAA)', 'Acid α-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available', 'The analysis revealed that the amino acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the acid alpha-glucosidase.', 'Pompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase.', 'Glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid alpha-glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness.', 'Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease.', 'The nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease, consisting of 2 each of the infantile, childhood and adult types.', 'Pompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene.', 'Glycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen.', 'Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA).', 'Demonstration of acid alpha-glucosidase in different types of Pompe disease by use of an immunochemical method.', 'Acid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists.', 'Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy.', 'Ambulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease.', 'Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase.', 'Determination of acid alpha-glucosidase activity in blood spots as a diagnostic test for Pompe disease.', 'The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease', 'Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease', 'Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme', 'Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease', 'The nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease, consisting of 2 each of the infantile, childhood and adult types', 'As in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter', 'Glycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome', 'Pompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene', 'Glycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen', 'Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme.', 'Structural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease.', 'Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers.', 'The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease.', 'Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. ', 'Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease.', 'We describe an improved method for detecting deficiency of the acid hydrolase, alpha-1,4-glucosidase in leukocytes, the enzyme defect in glycogen storage disease Type II (Pompe disease).', 'Acid alpha-glucosidase (GAA) deficiency causes Pompe disease,', ' Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase. Trials with recombinant human acid alpha-glucosidase enzyme replacement therapy (ERT) show a decrease in left ventricular mass and improved function.', ' Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. Due to virtual absence of acid alpha-glucosidase, patients with classical infantile Pompe disease develop progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy.', 'Pompe disease is caused by the congenital deficiency of the lysosomal enzyme acid alpha-glucosidase.', 'The nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease,', ' Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA). Recently, small molecule pharmacological chaperones have been shown to increase protein stability and cellular levels for mutant lysosomal enzymes and have emerged as a new therapeutic strategy for the treatment of LSDs.', 'Acid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists.', 'Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase.', 'Glycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome.', 'Structural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease.', 'Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA).', 'Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease.', 'Ambulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease.', 'Mutations in alpha-glucosidase cause accumulation of glycogen in lysosomes, resulting in Pompe disease, a lysosomal storage disorder.', 'Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase.', 'Infantile Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme.']
['Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA))', 'Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme acid α-glucosidase (GAA), responsible for degradation of lysosomal glycogen.']
['yes']
Has small pox been eradicated from the world?
['small pox has been eradicated.', 'smallpox is now eradicated', 'In May 1980 the World Health Assembly in Geneva announced in solemn form the world-wide eradication of the small-pox and gave recommendations to the member countries for concluding measures concerning the small-pox vaccination, the foundation of vaccine reserves and the control of the epidemiological situation in the world.', 'As a result of vaccination, diseases such as polio and measles have been controlled and small pox has been eradicated', 'Small pox eradication from the world is the perfect example of the role of mass vaccination of the entire community of the universe. ', 'The French owe a lot to this Central Committee of Vaccine, which greatly contributed to fighting small pox and eradicating the disease finally.', 'Small pox eradication from the world is the perfect example of the role of mass vaccination of the entire community of the universe.', 'Also, the vaccine that Jenner used, which decreased the prevalence of Small Pox worldwide in his own time, and later was used to eradicate Small Pox altogether, is discussed in light of recent data..', 'the only known cases of smallpox happened from an outbreak in Birmingham, England caused by a laboratory accident in the year of 1979. On May the 8 th 1980 the disease was declared as eliminated from the world by the WHO (WHO-Resolution 33.33).']
['smallpox is now eradicated.', 'Yes, small pox has been eradicated.', 'smallpox is now eradicated', 'small pox has been eradicated.']
['yes']
What is the role of cohesins at the IFNG locus?
['Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus.', 'Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG. Hence, the ability of cohesin to constrain chromosome topology is used not only for the purpose of sister chromatid cohesion, but also to dynamically define the spatial conformation of specific loci. This new aspect of cohesin function is probably important for normal development and disease', 'Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG.', 'Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus', 'Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG', 'Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus.', 'Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG.']
['Cohesins form cell-type-specific long-range chromosomal cis-interactions at the developmentally regulated IFNG locus. Hence, the ability of cohesin to constrain chromosome topology is used not only for the purpose of sister chromatid cohesion, but also to dynamically define the spatial conformation of specific loci. This new aspect of cohesin function is probably important for normal development and disease.']
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What are the characteristics of the "Universal Proteomics Standard 2" (UPS2)?
['the UPS2 proteomic dynamic range standard introduced by The Association of Biomolecular Resource Facilities Proteomics Standards Research Group in 2006)', 'Universal Proteomics Standard sample with a dynamic range of 5 orders of magnitude (UPS2).']
['The UPS2 proteomic dynamic range standard was introduced by the Association of Biomolecular Resource Facilities Proteomics Standards Research Group in 2006 and it has a dynamic range of 5 orders of magnitude.']
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What is the main application of SWATH-MS in proteomics?
['it is a valuable resource for the selection of candidate proteotypic peptides for targeted proteomic experiments via Selected Reaction Monitoring (SRM) or SWATH-MS', 'SWATH-MS is a data-independent acquisition method that generates, in a single measurement, a complete recording of the fragment ion spectra of all the analytes in a biological sample for which the precursor ions are within a predetermined m/z versus retention time window.', "ew strategies, such as SWATH™ MS, which allows us to systematically characterize and quantify query sample sets of 'any protein of interest' in complex biological samples,", 'Here we present a new strategy that systematically queries sample sets for the presence and quantity of essentially any protein of interest. ']
['Using the method called SWATH-MS one might ask sample sets for the presence and quantity of essentially any protein of interest.']
['The identification and quantification of any protein.']
Is there an association between Histone H3.3 mutations and glioma?
