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What is the association between adiponectin and migraine?

['Increase in body fat, especially in gluteofemoral region, elevates adiponectin and leptin secretion which in turn impair inflammatory processes that could be contributing to migraine risk.', 'CONCLUSION: In this pilot study of women episodic migraineurs, the HMW\u2009:\u2009LMW ADP ratio level was associated with migraine severity and predictive of acute treatment response. ADP and the HMW\u2009:\u2009LMW ratio of ADP represent potential novel biomarkers and drug targets for episodic migraine.', 'Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. ', 'Obesity can be considered as a proinflammatory state in which increased inflammatory mediators, vascular hyperreactivity, plasma calcitonin gene-related peptide (CGRP) concentrations and decreased adiponectin concentrations are observed. These alterations can cause an increase in the frequency of migraine attacks developed of central sensitization, and thereafter, chronic migraine.', 'Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. ', 'Several adipocytokines appear to play an integral role in feeding and obesity--and have also been linked to pain. Among these proteins are adiponectin and leptin. The author reviews the regulation of adipose tissue and feeding and provides an in-depth examination of adiponectin and leptin and their association with migraine.', 'CONCLUSION: Serum adiponectin levels are increased in women chronic daily headache (CDH) sufferers.', 'n this review we discuss the basic science of adiponectin and its potential connection to the pathophysiology of migraine. Future research may focus on how adiponectin levels are potentially altered during migraine attacks, and how that information can be potentially translated into migraine therapy.', 'Collectively, the results of our analysis suggest that a link between serum adiponectin and migraine remains elusive, at the best', 'Future research may focus on how adiponectin levels are potentially altered during migraine attacks, and how that information can be potentially translated into migraine therapy.']

['There is evidence to suggest that adiponectin plays a role in migraine. Increase in body fat elevates adiponectin and leptin secretion which in turn impair inflammatory processes that could be contributing to migraine risk. In episodic migraine patients, adiponectin was associated with migraine severity and predictive of acute treatment response. Serum adiponectin levels are increased in women chronic daily headache sufferers.']

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Are OATP1B1 and OATP1B3 associated with bilirubin transport?

['OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir. ', 'Examples of adaptive nontoxic changes in liver function, which may elevate direct (conjugated) and/or indirect (unconjugated) bilirubin above baseline levels, include reversible inhibition of UGT1A1-mediated bilirubin metabolism and OATP1B1-, OATP1B3-, or MRP2-mediated transport (Keogh.', 'Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively.', 'OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir.', 'However, because drug transporters also contribute to bilirubin elimination, the purpose of this work was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and BSEP of select test drugs known to elicit hyperbilirubinemia.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.', 'Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3.', 'Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.', 'The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia.', 'OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir', 'Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3', 'Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively', 'Examples of adaptive nontoxic changes in liver function, which may elevate direct (conjugated) and/or indirect (unconjugated) bilirubin above baseline levels, include reversible inhibition of UGT1A1-mediated bilirubin metabolism and OATP1B1-, OATP1B3-, or MRP2-mediated transport (Keogh', 'In vitro, faldaprevir inhibited key processes involved in bilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC50 0.45 µM), which conjugates bilirubin, and hepatic uptake and efflux transporters, organic anion-transporting polypeptide (OATP) 1B1 (IC50 0.57 µM), OATP1B3 (IC50 0.18 µM), and multidrug resistance-associated protein (MRP) 2 (IC50 6.2 µM), which transport bilirubin and its conjugates', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks', 'OATP1B1 (a.k.a. OATP-C, OATP2, LST-1, or SLC21A6) is a liver-specific organic anion uptake transporter and has been shown to be a higher affinity bilirubin uptake transporter than OATP1B3', 'In vitro OATP1B1 and OATP1B3 inhibition is associated with observations of benign clinical unconjugated hyperbilirubinemia.', 'Examples of adaptive nontoxic changes in liver function, which may elevate direct (conjugated) and/or indirect (unconjugated) bilirubin above baseline levels, include reversible inhibition of UGT1A1-mediated bilirubin metabolism and OATP1B1-, OATP1B3-, or MRP2-mediated transport (Keogh. Adv Pharmacol 63:1-42, 2012). ', 'Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. ', 'Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. ', 'OATP1B1 polymorphism is a major determinant of serum bilirubin level but not associated with rifampicin-mediated bilirubin elevation.', 'Unconjugated bilirubin (UCB) is taken up into hepatocytes by human organic anion transporting polypeptide 1B1 (OATP1B1; encoded for by the SLCO1B1 gene).', 'However, because drug transporters also contribute to bilirubin elimination, the purpose of this work was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and BSEP of select test drugs known to elicit hyperbilirubinemia. Test drugs investigated in this study were atazanavir and indinavir, which are associated with hyperbilirubinemia and elevations in serum transaminase; ritonavir and nelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, troglitazone, and trovafloxacin, which are associated with severe idiosyncratic hepatotoxicity exhibiting elevations in serum bilirubin and transaminase.', 'Test drugs investigated in this study were atazanavir and indinavir, which are associated with hyperbilirubinemia and elevations in serum transaminase; ritonavir and nelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, troglitazone, and trovafloxacin, which are associated with severe idiosyncratic hepatotoxicity exhibiting elevations in serum bilirubin and transaminase. Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively.', 'In vitro, faldaprevir inhibited key processes involved in bilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC50 0.45 µM), which conjugates bilirubin, and hepatic uptake and efflux transporters, organic anion-transporting polypeptide (OATP) 1B1 (IC50 0.57 µM), OATP1B3 (IC50 0.18 µM), and multidrug resistance-associated protein (MRP) 2 (IC50 6.2 µM), which transport bilirubin and its conjugates.', 'In vitro OATP1B1 and OATP1B3 inhibition is associated with observations of benign clinical unconjugated hyperbilirubinemia.', '3.\u2002\u2009The results indicated that in vivo Fi values >0.2 or R-values >1.5 for OATP1B1 or OATP1B3, but not UGT1A1, are associated with previously reported clinical cases of drug-induced unconjugated hyperbilirubinemia.', 'OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir.']

['Yes, OATP1B1 and OATP1B3 are involved in the transport of bilirubin.']

['yes']

Is pseudouridine a RNA modification?

['Pseudouridine (Ψ) is the most abundant of>150 nucleoside modifications in RNA. ', 'The number and position of the pseudouridines of Haloarcula marismortui and Deinococcus radiodurans large subunit RNA have been determined by a combination of total nucleoside analysis by HPLC-mass spectrometry and pseudouridine sequencing by the reverse transcriptase method and by LC/MS/MS.', 'Pseudouridine is the most abundant of more than 100 chemically distinct natural ribonucleotide modifications.']

['Yes, pseudouridine (Ψ) is the most abundant of>150 nucleoside modifications in RNA.']

['yes']

Are there any specific antidotes for dabigatran?

['Novel oral anticoagulants (NOACs)--apixaban, dabigatran, and rivaroxaban--have a significantly smaller risk of intracerebral hemorrhage (ICH). However, two facts make this situation complicated: First, the risk of hematoma expansion is unknown for NOACs. Second, there is no specific antidote for neither of the NOACs. ', 'However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect.', 'Given the absence of a specific antidote, the action to be taken in these situations must be defined. ', 'The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications;', 'Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. ', 'The lack of guidelines, protocols, and an established specific antidote to reverse the anticoagulation effect of dabigatran potentially increases the rates of morbidity and mortality in patients with closed head injury (CHI).', 'The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. ', 'NOA also have other unresolved problems: drug interactions are still possible, specific coagulation test to assess them must be developed, and no specific antidote is currently available in case of hemorrhagic complication.', " It is critical to identify and subsequently manage dabigatran etexilate toxicity because there is no specific antidote to reverse the drug's anticoagulant effects.", 'In the absence of a specific antidote for this novel oral anticoagulant medication, even in an emergency situation, successful surgical treatment was possible with an aggressive use of available prohaemostatic agents.', 'While these trial data are extremely encouraging, several practical issues (e.g., lack of specific antidote, safety of long-term treatment or cost-effectiveness in "real-life" clinical practice) still need to be elucidated.', 'In case of massive bleeding, management is unclear and none of these newer agents has a specific antidote that completely reverses its anticoagulant effect.', 'The short half-life of these new agents compensates for the lack of any specific antidote in many instances. ', 'As there is no specific antidote, the only treatment option is discontinuation of the drug and supportive management.', 'Currently, none of these new agents has a specific antidote, and little advise can be given on how to manage a major bleeding event.', 'Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. ']

['No specific antidote currently exists for dabigatran']

['no']

What is the mechanism of action of solanezumab?

['Anti-amyloid treatment in asymptomatic AD (A4) is a prevention trial aimed at treating older individuals with normal cognition but at risk of developing AD dementia on the basis of having biomarker evidence of amyloid (preclinical AD). They selected solanezumab for the anti-amyloid treatment for A4.', 'Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively', 'solanezumab, targeting monomeric Aβ', 'Immunotherapeutic agents have been developed to remove the neurotoxic amyloid β42 protein and prevent the hypothesized amyloid β42-induced neurotoxicity and neurodegeneration. The most notable of these immunotherapies are bapineuzumab and solanezumab.', 'Aβ removal and improved cognitive function in animal models of AD. Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab,', 'solanezumab, an anti-β-amyloid (Aβ) antibody', 'Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed', 'Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. ', "Solanezumab (LY2062430) is a humanized monoclonal antibody that binds to the central region of β-amyloid, a peptide believed to play a key role in the pathogenesis of Alzheimer's disease (AD).", 'Solanezumab is a humanized anti-amyloid β monoclonal antibody being developed as a passive immunization treatment to slow the progression of Alzheimer disease (AD). ', "This situation was encountered in the development of LY2062430, a therapeutic mid-domain monoclonal anti-amyloid beta peptide (Aβ) antibody undergoing clinical trials for the treatment of Alzheimer's disease. ", 'Solanezumab is a monoclonal antibody that binds to β-amyloid (Aβ), a protein that plays a key role in the pathogenesis of AD.', 'Solanezumab can neutralize soluble Aβ peptides,', 'LY2062430 (solanezumab) is a humanized monoclonal antibody being studied as a putative disease-modifying treatment of AD.']

["Solanezumab is a monoclonal anti-amyloid beta peptide (Aβ) antibody. It has been tested for treatment of Alzheimer's disease patients.", 'Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species.']

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What is the function of the protein encoded by the gene PABPC4?

['In testis mRNA stability and translation initiation are extensively under the control of poly(A)-binding proteins (PABP).', 'Taken together, our findings indicate that PABPC4 may play a role in the pathogenesis of colorectal cancer.', 'Consistent with these biochemical activities, plus corresponding histological profiles, the identified RNA processing factors are predicted to collectively drive post-transcriptional expression of an alternative exome that fuels finishing steps of sperm maturation and fitness.', 'This is the first evidence that PABPCs have a targeted role in hTERT regulation leading to a growth advantage in cells expressing HPV16 E6.', 'to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4,', 'and with the exception of PABP4, appear to be restricted in their expression to a small number of cell types. ', 'PABPC4 (p(Het) = 0.034) for HDL-C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults.', 'In addition, PABP4 was associated with the poly(A) tract of pre-mRNA']

['The main function of PABPC4 is in mRNA stability and translation initiation. PABPC4 may also play a role in chronic inflammation and in the pathogenesis of colorectal cancer.']

['PABC4 is important for mRNA stability and translation initiation, in chronic inflammation and in the pathogenesis of colorectal cancer.']

What is the function of yeast Clr4 on chromatin?

['Mutations in the clr4+, rik1+ and swi6+ genes dramatically reduce silencing at certain centromeric regions and cause elevated chromosome loss rates', 'The Swi6 protein was found to be delocalised from all three silent chromosomal regions, and dispersed within the nucleus, in both clr4 and rik1 mutant cells. ', 'Mutations in clr4, rik1 and swi6 also result in elevated sensitivity to reagents which destabilise microtubules and show a synergistic interaction with a mutation in the beta-tubulin gene (nda3).', 'These observations suggest that clr4+ and rik1+ must play a role in the assembly of Swi6p into a transcriptionally silent, inaccessible chromatin structure at fission yeast centromeres which is required to facilitate interactions with spindle microtubules and to ensure normal chromosome segregation.', 'The chromo and SET domains of the Clr4 protein are essential for silencing in fission yeast.', 'Like Su(var)3-9p, Clr4p contains SET and chromo domains, motifs found in proteins that modulate chromatin structure.', 'Surprisingly, RNA differential display experiments demonstrated that clr4+ can mediate transcriptional activation of certain other loci.', 'These results show that clr4 plays a critical role in silencing at mating-type loci and centromeres through the organization of repressive chromatin structure and demonstrate a new, activator function for Clr4p.', 'Clr4 is known to regulate silencing and switching at the mating-type loci and to affect chromatin structure at centromeres. ', 'Mutations in Cul4 result in defective localization of Clr4 and loss of silencing at heterochromatic loci.', 'The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast.', 'In a strain lacking the histone methyltransferase Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus.', 'Cut4 and Cut9 interact directly with Swi6/HP1 and Clr4, whereas the mutant Cut4 does not, suggesting that a direct physical interaction of APC subunits Cut4 and Cut9 with Swi6 and Clr4 is instrumental in heterochromatin assembly.', 'Thus, APC and heterochromatin proteins Swi6 and Clr4 play a mutually cooperative role in heterochromatin assembly, thereby ensuring chromosomal integrity, inheritance, and segregation during mitosis and meiosis.', 'Positive feedback mechanisms that link the RNAi pathway and the Clr4/Suv39h1 histone H3K9 methyltransferase complex (Clr-C) result in requirements for H3K9 methylation for full siRNA production and for siRNA production to achieve full histone methylation.', 'Heterochromatin assembly in fission yeast depends on the Clr4 histone methyltransferase, which targets H3K9.', 'These analyses place Sir2 and H3K14 deacetylation upstream of Clr4 recruitment during heterochromatin assembly.', 'These results show that clr4 plays a critical role in silencing at mating-type loci and centromeres through the organization of repressive chromatin structure and demonstrate a new, activator function for Clr4p', 'These results show that clr4 plays a critical role in silencing at mating-type loci and centromeres through the organization of repressive chromatin structure and demonstrate a new, activator function for Clr4p..']

['Clr4 is known to regulate silencing and switching at the mating-type loci and to affect chromatin structure at centromeres. The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast. Heterochromatin assembly in fission yeast depends on the Clr4 histone methyltransferase, which targets H3K9.']

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How does regular physical activity impact life expectancy?

['["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."]']

Regular physical activity increases life expectancy, but it is unclear if high-intensity sports activities further increase life expectancy.

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Is the regulation of Vsr endonuclease independent of the growth phase of bacteria?

['Growth phase-dependent regulation of Vsr endonuclease', 'Vsr endonuclease levels are growth phase dependent.', 'Growth phase-dependent regulation of Vsr endonuclease may contribute to 5-methylcytosine mutational hot spots in Escherichia coli.', 'Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent.', 'Vsr endonuclease, which initiates very short patch repair, has been hypothesized to regulate mutation in stationary-phase cells.', 'The efficiency of the two pathways changes during the bacterial life cycle; MMR is more efficient during exponential growth and VSP repair is more efficient during the stationary phase.', 'Overexpression of Vsr does dramatically increase the stationary-phase reversion of a Lac- frameshift allele, but the absence of Vsr has no effect.', 'Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent', 'The efficiency of the two pathways changes during the bacterial life cycle; MMR is more efficient during exponential growth and VSP repair is more efficient during the stationary phase', 'Vsr endonuclease, which initiates very short patch repair, has been hypothesized to regulate mutation in stationary-phase cells']

['The regulation of Vsr endonuclease levels is growth phase dependent.']

['no']

What is DENdb?

['DENdb: database of integrated human enhancers', 'We developed DENdb, a centralized on-line repository of predicted enhancers derived from multiple human cell-lines. DENdb integrates enhancers predicted by five different methods generating an enriched catalogue of putative enhancers for each of the analysed cell-lines. DENdb provides information about the overlap of enhancers with DNase I hypersensitive regions, ChIP-seq regions of a number of transcription factors and transcription factor binding motifs, means to explore enhancer interactions with DNA using several chromatin interaction assays and enhancer neighbouring genes. DENdb is designed as a relational database that facilitates fast and efficient searching, browsing and visualization of information. ', 'DENdb: database of integrated human enhancers.', 'We developed DENdb, a centralized on-line repository of predicted enhancers derived from multiple human cell-lines.', 'DENdb is designed as a relational database that facilitates fast and efficient searching, browsing and visualization of information.', 'DENdb integrates enhancers predicted by five different methods generating an enriched catalogue of putative enhancers for each of the analysed cell-lines.', 'DENdb provides information about the overlap of enhancers with DNase I hypersensitive regions, ChIP-seq regions of a number of transcription factors and transcription factor binding motifs, means to explore enhancer interactions with DNA using several chromatin interaction assays and enhancer neighbouring genes.', 'We developed DENdb, a centralized on-line repository of predicted enhancers derived from multiple human cell-lines', 'DENdb integrates enhancers predicted by five different methods generating an enriched catalogue of putative enhancers for each of the analysed cell-lines', 'DENdb provides information about the overlap of enhancers with DNase I hypersensitive regions, ChIP-seq regions of a number of transcription factors and transcription factor binding motifs, means to explore enhancer interactions with DNA using several chromatin interaction assays and enhancer neighbouring genes', 'DENdb is designed as a relational database that facilitates fast and efficient searching, browsing and visualization of information', 'Database URL: http://www.cbrc.kaust.edu.sa/dendb/.<CopyrightInformation>© The Author(s) 2015', 'DENdb: database of integrated human enhancers.', 'Database URL: http://www.cbrc.kaust.edu.sa/dendb/..', 'We developed DENdb, a centralized on-line repository of predicted enhancers derived from multiple human cell-lines.', 'DENdb is designed as a relational database that facilitates fast and efficient searching, browsing and visualization of information.', 'DENdb integrates enhancers predicted by five different methods generating an enriched catalogue of putative enhancers for each of the analysed cell-lines.', 'DENdb provides information about the overlap of enhancers with DNase I hypersensitive regions, ChIP-seq regions of a number of transcription factors and transcription factor binding motifs, means to explore enhancer interactions with DNA using several chromatin interaction assays and enhancer neighbouring genes.']

['DENdb is a centralized on-line repository of predicted enhancers derived from multiple human cell-lines. DENdb integrates enhancers predicted by five different methods generating an enriched catalogue of putative enhancers for each of the analysed cell-lines. DENdb provides information about the overlap of enhancers with DNase I hypersensitive regions, ChIP-seq regions of a number of transcription factors and transcription factor binding motifs, means to explore enhancer interactions with DNA using several chromatin interaction assays and enhancer neighbouring genes. DENdb is designed as a relational database that facilitates fast and efficient searching, browsing and visualization of information.']

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What is the genetic basis of propionic acidemia?