['PURPOSE: Histone H3.3 (H3F3A) mutation in the codon for lysine 27 (K27M) has been found as driver mutations in pediatric glioblastoma and has been suggested to play critical roles in the pathogenesis of thalamic gliomas and diffuse intrinsic pontine gliomas. We report a case of thalamic glioma with H3F3A K27M mutation, which was detected in both the primary tumor diagnosed as diffuse astrocytoma obtained during the first surgery and also in the tumor diagnosed as anaplastic astrocytoma obtained at the second surgery.', 'CONCLUSION: This report demonstrates minute neuroradiological and pathological features of malignant transformation from thalamic low grade glioma with H3F3A K27M mutation.', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.', 'The pathological diagnosis was anaplastic oligodendroglioma, and we identified a mutation in histone H3.3 in the tumor specimen.', 'CONCLUSIONS: Pediatric brainstem oligodendroglial tumors can include histone H3.3-mutated tumors and have a tendency to disseminate throughout the neuroaxis at the time of relapse.', 'We highlight the genetic aberrations recently discovered in isocitrate dehydrogenase, alpha thalassemia/mental retardation syndrome X-linked, death-domain-associated protein, histone H3.3, and telomerase reverse transcriptase and discuss how these mutations lead to unexpected changes in the epigenetic landscape in gliomas.', 'Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood', 'Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors', 'The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression', 'A lesson learned from the H3.3K27M mutation found in pediatric glioma: a new approach to the study of the function of histone modifications in vivo', 'Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature.', 'Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3.', 'Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma.', 'Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults.', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.', 'Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs).', 'Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation.', 'Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1).', 'Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.']
['Yes, histone H3.3 mutation in the codon for lysine 27 has been found as driver mutations in pediatric glioblastoma and has been suggested to play critical roles in the pathogenesis of thalamic gliomas and diffuse intrinsic pontine gliomas.']
['yes']
is there an increase in ultrasound comets after intense exercise?
['Healthy athletes developed subclinical increase in pulmonary water content immediately after an Ironman race at sea level, as shown by the increased number of ULCs related to cardiac changes occurring during exercise.', 'Increased EVLW is associated with estimated PCWP and indices of left ventricular systolic and diastolic dysfunction. The additional exercise-induced increase of PCWP, the worsening of left ventricular diastolic function, and extensive wall-motion abnormalities correlate with variations of EVLW.', ' Among them chest ultrasonography can detect and quantify the extravascular lung water, creating "comet-tail" ultrasound artefacts (ULCs) from water-thickened pulmonary interlobular septa.', ' In top-level breath-hold divers, chest sonography frequently reveals an increased number of ULCs after immersion, indicating a relatively high prevalence of (often subclinical) reversible extravascular lung water accumulation.']
['Strenuous exercise and exercise perfomed in extreme conditions provoke increase in interstitial pulmonary water content as shown by the increased number of ultrasuond comets']
['yes']
Which is the "bonding hormone"?
['The neurohypophysial hormone oxytocin (OXT) and its receptor (OXTR) have critical roles in the regulation of pro-social behaviors, including social recognition, pair bonding, parental behavior, and stress-related responses.', 'Neuropeptide hormone oxytocin has roles in social bonding, energy metabolism, and wound healing contributing to good physical, mental and social health. ', "Oxytocin is known as the 'love hormone' due its role in promoting mother-child and pair bonding.", 'The oxytocin (OT) hormone pathway is involved in numerous physiological processes, and one of its receptor genes (OXTR) has been implicated in pair bonding behavior in mammalian lineages.', 'oxytocin, a hormone involved in parent-offspring bonding']
["Oxytocin is known as the 'bonding hormone' due its role in promoting mother-child and pair bonding."]
['Oxytocin']
Which are the triad symptoms of pheochromocytoma?
['Diaphoresis (LR+ 2.2, LR- 0.45), Palpitation (LR+ 1.9, LR- 0.52) and headache (LR+ 1.6, LR- 0.24) were significant symptoms in clinical diagnosis of pheochromocytoma. ', 'In the 52 cases analyzed, 40 of the patients had symptoms: 31 patients had hypertension; 10 had the triad of palpitations, diaphoresis, and headaches; and all had elevated urinary metanephrine concentrations.', ' The symptoms and signs of pheochromocytoma include the classic triad of episodic headache, increased sweating, and palpitations. ', 'Among the presenting symptoms, episodes of palpitations, headaches, and profuse sweating are typical and constitute a classic triad.', 'The classic triad of symptoms are episodic headache, excessive sweating and palpitation. ', 'The symptoms and signs of pheochromocytoma include the classic triad of episodic headache, increased sweating, and palpitations.', 'Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients.', 'The symptoms and signs of pheochromocytoma include the classic triad of episodic headache, increased sweating, and palpitations', 'Pheochromocytoma in pregnancy is rare, and if unrecognized, can cause serious perinatal morbidity and mortality.A patient with severe hypertension, postpartum pulmonary edema, and a recognized pheochromocytoma is described.Abdominal palpation after vaginal childbirth reproduced the diagnostic triad of hypertension, headaches, and palpitations', 'Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients', 'Although hypertension, headache, and diaphoresis are common symptoms in a dialyzed patient, pheochromocytoma has to be eliminated in the presence of this clinical triad', 'Pheochromocytomas are catecholamine producing tumors that classically present with the triad of sweating, palpitations and headache.9-year-old boy whose only presenting complaints were polyuria and polydipsia for 2 years.Routine measurement of blood pressure detected mild hypertension, and subsequent investigations revealed bilateral pheochromocytoma.Surgical removal of the tumors resulted in complete resolution of polyuria and polydipsia.The case highlights the importance of measuring BP for children as part of physical examination', 'The symptoms and signs of pheochromocytoma include the classic triad of episodic headache, increased sweating, and palpitations.', 'Although hypertension, headache, and diaphoresis are common symptoms in a dialyzed patient, pheochromocytoma has to be eliminated in the presence of this clinical triad.', 'Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients.', 'In the 52 cases analyzed, 40 of the patients had symptoms: 31 patients had hypertension; 10 had the triad of palpitations, diaphoresis, and headaches; and all had elevated urinary metanephrine concentrations.', 'The classic triad of symptoms are episodic headache, excessive sweating and palpitation.', 'The clinical symptoms of these tumors vary from isolated hypertension or hypertension accompanied by paroxysmal episodes -including the classical triad of headache, palpitations and diaphoresis-to potentially serious manifestations such as acute pulmonary edema, arrhythmias and sudden death.', 'A very few symptoms were specific, like the triad "headaches, sweating, palpitations" whose onlyone third of patients was concerned by.', 'Classically, a triad of symptoms includes sweating, palpitations, and headache.', 'The triad of diaphoresis, tachycardia, and headache in hypertensive patients is highly suggestive of pheochromocytoma.', 'A very few symptoms were specific, like the triad "headaches, sweating, palpitations" whose onlyone third of patients was concerned by.', 'We noticed, like others, when the triad of headache, sweating and palpitations is accompanied by hypertension, the diagnosis of pheochromocytoma can be made with specify and sensitivity over 93%.']
['The classic triad of symptoms are episodic headache, excessive sweating (diaphoresis) and palpitation.']
['headache', 'excessive sweating', 'diaphoresis', 'palpitation']
What memory problems are reported in the " Gulf war syndrome"?
['The strongest associations were for mood swings (OR 20.9, 95%CI 16.2-27.0), memory loss/lack of concentration (OR 19.6, 95% CI 15.5-24.8), night sweats (OR 9.9, 95% CI 6.5-15.2), general fatigue (OR 9.6, 95% CI 8.3-11.1) and sexual dysfunction (OR 4.6, 95%CI 3.2-6.6).', 'The symptoms include incapacitating fatigue, musculoskeletel and joint pains, headaches, neuropsychiatric disorders, affect changes, confusion, visual problems, changes of gait, loss of memory, lymphadenopathies, respiratory impairment, impotence, and urinary tract morphological and functional alterations. ', 'In early 1992, U.S. troops returning from the Gulf War began reporting a variety of nonspecific symptoms such as fatigue, skin rash, headache, muscle and joint pain, and loss of memory. These reports marked the beginning of what was to be identified as the Gulf War Syndrome (GWS). ', 'We report on a 29-year-old man who suffered from dysmnesia, disturbance of orientation, cognitive impairment, and double vision. His history revealed several front-line operations in 1990 and 1991 during the Gulf War. ', 'Neuropsychological tests disclosed severe cognitive impairment especially concerning memory.', 'A cluster of common health problems included: skin rash, cough, depression, unintentional weight loss, insomnia, and memory problems.', 'Syndromes 1 ("impaired cognition," characterized by problems with attention, memory, and reasoning, as well as insomnia, depression, daytime sleepiness, and headaches), 2 ("confusion-ataxia," characterized by problems with thinking, disorientation, balance disturbances, vertigo, and impotence), and 3 ("arthro-myo-neuropathy," characterized by joint and muscle pains, muscle fatigue, difficulty lifting, and extremity paresthesias) represented strongly clustered symptoms; whereas, syndromes 4 ("phobia-apraxia"), 5 ("fever-adenopathy"), and 6 ("weakness-incontinence") involved weaker clustering and mostly overlapped syndromes 2 and 3. ']
['Loss of memory and dysmnesia are memory problems reported in the " Gulf war syndrome". Patients suffering from this syndrome often have other\nnonspecific symptoms such as fatigue, skin rash, headache, muscle and joint pain and sexual dysfunction.']
['loss of memory', 'dysmnesia']
Which drugs have been found effective for the treatment of chordoma?
['The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures.', 'Vincristine, doxorubicin, etoposide, cisplatin, and fludarabine, each at a concentration of 10 μM, decreased the number of chordoma cells when given alone down to 11%, 0%, 30%, 67%, and 3%, respectively. Etoposide and cisplatin, each at a concentration of 10 μM, reduced the percentage of viable chordoma cells in a more effective way when given with 1 μM ATRA simultaneously, reducing the number of viable cells to 14% and 9%, respectively.', 'Percutaneous intratumoral injection with pingyangmycin lipiodol emulsion for the treatment of recurrent sacrococcygeal chordomas', 'Preliminary results showed that PIIT with pingyangmycin lipiodol emulsion under fluoroscopic guidance is effective and safe and may be considered as a treatment option.', 'Percutaneous intratumoral injection with pingyangmycin lipiodol emulsion for treatment of recurrent sacrococcygeal chordomas', 'During the follow-up (median time of 21.7 months, range 10-26 months), all the patients showed obviously reduced tumor size and VAS, and partial remission was achieved in 6 patients and stable disease (SD) in 1 patient.', 'Fluoroscopy-guided percutaneous intratumoral injection of PLE can be effective and safe and may serve as a alternative for treatment of recurrent sacrococcygeal chordomas.', 'The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029. The cytotoxicity of the combination of SD-1029 and chemotherapeutic drugs is significantly better than either agent alone. Phosphorylation of Stat3 in chordoma cells in vitro and cellular proliferation in three-dimensional culture were inhibited by SD-1029.', 'In conclusion, the Stat3 pathway is constitutively activated in chordomas and the level of expression may serve as a predictor for prognosis. Blockade of the Stat3 pathway represents a potential strategy for future treatment.']
['Established chordoma cell lines, and patient-derived primary cell cultures, as well as chordoma tumors in vivo were found to be sensitive to treatment with bortezomib, vincristine, doxorubicin, etoposide, cisplatin, fludarabine and SD-1029 Stat3 inhibitor. Moreover, percutaneous intratumoral injection with pingyangmycin lipiodol emulsion was shown to be effective against chordoma. It should be stressed that combination treatment with the use of the above drugs was always able to increase the therapeutic potency.']
['bortezomib', 'vincristine', 'doxorubicin', 'etoposide', 'cisplatin', 'fludarabine', 'SD-1029 Stat3 inhibitor', 'pingyangmycin lipiodol emulsion']
What is the mode of inheritance of long QT Jervell and Lange-Nielsen syndrome?
['Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death.', 'KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness', 'Jervell and Lange-Nielsen syndrome (JLNS) is characterized by sensorineural deafness, QT prolongation, abnormal T waves, ventricular tachyarrhythmias, and autosomal recessive inheritance.', 'Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation.', 'Jervell and Lange-Nielsen syndrome (MIM 220400; JLNS), is a rare form of profound congenital deafness combined with syncopal attacks and sudden death due to prolonged QTc; it is an autosomal recessive trait. ', 'Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. ', 'The Jervell and Lange-Nielsen syndrome (JLNS) is characterized by prolongation of the QT interval, deafness, and autosomal-recessive inheritance, and the Romano-Ward syndrome is characterized by a prolonged QT interval, autosomal-dominant inheritance, and no deafness. ']
['Jervell and Lange-Nielsen long QT syndrome (JLNS) is characterized by autosomal recessive mode of inheritance']
['autosomal recessive']
What is the action of molindone?