['utations in the PCCA or PCCB genes coding for alpha and beta subunits of propionyl CoA carboxylase can cause propionic acidemia', 'propionic acidemia (PA) can result from mutations in either of the genes PCCA or PCCB, which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme propionyl CoA-carboxylase', 'eficiency of propionyl-CoA carboxylase (PCC; alpha 4 beta 4) results in the rare, autosomal recessive disease propionic acidemia', 'PA is caused by mutations in either the PCCA or PCCB genes encoding the α- and β-subunits of the PCC enzyme ', 'eficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia', 'Recent studies have identified the genomic mutations in the genes PCCA and PCCB', 'ropionic acidemia is an organic acidemia that can lead to metabolic acidosis', 'plicing defects account for 16% of the mutant alleles in the PCCA and PCCB genes, encoding both subunits of the propionyl-CoA carboxylase (PCC) enzyme, defective in propionic acidemia', 'ropionic acidemia (PA) is an autosomal recessive disorder of metabolism caused by a deficiency of propionyl-coenzyme A carboxylase (PCC)', 'In the PA patients, we have identified four different changes in the PCCA gene, including one novel one (c.414+5G>A) affecting the splicing process', 'utations in either the PCCA or PCCB genes are responsible for propionic acidemia (PA)', 'Propionic acidemia is a common organic acidemia, caused by deficiency of propionyl-CoA carboxylase (PCC), which catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a dodecameric enzyme of alpha-PCC and beta-PCC subunits, nuclearly encoded by genes PCCA and PCCB, respectively. Mutation in either gene cause propionic acidemia', 'PA is inherited in an autosomal recessive fashion involving mutations in PCCA or PCCB encoding the alpha and beta subunits of propionyl-CoA carboxylase (PCC)', 'Two siblings affected with propionic acidemia were screened for putative mutations in PCCA and PCCB genes coding alpha and beta subunits of propionyl-coenzyme A (CoA) carboxylase', 'ropionic acidemia results from mutations in either of the two genes, PCCA or PCCB, that encode the two subunits of the propionyl-CoA carboxylase (PCC) enzyme', 'utations in the PCCA or PCCB genes, encoding both subunits of propionyl-CoA carboxylase, result in propionic acidemia', ' we analyze splicing mutations identified in propionic acidemia patients to clarify their functional effects and their involvement in the disease phenotype. Two mutations in the PCCA gene detected in homozygous patients and involving consensus splice sequences ', 'An enzyme deficiency can result from mutations in either PCCA or PCCB.', '(PA) is an inborn error of organic acid metabolism caused by a deficiency of propionyl-CoA carboxylase.', 'Mutations in either gene cause PA and to date, up to 47 different allelic variations in the PCCB gene have been identified in different population', 'ropionic acidemia (PA) is a recessive disorder caused by a deficiency of propionyl-CoA carboxylase (PCC), a dodecameric enzyme composed of two different proteins alpha-PCC and beta-PC', 'PCC is a multimeric protein composed of two different alpha- and beta-PCC subunits, nuclearly encoded by the PCCA and PCCB genes, respectively. Mutations in either gene cause the clinically heterogeneous disease propionic acidemia', 'More than 24 mutations have been found in the PCCA gene in patients with PA, ', 'ropionic acidemia (PA, MIM 232000 and 232050) is caused by a deficiency of mitochondrial biotin-dependent propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a heteropolymeric enzyme composed of alpha and beta subunits, which are encoded by the PCCA and PCCB genes, respectively', 'Approximately 60 mutations have been reported in the nuclear genes PCCA and PCCB that encode the two PCC subunits', 'eficiency of propionyl-CoA carboxylase (PCC) results in propionic acidemia', 'ropionic acidemia can result from mutations in the PCCA or PCCB genes encoding the alpha and beta subunits', 'ropionic acidemia is an inherited metabolic disorder caused by deficiency of propionyl-CoA carboxylase, a dodecameric enzyme composed of alpha-PCC and beta-PCC subunits ', 'A genetic deficiency of PCC activity causes propionic acidemia, a potentially fatal disease with onset in severe cases in the newborn period. Affected patients may have mutations of either the PCCA or PCCB gene.', 'PCC is composed of two equal subunits, alpha and beta, which are encoded by two separate genes at two distinct human loci. Mutations of either gene in humans results in propionic acidemia (PA)', 'Deficiency of PCC results in propionic acidemia (PA), a metabolic disorder', ' PCC consists of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. Inherited PCC deficiency due to mutations in either gene results in propionic acidemia (PA),', 'mutations in the PCCA and PCCB genes causing propionic acidemia', 'Mutations in the PCCA and PCCB genes, which encode the a and b subunits of this heteropolymer, result in propionic acidemia (PA)', 'ropionic acidemia is a rare autosomal recessive disorder of intermediary metabolism. It is caused by a deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a heteropolymeric protein composed of two subunits, alpha and beta', 'ropionic acidemia is an autosomal recessive disorder caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase (PCC). PCC is composed of two subunits, alpha and beta, encoded by the PCCA and PCCB genes,', 'Propionyl-CoA carboxylase (PCC) is a mitochondrial biotin-dependent enzyme composed of an equal number of alpha and beta subunits. Mutations in the PCCA (alpha subunit) or PCCB (beta subunit) gene can cause the inherited metabolic disease propionic acidemia (PA), which can be life threatening in the neonatal period. Lack of data on the genomic structure of PCCB has been a significant impediment to full characterization of PCCB mutant chromosomes. In this study, we describe the genomic organization of the coding sequence of the human PCCB gene and the characterization of mutations causing PA in a total of 29 unrelated patients-21 from Spain and 8 from Latin America. The implementation of long-distance PCR has allowed us to amplify the regions encompassing the exon/intron boundaries and all the exons. The gene consists of 15 exons of 57-183 bp in size. All splice sites are consistent with the gt/ag rule. The availability of the intron sequences flanking each exon has provided the basis for implementation of screening for mutations in the PCCB gene. A total of 56/58 mutant chromosomes studied have been defined, with a total of 16 different mutations detected. The mutation spectrum includes one insertion/deletion, two insertions, 10 missense mutations, one nonsense mutation, and two splicing defects. Thirteen of these mutations correspond to those not described yet in other populations. The mutation profile found in the chromosomes from the Latin American patients basically resembles that of the Spanish patients.', 'Inherited deficiency of PCC due to mutations in either the PCCA or the PCCB gene results in propionic acidemia (PA)', 'Mutations of the PCCA (alpha subunit) or PCCB (beta subunit) gene cause the inherited metabolic disease, propionic acidemia', 'We have detected three types of mutation in the same exon of the coding sequence of beta-subunit of PCC', 'ropionic acidemia is an inborn error of organic acid metabolism caused by deficiency of propionyl-CoA carboxylase', 'we have identified two mutations of the PCCB gene in a propionic acidemia patient', 'ropionic acidemia is an inherited disorder of organic acid metabolism that is caused by deficiency of propionyl-CoA carboxylase (PCC; EC 6.4.1.3). Affected patients fall into two complementation groups, pccA and pccBC (subgroups B, C, and BC), resulting from deficiency of the nonidentical alpha and beta subunits of PCC', 'ropionic acidemia (PA) is an autosomal recessive inborn error', 'It is caused by a deficiency of propionyl-CoA carboxylase', 'PCC is a heteropolymeric enzyme composed of alpha- and beta-subunits.', 'Mutation analysis confirmed the diagnosis of propionic acidemia (PA) with compound heterozygosity for 2 new missense mutations L417W/Q293E in the PCCA gene']

['Mutations in the PCCA or PCCB genes, encoding both subunits of propionyl-CoA carboxylase.']

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During which stage of the cell cycle is cohesin deposited on the yeast genome?

['In the budding yeast, cohesin is loaded onto the chromosome during the late G1 phase, establishes sister chromatid cohesion concomitant with DNA replication, and dissociates by the telophase. ', 'Sister chromatid cohesion is mediated by cohesin, but the process of cohesion establishment during S-phase is still enigmatic.', 'Instead, we find that cohesin stability increases at the time of S-phase in a reaction that can be uncoupled from DNA replication.', 'By using "single-copy" derivatives of the 2-microm plasmid, we demonstrate that recruitment of cohesin at STB during S phase indeed translates into cohesion between plasmid molecules.', 'In cells recovering from nocodazole-induced spindle depolymerization and G(2)/M arrest, cohesin-STB association can be established coincident with spindle restoration.', 'This postreplication recruitment of cohesin is not functional in equipartitioning. ', 'We have used chromatin immunoprecipitation coupled with microarray analysis (ChIP chip) to produce a genome-wide description of cohesin binding to meiotic and mitotic chromosomes of Saccharomyces cerevisiae.', 'Cohesin sites are highly conserved in meiosis and mitosis, suggesting that chromosomes share a common underlying structure during different developmental programs.', 'Cohesin complex acts in the formation and maintenance of sister chromatid cohesion during and after S phase.', " Proteolytic cleavage of cohesin's Sccl subunit at the metaphase to anaphase transition is essential for sister chromatid separation and depends on a conserved protein called separin.", "Four of these proteins, Scc1p, Scc3p, Smc1p, and Smc3p, are subunits of a 'Cohesin' complex that binds chromosomes from late G1 until the onset of anaphase.", 'It is necessary for the establishment of cohesion during DNA replication but not for its maintenance during G2 and M phases.', 'Here, we show that cohesin destruction in metaphase is sufficient for segregation of much of the budding yeast genome, but not of the long arm of chromosome XII that contains the rDNA repeats.', 'In this review, we have discussed the life cycle of cohesin during both mitotic and meiotic cell divisions including the structure and architecture of cohesin complex, relevance of cohesin associated proteins, mechanism of cohesin loading onto the chromatin, cohesion establishment and the mechanism of cohesin disassembly during anaphase to separate the sister chromatids.', 'Cohesin association with G1 chromosomes requires continued activity of the cohesin loader Mis4/Ssl3, suggesting that repeated loading cycles maintain cohesin binding.', 'Cdc14 phosphatase induces rDNA condensation and resolves cohesin-independent cohesion during budding yeast anaphase.', 'Cohesins are deposited by a conserved heterodimeric loading complex composed of the Scc2 and Scc4 proteins in Saccharomyces cerevisiae, but how the Scc2/Scc4 deposition complex regulates the spatiotemporal association of cohesin with chromosomes is not understood. We examined Scc2 chromatin association during the cell division cycle and found that the affinity of Scc2 for chromatin increases biphasically during the cell cycle, increasing first transiently in late G1 phase and then again later in G2/M.']

['In the budding yeast, cohesin is loaded onto the chromosome during the late G1 phase, establishes sister chromatid cohesion concomitant with DNA replication, and dissociates by the telophase.', 'In the budding yeast, cohesin is loaded onto the chromosome during the late G1 phase, establishes sister chromatid cohesion concomitant with DNA replication, and dissociates by the telophase. ', 'Cohesin association with G1 chromosomes requires continued activity of the cohesin loader Mis4/Ssl3, suggesting that repeated loading cycles maintain cohesin binding. In mammalian cells, cohesin binding to chromatin is dynamic in G1, but becomes stabilized during S-phase. Instead, we find that cohesin stability increases at the time of S-phase in a reaction that can be uncoupled from DNA replication. Budding yeast Scc1p/Mcd1p, an essential subunit, is cleaved and dissociates from chromosomes in anaphase, leading to sister chromatid separation.']

['S-phase']

Which classes of endogenous retroelements are known to date?

['Transposons are divided into two general classes based on their transposition intermediate (DNA or RNA). Only one subclass, the non-LTR retrotransposons, which includes the Long INterspersed Element-1 (LINE-1 or L1), is currently active in humans as indicated by 96 disease-causing insertions', 'Diversity of LTR-retrotransposons and Enhancer/Suppressor Mutator-like transposons in cassava', 'Members of two classes of LTR-retrotransposons, Ty1/copia-like and Ty3/gypsy-like, and of Enhancer/Suppressor Mutator (En/Spm)-like transposons were isolated and characterised', 'Mammalian LINE-1 (L1) elements belong to the superfamily of autonomously replicating retrotransposable elements that lack the long terminal repeated (LTR) sequences typical of retroviruses and retroviral-like retrotransposons']

['Endogenous retroelements fall into two distinct classes: retrotransposons containing LTRs (Long Terminal Repeats), and retrostransposons lacking LTRs.']

['retrotransposons containing LTRs (Long Terminal Repeats)', 'retrostransposons lacking LTRs (Long Terminal Repeats)']

What is the scope of the OMIA database?

['Online Mendelian Inheritance in Animals (OMIA),', 'Online Mendelian Inheritance in Animals (OMIA)', 'nline Mendelian Inheritance in Animals (OMIA) ', 'Online Mendelian Inheritance in Animals (OMIA)', 'Online Mendelian Inheritance in Animals (OMIA)', 'Online Mendelian Inheritance in Animals (OMIA) is a comprehensive, annotated catalogue of inherited disorders and other familial traits in animals other than humans and mice', 'Structured as a comparative biology resource, OMIA is a comprehensive resource of phenotypic information on heritable animal traits and genes in a strongly comparative context, relating traits to genes where possible. ']

['Online Mendelian Inheritance in Animals (OMIA) is a comprehensive, annotated catalogue of inherited disorders and other familial traits in animals. OMIA is a comprehensive resource of phenotypic information on heritable animal traits and genes in a strongly comparative context, relating traits to genes where possible.']

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Is the microRNA 132 (miR-132) involved in brain pathologies?

['miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present in schizophrenia.', "micro-RNAs encoding miR-9, miR-124a, miR-125b, miR-128, miR-132 and miR-219 are abundantly represented in fetal hippocampus, are differentially regulated in aged brain, and an alteration in specific micro-RNA complexity occurs in Alzheimer hippocampus. These data are consistent with the idea that altered micro-RNA-mediated processing of messenger RNA populations may contribute to atypical mRNA abundance and neural dysfunction in Alzheimer's disease brain.", 'Levels of several microRNA (miR-10a, -10b, -212, -132, -495) were significantly altered. One of them (miR-132) has been reported to be highly inducible by growth factors and to be a key regulator of neurite outgrowth. Moreover, miR-132-recognition sequences were detected in the mRNA transcripts of two differentially expressed proteins. MicroRNA may thus represent novel biomarkers for neuronal malfunction and potential therapeutic targets for human neurodegenerative diseases.', 'Expression of key neuronal microRNAs-including mir-9/9*, mir-124 and mir-132-is repressed in the brains of human HD patients and mouse models.', 'To determine if production of miR-132 is regulated by neuronal activity its expression in mouse brain was monitored by quantitative RT-PCR (RT-qPCR)', 'Expression levels of primary and mature-miR-132 increased significantly between postnatal Days 10 and 24. We conclude that miR-132 is an activity-dependent microRNA in vivo, and may contribute to the long-lasting proteomic changes required for experience-dependent neuronal plasticity.', 'We investigated how prior seizure preconditioning affects the miRNA response to status epilepticus evoked by intra-amygdalar kainic acid in mice.', 'Increased miR-132 levels were matched with increased binding to Argonaute-2, a constituent of the RNA-induced silencing complex. In tolerant animals, expression responses of >40% of the injury-group-detected miRNAs differed, being either unchanged relative to control or down-regulated, and this included miR-132. In vivo microinjection of locked nucleic acid-modified oligonucleotides (antagomirs) against miR-132 depleted hippocampal miR-132 levels and reduced seizure-induced neuronal death. Thus, our data strongly suggest that miRNAs are important regulators of seizure-induced neuronal death.', "Preconditioning describes the ischemic stimulus that triggers an endogenous, neuroprotective response that protects the brain during a subsequent severe ischemic injury, a phenomenon known as 'tolerance'.", 'Downregulation of miR-132 is consistent with our finding that preconditioning ischemia induces a rapid increase in MeCP2 protein, but not mRNA, in mouse cortex. These studies reveal that ischemic preconditioning regulates expression of miRNAs and their predicted targets in mouse brain cortex, and further suggest that miRNAs and MeCP2 could serve as effectors of ischemic preconditioning-induced tolerance.', "Huntington's disease (HD) is a genetic neurodegenerative disease caused by abnormal CAG expansion. MicroRNAs (miRNAs) are short RNA molecules regulating gene expression, and are implicated in a variety of diseases including HD.", 'Nine miRNAs (miR-22, miR-29c, miR-128, miR-132, miR-138, miR-218, miR-222, miR-344, and miR-674*) were commonly down-regulated in both the 12-month-old YAC128 and 10-week-old R6/2 mice.', 'transgenic HD mice have abnormal miRNA biogenesis. This information should aid in future studies on therapeutic application of miRNAs in HD.', 'miR-132 directly targets the neuronal splicing factor polypyrimidine tract-binding protein 2 (PTBP2), which protein levels were increased in PSP patients. miR-132 overexpression or PTBP2 knockdown similarly affected endogenous 4R:3R-tau ratios in neuronal cells. Finally, we provide evidence that miR-132 is inversely correlated with PTBP2 during post-natal brain development at the time when 4R-tau becomes expressed. Taken together, these results suggest that changes in the miR-132/PTBP2 pathway could contribute to the abnormal splicing of tau exon 10 in the brain, and sheds light into the potential role played by miRNAs in a subset of tauopathies.', "reports of microRNA (miR) modulators of both neuronal and immune processes (here termed NeurimmiRs) predict therapeutic potential for manipulating NeurimmiR levels in diseases affecting both the immune system and higher brain functions, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and anxiety-related disorders. In our opinion, NeurimmiRs that function within both the nervous and the immune systems, such as miR-132 and miR-124, may act as 'negotiators' between these two interacting compartments."]

['Yes. MicroRNA 132 (miR-132), is involved in brain pathologies.']

['yes']

Is alemtuzumab effective for remission induction in patients diagnosed with T-cell prolymphocytic leukemia?

['Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab consolidation is effective in T-cell prolymphocytic leukemia', 'A central need in this historically refractory tumor is the controlled evaluation of multiagent chemotherapy and its combination with the currently most active single agent, alemtuzumab. ', 'FMC-A is a safe and efficient protocol in T-PLL, which compares favorably to published data.', 'Currently, the best treatment for T-PLL is IV alemtuzumab, which has resulted in very high response rates of more than 90% when given as frontline treatment and a significant improvement in survival. ', 'The patient failed to respond to standard ALL induction chemotherapy, but achieved complete remission following treatment with a fludarabine and alemtuzumab-based regimen.', 'Here we present a rare case of concurrent T-PLL and Kaposi sarcoma who achieved a complete hematologic and cytogenetic remission after a very short course of treatment with alemtuzumab.', ' Recent studies with single-agent alemtuzumab, an anti-CD52 monoclonal antibody, have shown improved response rates and survival in patients with T-cell prolymphocytic leukemia and cutaneous T-cell lymphoma. ', 'The CD52 antigen is expressed at high density on the malignant T-cells and therapy with alemtuzumab, a humanized IgG1 antibody that targets this antigen, has produced promising results. ', 'With the introduction of alemtuzumab, most patients who progressed despite treatment with pentostatin had a major response with a complete remission rate higher than that obtained with pentostatin when used as a first line.', 'Alemtuzumab (anti-CD52, Campath-1H) has recently been shown to be effective in the treatment of a range of hematological malignancies, including B-cell chronic lymphocytic leukemia and T-cell prolymphocytic leukemia.', 'Here we report the outcome of two patients with CD4-positive T cell prolymphocytic leukemia treated with CAMPATH-1H. Both patients responded rapidly to treatment and subsequently developed CD4 lymphopenia.', 'T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. ', 'CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). ', 'The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. ', 'For example, most patients with T-cell prolymphocytic leukemia, including those with large tumor burdens and high peripheral white blood cell counts, will enter complete remission using the antibody CAMPATH-1H without any evidence of tumor lysis.', 'Overall response rate to FMC was 68%, comprising 6 complete remissions (all bone-marrow confirmed) and 11 partial remissions. Alemtuzumab consolidation increased the intent-to-treat overall response rate to 92% (12 complete remissions; 11 partial remissions). ']

['Yes, alemtuzumab (anti-CD52, Campath-1H) is effective for remission induction in patients diagnosed with T-cell prolymphocytic leukemia. Alemtuzumab can be administered in combination with other chemotherapeutic agents or as mono-therapy. Response rate to alemtuzumab is more than 90%. Alemtuzumab therapy is associated with improved survival of T-cell prolymphocytic leukemia patients.']

['yes']

What are presynapses and how do they differ from postsynapses in terms of their localization and function?

['["Neurexins and neuroligins are two distinct families of single-pass transmembrane proteins localized at pre- and postsynapses, respectively. ", "presynaptic neurexins", "best-characterized transsynaptic interactions are formed by presynaptic neurexins, which bind to diverse postsynaptic ligands.", "presynaptic neurexin"]']

Presynapses and postsynapses are two distinct regions in a synaptic connection. Presynapses refer to the area before the synaptic cleft where neurotransmitters are released, while postsynapses are the area after the synaptic cleft where neurotransmitter receptors are located. In terms of localization, presynapses are typically found on the axon terminal of the presynaptic neuron, while postsynapses are located on the dendrites or cell body of the postsynaptic neuron. Functionally, presynapses release neurotransmitters to signal the postsynaptic neuron, while postsynapses receive and respond to these signals through neurotransmitter receptors.

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What is the inheritance pattern of Li–Fraumeni syndrome?

['It therefore appears that the LFS phenotype has been conferred by an aberrant gene, showing a dominant pattern of inheritance, which may be acting to compromise normal p53 function rather than by a mutation in p53 itself.', 'In addition, there seem to be predispositions to a wider range of different, but well-defined neoplasms: e.g., adenocarcinomatosis of the colon and the endometrium, or the Li-Fraumeni/SBLA syndrome. The latter shows a spectrum of sarcoma, brain tumours, breast cancer, leukaemias, lung and adenocortical cancer. The genes leading to these types of dominantly inherited predispositions appear to be the tentatively so-called tumour suppressor genes, for which the Rb gene serves as a model', 'he Li-Fraumeni syndrome is a rare autosomal-dominant disease whose hallmark is a predisposition to a wide range of cancers among members of a family.', 'Li-Fraumeni Syndrome (LFS) is characterized by early-onset carcinogenesis involving multiple tumor types and shows autosomal dominant inheritance.', 'BACKGROUND: Li-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene.', 'Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant, human familial cancer predisposition', 'The Li-Fraumeni syndrome is a rare autosomal-dominant disease whose hallmark is a predisposition to a wide range of cancers among members of a family']

['Li-Fraumeni syndrome shows autosomal dominant inheritance.']

['Autosomal dominant']

What is the correlation between SPARC expression and growth inhibition in human cancer?

['Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival.', 'Our studies showed that inhibition of HDAC decreased NB proliferation, and induced caspase activity and G1 growth arrest. Expression patterns of cancer-related genes were modulated by VPA. The expression of THBS1, CASP8, SPARC, CDKN1A, HIC1, CDKN1B, and HIN1 was upregulated, and that of MYCN and TIG1 was downregulated.', 'In this study, we demonstrate that expression of SPARC inhibits medulloblastoma cell proliferation.', 'Concomitantly, SPARC was upregulated in all ccRCC cells, suggesting that Ukrain could also affect cell proliferation by cell cycle inhibition, as supported by the cell cycle analysis, as SPARC also acts as a cell cycle inhibitor.', 'SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells', 'We found that depletion of SPARC induces G2/M cell cycle arrest and tumor growth inhibition with activation of p53 and induction of p21(Cip1/Waf1) acting as a checkpoint, preventing efficient mitotic progression.', 'Knockdown of SPARC expression in H322 and A549 cells led to suppression of cell invasion, comparable to that observed in KLF4-transfected cells. Moreover, retrovirus-mediated restoration of SPARC expression in KLF4-transfected cells abrogated KLF4-induced anti-invasion activity. Together, our results indicate that KLF4 inhibits lung cancer cell invasion by suppressing SPARC gene expression.', 'To validate the potential of SPARC as a therapeutic target, we examined the effect of the knockdown of SPARC with SPARC-specific siRNA on the growth of human melanoma cell lines. SPARC siRNAs exerted a potent knockdown effect. Silencing of SPARC resulted in growth inhibition with G(1) arrest accompanied by accumulation of p21, a G(1) cyclin-dependent kinase inhibitor, in MeWo and CRL1579 cells. Moreover, the induction of p53 was observed in MeWo cells, but not in CRL1579 cells. Conditioned media containing SPARC from MeWo cells could not restore the growth of SPARC-silenced MeWo cells. This result suggests that intracellular SPARC, but not secreted SPARC, is involved in cell proliferation', 'In vivo experiments revealed that SPARC overexpression in HCC cells inhibited their tumorigenic capacity and increased animal survival through a mechanism that partially involves host macrophages. Our data suggest that SPARC overexpression in HCC cells results in a reduced tumorigenicity partially through the induction of mesenchymal-to-epithelial transition (MET).', 'Finally, we demonstrated that SPARC, which has been previously associated with meningioma invasiveness, was increased in aggressive meningiomas.', 'We found that the leukemic cells of AML patients with MLL gene rearrangements express low to undetectable amounts of SPARC whereas normal hematopoietic progenitors and most AML patients express this gene. SPARC RNA and protein levels were also low or undetectable in AML cell lines with MLL translocations. Consistent with its tumor suppressive effects in various solid tumor models, exogenous SPARC protein selectively reduced the growth of cell lines with MLL rearrangements by inhibiting cell cycle progression from G1 to S phase.', 'These data indicate that SPARC plays an essential role in tumor evasion from immune surveillance through the inhibition of the antitumor PMN activity.', 'We conclude that SPARC is inhibitory to human breast cancer cell proliferation, and does not stimulate migration, in contrast to its stimulatory effects reported for melanoma (proliferation and migration) and glioma (migration) cells. Similar growth repression by SPARC has been reported for ovarian cancer cells, and this may be a common feature among carcinomas.', 'Furthermore, SPARC delayed but did not inhibit tumor growth. The patterns of invasion and the extent of growth delay correlated with the level of SPARC expression.']

['Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell-cell and cell-matrix interactions. SPARC seems to act as a tumour suppressor, as it has been found that loss of SPARC accelerates the development of certain types of cancer, whereas its expression impairs tumor growth. However it has also been associated with a aggressive phenotypes of some tumours. The role of SPARC may depend on its subcellular localization.']

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Has the protein SETMAR (Metnase) a transposase domain?

['Metnase (SETMAR) is a SET-transposase fusion protein that promotes nonhomologous end joining (NHEJ) repair in humans.', 'The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations.', ' Metnase (also termed SETMAR) is a fusion of a histone methylase and transposase protein that arose specifically in primates. ', 'the only intact Hsmar1 transposase gene exists within a chimeric SET-transposase fusion protein referred to as Metnase or SETMAR. ', 'The Metnase transposase has been remarkably conserved through evolution;', "Metnase (also known as SETMAR) is a SET and transposase fusion protein in humans and plays a positive role in double-strand break (DSB) repair. While the SET domain possesses histone lysine methyltransferase activity, the transposase domain is responsible for 5'-terminal inverted repeat (TIR)-specific binding, DNA looping, and DNA cleavage activities. ", 'Metnase is a fusion gene comprising a SET histone methyl transferase domain and a transposase domain derived from the Mariner transposase.', 'ulated by the DNA repair component Metnase (also termed SETMAR). Metnase contains a SET histone methylase and transposase nuclease domain', 'Metnase is a human SET and transposase domain protein ', 'The human set and transposase domain protein Metnase', ' of transposase-related sequences in humans are pseudogenes. We recently isolated and characterized a SET and transposase domain protein termed Metnase that promotes DNA double-strand break (DSB) repair by non-homologous end-joining (NHEJ). Both the SET and transposase domain were required for its NHEJ activity.', 'Metnase, also known as SETMAR, is a SET and transposase fusion protein with an undefined role in mammalian DNA repair.', 'Biochemical characterization of a SET and transposase fusion protein, Metnase: i', 'Metnase (SETMAR) is a SET and transposase fusion protein that promotes in vivo end joining activity and mediates genomic integration of foreign DNA. ', ' This transposase coding region is part of the SETMAR gene, in which a histone methylatransferase SET domain is fused to an Hsmar1 transposase domain. ', 'The human SETMAR protein preserves most of the activities of the ancestral Hsmar1 transposase.', 'ere we investigate the activity of the human SETMAR protein, a highly expressed fusion between a histone H3 methylase and a mariner family transposase.', 'SETMAR, a new primate chimeric gene resulting from fusion of a SET histone methyltransferase gene to the transposase gene of a mobile element.', 'We identified a protein, termed Metnase, that has a SET domain and a transposase/nuclease domain. ', 'Metnase has a nuclease domain that shares homology with the Transposase family.', 'Metnase (also called SETMAR) is a SET and transposase domain protein that promotes both DNA double-strand break (DSB) repair and restart of stalled replication forks. ']

['Yes, the protein SETMAR (Metnase) has a transposase domain.']

['yes']

What is the mechanism of action of abiraterone?

['The recognition of sustained androgen dependence of CRPC has led to the identification of more potent and selective inhibitors of androgen synthesis and androgen-receptor signaling, such as abiraterone and enzalutamide, respectively.', 'This review summarizes the rationale, mechanism of action and relevant clinical data of abiraterone acetate , an oral androgen biosynthesis inhibitor, in the management of CRPC.', 'Sipuleucel-T, an immunotherapeutic vaccine, is now available in the US for patients with non-metastatic CRPC and abiraterone, an oral enzyme inhibitor of androgen biosynthesis, as well as cabazitaxel, a cytotoxic chemotherapeutic, have been approved for the treatment of metastatic CRPC.', 'Abiraterone (17-(3-pyridyl)androsta-5,16-dien-3beta-ol, 1) is a potent inhibitor (IC50 4 nM for hydroxylase) of human cytochrome P45017alpha.']

['Abiraterone acts by inhibiting cytochrome P450 17α-hydroxylase (CYP17A1), a critical step in androgen biosynthesis, thus leading to inhibition of androgen biosynthesis.']

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Is there evidence to suggest that triiodothyronine has neuroprotective properties in traumatic brain injury?

['Exogenous T3 administration provides neuroprotection in a murine model of traumatic brain injury.', 'Treatment with T3 (1.2μg/100g body weight, i.p.) 1h after TBI resulted in a significant improvement in motor and cognitive recovery after CCI, as well as in marked reduction of lesion volumes. ', 'Western blot analysis revealed the ability of T3 to reduce brain trauma through modulation of cytoplasmic-nuclear shuttling of nuclear factor-κB (NF-κB). Twenty-four hours after brain trauma, T3-treated mice also showed significantly lower number of TUNEL(+) apoptotic neurons and curtailed induction of Bax, compared to vehicle control. In addition, T3 significantly enhanced the post-TBI expression of the neuroprotective neurotrophins (BDNF and GDNF) compared to vehicle. ', 'The stimulating effect of T3 on peripheral nerve regeneration may have considerable therapeutic potential.', "The present study provides evidence that the peripheral nervous system has its own system responsible for the local production of 3,5,3'-triiodothyronine, which may play a key role during the regeneration process.", "Although it has been hypothesized that T3 may facilitate neuronal regeneration after CNS injury, the 5'-D2 response to brain injury is unknown.", 'The outcome after brain injury is closely correlated with the intensity of these changes, particularly with catecholamine plasma levels and the severity of the low triiodothyronine syndrome.', 'The thyroid hormones triiodothyronine (T3) and L-thyroxine appear to enhance regeneration in the peripheral and central nervous system (CNS). ', 'T3 treatment influenced the general levels of incorporation of all treated groups over all days postoperation.', 'T3 effects appear to involve an increased sensitivity of the cells of the injured nervous system to the hormone.', 'T3, when administered over an 8 week period, stimulated axonal regeneration in the dorsal cortex and corpus callosum and promoted healing of the wound in the corpus callosum. The results of this investigation suggest that the use of T3 in the clinical treatment of injury to the central nervous system may be of less value than the work of earlier authors had indicated.', 'In addition, T3 significantly enhanced the post-TBI expression of the neuroprotective neurotrophins (BDNF and GDNF) compared to vehicle']

['Yes, it has been demonstrated that triiodothyronine exerts neuroprotective properties in traumatic brain injury setting.']

['yes']

What is the Arnold-Chiari syndrome?

['Arnold Chiari syndrome is a condition characterized by herniation of the cerebellar tonsils through the foramen magnum.', 'The Arnold-Chiari malformation is very rare hindbrain abnormalities characterized by herniation of the hindbrain through the foramen magnum.', 'The origin of Arnold-Chiari syndrome is connected with narrowness in the posterior fossa, particularly with narrowing of the arachnoid spaces.', 'Arnold-Chiari Syndrome I is a malformation of the cervicomedullary junction, manifesting usually with downbeat nystagmus, palsy of the caudal cerebral nerves, headache, and vertigo.']

['Arnold Chiari syndrome is a condition characterized by herniation of the cerebellar tonsils through the foramen magnum, manifesting usually with downbeat nystagmus, palsy of the caudal cerebral nerves, headache, and vertigo.']

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List features of the DEND syndrome.

['Some mutations in this gene, including p.Q52R, are associated with the developmental delay, epilepsy, neonatal diabetes (DEND) syndrome.', 'Developmental delay was noted on follow-up which raised the possibility of intermediate DEND syndrome.', 'We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene. ', 'They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). ', ' Wide phenotype variability is associated with single ABCC8 mutations, ranging from transient or permanent neonatal diabetes (ND) with or without developmental delay (DEND syndrome) to very mild phenotypes. ', 'Specific uncommon mutations KCNJ11give rise to a syndrome defined as developmental delay, epilepsy, and neonatal diabetes (DEND), or - more frequently - to a milder sub-type lacking epilepsy, denoted as intermediate-DEND (iDEND).', 'Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome. ', ' The patient with the V59M mutation successfully switched from insulin injections to oral glibenclamide; 2 years of follow-up revealed that the patient had intermediate developmental delay, epilepsy and neonatal diabetes (DEND) syndrome. ', 'Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome.', 'We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene.', 'There is a striking genotype-phenotype relationship with specific Kir6.2 mutations being associated with transient neonatal diabetes, permanent neonatal diabetes alone, and a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome.', 'In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome).', 'Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene.', 'It is proposed that some patients with KCNJ11 mutations have neurological features that are part of a discrete neurological syndrome termed developmental Delay, Epilepsy and Neonatal Diabetes (DEND), but there are also neurological consequences of chronic or acute diabetes. ', 'Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM.', 'In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome).', 'We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene.', 'It is proposed that some patients with KCNJ11 mutations have neurological features that are part of a discrete neurological syndrome termed developmental Delay, Epilepsy and Neonatal Diabetes (DEND), but there are also neurological consequences of chronic or acute diabetes.', 'We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy.', 'Some patients have DEND syndrome (developmental delay, epilepsy and neonatal diabetes) with the neurological features arising from mutated KATP channels in muscle, nerve and brain.', 'Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome.', 'Intermediate developmental delay, epilepsy and neonatal diabetes mellitus (DEND) syndrome as a result of a 59V>M Kir6.2 mutation.', 'Five patients with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome had unique mutations not associated with other phenotypes.', 'Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome.', 'We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene. Thus, our case reinforces that most cases with DEND syndrome are insensitive to SU.', 'Some patients have DEND syndrome (developmental delay, epilepsy and neonatal diabetes) with the neurological features arising from mutated KATP channels in muscle, nerve and brain.', 'We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene.', 'It is proposed that some patients with KCNJ11 mutations have neurological features that are part of a discrete neurological syndrome termed developmental Delay, Epilepsy and Neonatal Diabetes (DEND), but there are also neurological consequences of chronic or acute diabetes.']

['Clinical features of the DEND syndrome include developmental delay, epilepsy and neonatal diabetes.']

['developmental delay', 'epilepsy', 'neonatal diabetes']

List sclerostin interaction partners.

[' Several previously unidentified full-length sclerostin-interacting proteins such as alkaline phosphatase, carbonic anhydrase, gremlin-1, fetuin A, midkine, annexin A1 and A2, and collagen α1, which have established roles in bone formation or resorption processes, were bound to the sclerostin-MBP amylose resin but not to the MBP amylose resin. Other full-length sclerostin-interacting proteins such as casein kinase II and secreted frizzled related protein 4 that modulate Wnt signaling were identified. Several peptides derived from proteins such as Phex, asporin and follistatin that regulate bone metabolism also bound sclerostin. ', 'We identified an interaction between sclerostin and the carboxyl-terminal portion of the receptor tyrosine-protein kinase erbB-3.', 'Sclerostin, SOST, the gene affected in this disease, has been postulated to exert its activity by functioning as a BMP antagonist. However, recent evidence indicates that SOST is highly related to Wise, which can also modulate the Wnt pathway by binding to LRP5 and LRP6.', 'Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity.', 'We show that recombinant sclerostin and noggin bound to each other with high affinity (K(D) = 2.92 nm).']

['alkaline phosphatase\ncarbonic anhydrase\ngremlin-1\nfetuin A\nmidkine\nannexin A1 \nannexin A2\ncollagen α1\ncasein kinase II \nsecreted frizzled related protein 4\nPhex\nasporin\nfollistatin\nerbB-3\nLRP5 \nnoggin']

['alkaline phosphatase', 'carbonic anhydrase', 'gremlin-1', 'fetuin A', 'midkine', 'annexin A1', 'annexin A2', 'collagen α1', 'casein kinase II', 'secreted frizzled related protein 4', 'Phex', 'asporin', 'follistatin', 'erbB-3', 'LRP5', 'noggin']

Is farnesoid X receptor (FXR) a nuclear receptor?

['Farnesoid X receptor (FXR) belongs to the ligand-activated nuclear receptor superfamily, and functions as a transcription factor regulating the transcription of numerous genes involved in bile acid homeostasis, lipoprotein and glucose metabolism', ' Farnesoid X receptor (FXR) is an ascending target for metabolic and inflammatory diseases. As a nuclear receptor, FXR exhibits many physiological effects in transcription control of several genes.', ' FXR is a member of the nuclear receptor superfamily which is also highly expressed in the liver. ', 'Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas', 'Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily.', 'the nuclear receptor farnesoid X receptor ', ' farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. ', 'T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist,', ' Farnesoid X receptor (FXR), a nuclear receptor (NR) and originally considered as a bile acid-activated transcriptional factor, ', ' The nuclear receptor farnesoid X receptor (FXR) plays a major role in the enterohepatic cycling of bile acids', 'Liver X receptors, LXRs, are ligand-activated transcription factors that belong to the group H nuclear receptor (NR) superfamily. ', 'The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades.', 'ncluding those of nuclear receptors, primarily farnesoid X receptor (FXR), ', 'ile acids and their cognate nuclear receptor, FXR,', 'Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis.', 'he activation of the nuclear receptor farnesoid X receptor (FXRα)', 'bile acid-activated nuclear receptor farnesoid X receptor (FXR)', ' nuclear receptor signaling, notably by the farnesoid X receptor (FXR', 'FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism.', 'The role of the nuclear receptor FXR is unclear.', 'nuclear receptor FXR ', 'a member of the nuclear receptor superfamily of ligand-activated transcription factors,', 'Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis.']

['Yes, farnesoid X receptor (FXR) is a nuclear receptor.']

['yes']

Which gene is mutated in a subtype of arrhythmogenic right ventricular cardiomyopathy known as Naxos disease?

['Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive.', 'Loss-of-function mutation of Jup has been associated with Naxos disease, which is characterized by arrhythmogenic cardiomyopathy and the cutaneous disorder palmoplantar keratoderma.', 'Previously, we have shown that genetic ablation of Jup in cardiomyocytes in mice leads to arrhythmogenic cardiomyopathy similar to Naxos disease in humans.', 'As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. ', 'One is a C-terminal mutation causing Naxos disease, a recessive syndrome of arrhythmogenic right ventricular cardiomyopathy (ARVC) and abnormal skin and hair.', 'In this study, we examined the effects of two different mutations in plakoglobin on cell migration, stiffness, and adhesion', 'Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder associated with arrhythmias and sudden death. A recessive mutation in the gene encoding plakoglobin has been shown to cause Naxos disease, a cardiocutaneous syndrome characterized by ARVC and abnormalities of hair and skin.', 'Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes.', 'We tested the hypothesis that defective interactions between adhesion junctions and the cytoskeleton caused by the plakoglobin mutation in Naxos disease lead to remodeling of gap junctions and altered expression of the major gap junction protein, connexin43. ', 'Naxos disease, a recessive form of arrhythmogenic right ventricular cardiomyopathy, is associated with a high incidence of arrhythmias and sudden cardiac death. Naxos disease is caused by a mutation in plakoglobin, a protein that links cell-cell adhesion molecules to the cytoskeleton.', 'However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC.', 'Naxos disease is a recessively inherited ARVC caused by a mutation in the gene encoding plakoglobin (cell adhesion protein) in which the cardiac phenotype is associated with palmoplantar keratoderma and woolly hair. ', 'Autosomal recessive ARVC caused by a mutation in plakoglobin was 100% penetrant by adolescence. Affected subjects who were homozygous experienced progressive disease with adverse prognosis.', 'Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant heart muscle disorder that causes arrhythmia, heart failure, and sudden death. Previously we mapped the genetic locus for the triad of autosomal recessive ARVC, palmoplantar keratoderma, and woolly hair (Naxos disease) to chromosome 17q21, in which the gene for plakoglobin is encoded. This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin.', 'Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).', 'Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease).']

['Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder associated with arrhythmias and sudden death. A recessive mutation in the gene encoding plakoglobin has been shown to cause Naxos disease, a cardiocutaneous syndrome characterized by ARVC and abnormalities of hair and skin.', 'Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder associated with arrhythmias and sudden death. A recessive mutation in the gene encoding plakoglobin has been shown to cause Naxos disease, a cardiocutaneous syndrome characterized by ARVC and abnormalities of hair and skin. ', 'A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive.', 'A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, had been identified in Naxos Disease patients, a subset of ARVC, which is characterized by cutaneous disorder.']

['The Plakoglobin gene', 'plakoglobin[jup]']

How many periods of regulatory innovation led to the evolution of vertebrates?

['Three periods of regulatory innovation during vertebrate evolution.', 'To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.', 'Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.', 'Our analysis identified three extended periods in the evolution of gene regulatory elements. ', 'Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.', 'Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.', 'We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements.', 'Our analysis identified three extended periods in the evolution of gene regulatory elements.', 'Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.']

['Investigators proposed that there have been three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.']

['Three']

Are there any Decision support systems for chronic pain management ?

['a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS)', 'We based the DSS on the existing ATHENA-DSS', 'Use of this iterative process led to development of a multifunctional DSS', 'interactive decision dashboard format', 'We created a computerized, interactive clinical decision dashboard ', 'Interactive decision dashboards can be adapted for clinical use and have the potential to foster informed decision making.', 'Clinical decision support systems are promising tools for improving behavioral medicine care for chronic pain.', 'Improving Patient Safety Using ATHENA-Decision Support System Technology: ', 'ATHENA-DSS is an automated decision support system developed in a collaboration between Stanford University and the U.S. Department of Veterans Affairs (VA) to increase guideline-adherent prescribing and to change physician behavior.', "The use of a computer-based decision support system facilitates primary care physicians' management of chronic pain.", 'The use of a CBDS system may improve the ability of PCPs to manage chronic pain and may also facilitate screening of consults to optimize specialist utilization.']

['Yes, there is a variety of decision support systems for chronic pain management.', "Clinical decision support systems are promising tools for improving behavioral medicine care for chronic pain.The use of a computer-based decision support system facilitates primary care physicians' management of chronic pain."]

['yes']

From which tissue was the NCI-H520 cell-line derived?

['The nanostructures target the cells with high affinity and specificity via the specific interaction between the aptamer (a 45-base oligonucleotide) and the cell, and distinguish A549 cells from other types of cancer cells (HeLa and MCF-7 cells) and subtypes of lung cancer cells (NCI-H157, NCI-H520, NCI-H1299, and NCI-H446 cells). ', 'Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcinoma cells revealed that Msi1 was enriched in spheroid cultures of tumor cells and in the CD133+ cell population. ', 'BHLHB3 gene overexpression inhibited colony formation of A549, NCI-H520 and NCI-H596 lung cancer cells. ', 'Cellular proliferation was inhibited in non-small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression.', 'Human NCI-H520 cancer cells transfected with PDCD5 cDNA showed decreased colony-forming ability. ', 'In 4 lung cancer cell strains, BNIP3L protein was not detected in A549, NCI-H460, NCI-H446, except for NCI-H520, in which the protein expression level was slightly lower than that in immortal bronchial epithelial cell strain HBE4-E6/E7.', 'We show that CLN3 mRNA and protein are overexpressed in glioblastoma (U-373G and T98g), neuroblastoma (IMR-32 and SK-N-MC), prostate (Du145, PC-3, and LNCaP), ovarian (SK-OV-3, SW626, and PA-1), breast (BT-20, BT-549, and BT-474), and colon (SW1116, SW480, and HCT 116) cancer cell lines but not in pancreatic (CAPAN and As-PC-1) or lung (A-549 and NCI-H520) cancer cell lines.', 'NSCLC cell lines NCI-H520 and H460, which have no endogenous Cyr61, formed 60-90% fewer colonies after being transfected with a Cyr61 cDNA expression vector than cells transfected with the same amount of empty vector.', 'Importantly, the non-small cell lung carcinoma cell lines expressed either liver-specific (non-neuronal) mRNA (cell line A549) or predominantly the neuronal (cell line NCI-H520) AADC message. ', "The antitumor effect of CGP41251 (4'-N-benzoyl staurosporine), a selective protein kinase C (PKC) inhibitor, was examined on two kinds of human non-small cell lung cancer (NSCLC) cell lines (adenocarcinoma: A549 and squamous cell carcinoma: NCI-H520)."]