['As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.', 'All antipsychotic drug treatments examined in this study caused a statistically significant up-regulation of both the long and short isoforms of the D2 receptor mRNAs in the prefrontal and temporal cortex. ', 'Other drugs of the typical (molindone and pimozide) and atypical (remoxipride) classes had no effect on D4 mRNA levels in either cortical or striatal tissue. ', ' Loxapine is an alternative when sedation is necessary and molindone is useful if a short-acting antipsychotic is required. ', 'Neuroleptics with a clearly documented liability for producing extrapyramidal side effects (EPS) such as chlorpromazine, fluphenazine, haloperidol, loxapine, metoclopramide and molindone elevated FLI in the dorsolateral striatum.', 'Pretreatment with molindone (0.45 and 0.8 mg/kg IP), in doses reported to selectively block the presynaptic DA receptors, not only decreased the cataleptic effect of AP but also reversed the AP antagonism of methamphetamine stereotypy.', ' The antagonist molindone exhibits selectivity for cortical serotonin-stimulated cyclase versus dopamine-stimulated cyclase and may prove useful for further elucidating the sites of lisuride action. ', 'Molindone in low intravenous doses (0.4-0.8 mg/kg) was found to reverse d-amphetamine and apomorphine induced depression of DA neurons and to block apomorphine induced depression of these cells. Molindone was also found to increase dopamine synthesis and dihydroxyphenylactic acid levels in the striatum and olfacotry tubercles. In all of these respects molindone behaves identically to most classical neuroleptics. However, unlike most antipsychotic drugs previously tested, molindone failed to increase the baseline firing rate of DA cells and blocked haloperidol induced increases in DA neuron activity. In this regard molindone most closely resembles thioridazine and clozapine. ']
['Molindone is a short-acting antipsychotic.\nMolindone, along with other antipsychotic drugs which elicit little or no Parkinsonism, bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.\nMolindone is D2-selective in vitro and has a dual D1-D2 receptor profile in vivo.\nMolindone can selectively block the presynaptic DA receptors.\nMolindone causes a statistically significant up-regulation of both the long and short isoforms of the D2 receptor mRNAs in the prefrontal and temporal cortex, but has no effect on D4 mRNA levels in either cortical or striatal tissue.\nMolindone elevates Fos-like immunoreactivity (FLI) in the dorsolateral striatum.\nMolindone exhibits selectivity for cortical serotonin-stimulated cyclase versus dopamine-stimulated cyclase.\nMolindone in low intravenous doses (0.4-0.8 mg/kg) was found to reverse d-amphetamine and apomorphine induced depression of DA neurons and to block apomorphine induced depression of these cells. Molindone was also found to increase dopamine synthesis and dihydroxyphenylactic acid levels in the striatum and olfacotry tubercles. In all of these respects molindone behaves identically to most classical neuroleptics. However, unlike most antipsychotic drugs previously tested, molindone failed to increase the baseline firing rate of DA cells and blocked haloperidol induced increases in DA neuron activity. In this regard molindone most closely resembles thioridazine and clozapine.']
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Which mechanisms underlie adaptive mutagenesis (stationary-phase mutagenesis) in Bacillus subtilis?
['under conditions of nutritional stress, the processing of deaminated bases in B. subtilis may normally occur in an error-prone manner to promote adaptive mutagenesis.', "the B. subtilis' ability to accumulate chromosomal mutations under conditions of starvation is influenced by cell differentiation and transcriptional derepression, as well as by proteins homologous to transcription and repair factors.", 'the loss of Mfd has a depressive effect on stationary-phase mutagenesis.', 'In Bacillus subtilis, transcription-associated mutagenesis has been shown to be independent of recombination-dependent repair and, in some cases, of the Y DNA polymerases. Central to stationary-phase mutagenesis in B. subtilis is the requirement for Mfd, transcription coupling repair factor', 'Oxidative stress-induced DNA damage has been associated with generation of adaptive His(+) and Met(+) but not Leu(+) revertants in strain Bacillus subtilis YB955', 'an interplay between MutY and MutSL (mismatch repair system [MMR]) plays a pivotal role in the production of adaptive Leu(+) revertants.', 'MMR regulation of the mutagenic/antimutagenic properties of MutY promotes stationary-phase mutagenesis in B. subtilis cells.', 'To further examine the correlation between transcription and adaptive mutation, we placed a point-mutated allele, leuC427, under the control of an inducible promoter and assayed the level of reversion to leucine prototrophy under conditions of leucine starvation. Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels.', 'a Bacillus subtilis strain deficient in mismatch repair (MMR; encoded by the mutSL operon) promoted the production of stationary-phase-induced mutations', 'starved B. subtilis cells lacking a functional error prevention GO (8-oxo-G) system (composed of YtkD, MutM, and YfhQ) had a dramatic propensity to increase the number of stationary-phase-induced revertants.', 'the occurrence of mutations is exacerbated by reactive oxygen species in nondividing cells of B. subtilis having an inactive GO system.', 'the absence or depression of both the MMR and GO systems contributes to the production of stationary-phase mutants in B. subtilis.', 'oxidative stress is a mechanism that generates genetic diversity in starved cells of B. subtilis, promoting stationary-phase-induced mutagenesis in this soil microorganism', 'this type of mutagenesis is subject to regulation involving at least two of the genes that are involved in the regulation of post-exponential phase prokaryotic differentiation, i.e., comA and comK.', 'a functional RecA protein was not required for this type of mutagenesis.', 'These data suggest a role for YqjH in the generation of at least some types of stationary-phase-induced mutagenesis.', 'Error-prone processing of apurinic/apyrimidinic (AP) sites by PolX underlies a novel mechanism that promotes adaptive mutagenesis in Bacillus subtilis.', 'Roles of YqjH and YqjW, homologs of the Escherichia coli UmuC/DinB or Y superfamily of DNA polymerases, in stationary-phase mutagenesis and UV-induced mutagenesis of Bacillus subtilis.', 'Mismatch repair modulation of MutY activity drives Bacillus subtilis stationary-phase mutagenesis.', 'Novel role of mfd: effects on stationary-phase mutagenesis in Bacillus subtilis.', 'Defects in the error prevention oxidized guanine system potentiate stationary-phase mutagenesis in Bacillus subtilis.', 'Central to stationary-phase mutagenesis in B. subtilis is the requirement for Mfd, transcription coupling repair factor, which suggests a novel mechanism from those described in other model systems.', 'In conclusion, our results support the idea that oxidative stress is a mechanism that generates genetic diversity in starved cells of B. subtilis, promoting stationary-phase-induced mutagenesis in this soil microorganism.', 'Previous studies showed that a Bacillus subtilis strain deficient in mismatch repair (MMR; encoded by the mutSL operon) promoted the production of stationary-phase-induced mutations.', 'subtilis can be generated through a novel mechanism mediated by error-prone processing of AP sites accumulated in the stationary phase by the PolX DNA polymerase']
["Increased transcription levels potentiate adaptive mutagenesis. Central to stationary-phase mutagenesis in B. subtilis is the requirement for Mfd protein (transcription repair coupling factor). The B. subtilis' ability to accumulate chromosomal mutations under conditions of starvation is influenced by cell differentiation and transcriptional derepression, as well as by proteins homologous to transcription and repair factors. Under conditions of nutritional stress, the processing of deaminated bases in B. subtilis may normally occur in an error-prone manner to promote adaptive mutagenesis. A functional RecA protein is not required for adaptive mutagenesis, which seems to be independent of recombination-dependent repair and, in some cases, of the Y DNA polymerases. Oxidative stress-induced DNA damage has been associated with adaptive mutagenesis. The occurrence of such mutations is exacerbated by reactive oxygen species. Starved B. subtilis cells lacking a functional error prevention GO (8-oxo-G) system (composed of YtkD, MutM, and YfhQ) had a dramatic propensity to increase the number of stationary-phase-induced revertants. The MMR (encoded by the mutSL operon) protects B. subtilis from stationary-phase mutations. The MMR modulation of the mutagenic/antimutagenic properties of MutY regulates stationary-phase mutagenesis. Two of the genes that are involved in the regulation of post-exponential phase prokaryotic differentiation, comA and comK, are involved in adaptive mutagenesis. Also, YqjH, a homolog of DinB protein, plays a role in stationary phase mutagenesis."]