['Non-small cell lung cancer (NSCLC) cell line NCI-H520. \nSquamous cell carcinoma cell line NCI-H520.', 'The NCI-H520 cell-line is derived from human non-small cell lung cancer tissue.']

['Squamous cell carcinoma', 'Non-small cell lung cancer', 'Lung']

Entresto is composed of which two drugs?

['The PARADIGM-HF study, a large outcome trial in heart failure and reduced ejection fraction (HFrEF), has recently shown improved cardiovascular outcomes with sacubitril/valsartan (Entresto®, Novartis), still commonly referred to as LCZ696, compared to ACE-inhibitor therapy, possibly leading us to a new era for heart failure (HF) treatment. ', 'This article reviews the background, current knowledge and data supporting the use of sacubitril/valsartan (Entresto(®) ), the newly FDA-approved medication that dually inhibits angiotensin and neprilysin, in the treatment of heart failure.', '▼ Sacubitril valsartan (Entresto-Novartis) is a new oral drug licensed for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction.', 'Rhabdomyolysis After Coadministration of Atorvastatin and Sacubitril/Valsartan (Entresto™) in a 63-Year-Old Woman.', 'A 63-year-old woman previously stable on a regimen of atorvastatin 40\xa0mg daily, carvedilol 25\xa0mg twice daily, digoxin 0.125\xa0mg daily, furosemide 40\xa0mg daily, spironolactone 25\xa0mg daily, rivaroxaban 15\xa0mg daily, and enalapril 20\xa0mg twice daily for heart failure developed rhabdomyolysis 26\xa0days after enalapril was stopped and sacubitril/valsartan (Entresto™) started.', 'Sacubitril/valsartan [LCZ696 (Entresto), Novartis Pharmaceuticals Corp.] is the first in a new class of drugs that combines neprilysin inhibition with angiotensin II receptor antagonism, the combination of which acts to increase endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system.', 'In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex.', 'Sacubitril/valsartan (Entresto) for chronic heart failure; brexpiprazole (Rexulti) for major depressive disorder and schizophrenia; and lumacaftor/ivacaftor (Orkambi) for cystic fibrosis involving specific CFTR mutations.', 'Sacubritil∗valsartan (Entresto, Novartis, still commonly referred to as LCZ696) is a combination drug described as a new class of dual-acting angiotensin receptor-neprilysin inhibitor (ARNi).', 'The molecular combination of sacubitril and valsartan (Entresto) is a new drug for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.', '▼ Sacubitril valsartan (Entresto-Novartis) is a new oral drug licensed for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction.(1) It is described as an angiotensin receptor neprilysin inhibitor and contains the neprilysin inhibitor, sacubitril and the angiotensin II receptor antagonist, valsartan.(1-3) Here, we review the evidence for sacubitril valsartan and consider its place in the management of heart failure.']

['Entresto is composed of sacubitril and valsartan. It is newly FDA-approved medication that dually inhibits angiotensin and neprilysin, in the treatment of heart failure.']

['sacubitril', 'valsartan']

What are the characteristics of Christianson syndrome?

['Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). ', 'We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.', 'The single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.', 'Among these are classic disorders such as Angelman syndrome and MECP2-related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with mutations in CASK, CDKL5, CREBBP, and EP300 (Rubinstein-Taybi syndrome), FOXG1, SLC9A6 (Christianson syndrome), and TCF4 (Pitt-Hopkins syndrome).', 'Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures.', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia.', 'Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.', 'Mutations in the SLC9A6 gene cause Christianson syndrome in boys.', 'A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES).', 'Mutations in the SLC9A6 gene cause Christianson syndrome in boys. ', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. ', 'Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. ', 'In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. ', 'Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.', 'Mutations in the SLC9A6 gene cause Christianson syndrome in boys.', 'Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures.', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.', 'In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 / years.', 'Christianson syndrome (CS) is an X-linked neurodevelopmental disorder caused by deleterious mutations in SLC9A6.', 'This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia.', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6.', 'The microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include Phelan–McDermid syndrome (chromosome 22q13.3 deletion), MBD5 haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.', 'The single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome. They also include disorders due to mutations in HERC2, adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and ATRX.', ' Christianson syndrome (CS) is an X-linked neurodevelopmental disorder caused by deleterious mutations in SLC9A6. Affected families organized the inaugural Christianson Syndrome Association conference to advance CS knowledge and develop questions that may be prioritized in future research.', 'Among these are classic disorders such as Angelman syndrome and MECP2-related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with mutations in CASK, CDKL5, CREBBP, and EP300 (Rubinstein-Taybi syndrome), FOXG1, SLC9A6 (Christianson syndrome), and TCF4 (Pitt-Hopkins syndrome).', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly,', 'The single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.', 'Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.', 'Mutations in the SLC9A6 gene cause Christianson syndrome in boys.', 'Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.', 'Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.']

['Christianson syndrome (CS) is caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). Patients present with prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, are common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.']

[]

List Parkin binding partners

['In addition to two known binding partners (HSP90, CDC37), 12 proteins were identified using the TAP assay; four of which are mitochondrially localized (GRP75, HSP60, LRPPRC, and TUFM).', 'We find that parkin binds PICK1 via a PDZ-mediated interaction, which predominantly promotes PICK1 monoubiquitination rather than polyubiquitination. ', 'We have identified the 20S proteasomal subunit alpha4 (synonyms: PSMA7, XAPC7, subunit alpha type 7) as a new interacting partner of parkin.', 'we cloned parkin-binding protein using a yeast two-hybrid system and identified a putative G protein-coupled receptor protein,which we named the Pael receptor (Pael-R)', ", whose interactions with CASK are reviewed here, include the Parkinson's disease molecule parkin, "]

['HSP90\nCDC37\nGRP75\nHSP60\nLRPPRC\nTUFM\nPICK1\nPSMA7\nPael receptor']

['HSP90', 'CDC37', 'GRP75', 'HSP60', 'LRPPRC', 'TUFM', 'PICK1', 'PSMA7', 'XAPC7', 'Pael receptor']

Is there an association between TERT promoter mutation and survival of glioma patients?

['Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas.', "Kaplan-Meier's survival analysis showed that TERT promoter mutation (P=0.037), Isocitrate dehydrogenase (IDH) mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P=0.007) and OS (P=0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.", 'RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). ', 'TERT promoter mutations lead to high transcriptional activity under hypoxia and temozolomide treatment and predict poor prognosis in gliomas.', 'Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.', 'TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. ', 'Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months.', 'Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.CONCLUSION: TERT promoter mutations were specific to gliomas. ', 'We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. ', 'Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. ', 'In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). ', 'The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas.', 'Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.']

['Yes, TERT mutation is associated with survival of glioma patients and was suggested as a bio-marker of gliomas.']

['yes']

Which brain structures have been investigated as potential targets for deep brain stimulation of patients suffering from major depression?

['Deep brain stimulation (DBS) is under scientific evaluation as a new treatment option for these treatment-resistant patients. First clinical studies with small samples have been stimulated at the subgenual cingulate gyrus (Cg25/24), the anterior limb of the capsula interna (ALIC), and the nucleus accumbens (NAcc). ', 'New hypothesis-guided targets (e.g., medial forebrain bundle, habenula) are about to be assessed in clinical trials. ', 'Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) has antidepressant effects in patients suffering from treatment-resistant depression (TRD). ', 'The ventral striatum, including the head of the caudate nucleus and the nucleus accumbens, is a putative target for deep brain stimulation (DBS) in the treatment of obsessive-compulsive disorder (OCD) and major depression (MD). ', 'High frequency stimulation was successfully applied in several small samples of patients with treatment-resistant depression when the stimulation focused on different areas, e.g., nucleus accumbens, the lateral habenula or cortical areas.', 'We recorded electrophysiological activity directly from the nucleus accumbens of five patients undergoing deep brain stimulation for treatment of refractory major depression. ', 'Functional inhibition of the lateral habenula via deep brain stimulation (DBS) has antidepressive properties.', 'Because a prominent clinical feature of depression is anhedonia--the inability to experience pleasure from previously pleasurable activities--and because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression.', 'These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression.', 'Deep brain stimulation of the ventral caudate nucleus markedly improved symptoms of depression and anxiety until their remission, which was achieved at 6 months after the start of stimulation (HDRS < or = 7 and HARS < or = 10).', 'No neuropsychological deterioration was observed, indicating that DBS of the ventral caudate nucleus could be a promising strategy in the treatment of refractory cases of both OCD and major depression.', 'Comparisons of clinical outcomes and anatomical data on electrode positioning showed that caudate nucleus stimulation preferentially alleviated OCD manifestations, whereas nucleus accumbens stimulation improved depressive symptoms. ']

['Subgenual cingulate gyrus, the anterior limb of the capsula interna, nucleus accumbens, medial forebrain bundle, habenula, and caudate nucleus have been investigated as potential targeted for the deep brain stimulation of patients suffering from major depression.']

['subgenual cingulate gyrus', 'anterior limb of the capsula interna', 'nucleus accumbens', 'medial forebrain bundle', 'habenula', 'ventral caudate nucleus']

What is the effect of methotrexate in treating uveitis due to juvenile idiopathic arthritis ?

['To characterize disease-modifying antirheumatic drug (DMARD) use for children with juvenile idiopathic arthritis (JIA) in the United States and to determine patient factors associated with medication use.', 'Among children without systemic arthritis, methotrexate use was most strongly associated with uveitis (OR 5.2, 95% CI 3.6-7.6), anticitrullinated protein antibodies (OR 4.5, 95% CI 1.7-12), and extended oligoarthritis (OR 4.1, 95% CI 2.5-6.6)', 'About three-quarters of all children with JIA in the CARRA Registry received nonbiologic DMARD. Nearly one-half received biologic DMARD, and their use was strongly associated with RF-positive polyarthritis, PsA, uveitis, and systemic arthritis.', 'pediatric JIA patients who were being treated with MTX for active uveitis', 'Eighteen patients (18/22; 82%) showed improvement of their uveitis with a significant decrease in activity of AC inflammation after a minimal period of 3 months of MTX treatment. A topical steroid-sparing effect was observed when MTX was administered for a period of 3 to 9 months', "Most experience among DMARD's/ immunosuppressive drugs has been obtained with methotrexate (MTX) in juvenile idiopathic arthritis. However, controlled studies in uveitis are still missing, so that treatment with MTX and all other immunosuppressive drugs (ciclosporine A, azathioprine, mycophenolate mofetil) only reaches an evidence level III (expert opinion, clinical experience or descriptive study)", 'The data suggest that MTX is very effective in controlling inflammation of uveitis in patients with JIA. However, additional topical steroids or systemic immunosuppressive drugs are often required.', 'The risk factor for development of early cataract requiring surgery in children with JIA-associated uveitis is the presence of posterior synechia at the time of diagnosis of uveitis. However, early treatment with MTX is associated with a mean delay in the development of cataract requiring surgery of 3.5 years.', 'MTX seems to be an effective therapy for JIA associated uveitis.']

["The first-line standard therapy for uveitis is topical and systemic corticosteroids, often reinforced by methotrexate as a second-line disease-modifying antirheumatic drug (DMARD). MTX has a topical steroid sparing effect as well. Early treatment with MTX is advocated to prevent complications such as cataract. There are no trial data on the effect of MTX. Most experience among DMARD's/ immunosuppressive drugs has been obtained with methotrexate (MTX) in juvenile idiopathic arthritis. However, controlled studies in uveitis are still missing, so that treatment with MTX and all other immunosuppressive drugs (ciclosporine A, azathioprine, mycophenolate mofetil) only reaches an evidence level III (expert opinion, clinical experience or descriptive study). Biologic DMARDs can be used with Methotrexate in refractory uveitis as well."]

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Is hypersensitivity to DNA crosslinking agents a hallmark of Fanconi anemia?

['The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network', 'FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability.', 'Fanconi anemia (FA) is a rare genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin.', 'Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy.', 'Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia.', 'Fanconi anemia (FA) is one of several genetic diseases with characteristic cellular hypersensitivity to DNA crosslinking agents which suggest that FA proteins may function as part of DNA repair processes.', 'Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear.', 'Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents.', 'Fanconi anemia (FA) is a heterogeneous disease associated with a bone marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents.', 'Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents.', 'Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure, increased cancer risk and hypersensitivity to DNA cross-linking agents, implying a role for this pathway in the maintenance of genomic stability.', 'Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents.', 'Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark.', 'Fanconi Anemia (FA) is an autosomal recessive disease characterized by chromosome instability, cellular hypersensitivity to DNA cross-linking agents, and increased predisposition to malignancies.', 'The Bloom protein (BLM) and Topoisomerase IIIalpha are found in association with proteins of the Fanconi anemia (FA) pathway, a disorder manifesting increased cellular sensitivity to DNA crosslinking agents.', 'Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability.', 'Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure.', 'FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents.', 'Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C.', 'At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia.', 'DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking.', 'Fanconi anemia (FA), an autosomal recessive disorder of children, is characterized by congenital or childhood aplastic anemia, multiple developmental anomalies, increased incidence of myeloid leukemia, increased spontaneous chromosome breakage, and cellular and chromosomal hypersensitivity to DNA bifunctional crosslinking and alkylating agents.', 'elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents', 'Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability', 'One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC)', 'Furthermore, the cytological hallmark of FA, the DNA crosslink-induced radial chromosome formation, exemplifies an innate impairment in the repair of these particularly cytotoxic DNA lesions [A.D', 'Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear', 'Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia', 'Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy', 'Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents', 'Fanconi anemia (FA) is a human autosomal disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinking agents such as mitomycin C and diepoxybutane', 'The Fanconi anemia pathway promotes DNA glycosylase-dependent excision of interstrand DNA crosslinks.', 'DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking', 'FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents', 'The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations']

['Yes, hypersensitivity to DNA crosslinking agents is one of the hallmarks of Fanconi anemia, the others being defective FANCD2 monoubiquitination, and genomic instability.']

['yes']

Which multiple kinase inhibitors are used in cancer therapy?

['These inhibitors generally hinder the phosphorylation of several protein kinases of membrane receptors, such as vascular endothelial growth factor receptors, platelet-derived growth factor receptors, the human epidermal growth factor receptor family, and cytoplasmic receptors such as c-Kit, Raf kinase, and FLT3.', 'These inhibitors include ZD6474, SU11248, AEE 788, sorafenib, vatalanib, and AG-013736.']

['Multiple kinase inhibitors used in cancer therapy include ZD6474, SU11248, AEE 788, sorafenib, vatalanib, and AG-013736.']

['ZD6474', 'SU11248', 'AEE 788', 'sorafenib', 'vatalanib', 'AG-013736']

What is known about MER41 repeat sequences?

['We report eleven new families of MEdium Reiteration frequency (MER) interspersed repeats in the genomes of Primates, Rodentia, and Lagomorpha. Two families of the human repeats, MER 46 and MER 47, represent non-autonomous DNA transposons. These sequences are flanked by TA target site duplications and have terminal inverted repeats (TIRs) similar to TIRs of DNA transposons. The sequences of five other families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses. A potential involvement of some of the reported MER repeats in the regulation of transcription and genetic rearrangements is suggested. Age estimations place the origin of most MER repeats at the time of decline in MIR (Mammalian-wide Interspersed Repeats) retroposition and before the origin of the Alu family', 'MER41 repeat sequences contain inducible STAT1 binding sites', 'Contrary to previous claims, we find no evidence that STAT1 binds to multiple distinct motifs upon interferon-gamma stimulation in vivo. While a large majority of genomic sites with high ChIP-seq signal is associated with a nucleotide sequence resembling a STAT1 binding site, only a very small subset of the over 5 million potential STAT1 binding sites in the human genome is covered by ChIP-seq data. Furthermore a surprisingly large fraction of the ChIP-seq signal (5%) is absorbed by a small family of repetitive sequences (MER41). The observation of the binding of activated STAT1 protein to a specific repetitive element bolsters similar reports concerning p53 and other TFs, and strengthens the notion of an involvement of repeats in gene regulation. Incidentally MER41 are specific to primates, consequently, regulatory mechanisms in the IFN-STAT pathway might fundamentally differ between primates and rodents. On a methodological aspect, the presence of large numbers of nearly identical binding sites in repetitive sequences may lead to wrong conclusions about intrinsic binding preferences of TF as illustrated by the spacing analysis STAT1 tandem motifs. Therefore, ChIP-seq data should be analyzed independently within repetitive and non-repetitive sequences', 'MER41 repeat sequences contain inducible STAT1 binding sites.', 'The sequences of five other families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses.', 'Furthermore a surprisingly large fraction of the ChIP-seq signal (5%) is absorbed by a small family of repetitive sequences (MER41).', 'Incidentally MER41 are specific to primates, consequently, regulatory mechanisms in the IFN-STAT pathway might fundamentally differ between primates and rodents.', 'The sequences of five other families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses.', 'Furthermore a surprisingly large fraction of the ChIP-seq signal (5%) is absorbed by a small family of repetitive sequences (MER41).', 'Incidentally MER41 are specific to primates, consequently, regulatory mechanisms in the IFN-STAT pathway might fundamentally differ between primates and rodents.', 'The sequences of five other families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses', 'Furthermore a surprisingly large fraction of the ChIP-seq signal (5%) is absorbed by a small family of repetitive sequences (MER41)', 'Incidentally MER41 are specific to primates, consequently, regulatory mechanisms in the IFN-STAT pathway might fundamentally differ between primates and rodents']

['We report eleven new families of MEdium Reiteration frequency (MER) interspersed repeats in the genomes of Primates, Rodentia, and Lagomorpha. Two families of the human repeats, MER 46 and MER 47, represent non-autonomous DNA transposons. These sequences are flanked by TA target site duplications and have terminal inverted repeats (TIRs) similar to TIRs of DNA transposons. The sequences of five other families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses. A potential involvement of some of the reported MER repeats in the regulation of transcription and genetic rearrangements is suggested. Age estimations place the origin of most MER repeats at the time of decline in MIR (Mammalian-wide Interspersed Repeats) retroposition and before the origin of the Alu familyMER41 repeat sequences contain inducible STAT1 binding sites', 'The sequences of five families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses. Age estimations place the origin of most MER repeats at the time of decline in MIR (Mammalian-wide Interspersed Repeats) retroposition and before the origin of the Alu family. MER41 repeat sequences contain inducible STAT1 binding sites. The observation of the binding of activated STAT1 protein to a specific repetitive element bolsters similar reports concerning p53 and other TFs, and strengthens the notion of an involvement of repeats in gene regulation.', 'We report eleven new families of MEdium Reiteration frequency (MER) interspersed repeats in the genomes of Primates, Rodentia, and Lagomorpha. Two families of the human repeats, MER 46 and MER 47, represent non-autonomous DNA transposons. These sequences are flanked by TA target site duplications and have terminal inverted repeats (TIRs) similar to TIRs of DNA transposons. The sequences of five other families of repeats, MER41, MER48, MER50, MER51, and RMER3, resemble long terminal repeats of retroviruses. A potential involvement of some of the reported MER repeats in the regulation of transcription and genetic rearrangements is suggested. Age estimations place the origin of most MER repeats at the time of decline in MIR (Mammalian-wide Interspersed Repeats) retroposition and before the origin of the Alu family MER41 repeat sequences contain inducible STAT1 binding sites ']

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How do gluten proteins affect celiac disease development through enzyme and immune interactions?

['["Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. ", "Celiac disease (CD) is an autoimmune enteropathy initiated and sustained by the ingestion of gluten in genetically susceptible individuals. It is caused by a dysregulated immune response toward both dietary antigens, the gluten proteins of wheat, rye, and barley, and autoantigens, the enzyme tissue transglutaminase (TG2)", "Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies", "Transglutaminase 2 (TG2) catalyzes cross-linking or deamidation of glutamine residues in peptides and proteins. The in vivo deamidation of gliadin peptides plays an important role in the immunopathogenesis of celiac disease (CD).", "Tissue transglutaminase (TG2) modifies proteins and peptides by transamidation or deamidation of specific glutamine residues. TG2 also has a central role in the pathogenesis of celiac disease. The enzyme is both the target of disease-specific autoantibodies and generates deamidated gliadin peptides recognized by intestinal T cells from patients."]', '["Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. ", "Celiac disease (CD) is an autoimmune enteropathy initiated and sustained by the ingestion of gluten in genetically susceptible individuals. It is caused by a dysregulated immune response toward both dietary antigens, the gluten proteins of wheat, rye, and barley, and autoantigens, the enzyme tissue transglutaminase (TG2)", "Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies", "Transglutaminase 2 (TG2) catalyzes cross-linking or deamidation of glutamine residues in peptides and proteins. The in vivo deamidation of gliadin peptides plays an important role in the immunopathogenesis of celiac disease (CD).", "Tissue transglutaminase (TG2) modifies proteins and peptides by transamidation or deamidation of specific glutamine residues. TG2 also has a central role in the pathogenesis of celiac disease. The enzyme is both the target of disease-specific autoantibodies and generates deamidated gliadin peptides recognized by intestinal T cells from patients."]']