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Which are the major phycobiliproteins present in cyanobacteria?
['An extensive range of pigments including phycobiliproteins are present in algae. C-phycocyanin (C-PC), a phycobiliprotein, is one of the key pigments of Spirulina', 'Spirulina platensis produces nutraceutical product C-phycocyanin (C-PC)', 'C-Phycocyanin (C-Pc) is one of the major biliprotein pigments of unicellular cyanbacterium of Spirulina platenesis', 'Marine Synechococcus owe their specific vivid color (ranging from blue-green to orange) to their large extrinsic antenna complexes called phycobilisomes, comprising a central allophycocyanin core and rods of variable phycobiliprotein composition.', 'Three major pigment types can be defined depending on the major phycobiliprotein found in the rods (phycocyanin, phycoerythrin I or phycoerythrin II)', 'Phycocyanin--a major phycobiliprotein constitutively produced by many cyanobacteria--', 'R-phycoerythrin was isolated and purified from a red alga, Polysiphonia urceolata Grev', 'C-phycocyanin (C-PC), one of the major phycobiliproteins of Spirulina platensis (a blue-green alga)', 'C-Phycocyanin (C-PC), the major light harvesting biliprotein from Spirulina platensis is of greater importance because of its various biological and pharmacological properties.', 'B-Phycoerythrin (B-PE) is a major light-harvesting pigment of microalgae.', 'Phycoerythrin is a major light-harvesting pigment of red algae and cyanobacteria that is widely used as a fluorescent probe and analytical reagent. In this paper, B-phycoerythrin and R-phycocyanin in native state, from the red alga Porphyridium cruentum were obtained by an inexpensive and simple process.', 'Phycobiliproteins are derived from the photosynthetic apparatus of cyanobacteria and eukaryotic algae.', 'the three major phycobiliprotein types, namely allophycocyanin, phycocyanin, and phycoerythrin', 'Phycoerythrin is a major light-harvesting pigment of red algae and cyanobacteria widely used as a fluorescent probe.', 'allophycocyanin (APC)', 'R-phycoerythrin is the major light-harvesting pigment protein of most red algal phycobilisomes.', 'The purified protein had three absorption peaks at 498, 535, and 565 nm and displayed a fluorescence maximum at 580 nm, which was consistent with the typical spectrum of R-phycoerythrin. The purified R-PE was also identified with electrophoresis.', 'Phycobilisomes, the major light-harvesting complexes of cyanobacteria are multimolecular structures made up of chromophoric proteins called phycobiliproteins and non chromophoric linker polypeptides.', 'We report here the isolation and nucleotide sequence of the genes, cpeA and cpeB, which in Calothrix PCC 7601 encode the alpha and beta subunits of phycoerythrin, one of the major phycobiliproteins.', 'The major light-harvesting complex in eukaryotic red algae and prokaryotic cyanobacteria is the phycobilisome, a water-soluble complex located on the outer surface of the photosynthetic membranes and composed of both pigmented phycobiliproteins (85%) and non-pigmented linker (15%) polypeptides.', 'Phycocyanin is a major protein produced by cyanobacteria, but very few phycocyanin-producing strains have been reported.', 'In the present work, phycocyanin (PC) and phycoerythrin (PE) from a Nostoc species are proposed as protein markers for electrophoretic techniques.', 'Rod structure of a phycoerythrin II-containing phycobilisome. I. Organization and sequence of the gene cluster encoding the major phycobiliprotein rod components in the genome of marine Synechococcus sp. WH8020.', 'We now present data showing that the allophycocyanin genes and a second set of phycocyanin genes are transcribed into major mRNAs of 1400 and 1600 bases, respectively', 'The amino acid sequences deduced from both rpeA and rpeB present strong homologies with those previously reported for phycoerythrin subunits of cyanobacteria, rhodophyta, and cryptomonads', 'These transcripts are present in RNA isolated from cultures grown in red and green light, although lower levels of the 1600-base phycocyanin transcript are present in cells grown in green light', 'Phycocyanin is a major protein produced by cyanobacteria, but very few phycocyanin-producing strains have been reported', 'The major light-harvesting complex in eukaryotic red algae and prokaryotic cyanobacteria is the phycobilisome, a water-soluble complex located on the outer surface of the photosynthetic membranes and composed of both pigmented phycobiliproteins (85%) and non-pigmented linker (15%) polypeptides', 'Phycocyanin--a major phycobiliprotein constitutively produced by many cyanobacteria--holds several promising applications in diagnostics, biomedical research, and therapeutics', 'Phycobilisomes, the major light-harvesting complexes of cyanobacteria are multimolecular structures made up of chromophoric proteins called phycobiliproteins and non chromophoric linker polypeptides']
['Phycobiliproteins are derived from the photosynthetic apparatus of cyanobacteria and eukaryotic algae, and form their large extrinsic antenna complexes called phycobilisomes. Phycobilisomes have a core composed from allophycocyanin (APC) and rods, which are of variable phycobiliprotein composition. C-Phycocyanin (C-Pc) is one of the major light harvesting biliprotein pigments constitutively produced by many cyanobacteria, such as Spirulina platenesis (a blue-green alga). B-Phycoerythrin (B-PE) is an other major light-harvesting pigment found in red algae and cyanobacteria. R-phycoerythrin (R-PE) is the major light-harvesting pigment protein of most red algal phycobilisomes.']
['allophycocyanin (APC)', 'C-Phycocyanin (C-Pc)', 'B-Phycoerythrin (B-PE)', 'R-phycoerythrin (R-PE)']
Is Rac1 involved in cancer cell invasion?
['In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells.', 'These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling.', 'These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes.', 'Activated PAR1 induced RhoA and Rac1 phosphorylation, and subsequent overexpression of myosin IIA and filamin B which are stress fiber components that were identified by PMF analysis of peptide mass data obtained by MALDI-TOF/MS measurement. ', 'These results demonstrate that PAR1 activation induces cell morphological change associated with cell motility via Rho family activation and cytoskeletal protein overexpression, and has a critical role in gastric cancer cell invasion and metastasis.', 'Rac1 was found to be required for actopaxin-induced matrix degradation whereas inhibition of myosin contractility promoted degradation in the phosphomutant-expressing Quint cells, indicating that a balance of Rho GTPase signaling and regulation of cellular tension are important for the process.', 'Taken together, this study demonstrates a new role for actopaxin phosphorylation in matrix degradation and cell invasion via regulation of Rho GTPase signaling.', 'BART inhibits pancreatic cancer cell invasion by Rac1 inactivation through direct binding to active Rac1', 'We report that Binder of Arl Two (BART) plays a role in inhibiting cell invasion by regulating the activity of the Rho small guanosine triphosphatase protein Rac1 in pancreatic cancer cells.', 'BART interacts with active forms of Rac1, and the BART-Rac1 complex localizes at the leading edges of migrating cancer cells. Suppression of BART increases active Rac1, thereby increasing cell invasion. Treatment of pancreatic cancer cells in which BART is stably knocked down with a Rac1 inhibitor decreases invasiveness. Thus, BART-dependent inhibition of cell invasion is likely associated with decreased active Rac1.', 'The Rac1 inhibitor inhibits the lamellipodia formation that is stimulated by suppression of BART.', 'Our results imply that BART regulates actin-cytoskeleton rearrangements at membrane ruffles through modulation of the activity of Rac1, which, in turn, inhibits pancreatic cancer cell invasion.', 'It has been reported as an important inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloproteases to the extracellular media, and the cleavage of a P-cadherin soluble form with pro-invasive activity. Intracellularly, this protein interferes with the endogenous cadherin/catenin complex, inducing p120-catenin delocalization to the cytoplasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton.', 'Targeted down-regulation of RhoC led to sustained activation of Rac1 GTPase and morphological, molecular and phenotypic changes reminiscent of epithelial to mesenchymal transition.', 'We also find that Rac1 GTPase mediates tight binding of prostate cancer cells to bone marrow endothelial cells and promotes retraction of endothelial cells required for tumor cell diapedesis.', 'Finally, Rac1 leads to β1 integrin activation, suggesting a mechanism that Rac1 can mediate tight binding with endothelial cells.', 'Together, our data suggest that Rac1 GTPase is key mediator of prostate cancer cell-bone marrow endothelial cell interactions.', 'Furthermore, expression of dominant-negative Rac1 (T17N) could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration.', 'Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Rac1, generation of ROS and subsequent activation of PI3K/Akt and PAK1.', 'Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1, and cdc42, are important molecules for linking cell shape and cell-cycle progression because of their role in both cytoskeletal arrangements and mitogenic signaling.', 'The suppression of MMP-2 expression by CTXG led to an inhibition of SW620 cells invasion and migration by inactivating Rac1 and Cdc42 but not RhoA GTPase.', 'In conclusion, our data demonstrate that CTXG exerted anti-invasion action in SW620 cells by targeting MMP-2 though regulating the activities of Rac1, Cdc42 and their downstream transcriptional factor AP-1.', 'ctivation of H-Ras and Rac1 correlates with epidermal growth factor-induced invasion in Hs578T and MDA-MB-231 breast carcinoma cells', 'We have previously shown that H-Ras, but not N-Ras, induces an invasive phenotype mediated by small GTPase Rac1 in MCF10A human breast epithelial cells.', 'Moreover, siRNA-knockdown of Rac1 significantly inhibited the EGF-induced invasiveness in these cells.', 'Our data demonstrate that the activation of H-Ras and the downstream molecule Rac1 correlates with EGF-induced breast cancer cell invasion, providing important information on the regulation of malignant progression in mammary carcinoma cells.', 'At 50% growth-inhibiting concentration, icariin significantly suppressed tumor cells migration and invasion, which were traceable to down-regulation of Rac1 and VASP. ', 'These results indicate that icariin exerts negative effects on tumor cell invasion and migration via the Rac1-dependent VASP pathway and may be a potential anti-cancer drug.', 'RhoGDI2 modulates the invasiveness and metastatic ability of cancer cells through regulation of Rac1 activity.', 'We also showed that GBM cells secrete Sema3A endogenously, and RNA interference-mediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity.', 'LMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion', 'Here, we report for the first time that engulfment and cell motility 1 (ELMO1) and dedicator of cytokinesis 1 (Dock180), a bipartite Rac1 guanine nucleotide exchange factor (GEF), are evidently linked to the invasive phenotype of glioma cells.', 'Inhibition of endogenous ELMO1 and Dock180 expression significantly impeded glioma cell invasion in vitro and in brain tissue slices with a concomitant reduction in Rac1 activation.', 'Members of the Rac family of small GTPases are known to act as regulators of actin cytoskeletal structures and strongly influence the cellular processes of integrin-mediated adhesion and migration. Even though hyperactivated Rac proteins have been shown to influence metastatic processes, these proteins have never been directly linked to metastatic progression. ', 'We show that increased activation of Rac proteins directly correlates with increasing metastatic potential in a panel of cell variants derived from a single metastatic breast cancer cell line (MDA-MB-435).', 'Expression of a dominant active Rac1 or a dominant active Rac3 resulted in a more invasive and motile phenotype.', 'Moreover, expression of either dominant negative Rac1 or dominant negative Rac3 into the most metastatic cell variant resulted in decreased invasive and motile properties.', 'This study correlates endogenous Rac activity with high metastatic potential and implicates Rac in the regulation of cell migration and invasion in metastatic breast cancer cells. Taken together, these results suggest a role for both the Rac1 and Rac3 GTPases in human breast cancer progression.']