Gluten proteins from wheat, rye, and barley are the dietary antigens that trigger the dysregulated immune response in genetically susceptible individuals with celiac disease. These gluten proteins interact with the enzyme tissue transglutaminase 2 (TG2), leading to the generation of deamidated gliadin peptides. TG2 catalyzes the deamidation of specific glutamine residues in peptides and proteins, which plays a crucial role in the immunopathogenesis of celiac disease. The deamidated gliadin peptides are recognized by intestinal T cells, further contributing to the autoimmune response in celiac disease.

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Can we use prodrug amifostine to protect healthy cell during chemotherapy?

['CYP), a commonly prescribed chemotherapy drug, has multiple adverse side effects including alteration of taste. The effects on taste are a cause of concern for patients as changes in taste are often associated with loss of appetite, malnutrition, poor recovery and reduced quality of life. Amifostine is a cytoprotective agent that was previously shown to be effective in preventing chemotherapy-induced mucositis and nephrotoxicity.', 'In vivo mesna and amifostine do not prevent chloroacetaldehyde nephrotoxicity in vitro', 'Amifostine protects bone marrow from benzene-induced hematotoxicity in mice.', 'Amifostine treatment in benzene-exposed mice significantly improved blood cell counts, and morphological and histopathological signs of hematotoxicity in the bone marrow as well as in the spleen. Moreover, amifostine prevented benzene-induced bone marrow and spleen cell apoptosis and rescinded the inhibition of cell proliferation induced by benzene exposure. Finally, amifostine significantly inhibited the levels of reactive oxidative species and lipid peroxidation induced by benzene exposure.', 'Amifostine-antioxidant drug in anticancer therapy.', '. Amifostine alone is inactive chemically, but active metabolite amifostine WR-1065 has been assumed to protect the healthy tissues during antineoplastic therapy by bounding of anticancer drug, causing their detoxification and/or eliminating the free radicals generated during radiation and cytostatic therapy', 'Doxorubicin induces apoptosis in germ line stem cells in the immature rat testis and amifostine cannot protect against this cytotoxicity', 'Amifostine was developed to protect normal tissues from radiation exposure', '(AMF) has been shown to protect some normal tissues from acute effects of radiation therapy +/- chemotherapy', 'Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.', 'Amifostine inhibits angiogenesis in vivo', 'Amifostine has shown to selectively protect normal tissues against cytotoxic and mutagenic effects of several anti-neoplastic drugs, such as alkylating agents, organoplatinum compounds, anthracyclines, taxanes, and ionising radiati', 'Amifostine (Ethyoltrade mark, Alza Pharmaceuticals) is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[3- aminopropyl)amino]dihydrogen phosphate. It is a prodrug of free thiol (WR-1065) that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project', 'Preclinical studies demonstrate that amifostine has the potential to selectively protect normal tissues from the harmful effects of radiation without significantly protecting neoplastic tissue. The potential value of such an agent includes reducing treatment-related toxicity and the opportunity for radiation dose escalation in the curative treatment of cancer. An increasing number of human clinical trials have been conducted that define the toxicity profile and efficacy of radioprotection by amifostine when used during fractionated radiation therapy', 'Radioprotective effects of amifostine.']

['Effective radiotherapy for patients with cancer should include maximal tumor cell killing with minimal injury to normal tissue. However, current radiation doses that can be delivered without causing severe damage to surrounding normal tissues are often insufficient to eradicate a tumor. Recently, a number of agents have been developed to protect normal tissue from the harmful effects of antitumor therapies. The aminothiol amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) has been the subject of extensive research as a prospective protector. While this drug has been approved for use to reduce toxicities associated with cisplatin, several studies also have demonstrated that amifostine protects normal tissues from both acute and late radiation damage without protecting the tumor. Consequently, higher radiation doses could be used with less than or equal risk to surrounding normal tissues.']

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Can NADPH oxidase be inhibited by apocynin and diphenylene iodonium?

['Ang II treatment also led to a significant increment in intracellular reactive oxygen species generation, which could be fully abolished by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors apocynin or diphenylene iodonium, indicating that Ang II enhanced oxidative stress via a NADPH oxidase-dependent manner.', 'NOX inhibitors (diphenylene iodonium (DPI) or apocynin) were able to achieve similar results to that of ML-7 except no effect on MLCK activity and MLC20 phosphorylation. ', 'Significant reductions of AII effects on podocyte TRPC6 were also observed after pretreatment with NADPH oxidase inhibitors apocynin or diphenylene iodonium (DPI). ', 'Furthermore, inhibition of NOX-mediated ROS production with apocynin, diphenylene iodonium (DPI) or NOX2 docking sequence (Nox2ds)-tat peptide during these first 4h of PE stimulation significantly inhibited PE-induced hypertrophy of H9c2 cells, both after 24 and 48h of PE stimulation. ', 'Remarkably, Ang-II induced reactive oxygen species (ROS) via a NAD(P)H oxidase-dependent mechanism, as shown by inhibition of ROS production via the NAD(P)H oxidase inhibitors diphenylene iodonium (DPI) and apocynin. ', 'Moreover, NADPH oxidase activation by beta CD (145.5+/-9.0%; control: 98.6+/-1.6%) was also abrogated by the NADPH oxidase inhibitors apocynin (100.4+/-3.2%) and diphenylene iodonium (9.5+/-3.3%).', 'We used structurally diverse NADPH oxidase inhibitors, aminoethyl-benzenesulfonylfluoride (AEBSF, 100-1000microM), apocynin (100-1000microM), and diphenylene iodonium (DPI, 3-30microM), to inhibit intrinsic NADPH oxidase activity in N27 cells.', 'Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol.', 'With the use of dihydroethidium as a superoxide indicator, C(2)-ceramide was found to increase superoxide production in the endothelial cells of small coronary arteries, which was inhibited by the NADPH oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium.', 'The contractile responses to U46619 in isolated PA were inhibited by PEG-catalase and the NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin.', 'The effects of diphenylene iodonium (DPI) and apocynin, inhibitors of NADPH oxidase, on key parameters of PSC activation were evaluated in vitro.', 'These effects could be inhibited by diphenylene iodonium and apocynin, indicating a self-cycle regulated by NADPH oxidase in microglial activation in response to oAâ.', 'Diphenylene iodonium is an inhibitor of the respiratory burst-generating NADPH oxidase of phagocytes.', 'NADPH oxidase inhibitors [diphenylene iodonium (DPI) and apocynin (4-hydroxy-3-methoxy-acetophenone)] prevented the microglial activation induced by oAâ, suggesting that NADPH oxidase activation was involved in microglial activation.', 'In addition, inhibitors of NADPH oxidase (diphenylene iodonium or apocynin) also prevented microglia proliferation, suggesting that this may be the source of hydrogen peroxide.', 'Inhibitors of NADPH oxidase (diphenylene iodonium, apocynin, D-(+)-neopterine) also significantly blunted the generation of reactive oxygen species, activation of K(+), Cl(-)-cotransport and apoptosis induced by N-ethylmaleimide.', 'With the use of dihydroethidium as a superoxide indicator, C(2)-ceramide was found to increase superoxide production in the endothelial cells of small coronary arteries, which was inhibited by the NADPH oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium.', 'NADPH-dependent superoxide production by the solubilized oxidase of neutrophils was inhibited 36% by diphenylene iodonium at a 1:1 stoichiometry with the enzyme flavoprotein content.', 'These effects could be inhibited by diphenylene iodonium and apocynin, indicating a self-cycle regulated by NADPH oxidase in microglial activation in response to oAβ', 'Moreover, CSE-regulated COX-2, PGE(2), and IL-6 generation was inhibited by pretreatment with TLR4 Ab; inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride and apocynin), p38 MAPK (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-kappaB (helenalin); a ROS scavenger (N-acetyl-l-cysteine); and transfection with siRNA of TLR4, MyD88, TRAF6, Src, p47(phox), p38, p42, JNK2, or p65', 'Treatment of the cells with the NADPH oxidase inhibitors, apocynin and diphenylene iodonium, inhibited these effects', 'With the use of dihydroethidium as a superoxide indicator, C(2)-ceramide was found to increase superoxide production in the endothelial cells of small coronary arteries, which was inhibited by the NADPH oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium', 'UVB irradiation generated ROS in a dose-dependent manner, and this was significantly inhibited by diphenylene iodonium (DPI), apocynin (Apo) and neopterine (Neo), inhibitors of the NADPH oxidase, and indomethacin (Indo), a cyclooxygenase (COX) inhibitor, but not by the mitochondrial electron transport inhibitors and other cytosolic enzyme inhibitors', 'In RBA-1 cells, JEV induced MMP-9 expression and promoter activity, which was inhibited by pretreatment with inhibitors of NADPH oxidase (diphenylene iodonium chloride or apocynin), MAPKs (U0126, SB203580 or SP600125) and a ROS scavenger (N-acetylcysteine), or transfection with siRNAs of p47(phox) , ERK1, JNK2 and p38', 'Such discharge of Dectin-1-reactive β-glucan from macrophage cells was inhibited by either NADPH oxidase inhibitors (apocynin and diphenylene iodonium) or radical scavengers (N-acetyl cysteine and MCI-186)', 'The contractile responses to U46619 in isolated PA were inhibited by PEG-catalase and the NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin', 'ANG II further increased superoxide production in LP only, and this was inhibited by coincubation with diphenylene iodonium or apocynin (inhibitor of NADPH oxidase complex)', 'Our results showed that IL-1beta enhanced HTSMCs-monocyte adhesion through up-regulation of VCAM-1, which was inhibited by pretreatment with selective inhibitors of PKCalpha (Gö6976), c-Src (PP1), NADPH oxidase [diphenylene iodonium (DPI) and apocynin (APO)], intracellular calcium chelator (BAPTA/AM), PI-PLC (U73122), CaM (calmidazolium chloride), CaM kinase II (KN62), p300 (garcinol), NF-kappaB (Bay11-7082), HDAC (trichostatin A), and ROS scavenger [N-acetyl-L-cysteine (NAC)] or transfection with siRNAs of MyD88, PKCalpha, Src, p47(phox), p300, and HDAC4.', 'Here we show that cAMP-dependent decidualization can be attenuated or enhanced upon treatment of primary cultures with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenylen iodonium) or activator (apocynin), respectively. ', 'With the use of dihydroethidium as a superoxide indicator, C(2)-ceramide was found to increase superoxide production in the endothelial cells of small coronary arteries, which was inhibited by the NADPH oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium. ', 'The inhibition of NAD(P)H oxidase by apocynin and diphenylene iodonium, and of the mitochondrial electron transport system at complex II by thenoyltrifluoroacetone (TTFA), significantly inhibited both AGE-induced ROS production and VCAM-1 expression, whereas these effects were potentiated by rotenone and antimycin A, specific inhibitors of mitochondrial complex I and III, respectively. ', 'Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. ', 'Treatment of the cells with the NADPH oxidase inhibitors, apocynin and diphenylene iodonium, inhibited these effects. ', 'The G6PD inhibitor DHEA and the inhibitors of NADPH oxidase apocynin and diphenylene iodonium (DPI) prevented both superoxide generation and capacitation in human spermatozoa, but whereas DPI and DHEA inhibited PPP, apocynin did not influence it, suggesting that PPP activation during capacitation is not a response to increased oxidative stress but exerts a role by supplying reducing equivalents to oxygen.', 'Ang II induced a time-dependent increase in Rac1 activation and O(2)(*-) production in Neuro-2A cells, and this was abolished by pretreatment with AdN17Rac1 or the NADPH oxidase inhibitors apocynin or diphenylene iodonium. ', 'Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol.', 'In RBA-1 cells, JEV induced MMP-9 expression and promoter activity, which was inhibited by pretreatment with inhibitors of NADPH oxidase (diphenylene iodonium chloride or apocynin), MAPKs (U0126, SB203580 or SP600125) and a ROS scavenger (N-acetylcysteine), or transfection with siRNAs of p47(phox) , ERK1, JNK2 and p38.', 'These effects could be inhibited by diphenylene iodonium and apocynin, indicating a self-cycle regulated by NADPH oxidase in microglial activation in response to oAβ.', 'Treatment of the cells with the NADPH oxidase inhibitors, apocynin and diphenylene iodonium, inhibited these effects.', 'UVB irradiation generated ROS in a dose-dependent manner, and this was significantly inhibited by diphenylene iodonium (DPI), apocynin (Apo) and neopterine (Neo), inhibitors of the NADPH oxidase, and indomethacin (Indo), a cyclooxygenase (COX) inhibitor, but not by the mitochondrial electron transport inhibitors and other cytosolic enzyme inhibitors.', 'Such discharge of Dectin-1-reactive β-glucan from macrophage cells was inhibited by either NADPH oxidase inhibitors (apocynin and diphenylene iodonium) or radical scavengers (N-acetyl cysteine and MCI-186).', 'Our results showed that IL-1beta enhanced HTSMCs-monocyte adhesion through up-regulation of VCAM-1, which was inhibited by pretreatment with selective inhibitors of PKCalpha (Gö6976), c-Src (PP1), NADPH oxidase [diphenylene iodonium (DPI) and apocynin (APO)], intracellular calcium chelator (BAPTA/AM), PI-PLC (U73122), CaM (calmidazolium chloride), CaM kinase II (KN62), p300 (garcinol), NF-kappaB (Bay11-7082), HDAC (trichostatin A), and ROS scavenger [N-acetyl-L-cysteine (NAC)] or transfection w', 'Moreover, CSE-regulated COX-2, PGE(2), and IL-6 generation was inhibited by pretreatment with TLR4 Ab; inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride and apocynin), p38 MAPK (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-kappaB (helenalin); a ROS scavenger (N-acetyl-l-cysteine); and transfection with siRNA of TLR4, MyD88, TRAF6, Src, p47(phox), p38, p42, JNK2, or p65.', 'The use of diphenylene iodonium, an inhibitor of NADPH oxidase, to investigate the antimicrobial action of human monocyte derived macrophages.', 'NADPH oxidase inhibitors [diphenylene iodonium (DPI) and apocynin (4-hydroxy-3-methoxy-acetophenone)] prevented the microglial activation induced by oAβ, suggesting that NADPH oxidase activation was involved in microglial activation.', 'Furthermore, inhibition of NOX-mediated ROS production with apocynin, diphenylene iodonium (DPI) or NOX2 docking sequence (Nox2ds)-tat peptide during these first 4h of PE stimulation significantly inhibited PE-induced hypertrophy of H9c2 cells, both after 24 and 48h of PE stimulation.', 'We compared the pharmacological profiles of the commonly used NADPH oxidase inhibitors, diphenylene iodonium (DPI), apocynin and 4-(2-amino-ethyl)-benzolsulphonyl-fluoride (AEBSF), as well as the novel triazolo pyrimidine VAS3947.', 'IL-1beta and TNF-alpha rapidly stimulated the rate of hydrogen peroxide produced by isolated microglia, and this was inhibited by diphenylene iodonium, implying that the cytokines were acting directly on microglia to stimulate the NADPH oxidase.', 'The fractions achieved the same effects that known NADPH oxidase inhibitors, such as diphenylene iodonium and apocynin, but they presented better hydrosolubility.', 'Ang II induced a time-dependent increase in Rac1 activation and O(2)(*-) production in Neuro-2A cells, and this was abolished by pretreatment with AdN17Rac1 or the NADPH oxidase inhibitors apocynin or diphenylene iodonium.']

['Yes, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be inhibited by apocynin or diphenylene iodonium (DPI).']

['yes']

What is the role of Hsp90 inhibition in cancer therapy?

['Geldanamycin (GA) can be considered a relatively new component with a promising mode of action against human malignancies. It specifically targets heat shock protein 90 (Hsp90) and interferes with its function as a molecular chaperone.', 'In toto, we have evinced the dose-dependent and cell line-specific actions of geldanamycin on cell cycle progression, survival and motility of human bladder cancer cells, due to downregulation of critical Hsp90 clients and subsequent disruption of signaling -oncogenic- integrity.', 'Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy', 'Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt, and NF-κB, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis.', 'In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT.', 'The Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), which simultaneously inactivated both Akt and ERK signaling at noncytocidal concentrations, synergistically potentiated the cytotoxicity of CDDP against BCICs by enhancing CDDP-induced apoptosis in vitro.', 'We have demonstrated that, upon 17-AAG treatment, bladder cancer cells are arrested in the G1 phase of the cell cycle and eventually undergo apoptotic cell death in a dose-dependent manner. Furthermore, 17-AAG administration was shown to induce a pronounced downregulation of multiple Hsp90 protein clients and other downstream effectors, such as IGF-IR, Akt, IKK-α, IKK-β, FOXO1, ERK1/2 and c-Met, resulting in sequestration-mediated inactivation of NF-κB, reduced cell proliferation and decline of cell motility.', 'In total, we have clearly evinced a dose-dependent and cell type-specific effect of 17-AAG on cell cycle progression, survival and motility of human bladder cancer cells, due to downregulation of multiple Hsp90 clients and subsequent disruption of signaling integrity.', 'Low dose geldanamycin inhibits hepatocyte growth factor and hypoxia-stimulated invasion of cancer cells', 'GA downregulated Met by inhibiting new protein maturation, thereby dampening HGF signaling.', 'HGF and chemical hypoxia with CoCl2 cooperatively promoted in vitro invasion and vascular endothelial growth factor (VEGF) secretion, while CoCl2 but not HGF activated urokinase-type plasminogen activator and matrix metalloproteinase 2, both of which promote invasion and angiogenesis. Low dose GA (100 nmol/L) inhibited these processes by suppressing both HGF and HIF-1 pathways.', 'Notably, brief GA pretreatment inhibited in vitro invasion and VEGF secretion induced by HGF as effectively as did continuous treatment.', 'Moreover, we found that GA inhibited activation of focal adhesion kinase, focal adhesion assembly, and actin reorganization induced by HGF and integrin engagement by extracellular matrix.', 'GA widely suppresses extrinsic stimuli-induced signaling that contribute to tumor invasion and angiogenesis in this bladder carcinoma model, suggesting the utility of Hsp90 inhibitors in preventing tumor progression and metastasis.', 'upon geldanamycin treatment, bladder cancer cells are prominently arrested in the G1 phase of cell cycle and eventually undergo programmed cell death via combined activation of apoptosis and autophagy.', 'geldanamycin administration proved to induce prominent downregulation of several Hsp90 protein clients and downstream effectors, such as membrane receptors (IGF-IR and c-Met), protein kinases (Akt, IKKα, IKKβ and Erk1/2) and transcription factors (FOXOs and NF-κΒ), therefore resulting in the impairment of proliferative -oncogenic- signaling and reduction of cell motility', '17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin antibiotic, specifically targets heat shock protein 90 (Hsp90) and interferes with its function as a molecular chaperone that maintains the structural and functional integrity of various protein clients involved in cellular signalin']

['Hsp90 inhibition is followed by G1/S cell cycle arrest, downregulation of key signalling proteins such as IGF-IR, Akt, IKK-α, IKK-β, FOXO1, ERK1/2 and c-Met, and sequestration-mediated inactivation of NF-κB, resulting in disruption of oncogenic signalling integrity, reduced cell proliferation, decline of cell motility, enhanced apoptotic cell death, and finally, sensitization of cancer cells to additional chemotherapy and/or radiotherapy.']

[]

Can we detect DNA strand asymmetries using dinucleotide relative abundance "genomic signatures"?

['comparing the heterogeneities of bacterial genomes with respect to strand-independent first- and second-order features, (i) G + C content and (ii) dinucleotide relative abundance,', 'the concept of a genomic signature was introduced with the observation of species-type specific Dinucleotide Relative Abundance Profiles (DRAPs); dinucleotides were identified as the subsequences with the greatest bias in representation in a majority of genomes.', 'dinucleotide relative abundance values (the genomic signature)', 'The dinucleotide relative abundance profile can be regarded as a genomic signature because, despite diversity between species, it varies little between 50 kilobase or longer windows on a given genome.', 'The profile is computed from the base step "odds ratios" that compare dinucleotide frequencies to those expected under the assumption of stochastic equilibrium (thorough shuffling). ', 'The genome signatures (dinucleotide relative abundance values)', 'Early biochemical experiments measuring nearest neighbor frequencies established that the set of dinucleotide relative abundance values (dinucleotide biases) is a remarkably stable property of the DNA of an organism.', "the set of dinucleotide biases constitutes a 'genomic signature' that can discriminate sequences from different organisms.", 'the set of dinucleotide odds ratio (relative abundance) values constitute a signature of each DNA genome', 'Dinucleotide relative abundance extremes: a genomic signature.', 'The dinucleotide relative abundance profile can be regarded as a genomic signature because, despite diversity between species, it varies little between 50 kilobase or longer windows on a given genome.', 'Previously, the concept of a genomic signature was introduced with the observation of species-type specific Dinucleotide Relative Abundance Profiles (DRAPs); dinucleotides were identified as the subsequences with the greatest bias in representation in a majority of genomes.', 'Comparisons within and between species sample sequences are based on the profile of dinucleotide relative abundance values (The profile is rho*XY = f*XY/f*Xf*Y for all XY, where f*X denotes the frequency of the nucleotide X and f*XY denotes the frequency of the dinucleotide XY, both computed from the sequence concatenated with its inverted complement).', 'Dinucleotide relative abundances (i.e., dinucleotide representations normalized by the component nucleotide frequencies) are consonant with respect to the leading and lagging strands']

['The set of dinucleotide relative abundances can be regarded as a genomic signature because, despite diversity between species, it varies little between 50 kilobase or longer windows on a given genome. Thus, dinucleotide relative abundance profiles are species-type specific. These profiles are computed from the base step "odds ratios" that compare dinucleotide frequencies to those expected under the assumption of stochastic equilibrium (thorough shuffling). Dinucleotide relative abundance "genomic signatures" are strand-independent second-order DNA features. Thus, they cannot be used to detect DNA strand asymmetries.']