['A number of signalling pathways have been found to converge to and activate Rac1, which, in turn, activates a number of downstream targets to control actin-cytoskeleton rearrangements at membrane ruffles, as well as formation and activity of lamellipodia, to regulate the migratory processes leading to cell invasion.']
['yes']
Is macroautophagy a selective degradation process?
['Selective autophagy', 'Macroautophagy (autophagy) is a bulk degradation system for cytoplasmic components and is ubiquitously found in eukaryotic cells', 'Here we show that selective autophagy downregulates Ty1 transposition', 'We propose that selective autophagy safeguards genome integrity against excessive insertional mutagenesis caused during nutrient starvation by transposable elements in eukaryotic cells.', 'Moreover, it is becoming apparent that proteins, organelles, and pathogens can be targeted for autophagic clearance by selective mechanisms', 'Cell spreading required ref(2)P, the Drosophila p62 multiadaptor, implicating selective autophagy as a novel mechanism for modulating cortical dynamics', 'The selective macroautophagic degradation', 'There is growing evidence that macroautophagic cargo is not limited to bulk cytosol in response to starvation and can occur selectively for substrates, including aggregated proteins.', 'It remains unclear, however, whether starvation-induced and selective macroautophagy share identical adaptor molecules to capture their cargo. Here, we report that Alfy, a phosphatidylinositol 3-phosphate-binding protein, is central to the selective elimination of aggregated proteins.', 'We propose that Alfy plays a key role in selective macroautophagy by bridging cargo to the molecular machinery that builds autophagosomes.', 'Thus, cytoplasmic NBR1 might be important to maintain basal levels of selective macroautophagy in these neurons.', 'we could show that Smatg8 and Smatg4 are not only required for nonselective macroautophagy, but for selective macropexophagy as well.', 'The latter is performed by proteasome-mediated degradation, chaperone-mediated autophagy (CMA), and selective macroautophagy,', 'Here we demonstrate a role for PtdIns 4-kinases and PtdIns4P 5-kinases in selective and nonselective types of autophagy in yeast.', 'Macroautophagy (hereafter autophagy) is a degradative cellular pathway that protects eukaryotic cells from stress, starvation, and microbial infection.', 'Previously, we showed that macroautophagy is necessary for conidiation in the rice-blast fungus Magnaporthe oryzae. Here, we analyzed the physiological function(s) of selective autophagy in Magnaporthe', 'Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins.', 'Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins.', "Whole organelle turnover is mediated through macroautophagy, a process by which autophagosomes deliver mitochondria to the lysosome for hydrolytic degradation. While mitochondrial autophagy can occur as part of a nonselective upregulation of autophagy, selective degradation of damaged or unneeded mitochondria (mitophagy) is a rapidly growing area in development, cancer, and neurodegeneration, particularly with regard to Parkinson's disease", 'BAG3 was recently described as a mediator of a novel macroautophagy pathway that uses the specificity of heat shock protein 70 (HSP70) to misfolded proteins and also involves other protein partners, such as HSPB8.', 'two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy)', 'Here we show that whole mitochondria are turned over via macroautophagy.', 'Does Huntingtin play a role in selective macroautophagy?', 'In the discussion here I suggest that Htt may have a normal function in the lysosomal mechanism of selective macroautophagy involved in its own degradation', 'Macroautophagy induced by ethanol seemed to be selective for damaged mitochondria and accumulated lipid droplets, but not long-lived proteins, which could account for its protective effects', 'Although macroautophagy can be nonspecific, there are many examples of selective sequestration including pexophagy, mitophagy and the cytoplasm to vacuole targeting (Cvt) pathway.', 'Mitochondria autophagy (mitophagy) is the process of selective degradation of mitochondria that has an important role in mitochondrial quality control.', 'One of the genes identified, YLR356W, is required for mitophagy, but not for macroautophagy or other types of selective autophagy.', 'A genomic screen for yeast mutants defective in selective mitochondria autophagy.', 'Mitophagy is the process of selective mitochondrial degradation via autophagy, which has an important role in mitochondrial quality control.', 'Analysis of this set of targeted deletion mutants demonstrated that loss of any of the 16 genes necessary for nonselective macroautophagy renders the fungus unable to cause rice blast disease, due to impairment of both conidial programmed cell death and appressorium maturation. In contrast, genes necessary only for selective forms of autophagy, such as pexophagy and mitophagy, are dispensable for appressorium-mediated plant infection.', 'This gene is not required for other types of selective autophagy or for nonspecific macroautophagy.', 'However, in contrast to the core autophagy genes such as atg5 and atg7, expression of ulk1 is not essential for induction of macroautophagy in response to nutrient deprivation or for survival of newborn mice. Together, these data suggest that the ATG1 homologue, Ulk1, is a component of the selective autophagy machinery that leads to the elimination of organelles in erythroid cells rather that an essential mechanistic component of autophagy.', 'Growing evidence supports an active role for dysregulated macroautophagy (autophagic stress) in neuronal cell death and neurodegeneration. Alterations in mitochondrial function and dynamics are also strongly implicated in neurodegenerative diseases. Interestingly, whereas the core autophagy machinery is evolutionarily conserved and shared among constitutive and induced or selective autophagy, recent studies implicate distinct mechanisms regulating mitochondrial autophagy (mitophagy) in response to general autophagic stimuli.', 'We discovered that activation of the UPR in yeast also induces a new branch of macroautophagy that selectively targets the ER. We term this process "ER-phagy", in analogy to pexophagy and mitophagy, the two other known forms of organelle-specific marcoautophagy. ER-phagy involves the generation of autophagosomes that selectively include ER membranes and whose delimiting double membranes also derive, at least in part, from the ER.', 'This suggests that in fungi an organism-specific form of selective autophagy may occur, for which specialized Atg proteins have evolved.', 'ransfer of Y. lipolytica cells from oleate/ethylamine to glucose/ammonium chloride medium leads to selective macroautophagy of peroxisomes.', 'Insulin-dependent signaling regulates azurophil granule-selective macroautophagy in human myeloblastic cells.', 'We show that insulin-dependent signals regulate azurophil granule-selective