['no']

Can methylenetetrahydrofolate reductase (MTHFR) gene mutations cause homocystinuria?

['Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. ', 'Several mutations seen in methylenetetrahydrofolate reductase (MTHFR) give rise to the formation of hyperhomocysteinemia and homocystinuria, a considerable risk factor for cardiovascular and cerebrovascular disorders, by leading to enzymatic inactivation.', 'At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine.', 'Response to treatment demonstrated B(6)-non-responsive homocystinuria. Molecular study showed compound heterozygous T353\xa0N and D444\xa0N mutations of the cystathionine beta-synthase (CBS) gene, and also a C667T homozygous mutation of the methylenetetrahydrofolate-reductase (MTHFR) gene. ', 'Our case is atypical because of the absence of thromboembolism and the mild phenotype, in spite of being B(6)-non-responsive, and the association of a rare compound heterozygous mutation of the CBS gene and also an homozygous mutation of the MTHFR gene.', 'Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency.', 'Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism. Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause homocystinuria or mild hyperhomocysteinemia. Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia.', 'Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the regulation of plasma homocysteine levels. MTHFR deficiency, an autosomal recessive disorder, results in homocystinuria and hypomethioninaemia and presents with highly variable symptoms affecting many organs but predominantly the central nervous system. ', 'Some methylenetetrahydrofolate reductase (MTHFR) gene mutations cause hyperhomocysteinemia and homocystinuria.', 'Rare mutations in the MTHFR gene have been associated with autosomal recessive MTHFR deficiency leading to homocystinuria.', 'Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria.', 'Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene.', 'The results of our study render the full-length characterisation of affected alleles in severe homocystinuria and moderate hyperhomocysteinaemia due to MTHFR deficiency and provide a basis for investigating the regulation of the human MTHFR gene.', 'Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia.', 'Different MTHFR mutations lead either to severe homocystinuria as a multisystem disorder or to moderate hyperhomocysteinaemia, which is a common risk factor for disorders ranging from cardiovasculopathy to spina bifida.', 'We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis.', 'On the contrary, thermolabile MTHFR caused by the 677C-->T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR.', 'We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis.', 'Some methylenetetrahydrofolate reductase (MTHFR) gene mutations cause hyperhomocysteinemia and homocystinuria', 'We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis', 'Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria', 'The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene', 'The 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis', 'Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM)', 'The 677C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinaemia', 'We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis. ', 'AIM: Some methylenetetrahydrofolate reductase (MTHFR) gene mutations cause hyperhomocysteinemia and homocystinuria. ', 'Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency.', 'Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later-onset neurological impairment, including developmental delay, motor dysfunction, and seizures. ', 'Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR) leads to deficient remethylation of homocysteine and is one of the causes of homocystinuria. ', 'Neurological disturbances have been described in homocystinuria caused by severe MTHFR deficiency. ', 'The 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis.', 'Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause homocystinuria or mild hyperhomocysteinemia.', 'The 677C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinaemia.', 'The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene.', 'Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia.', 'Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria.', 'Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency.', 'On the contrary, thermolabile MTHFR caused by the 677C-->T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR.']

['Yes, several methylenetetrahydrofolate reductase (MTHFR) gene mutations can cause homocystinuria and hyperhomocysteinemia.']

['yes']

What is the typical alteration of the thyroid profile metabolism early after coronary artery bypass graft surgery?

['FT3 concentration dropped significantly (p < 0.0001), reaching its lowest value 12 hours postoperatively. There were no significant differences between CPB and OPCAB patients. ', 'In on-pump CABG surgery, inflammatory effects encompass activation of total leukocytes, neutrophils and platelets, reduction of serum level of total proteins and albumin and decreased thyroid hormones levels, especially within first postoperative 24 hours.', 'Typical NTIS was observed in all patients, and the FT3 concentration was still reduced by postoperative day 5 (p<0.0001).', 'We could demonstrate that CPB induces a low T3 syndrome up to 3 days after surgery. Those patients with low T3 concentrations prior to surgery demonstrate postoperatively a more severe degree of nonthyroidal illness (NTI).', 'It is concluded that the coronary bypass operation evokes a rapid decline in T3, which is not normalized by the TSH induced response of the thyroid gland, while the post-operative period is characterized by a "low T3 state". ']

['Low T3 Syndrome is the more frequent alteration of thyroid hormone profile early after coronary artery bypass graft surgery.']

['Low T3 syndrome occurs frequently after CABG']

Is HER2 active only when it dimerizes?

['HER activation is driven by the formation of various dimer complexes between members of this receptor family.', 'rtuzumab is the first humanized monoclonal antibody in a new class of drugs, the HER dimerization inhibitors, approved by the Food and Drug', 'Pertuzumab is a novel anti-HER2 monoclonal antibody, which blocks HER2 dimerization with other ligand-activated HER family members. Here, we explored the complement-mediated anti-tumor effects of trastuzumab and pertuzumab on HER2-positive tumor cells of various histological origins.', 'ays. In this study, we report that an anti-HER2 monoclonal antibody (HER2Mab), which blocks HER2 dimerization with HER3, induces HER3 dimerization with EGFR in both low and high HER2 expressing cancer cells.', 'Recent evidence from both basic and clinical studies suggests that ERBB3 (HER3) serves as a key activator of downstream signaling through dimerization with other ERBB proteins and plays a critical role in the widespread clinical resistance to EGFR and HER2 targeting cancer therapies. ', 'HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways.', 'Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners.', 'Our results show that quantification of HER dimerization provides information about receptor activation that cannot be obtained by quantification of single receptors. ', 'Pertuzumab is a novel humanized monoclonal antibody that blocks human epidermal growth factor receptor 2 (HER2) dimerization. It was recently approved by the US FDA for use in combination with trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. ', 'he HER dimerization status may be more important than HER receptor expression per se in determining sensitivity or resistance to a given therapeutic agen', ' and HER2 dimerization inhibitors', 'One of the mechanisms by which tumor cell proliferation can be inhibited consists in hampering HER2 dimerization by targeting its extracellular domain with specific antibodies. ', 'Pertuzumab, a humanized monoclonal antibody, is the first HER2 dimerization inhibitor. It binds to the dimerization site on the HER2 domain and prevents ligand-driven pairing of HER2 with other HER receptors, thus inhibiting tumor cell growth and survival', 'Pertuzumab, another monoclonal antibody, is a HER2 dimerization inhibitor that binds to a different epitope on HER2 than trastuzumab and inhibits HER2 dimer formation with other HER family members such as HER3 and HER1. ']

['Yes, HER2 activation is driven by the formation of various dimer complexes between members of this receptor family.']

['yes']

Could divalent metal transporter 1 deficiency lead to anemia?

['The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic anemia. ', "Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery.", 'Deficiency of the divalent metal transporter 1 (DMT1) leads to hypochromic microcytic anemia. We have previously shown that DMT1 deficiency impairs erythroid differentiation and induces apoptosis of erythroid cells. ', 'We propose that DMT1 deficiency negatively affects metabolism and life span of mature erythrocytes; two other aspects of defective erythropoiesis which contribute to the pathophysiology of the disease.', 'Hypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be improved with high-dose erythropoietin supplementation. ', 'Belgrade rats exhibit microcytic, hypochromic anemia and systemic iron deficiency due to a glycine-to-arginine mutation at residue 185 in a metal ion transporter of a divalent metal transporter/divalent cation transporter/solute carrier 11 group A member 2 or 3 (DMT1/DCT1/SLC11A2), a member of the natural-resistance-associated macrophage protein (Nramp) family.', 'Deficiency of the divalent metal transporter 1 (DMT1) leads to hypochromic microcytic anemia', 'Belgrade rats exhibit microcytic, hypochromic anemia and systemic iron deficiency due to a glycine-to-arginine mutation at residue 185 in a metal ion transporter of a divalent metal transporter/divalent cation transporter/solute carrier 11 group A member 2 or 3 (DMT1/DCT1/SLC11A2), a member of the natural-resistance-associated macrophage protein (Nramp) family', 'BACKGROUND/AIMS: Deficiency of the divalent metal transporter 1 (DMT1) leads to hypochromic microcytic anemia. ', 'Microcytic anemia (mk/mk) mice defective in DMT1 and wild-type mice were exposed to either bleomycin or saline via intratracheal instillation and the resultant lung injury was compared. ', 'Deficiency of the divalent metal transporter 1 (DMT1) leads to hypochromic microcytic anemia.', 'The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis.', 'This mutation severely impairs the iron transport capability of DMT1, leading to systemic iron deficiency and anemia.']

['Yes, divalent metal transporter 1 (DMT1) deficiency could result in anemia, as DMT1 is a major iron transporter required for iron absorption and erythropoiesis. DMT1 deficiency impairs erythroid differentiation and induces apoptosis of erythroid cells.']

['yes']

What is sQTLseekeR?

['Identification of genetic variants associated with alternative splicing using sQTLseekeR.', 'We develop a statistical framework that uses a distance-based approach to compute the variability of splicing ratios across observations, and a non-parametric analogue to multivariate analysis of variance. We implement this approach in the R package sQTLseekeR and use it to analyze RNA-Seq data from the Geuvadis project in 465 individuals. We identify hundreds of single nucleotide polymorphisms (SNPs) as splicing QTLs (sQTLs), including some falling in genome-wide association study SNPs. By developing the appropriate metrics, we show that sQTLseekeR compares favorably with existing methods that rely on univariate approaches, predicting variants that behave as expected from mutations affecting splicing', 'Identification of genetic variants associated with alternative splicing using sQTLseekeR', 'Identification of genetic variants associated with alternative splicing using sQTLseekeR.']

['sQTLseekeR is an R package for the identification of genetic variants associated with alternative splicing. It is based on a statistical framework that uses a distance-based approach to compute the variability of splicing ratios across observations, and a non-parametric analogue to multivariate analysis of variance.']

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What are cancer driver genes?

['We constructed DriverDB (http://ngs.ym.edu.tw/driverdb/), a database which incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP, 1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to driver gene/mutation identification.', 'DriverDB: an exome sequencing database for cancer driver gene identification.', 'With the ability to fully sequence tumor genomes/exomes, the quest for cancer driver genes can now be undertaken in an unbiased manner.', 'Here we show that the combination of complementary methods allows identifying a comprehensive and reliable list of cancer driver genes. ', 'In summary, the catalog of driver genes and the methodology presented here open new avenues to better understand the mechanisms of tumorigenesis.', 'A subset of these mutations contribute to tumor progression (known as "driver" mutations) whereas the majority of these mutations are effectively neutral (known as "passenger" mutations)', 'The ability to differentiate between drivers and passengers will be critical to the success of upcoming large-scale cancer DNA resequencing projects.', " In fact, recent sequencing and resequencing (i.e., polymorphism identification) efforts have catalyzed the quest for protein kinase 'driver' mutations (i.e., those genetic alterations which contribute to the transformation of a normal cell to a proliferating cancerous cell) in distinction to kinase 'passenger' mutations which reflect mutations that merely build up in course of normal and unchecked (i.e., cancerous) somatic cell replication and proliferation.", 'This method was applied to available breast cancer, colorectal cancer, and glioblastoma sequence data, and identified Wnt/TGF-beta cross-talk, Wnt/VEGF signaling, and MAPK/focal adhesion kinase pathways as targets of rare driver mutations in breast, colorectal cancer, and glioblastoma, respectively.', 'Analysis of the frequency of specific mutations across different tumors has been able to identify some, but not all of the mutated genes that contribute to tumor initiation and progression.', 'We are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals.', "Major tumor sequencing projects have been conducted in the past few years to identify genes that contain 'driver' somatic mutations in tumor samples.", 'At the same time, we determined that some genes previously reported as drivers were not significant by the new analysis because mutations in these genes occurred mainly in tumors with large background mutation rates. ', 'Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity.', 'Herein we report a proof-of-principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver-passenger distinction.', 'Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.', 'Adjusting for background mutation frequency biases improves the identification of cancer driver genes.', 'The identification of cancer drivers is a major goal of current cancer research', 'We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers.']

['Recent sequencing and resequencing (i.e., polymorphism identification) efforts have catalyzed the quest for \'driver\' mutations (i.e., those genetic alterations which contribute to the transformation of a normal cell to a proliferating cancerous cell) in distinction to \'passenger\' mutations which reflect mutations that merely build up in course of normal and unchecked (i.e., cancerous) somatic cell replication and proliferation. Analysis of the frequency of specific mutations across different tumors has been able to identify some, but not all of the mutated genes that contribute to tumor initiation and progression. A subset of these mutations contribute to tumor progression (known as "driver" mutations) whereas the majority of these mutations are effectively neutral (known as "passenger" mutations).']

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What is Bartter syndrome?

['All forms of Bartter syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism', 'The mutations in the CLCNKB gene encoding the ClC-Kb chloride channel are responsible for Bartter syndrome type 3, one of the four variants of Bartter syndrome in the genetically based nomenclature.', 'Bartter syndrome (BS) is a hereditary disease, with an autosomal recessive or autosomal dominant mode of transmission. It is characterized by salt wasting hypochloraemic, hypokalaemic', 'Bartter syndrome Type III is caused by genetic alterations in the chloride channel kidney B (CLCNKB) gene and often presents in the first 2 years of life, known as classic Bartter syndrome.', 'Bartter syndrome encompasses a variety of inheritable renal tubular transport disorders characterized by hypokalemia and hypochloremic metabolic alkalosis.', 'Classic Bartter syndrome and neonatal Bartter syndrome have defects in genes that affect transport channels in the ascending loop of Henle, where as in Gitleman syndrome the defect occurs in the transport channels of the distal convoluted tubule.', 'Bartter syndrome type III and congenital anomalies of the kidney and urinary tract: an antenatal presentation.', "Bartter's syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis.", 'Bartter syndrome (BS) is a rare renal tubular disorder presenting with hypokalemic metabolic alkalosis, which is classified into five types', 'It has been described in patients with chronic diarrhoea, eating disorders, laxative abuse and primary hyperaldosteronism; also occasionally in Bartter syndrome (BS), in which severe hypokalaemia accompanies significant renal sodium and water losses, though rarely in Gitelman syndrome (GS), in which there is equally severe hypokalaemia, but only modest sodium losses.We hypothesized that hypokalaemic nephropathy may not be due to potassium depletion per se, but persistently elevated circulating levels of aldosterone, possibly with superimposed episodes of renal hypoperfusion.We searched UK and European data sets to retrospectively compare serum and urinary parameters in patients with GS and BS.', 'Acquired Bartter-like syndrome (BLS), characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal kidney function, can be induced by diuretics or antibiotics', 'lassic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene', 'clinical features of two renal tubular disorders characterized by sodium and potassium wasting: Bartter syndrome and Gitelman syndrome', 'Bartter syndrome is an autosomic recessive disease characterized by severe polyuria and sodium renal loss', 'The term "Bartter syndrome" encompasses a group of closely related inherited tubulopathies characterized by markedly reduced NaCl transport by the distal nephron. ', " true Bartter's syndrome, diagnosed as a normotensive, hyperreninaemic, hypokalaemic metabolic alkalosis with normal urine chloride excretion, low CH2O/(CH2O+CCl) ratio during maximal water diuresis and negative urine screen for diuretics", "Bartter's syndrome belongs to a group of hypokalemic renal channel diseases.", "Hypokalemia due to renal potassium wasting in the absence of hypertension, moderate metabolic alkalosis, hyperreninism and hyperaldosteronism suggest the presence of Bartter's syndrome.", ' Inherited hypokalemic renal tubulopathies are differentiated into at least three clinical subtypes: (1) the Gitelman variant of Bartter syndrome (GS); (2) hyperprostaglandin E syndrome, the antenatal variant of Bartter syndrome (HPS/aBS); and (3) the classic Bartter syndrome (cBS). ', 'Bartter syndrome, a group of autosomal recessive disorders that are characterized by markedly reduced or absent salt transport by the thick ascending limb of Henle. ', "Bartter's and Gitelman's syndromes are characterized by hypokalemia, normal to low blood pressure and hypochloremic metabolic alkalosis.", "Bartter's syndrome has been used to describe a spectrum of inherited renal tubular disorders with hypokalemic metabolic alkalosis and overlapping and additional clinical and biochemical features. ", 'antenatal variant of Bartter syndrome is characterized by a history of polyhydramnios, premature birth, metabolic alkalosis, hypokalemia, polyuria and renal', 'Most patients with Bartter syndrome have defects in transporters in the thick ascending limb of the loop of Henle, such as the Na-K-2Cl cotransporter, NKCC2, or the ATP-sensitive potassium channel, ROMK. ', "Gitelman's syndrome or familial hypokalemia-hypomagnesemia and Bartter syndrome share some common features but their prognosis is quite different.", 'Bartter syndrome is a group of inherited, salt-losing tubulopathies presenting as hypokalemic metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism', "Bartter's and Gitelman's syndromes are two different genetic renal diseases, but are both characterised by hypokalaemia and metabolic alkalosis. Bartter's syndrome is characterised by multiple gene mutations (Na-K-2Cl cotransporter; K(+) channels renal outer medullary potassium channel (ROMK); Cl channels, chloride channel Kb (ClCNKb); regulatory protein Barttin; and Ca(2+) -sensing receptor, CaSR) at the thick ascending limb of Henle's loop, "]

['All forms of Bartter syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism', 'All forms of hereditary Bartter syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism.']

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What is the definition and the biological role of epithelial-mesenchymal transition (EMT)

['Epithelial-to-mesenchymal transition (EMT) is a process known to contribute to metastasis in cancer and it is mainly characterized by loss of E-cadherin expression.', 'The TGF-β signaling pathway has an established role in promoting EMT by down-regulating E-cadherin via a number of transcription factors, such as Twist, Snail and Slug. EMT has also been reported to produce cells with stem cell-like properties. ', 'Epithelial to mesenchymal transition (EMT) has been hypothesized as a mechanism by which cells change phenotype during carcinogenesis, as well as tumor metastasis. ', 'Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF) -β, Wnt, and Notch signaling pathways, have been shown to induce EMT.', 'These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. ', 'Epithelial-mesenchymal transition (EMT) is suggested to be crucial for the development of an invasive and metastatic carcinoma cell phenotype. Therefore, the definition of this phenotype is of great clinical interest. ', 'Recent work has suggested that there may be a linkage between the stem cell phenotype and that induced by the process of epithelial-mesenchymal transition (EMT). EMT plays an important role in cell movement and organ formation during embryogenesis, and it is currently hypothesized to be a major mechanism by which epithelial cancers may generate cells that can form metastases. ', 'The term EMT (epithelial-mesenchymal transition) is used in many settings. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors.', 'The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma.', 'Epithelial to mesenchymal transition (EMT) plays an important role in many biological processes.', 'Epithelial-mesenchymal transition (EMT) is a biological process that drives polarized, immotile epithelial cells to undergo multiple biochemical changes to acquire a mesenchymal cell phenotype.', 'Epithelial-mesenchymal transition (EMT) is a biological process that drives polarized, immotile epithelial cells to undergo multiple biochemical changes to acquire a mesenchymal cell phenotype', 'Epithelial to mesenchymal transition (EMT) plays an important role in many biological processes']

['Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF) -β, Wnt, and Notch signaling pathways, have been shown to induce EMT. The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma.', 'This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Several oncogenic pathways such as transforming growth factor (TGF) -β, Wnt, and Notch signaling pathways, have been shown to induce EMT. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. EMT has also been reported to produce cells with stem cell-like properties. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Epithelial-to-mesenchymal transition (EMT) is a process known to contribute to metastasis in cancer and it is mainly characterized by loss of E-cadherin expression. ', 'This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. Several oncogenic pathways such as transforming growth factor (TGF) -β, Wnt, and Notch signaling pathways, have been shown to induce EMT. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. EMT has also been reported to produce cells with stem cell-like properties. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Epithelial-to-mesenchymal transition (EMT) is a process known to contribute to metastasis in cancer and it is mainly characterized by loss of E-cadherin expression. ']

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Which receptor is targeted by telcagepant?

['In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232.', 'Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: results from a randomized study in patients with migraine.', 'Olcegepant is the first selective CGRP receptor antagonist of proven efficacy in migraine. Olcegepant could only be administered intravenously and never taken beyond Phase II. Telcagepant is orally available and several completed Phase III trials have revealed positive results. ', 'Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine (http://www.merck.com/research/pipeline/home.html).', 'Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant, telcagepant, MK-3207 and BI 44370 TA) have displayed efficacy in the treatment of migraine. ', 'Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. ', 'BACKGROUND: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated.', 'The calcitonin gene-related peptide (CGRP) receptor antagonists (gepants)-olcegepant (BIBN 4096 BS), telcagepant (MK-0974), MK3207, and BI 44370 TA-are effective in treating acute migraine. ', 'Telcagepant, a calcitonin gene-related peptide receptor antagonist, is being developed for the acute treatment of migraine. ', 'The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men.', 'AIMS: To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). ', 'BACKGROUND: Telcagepant is an oral calcitonin gene-related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. ', 'BACKGROUND: The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. ', 'CONCLUSION: The apparently high doses of CGRP receptor antagonists, olcegepant and telcagepant needed for anti-migraine effect are not so high after all. ', 'Dose-response curves for headaches relief and adverse events (AEs) are presented for five triptans: sumatriptan, zolmitriptan, naratriptan, almotriptan, and frovatriptan, and the CGRP antagonist telcagepant.', 'INTRODUCTION: Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine.', 'Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. ', 'Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine.', 'In 3 randomized clinical trials (n = 1585) the calcitonin gene-related peptide antagonist telcagepant 300 mg orally had an incidence of adverse events similar to placebo when used in the acute treatment of migraine. ', 'BACKGROUND: Telcagepant is an oral calcitonin gene-related peptide receptor antagonist with acute antimigraine efficacy comparable to oral triptans', 'METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks.', 'A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described', 'Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine.', 'Sustained pain freedom and no adverse events as an endpoint in clinical trials of acute migraine treatments: application to patient-level data from a trial of the CGRP receptor antagonist, telcagepant, and zolmitriptan.', 'METHODS: The aim of this study was to evaluate new composite efficacy-plus-tolerability endpoints based on a post-hoc analysis of patient-level data from a previous randomized, placebo-controlled trial of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, and zolmitriptan in the acute treatment of migraine.', 'Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries.', 'MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. ', 'CONCLUSIONS: Our findings provide morphological and functional data on the presence of CGRP receptors in cerebral and meningeal arteries, which illustrates a possible site of action of telcagepant in the treatment of migraine.', 'Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries.', 'We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. ', 'These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.', 'Towards this end, the non-peptide CGRP receptor antagonists olcegepant and telcagepant have been shown to be effective in the acute treatment of migraine. While telcagepant is being pursued as a frontline abortive migraine drug in a phase III clinical trial, an oral formulation of a novel CGRP receptor antagonist, BI 44370, is currently in phase II clinical trials.', 'Telcagepant represents a new class of antimigraine drug-the calcitonin gene-related peptide receptor blockers. ', 'The CGRP receptor antagonists telcagepant and olcegepant (BIBN4096BS) have demonstrated clinical efficacy in the treatment of migraine and there is now a need to better understand how these molecules interact with the receptor. ', 'Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults.', 'Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. ', 'Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. ', 'Intravenous BIBN4096BS (olcegepant) and oral MK-0974 (telcagepant), two CGRP-receptor antagonists, were safe and effective in the treatment of migraine attacks in Phase I and II trials. ', 'Telcagepant (MK-0974) is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist and is currently under clinical development.']

['Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine.']

['calcitonin gene-related peptide']

What is the association of estrogen replacement therapy and intracranial meningioma risk?

['The meta-analyses yielded significantly increased risks for all CNS tumors, glioma and meningioma in users of estrogen-only [1.35 (1.22-1.49), 1.23 (1.06-1.42) and 1.31 (1.20-1.43), respectively] but not estrogen-progestin HT [1.09 (0.99-1.19), 0.92 (0.78-1.08) and 1.05 (0.95-1.16), respectively]; these differences were statistically significant (p<0.005 for each tumor type). There was no significant difference between glioma and meningioma risk in users of estrogen-only HT. The totality of the available evidence suggests an increased risk of all CNS tumors (and of glioma and meningioma separately) in users of estrogen-only HT. ', 'Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67). ', 'The relationship between current use of exogenous hormones and meningioma remains unclear, limited by the small numbers of patients currently on oral hormone medications and a lack of hormone receptor data for meningioma tumors.', 'Ever use of estradiol-only therapy was associated with an increased risk of meningioma (standardized incidence ratio = 1.29, 95% confidence interval: 1.15, 1.44). Among women who had been using estradiol-only therapy for at least 3 years, the incidence of meningioma was 1.40-fold higher (95% confidence interval: 1.18, 1.64; P<0.001) than in the background population. ', 'Estradiol-only therapy was accompanied with a slightly increased risk of meningioma.', 'Results from several prospective, large-scale studies indicate that postmenopausal hormone therapy may increase the risk for diagnosing meningioma by 30-80%, but there is no effect in regard to glioma. ', 'A retrospective study including more than 350,000 women, about 1400 of whom had developed meningioma, showed that the risk of meningioma was about twice as high in users of postmenopausal hormone replacement therapy as in non-users.', 'Compared with never users of HRT, the relative risks (RRs) for all incident CNS tumours, gliomas, meningiomas and acoustic neuromas in current users of HRT were 1.20 (95% CI: 1.05-1.36), 1.09 (95% CI: 0.89-1.32), 1.34 (95% CI: 1.03-1.75) and 1.58 (95% CI: 1.02-2.45), respectively, and there was no significant difference in the relative risks by tumour type (heterogeneity p = 0.2). ', 'BACKGROUND: Previous studies on association of exogenous female sex hormones and risk for meningioma have yielded conflicting results.', 'RESULTS: Postmenopausal hormonal treatment, use of contraceptives, or fertility treatment did not influence the risk of meningioma. ', 'CONCLUSIONS: Overall, we found little indication that reproductive factors or use of exogenous sex hormones affect meningioma risk.', 'Although not definitive, available data suggest an association between the use of hormone replacement therapy and increased meningioma risk. ', 'BACKGROUND: The role of exogenous hormone exposures in the development of meningioma is unclear, but these exposures have been proposed as one hypothesis to explain the over-abundance of such tumors in women.', 'RESULTS: Although risk of meningioma appeared modestly elevated in past OC users (OR = 1.5, 95% CI 0.8 - 2.7), and in current users (OR = 2.5, 95% CI 0.5 - 12.6), the confidence intervals were wide. ', 'Likewise, risk of meningioma was only weakly associated with past use of HRT (OR = 0.7, 95% CI 0.4 - 1.3), and not at all with current use of HRT (OR = 1.0, 95% CI 0.5 - 2.2). ', ' Overall, in post menopausal women, HRT use appeared to confer a non-significant protective effect, and was not associated with low or high PR expressing meningiomas.CONCLUSION: This study found little evidence of associations between meningioma and exogenous hormone exposures in women but did suggest that some hormonal exposures may influence tumor biology in those women who develop meningioma.', 'The increased odds ratios with African Americans was retained in post-menopausal women, while the protective odds ratios for pregnancy, smoking and oral contraceptives (OCs) became stronger in pre-menopausal women. The pattern by duration and timing of use does not suggest an etiologic role for OCs or hormone replacement therapy. ', 'The use of hormone replacement therapy in symptomatic postmenopausal women either with previously treated disease or with dormant tumors is discussed, but remains controversial.', 'Although not definitive, available data suggest an association between the use of hormone replacement therapy and increased meningioma risk.', 'OC use was associated with increased risk of a meningioma expressing less rather than more PR (OR = 3.2, 95% CI 1.3 - 8.0). ', 'In further analysis by hormone receptor status, there was some indication for an increased risk of progesterone receptor-positive meningiomas associated with oral contraceptive use (OR 1.39, 95% confidence interval 0.92-2.10) and other hormonal contraception (OR 1.50, 95% CI 0.95-2.36). ', 'Several studies indicate that use of hormone replacement therapy (HRT) is associated with an increased risk of intracranial meningioma, while associations between HRT use and risk of other brain tumors have been less explored.', 'available data suggest an association between the use of hormone replacement therapy and increased meningioma risk.', 'A significant positive association existed between meningioma risk and increased body mass index (p &lt; 0.01) while a significant negative association existed between meningioma risk and current smoking (p &lt; 0.01). Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67).', 'A higher risk of meningioma was observed among postmenopausal women who were current users of hormone replacement therapy (HR,', 'Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67). There was no association between use of fertility medications and meningioma risk.', 'Although not definitive, available data suggest an association between the use of hormone replacement therapy and increased meningioma risk.', 'A higher risk of meningioma was observed among postmenopausal women who were current users of hormone replacement therapy (HR, 1.79; 95% CI, 1.18-2.71) compared with never users.', 'Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67).']

['The association between hormone replacement therapy and meningioma risk is controversial. Increased risk of meningioma was demonstrated in estrogen-only hormonal replacement therapy. However, other studies did not find an association between hormonal replacement therapy and meningioma risk.']

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Which disease can be categorized using the Koos grading system?

['The patients had Koos Grade I or II tumors and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Class D hearing status preoperatively. ', 'METHODS: This is a retrospective review of 22 patients with VS Koos grade III and IV who were treated with STR followed by SRS. ', ' VS was characterized by its size (Koos classification) and the presence or not of a cystic component.', 'MAIN OUTCOME MEASURES: All data recorded were reviewed to access age, sex, tumor type, and tumor size according to the Koos classification and presenting symptoms. ', 'Facial nerve preservation surgery for koos grade 3 and 4 vestibular schwannomas.', 'Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas.', 'In all 333 patients microsurgical vestibular schwannoma (Koos grade 1: 12, grade 2: 34, grade 3: 62, and grade 4: 225) removal was performed.', 'Facial nerve preservation surgery for koos grade 3 and 4 vestibular schwannomas.', 'To report, in a retrospective study, outcomes for large Koos grade 3 and 4 vestibular schwannomas.', 'Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas.']

['Koos grading system is used for vestibular schwannoma.']

['vestibular schwannoma']

Which gene harbors the mutation T790M?

['Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. ', 'Two types of epidermal growth factor receptor (EGFR) mutations in exon 19 and exon 21 (ex19del and L858R) are prevalent in lung cancer patients and sensitive to targeted EGFR inhibition. A resistance mutation in exon 20 (T790M) has been found to accompany drug treatment when patients relapse. ', 'Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.', 'However, resistance to the EGFR TKIs develops mostly secondary to T790M mutation in exon 20. ', 'The T790M mutation in EGFR accounts for approximately half of all lung cancer cases with acquired resistance to the current clinical EGFR tyrosine kinase inhibitors.', 'In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib', 'Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested.', ' The EGFR T790M mutation is generally considered to be the molecular genetic basis of acquired TKI resistance', 'Prognostic impact of central nervous system metastases after acquired resistance to EGFR-TKI: poorer prognosis associated with T790M-negative status and leptomeningeal metastases.', 'In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, ', 'To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation ', 'Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene;']

['The T790M mutation refers to the mutation in exon 20 of the EGFR gene']

['EGFR', 'epidermal growth factor receptor']

What is HOCOMOCO?

['HOCOMOCO: a comprehensive collection of human transcription factor binding sites models.', 'We present the Homo sapiens comprehensive model collection (HOCOMOCO, http://autosome.ru/HOCOMOCO/, http://cbrc.kaust.edu.sa/hocomoco/) containing carefully hand-curated TFBS models constructed by integration of binding sequences obtained by both low- and high-throughput methods. To construct position weight matrices to represent these TFBS models, we used ChIPMunk software in four computational modes, including newly developed periodic positional prior mode associated with DNA helix pitch. We selected only one TFBS model per TF, unless there was a clear experimental evidence for two rather distinct TFBS models. We assigned a quality rating to each model. HOCOMOCO contains 426 systematically curated TFBS models for 401 human TFs, where 172 models are based on more than one data source.', 'We present the Homo sapiens comprehensive model collection (HOCOMOCO, http://autosome.ru/HOCOMOCO/, http://cbrc.kaust.edu.sa/hocomoco/) containing carefully hand-curated TFBS models constructed by integration of binding sequences obtained by both low- and high-throughput methods', 'HOCOMOCO contains 426 systematically curated TFBS models for 401 human TFs, where 172 models are based on more than one data source', 'HOCOMOCO: a comprehensive collection of human transcription factor binding sites models', 'We show that integration of TFBS data from various types of experiments into a single model typically results in the improved model quality probably due to partial correction of source specific technique bias. We present the Homo sapiens comprehensive model collection (HOCOMOCO, http://autosome.ru/HOCOMOCO/, http://cbrc.kaust.edu.sa/hocomoco/) containing carefully hand-curated TFBS models constructed by integration of binding sequences obtained by both low- and high-throughput methods. To construct position weight matrices to represent these TFBS models, we used ChIPMunk software in four computational modes, including newly developed periodic positional prior mode associated with DNA helix pitch. ']

['HOCOMOCO is a comprehensive collection of human transcription factor binding sites models constructed by integration of binding sequences obtained by both low- and high-throughput methods. HOCOMOCO contains 426 systematically curated TFBS models for 401 human TFs, where 172 models are based on more than one data source.']

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Describe Malgaigne fracture.

['Fractures of the transverse processes in the lumbar vertebrae occur as the result of major forces such as direct blunt trauma, violent lateral flexion-extension forces, avulsion of the psoas muscle, or Malgaigne fractures of the pelvis.', 'The anteroposterior radiographic view revealed ununited fractures at the left superior and inferior pubic ramus, noted as a type I Malgaigne fracture. ', 'Posterior urethral injuries occur more commonly with vertically applied forces, which typically create Malgaigne-type fractures. ', 'Patients with bilateral pubic rami fractures or Malgaigne fractures were particularly prone to additional injuries; therefore, abdominal CT examinations are recommended in these patients.', 'Pelvic fractures, especially those of a Malgaigne type, frequently occur in patients who are polytraumatized. ', 'The authours report the case of a 27-year-old man who had suffered a severe polytrauma with blunt thoracic injury, fracture of the lumbar spine, Malgaigne-type fracture of the pelvis and fracture of the femoral shaft on the right side, 10 years before.', 'The paper deals with the displacement of the uterus observed during management of Malgaigne type pelvic fracture in a 33 years old female. ', 'This problem was first described by Malgaigne in 1857 in his classic article on double vertical fractures of the pelvis, in which he described a 34-year-old woman with a pelvic fracture who subsequently died during childbirth.', 'Eleven cases of sacroiliac dislocation and/or fracture (Malgaigne pattern) were successfully reduced and stabilized using two threaded compression rods.', 'We compared the mechanical performance of the Orthofix pelvic external fixator with that of the Pittsburgh triangular frame (PTF) on eight fresh-frozen cadaver pelves with experimentally created Malgaigne (double-vertical) fracture/dislocations.', 'A 48-year-old woman developed symptomatic superior and inferior pubic rami fractures with a concomitant subluxation of the ipsilateral sacroiliac joint three years after pelvic irradiation for a gynecologic malignancy. ', 'Twenty-six of the thirty-two cadavera that were examined radiographically and dissected had a double break in the pelvic ring (Malgaigne pattern).', ' Initial hypotension, Malgaigne and bilateral pubic rami fractures, and blood requirements exceeding 2,000 cc were suggestive of abdominal trauma. ', ' Malgaigne-type fractures with sacroiliac disruptions were created in four cadaver pelvises. ', 'The authors report 7 cases involving the surgical treatment of unstable pelvic ring fractures (Malgaigne type) using two compression bars, as described by Tile. ', 'Malgaigne fracture is referred to pelvic ring disruption at two sites, and is often treated surgically for its instability. ', 'Sacral fractures are generally accompanied by pelvic ring fractures. ', 'Malgaigne fracture is referred to pelvic ring disruption at two sites, and is often treated surgically for its instability.', 'This problem was first described by Malgaigne in 1857 in his classic article on double vertical fractures of the pelvis, in which he described a 34-year-old woman with a pelvic fracture who subsequently died during childbirth', 'The authors report 7 cases involving the surgical treatment of unstable pelvic ring fractures (Malgaigne type) using two compression bars, as described by Tile', 'Another less frequently reported complication of pelvic fractures is the potential association with pregnancy and subsequent childbirth. This problem was first described by Malgaigne in 1857 in his classic article on double vertical fractures of the pelvis, in which he described a 34-year-old woman with a pelvic fracture who subsequently died during childbirth.', 'This problem was first described by Malgaigne in 1857 in his classic article on double vertical fractures of the pelvis, in which he described a 34-year-old woman with a pelvic fracture who subsequently died during childbirth. A review of the literature reveals numerous articles addressing potential problems with parturition subsequent to a pelvic fracture and several articles dealing with pelvic fractures occurring during pregnancy.', 'The authors report 7 cases involving the surgical treatment of unstable pelvic ring fractures (Malgaigne type) using two compression bars, as described by Tile.', 'This problem was first described by Malgaigne in 1857 in his classic article on double vertical fractures of the pelvis, in which he described a 34-year-old woman with a pelvic fracture who subsequently died during childbirth.']

['Bilateral pubic rami fractures are characteristic to Malgaigne fractures. Patients with Malgaigne fractures are particularly prone to additional injuries.']

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Is the Drosophila Translational Control Element (TCE) involved in spermatogenesis?

['Gene regulation in Drosophila spermatogenesis: analysis of protein binding at the translational control element TCE.', 'We have previously identified a 12 nucleotide long sequence element, the TCE, that was demonstrated to be necessary for translational control of expression in the male germ line of Drosophila melanogaster (Schäfer et al., 1990).', 'Gene regulation in Drosophila spermatogenesis: analysis of protein binding at the translational control element TCE', 'The Drosophila Translational Control Element (TCE) is required for high-level transcription of many genes that are specifically expressed in testes', 'Bioinformatic analyses of core promoter sequences from 190 genes that are specifically expressed in testes identified a 10 bp A/T-rich motif that is identical to the translational control element (TCE)', 'The Drosophila Translational Control Element (TCE) is required for high-level transcription of many genes that are specifically expressed in testes.']

['Yes. The Drosophila Translational Control Element (TCE), a 12 nucleotide long sequence element, was demonstrated to be necessary for translational control of expression in the male germ line of Drosophila melanogaster.']

['yes']

Which are the most commonly reported pathological states associated with the formation of DNA G-quadruplexes?

['Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were recently shown to be caused by expansion of a (GGGGCC)n/(GGCCCC)n repeat in the C9ORF72 gene', 'Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine.', 'Up-regulating relaxin expression by G-quadruplex interactive ligand to achieve antifibrotic action', 'Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.', 'We identified a G-rich sequence within exon 3 of BACE1 involved in controlling splice site selection', 'β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step in the proteolysis of the APP to the amyloid β-protein (Aβ), a process involved in the pathogenesis of Alzheimer disease', 'Anti-amyloidogenic processing of the amyloid precursor protein APP by α-secretase prevents formation of the amyloid-β peptide, which accumulates in senile plaques of Alzheimer disease patients. α-Secretase belongs to the family of a disintegrin and metalloproteases (ADAMs), and ADAM10 is the primary candidate for this anti-amyloidogenic activity', "Using circular dichroism spectroscopy, we demonstrate that a G-rich region between nucleotides 66 and 94 of the ADAM10 5'-UTR forms a highly stable, intramolecular, parallel G-quadruplex secondary structure under physiological conditions", 'FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability.', 'Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia', 'Recently, we have demonstrated that treatment with a G-quadruplex-interactive agent, telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines', 'A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia', 'We examined G-quadruplex interactive agent, telomestatin (SOT-095), for its ability to inhibit the proliferation of human leukemia cells, including freshly obtained leukemia cells.']

["There is a growing recognition for the profound role of G-quadruplexes in a wide spectrum of diseases, such as cancer, diabetes and cardiovascular disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were recently shown to be caused by expansion of a (GGGGCC)n/(GGCCCC)n repeat in the C9ORF72 gene. Treatment with a G-quadruplex interactive ligand was shown to achieve antifibrotic action. G-quadruplex forming sequences have also been linked with ADAM10 a primary candidate for anti-amyloidogenic activity in Alzheimer's. A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia."]

['Amyotrophic lateral sclerosis (ALS)', 'frontotemporal dementia (FTD)', "Alzheimer's disease", 'fibrosis', 'acute myeloid leukemia']

Which is the enzymatic activity of the myotubularin family of proteins?

['myotubularin family of phosphatases.', 'Myotubularin belongs to a large family of conserved lipid phosphatases that include both catalytically active and inactive myotubularin-related proteins (i.e., "MTMRs")', 'myotubalarin family phosphatase', 'MTMR2 is a member of the myotubularin family of inositol lipid phosphatases, ', 'Myotubularin related protein 2 (MTMR2) is a member of the myotubularin family of phosphoinositide lipid phosphatases. ', 'Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology.', 'Although myotubularin was thought to be a dual-specificity protein phosphatase, recent results indicate that it is primarily a lipid phosphatase, acting on phosphatidylinositol 3-monophosphate, and might be involved in the regulation of phosphatidylinositol 3-kinase (PI 3-kinase) pathway and membrane trafficking.', 'Myotubularin is the archetype of a family of highly conserved protein-tyrosine phosphatase-like enzymes. ', 'we and others have characterized myotubularin as a potent and specific phosphatidylinositol 3-phosphate 3-phosphatase. ', 'MTMR2 encodes a member of the myotubularin family of phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 3-phosphate (PI(3)P) and bisphosphate PI(3,5)P2. MTMR13 encodes a large, uncharacterized member of the myotubularin family.', 'Myotubularin-related proteins are a large subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids.', 'Myotubularin, the gene mutated in myotubular myopathy, functions as a lipid phosphatase with specificity for PtdIns(3)P.', 'The myotubularin family: novel phosphoinositide regulators.', 'The myotubularins are a large family of inositol polyphosphate 3-phosphatases that', 'The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity, dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P(2)] at the D-3 position.', 'Myotubularin phosphoinositide phosphatases in human diseases.', 'The MTM (myotubularin)/MTMR (myotubularin-related) protein family is comprised of 15 lipid phosphatases, of which nine members are catalytically active. ', 'The myotubularin family of lipid phosphatases ']

['The myotubularin family of proteins are lipid inositol phosphatases']

['lipid inositol phosphatase activity']

Is there a relationship between thyroid hormone altered metabolism and coronary artery disease?