macroautophagy in human myeloid cells.', 'By contrast, other organelles, including the mitochondria, endoplasmic reticulum, and Golgi apparatus remained intact, indicating that the macroautophagy selectively targeted azurophil granules.', 'Thus, insulin-dependent signals are responsible for the control of azurophil granule-selective macroautophagy via Akt-dependent pathways', 'Eukaryotic cells have the ability to degrade proteins and organelles by selective and nonselective modes of micro- and macroautophagy.', 'For example, pexophagy is a selective process for the regulated degradation of peroxisomes by autophagy.', 'We have characterized biochemically, morphologically, and genetically two distinct pathways for the selective degradation of peroxisomes in Pichia pastoris. These pathways are independently regulated and analogous to microautophagy and macroautophagy that have been defined in mammalian cells.', 'If we are willing to slightly modify our definition of autophagy, with a focus on "degradation of a cell\'s own components through the lysosomal/vacuolar machinery," we can include a newly documented process, programmed nuclear destruction (PND).', 'Autophagy is a lysosomal degradation pathway that can sequester cytosolic material, including organelles, nonspecifically in a process called nonselective macroautophagy, or target specific protein aggregates designated for destruction in a process called selective autophagy.', 'Selective macroautophagy uses double-membrane vesicles, termed autophagosomes, to transport cytoplasmic pathogens, organelles and protein complexes to the vacuole for degradation.', 'Autophagy (macroautophagy), a highly conserved eukaryotic mechanism, is a non-selective degradation process, helping to maintain a balance between the synthesis, degradation and subsequent recycling of macromolecules to overcome various stress conditions.', 'Whole organelle turnover is mediated through macroautophagy, a process by which autophagosomes deliver mitochondria to the lysosome for hydrolytic degradation.', 'Macroautophagy is a catabolic process by which the cell degrades cytoplasmic components through the lysosomal machinery.', 'Macroautophagy maintains cellular homeostasis through targeting cytoplasmic contents and organelles into autophagosomes for degradation.', 'Macroautophagy is a catabolic process by which cytosolic components are sequestered by double membrane vesicles called autophagosomes and sorted to the lysosomes/vacuoles to be degraded.', 'Macroautophagy (hereafter autophagy) is a cellular degradation process, which in yeast is induced in response to nutrient deprivation.', 'Macroautophagy was thought to be an unspecific bulk degradation process.', 'Autophagy is a highly regulated intracellular degradation process by which cells remove cytosolic long-lived proteins and damaged organelles, and can be monitored by imaging the incorporation of microtubule-associated light chain 3 (LC3) fused to a fluorescent protein (GFP or mCherry) into nascent autophagosomes.', 'Beside macroautophagy, there are several forms of selective autophagy, including chaperone-mediated autophagy (CMA), cytoplasm to vacuole targeting (Cvt), pexophagy and mitophagy.', 'Macroautophagy (commonly referred to as autophagy) is the process by which intact organelles and/or large portions of the cytoplasm are engulfed within double-membraned autophagic vacuoles for degradation.', 'This analysis demonstrated that Atg proteins required for non-selective macroautophagy are conserved from yeast to man, stressing the importance of this process in cell survival and viability.', 'Part of the degradation of intracellular proteins occurs in the lysosomes and is mediated by macroautophagy.']
['Yes. Macroautophagy (commonly referred to simply as autophagy) is a catabolic process conserved throughout the eukaryotes, and is distinct from other forms of autophagy by the formation of the autophagosome: this is a vesicle-like formation surrounded by a double membrane that sequesters the cytoplasmic material to be degraded. It was initially considered that macroautophagy was a bulk process; however, recent findings illustrate that specific cargos (ranging from misfolded or excess proteins, to organelles or even bacterial cells) can be selectively targeted to the pre-autophagosome membrane (i.e. the phagophore) and finally to the vacuoles/lysosomes for their degradation.']
['yes']
Is there any genetic determinant of hair pigmentation that could be useful in forensic analyses?
['a recent paper has reported the genetic determination of eye and hair color in samples up to 800 years old. ', ' Here, we demonstrate that human hair color is predictable from DNA variants with similarly high accuracies.', '12 genes previously associated with human hair color variation', ' several key pigmentation genes have been characterised, in particular the melanocortin 1 receptor gene (MC1R). Here, the function and known mutations of MC1R and other human pigmentation genes including ASIP, MATP, SLC24A5, TYR, TYRP1 and OCA2 are outlined, and a forensic test based on MC1R SNPs presented.', 'Recent studies have proved that there is a significant association between some genetic variants of the melanocortin 1 receptor (MC1R) gene and red hair color.', 'We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. ', 'Interactions between HERC2, OCA2 and MC1R may influence human pigmentation phenotype.', 'Several genome-wide association studies for pigmentation have now been conducted and identified single nucleotide polymorphism (SNP) markers in known, TYR, TYRP1, OCA2, SLC45A2, SLC24A5, MC1R, ASIP, KITLG and previously unknown SLC24A4, IRF4, TPCN2, candidate genes. ', ' five red hair colour (RHC) MC1R alleles, ', 'Naturally blond hair is rare in humans and found almost exclusively in Europe and Oceania. Here, we identify an arginine-to-cysteine change at a highly conserved residue in tyrosinase-related protein 1 (TYRP1) as a major determinant of blond hair in Solomon Islanders.']
['Yes, there are at least 12 genes associated with human hair color variation such as: TYR, TYRP1, OCA2, SLC45A2, SLC24A5, MC1R, ASIP and KITLG.']
['Yes, there are at least 12 genes associated with human hair color variation such as: TYR, TYRP1, OCA2, SLC45A2, SLC24A5, MC1R, ASIP and KITLG.']
What is the influence of patent expiry on ACE inhibitor prescribing.
['Generic switch after ramipril patent expiry is not associated with decreased pharmacy refill compliance: a retrospective study using the DAPI database.', 'The costs per DDD decreased for all three drugs and, as expected, these costs decrease more rapidly after patent expiry. Significant differences in the trend lines were found for enalapril and fluoxetine']
['Patent expiry has different effects on prescribing in different systems. It leads to decreased cost but no decreased refill compliance in countries like Sweden, Germany etc. In countries like Taiwan, where doctors profit directly from dispensing, patients are switched to ARBs which are more costly.']
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