['The results showed that higher levels of TSH within the reference range were independently associated with the presence of CAD only among subjects less than or equal to 65 years old, suggesting age might influence the relationship.', 'FT3 levels within the normal range were inversely correlated with the presence and severity of CAD. Moreover, lower FT3 concentrations were correlated with the Gensini score and independently predicted the presence and severity of CAD.', 'High TSH within the reference range was associated with increased risk of coronary death in women (P(trend) 0·005), but not in men. The risk of coronary death was also increased among women with subclinical hypothyroidism or subclinical hyperthyroidism, compared to women with TSH of 0·50-1·4 mU/l. ', ' Prevalence of CHD was more common in hypothyroid and moderate SCH patients.', 'The angiographic results were as follows: significant coronary disease (SH 28.1% vs. non-SH 43.8%; p=0.087); three-vessel disease (9.4% vs. 9.9%; p=0.919); two-vessel disease (12.5% vs. 13.4%; p=0.892); single-vessel disease (6.3% vs. 29.5%; p=0.051); minimal lesions (9.4% vs. 10.9%; p=0.794); and no coronary disease (62.4% vs, 45.3%; p=0.064).', 'Lower fT3 levels were predictive of both single-vessel (p = 0.012) and multivessel (p = 0.009) CAD. Through a multivariate logistic regression analysis, fT3 was still linked to the presence of CAD (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.34-0.68, p < 0.001).', 'Our study showed that FT(4) levels were associated with the presence and the severity of CAD. Also, this study suggests that elevated serum FT(4) levels even within normal range could be a risk factor for CAD. ', 'The present meta-analysis indicates that sub-clinical hypothyroidism is associated with both, a significant risk of CHD at baseline and at follow-up.', "The incidence of multi-vessel disease was higher in patients with high TSH level (p=0.026). TSH level showed a significant correlation with age (r=0.109, p=0.044) and Gensini's score (r=0.117, p=0.045). The multivariate analysis revealed that age (OR 2.39, p=0.001), diabetes (OR 3.74, p=0.001), creatinine (OR 2.06, p=0.008), and smoking (OR 1.85, p=0.045) were independent predictors for significant coronary artery disease, but TSH level did not predict coronary artery stenosis.", 'These data in patients referred for coronary angiography suggest that variation of thyroid function within the statistical normal range may influence the presence and severity of coronary atherosclerosis.']

['The major part of the studies and metaanalysis data show that hypothyroidism, both primary and secondary forms, is associated with higher incidence and severity of coronary artery disease.']

['yes']

What is the mechanism of action of APOBEC3G cytidine deaminase to inhibit HIV-1 replication?

['APOBEC3G inhibits HIV-1 RNA elongation by inactivating the viral trans-activation response element', 'Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis', 'HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription', 'The APOBEC3 deoxycytidine deaminase family functions as host restriction factors that can block replication of Vif (virus infectivity factor) deficient HIV-1 virions to differing degrees by deaminating cytosines to uracils in single-stranded (-)HIV-1 DNA. Upon replication of the (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite the uracils, thereby inducing C/G→T/A mutations that can functionally inactivate HIV-1', 'APOBEC3G is a member of this family that inhibits HIV-1 replication in the absence of the viral infectivity factor Vif. Inhibition of HIV replication occurs by both deamination of viral single-stranded DNA and a deamination-independent mechanism', 'Suppression of HIV-1 infection by APOBEC3 proteins in primary human CD4(+) T cells is associated with inhibition of processive reverse transcription as well as excessive cytidine deamination', 'These proteins exert their suppressive effects through the inhibition of viral reverse transcription as well as the induction of cytidine deamination within nascent viral cDNA', 'We demonstrate that APOBEC3 proteins impart a profound deficiency to reverse transcription from the initial stages of cDNA synthesis, as well as excessive cytidine deamination (hypermutation) of the DNAs that are synthesized', 'Without Vif, A3 proteins, particularly APOBEC3G (A3G) and APOBEC3F (A3F), inhibit HIV-1 replication by blocking reverse transcription and/or integration and hypermutating nascent viral cDNA. The molecular mechanisms of this antiviral activity have been primarily attributed to two biochemical characteristics common to A3 proteins: catalyzing cytidine deamination in single-stranded DNA (ssDNA) and a nucleic acid-binding capability that is specific to ssDNA or ssRNA', 'A host cytidine deaminase, APOBEC3G (A3G), inhibits replication of human immunodeficiency virus type 1 (HIV-1) by incorporating into virions in the absence of the virally encoded Vif protein (Deltavif virions), at least in part by causing G-to-A hypermutation.', 'APOBEC3F and APOBEC3G cytidine deaminases potently inhibit human immunodeficiency virus type 1 (HIV-1) replication by enzymatically inserting G-to-A mutations in viral DNA and/or impairing viral reverse transcription independently of their deaminase activity']

['During reverse transcription, APOBEC3G deaminates dC to dU in nascent minus-strand viral DNA, resulting in G-to-A hypermutation in the plus strand DNA to inhibit replication of HIV-1, due to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. In an additional line of antiviral defense, APOBEC3G induces deamination of the apical loop cytidine of the trans-activation response (TAR) element, a short stem-loop RNA structure required for binding of elongation factors during HIV-1 transcription elongation, resulting in accumulation of short viral transcripts and production of lower amounts of full-length HIV-1 transcripts in Vif-deficient HIV-1-infected cells.']

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What are viral vectors used for in optogenetics?

['To express ChR in neurons, the common expression systems include viral vectors, in utero electroporation, and transgenic animals, each with their advantages and limitations regarding the cost, expression pattern, and the required effort. ', 'In this review, the various strategies for selective genetic targeting of a defined neuronal population are discussed as well as the pros and cons of the use of transgenic animals and recombinant viral vectors for the expression of transgenes in a specific set of neurons.', 'We demonstrate how the ability to target astrocytes with cell-specific viral vectors to express optogenetic constructs helped to unravel some previously unsuspected roles of these inconspicuous cells.', 'Optogenetics, the use of light to stimulate or inhibit neural circuits via viral transduction of protein channels, has emerged as a possible method of treating epilepsy.', 'We demonstrate how the ability to target astrocytes with cell-specific viral vectors to express optogenetic constructs helped to unravel some previously unsuspected roles of these inconspicuous cells.', 'We conclude that a viral vector approach with a strong promoter is required for successful optogenetic stimulation of distal axons to evoke transmitter release in pre-autonomic PVN neurons.', 'RESULTS: Extracellular single-unit recordings were made from infralimbic (IL) pyramidal cells, IL interneurons and prelimbic (PL) pyramidal cells 2-3 weeks after intra-IL injection of a viral vector encoding channel rhodopsin 2 (ChR2) under the control of the CaMKII promoter (rAAV5/CaMKIIa-ChR2(H134R)-EYFP) or a control vector that lacked the ChR2 sequence (rAAV5/CaMKIIa-EYFP). ', 'We conclude that a viral vector approach with a strong promoter is required for successful optogenetic stimulation of distal axons to evoke transmitter release in pre-autonomic PVN neurons. ', 'We selectively expressed ChR2(H134R) in rostral VLM catecholaminergic neurons by injecting Cre-dependent adeno-associated viral vectors into the brain of adult dopamine-β-hydroxylase (DβH)(Cre/0) mice. ', 'We developed driver and double reporter mouse lines and viral vectors using the Cre/Flp and Cre/Dre double recombinase systems and established a new, retargetable genomic locus, TIGRE, which allowed the generation of a large set of Cre/tTA-dependent reporter lines expressing fluorescent proteins, genetically encoded calcium, voltage, or glutamate indicators, and optogenetic effectors, all at substantially higher levels than before. ', 'We generated rabies glycoprotein-pseudotyped lentiviral vectors that use a positive feedback loop composed of a Tet promoter driving both its own tetracycline-dependent transcription activator (tTA) ("TLoop") and channelrhodopsin-2-YFP (ChR2YFP). ', 'Optogenetic control of cardiomyocytes via viral delivery.', 'Here, we used an optogenetic approach, in which female rats received bilateral dorsal mPFC microinjections of viral constructs coding light-sensitive eNpHR3.0-eYFP or control eYFP protein and intracranial fiber optic implants. ', 'We transduced rat LC neurons by direct injection of a lentiviral vector expressing channelrhodopsin2 under the control of the PRS promoter. ', 'Here, we describe the construction of a blue-light-induced K(+) channel 1 (BLINK1) engineered by fusing the plant LOV2-J� photosensory module to the small viral K(+) channel Kcv. ', 'In parallel, remarkable success in the development of highly efficient viral vectors for ocular gene therapy led to new strategies of using these novel optogenetic tools for vision restoration. These recent findings show that novel optogenetic tools and viral vectors for ocular gene delivery are now available providing many opportunities to develop potential optogenetic strategies for vision restoration.']

['Viral vectors are used to express optogenetic constructs in selected cells.']

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Which enzyme is inhibited by Orteronel?

['PURPOSE: Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase.', 'The drug orteronel selectively blocked the lyase reaction of P450 17A1 but only in the case of Prog. ', 'Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats.', 'Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues.', 'Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. ', 'Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 \u2009>\u2009100 µm).', 'PURPOSE: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase.', 'Based on these observations, potent agents targeting the AR axis were developed: 1) inhibitors of CYP17 (a key enzyme in the production of androgens), such as abiraterone and orteronel; 2) AR antagonists that bind to AR and impair AR activation, such as enzalutamide and ARN-509. ', 'Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. ', 'Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids.', 'Phase I/II trial of orteronel (TAK-700)--an investigational 17,20-lyase inhibitor--in patients with metastatic castration-resistant prostate cancer.', 'Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones. ', 'Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17.', 'To achieve enhanced clinical benefits, new strategies are being explored that include selective inhibition of the C17,20-lyase activity of CYP17 and multi-targeting strategies that affect androgen synthesis and signalling at different points. Some of these strategies-including the drugs orteronel, VT-464 and galeterone--are supported by preclinical data and are being explored in the clinic.', 'Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. ', 'Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys.', 'Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. ', 'In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases.', 'Development and validation of an RP-HPLC method for the quantitation of Orteronel (TAK-700), a CYP17A1 enzyme inhibitor, in rat plasma and its application to a pharmacokinetic study.', 'Targeting the adrenal gland in castration-resistant prostate cancer: a case for orteronel, a selective CYP-17 17,20-lyase inhibitor.', 'A new CYP17 inhibitor, with more selective inhibition of 17,20-lyase over 17α-hydroxylase, orteronel (TAK-700), is currently undergoing phase III clinical trials in pre- and postchemotherapy CRPC. ', 'Effect of a novel 17,20-lyase inhibitor, orteronel (TAK-700), on androgen synthesis in male rats.', 'Orteronel (TAK-700), 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide, is a novel, non-steroidal, selective inhibitor of the 17,20-lyase activity of CYP17A--a key enzyme in the production of steroidal hormones--and is being developed as a therapy for PC. ', 'Orteronel inhibited 17,20-lyase activity in rats with an IC(50) of 1200 nM but did not inhibit 17α-hydroxylase or 11β-hydroxylase (CYP11B1) activity in rats at concentrations up to 10 μM.', 'Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys.', 'Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys.', ' In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. ', 'Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer.', 'Orteronel (TAK-700), 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide, is a novel, non-steroidal, selective inhibitor of the 17,20-lyase activity of CYP17A--a key enzyme in the production of steroidal hormones--and is being developed as a therapy for PC. The purpose of this study was to elucidate the inhibitory activity of orteronel, in particular its specificity for androgen synthesis enzymes, in male rats--an androgen-synthesis model that largely reflects this pathway in humans.', 'In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys.', 'In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys.', 'Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues', 'Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells', 'Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis', 'In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys', 'Orteronel inhibited 17,20-lyase activity in rats with an IC(50) of 1200 nM but did not inhibit 17α-hydroxylase or 11β-hydroxylase (CYP11B1) activity in rats at concentrations up to 10 μM', 'In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys', 'In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases', 'Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17', 'Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones.']

['Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. Orteronel is used for treatment for castration-resistant prostate cancer.']

['CYP17A1']

Does the protein mTOR regulate autophagy?

['autophagy is negatively regulated by the mammalian target of rapamycin receptor (mTOR)', 'Subjecting cells to starvation or rapamycin efficiently induces autophagy by inhibiting the MTOR signaling pathway triggering increased autophagic flux. ', 'Several pathways, including mTOR, have been shown to regulate autophagy.', 'these results provide insights into the mechanism by which hyperactivation of mTORC1 promotes breast cancer progression through increasing autophagy and Akt activation in vivo.', ' the canonical mTOR-controlled autophagy pathway', 'mTOR inhibition severely impairs liver regeneration and increases autophagy after PH', 'mTOR remains at a high level and inhibits autophagy.', 'AKT is involved in granulosa cell autophagy regulation via mTOR signaling during rat follicular development and atresia.', 'mammalian target of rapamycin (mTOR), a major negative regulator of autophagy.', 'mTOR suppresses granulosa cell autophagy', 'Mammalian target of rapamycin (mTOR), a potent suppressor of autophagy,', 'The mTOR signaling pathway integrates inputs from a variety of upstream stimuli to regulate diverse cellular processes including proliferation, growth, survival, motility, autophagy, protein synthesis and metabolism', 'The activation of mammalian target of rapamycin (mTOR) signaling pathway blocks the effects of ghrelin-induced autophagy and apoptosis,', ' inducing apoptosis and autophagy via the mTOR signaling pathway', ' The mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism.']

['mammalian target of rapamycin (mTOR) is a major negative regulator of autophagy.']

['yes']

What is the inheritance pattern of Emery-Dreifuss muscular dystrophy?

['. Loss-of-function truncation mutations in EMD, encoding the nuclear membrane protein emerin, cause X-linked Emery-Dreifuss muscular dystrophy (EDMD) characterized by localized contractures and skeletal myopathy in adolescence, sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a variably associated trait.', 'Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.', 'The Emery-Dreifuss muscular dystrophy is a form of muscular dystrophy that frequently presents early contractures and cardiac conduction defects, caused by emerin deficiency in the inner nuclear membrane of the muscular fibers.', 'compatible with X-linked inheritance form', 'The first patient was a member of a family with molecularly proven X-linked EDMD.', 'As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus.', 'contribute to disease severity in autosomal dominant EDMD.', 'The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined.', 'Emery-Dreifuss muscular dystrophy (EDMD) is a muscular disorder characterized by 1) early contracture of the elbows. Achilles tendons and post-cervical muscles, 2) slowly progressive muscle wasting and weakness with a humeroperoneal distribution, and 3) life-threatening cardiomyopathy with conduction block. Most of families with EDMD show X-linked recessive inheritance with mutations in the STA gene on chromosome Xq28, which encodes a protein named emerin. A rare autosomal dominant form of EDMD (AD-EDMD) is caused by mutations in lamin A/C gene (LMNA) on chromosome 1q21. Both emerin and lamin A/C are located in the inner surface membrane of the nucleus.', 'Emery-Dreifuss muscular dystrophy is an X-linked recessive myopathy. The patient had no familial background of the disease. This patient might have a sporadic inheritance pattern with severe cardiac involvement.', 'autosomal dominant Emery-Dreifuss muscular dystrophy,', 'Emery-Dreifuss muscular dystrophy is characterized by the clinical triad of early onset contractures of elbows, Achilles tendons and spine, wasting and weakness with a predominantly humero-peroneal distribution and life-threatening cardiac conduction defects and/or cardiomyopathy. Two main types of inheritance have been described: the X-linked form is caused by mutations in the STA gene on locus Xq28 and the gene for the autosomal dominant form (LMNA gene) has been localized on chromosome 1q11-q23. Recently, mutations in this LMNA gene have been also found to be responsible for the less frequent autosomal recessive form of the disease.', 'Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form.', 'including X-linked Emery-Dreifuss MD,', 'this form is not X-linked Emery-Dreifuss MD. We suggest that these patients represent a severe MD characterized by early onset distal wasting and severe rigidity of the spine, with probable autosomal recessive inheritance.', 'Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been studied both by DNA sequencing and by emerin protein expression. Fourteen had mutations in the X-linked emerin gene, while three showed evidence of autosomal inheritance. Twelve of the 14 emerin mutations caused early termination of translation.', 'One family presented a rare autosomal dominant variant of Emery-Dreifuss muscular dystrophy, another with X-linked recessive inheritance showed unusual intrafamilial variability.', 'Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant.', 'Tendon contractures may be a partial expression of this myopathic disorder, suggesting an autosomal dominant inheritance with variable penetrance. A muscular dystrophy clinically similar to that of the Emery-Dreifuss (EDMD) type can thus occur in women.', 'Since the disease was diagnosed in 3 brothers, the X-coupled recessive type of its inheritance is assumed. An opinion is advanced that the described form is a clinical variety of Emery-Dreyfus myodystrophy.', 'Emery-Dreifuss syndrome (EDS)', 'the term Emery-Dreifuss muscular dystrophy should be avoided. Instead, each case of EDS should be classified as myopathic or neurogenic with X chromosome recessive or autosomal dominant inheritance.', 'Emery-Dreifuss muscular dystrophy is a syndrome with five salient features: early and unusual contractures; humeroperoneal muscle wasting; the slow progression of weakness, beginning in childhood; cardiac conduction defects; and X-linked inheritance. We present two cases and detail other reports with a similar constellation of findings with apparent autosomal dominant inheritance.', 'Emery-Dreifuss muscular dystrophy with proximal weakness in both the upper and lower limbs and X-linked scapuloperoneal muscular dystrophy represent the same disorder.', 'There is at least one other report of autosomal dominant transmission of this clinical picture, which had previously only been reported as Emery-Dreifuss muscular dystrophy with X-linked recessive inheritance.']

['The inheritance pattern of Emery-Dreifuss muscular dystrophy (EDMD) can be X-linked, autosomal dominant or autosomal recessive.']

['X-linked', 'autosomal dominant', 'autosomal recessive']

Other than protein coding potential, what features set apart long non-coding RNAs from protein coding genes?

['Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths.', 'In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts', 'hey are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs.', 'They are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes.', 'Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain.', 'he proportion of conserved sequence (4.1%-5.5%) in these macroRNAs is comparable to the density of exons within protein-coding transcripts (5.2%). These macroRNAs, taken together, thus possess the imprint of purifying selection, thereby indicating their functionality.']

['Compared to protein coding genes, long non-coding RNAs (lncRNAs) display a bias towards two-exon transcripts. They are predominantly localized in the chromatin and nucleous. They are lower expressed and display a more tissue-specific expression pattern. LncRNAs are overall more weakly conserved than protein coding genes.']

[]

Which are the smallest known subviral pathogens of plants?

['Since the discovery of non-coding, small, highly structured, satellite RNAs (satRNAs) and viroids as subviral pathogens of plants , have been of great interest to molecular biologists as possible living fossils of pre-cellular evolution in an RNA world.', 'PFOR2 analysis of the small RNA libraries from grapevine and apple plants led to the discovery of Grapevine latent viroid (GLVd) and Apple hammerhead viroid-like RNA (AHVd-like RNA), respectively.', 'We show that viroids from the two known families are readily identified and their full-length sequences assembled by PFOR from small RNAs sequenced from infected plants. ', 'Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. ', 'Viroids are small, circular, single-stranded RNA molecules that cause several infectious plant diseases. ', 'Viroids: petite RNA pathogens with distinguished talents.', 'Subviral pathogens of plants: viroids and viroidlike satellite RNAs.', 'Contrary to earlier beliefs, viruses are not the smallest causative agents of infectious diseases. Single-stranded RNAs as small as 246 nucleotides exist in certain higher plants and cause more than a dozen crop diseases. These RNAs have been termed viroids.', 'Subviral pathogens of plants: the viroids', "Viroids, satellite RNAs, satellites viruses and the human hepatitis delta virus form the 'brotherhood' of the smallest known infectious RNA agents, known as the subviral RNAs.", 'Subviral pathogens of plants: the viroids.', 'Viroids, subviral pathogens of plants, are composed of a single-stranded circular RNA of 246-399 nucleotides.', 'During 1970 and 1971, I discovered that a devastating disease of potato plants is not caused by a virus, as had been assumed, but by a new type of subviral pathogen, the viroid. Viroids are so small--one fiftieth of the size of the smallest viruses--that many scientists initially doubted their existence. ', 'The database of the smallest known auto-replicable RNA species: viroids and viroid-like RNAs.', 'Viroids, satellite RNAs, satellites viruses and the human hepatitis delta virus form the &apos;brotherhood&apos; of the smallest known infectious RNA agents, known as the subviral RNAs.', ' Replicating circular RNAs are independent plant pathogens known as viroids, or act to modulate the pathogenesis of plant and animal viruses as their satellite RNAs. The rate of discovery of these subviral pathogens was low over the past 40 years because the classical approaches are technical demanding and time-consuming.']

['Contrary to earlier beliefs, viruses are not the smallest causative agents of infectious diseases. Single-stranded RNAs as small as 246 nucleotides exist in certain higher plants and cause more than a dozen crop diseases. These RNAs have been termed viroids. Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein.', 'Since the discovery of non-coding, small, highly structured, satellite RNAs (satRNAs) and viroids as subviral pathogens of plants , have been of great interest to molecular biologists as possible living fossils of pre-cellular evolution in an RNA world.']

['Viroids']

Which sports have a risk for commotio cordis?

['This study sought to characterize the demographics of commotio cordis globally in comparison to the U.S. experience.', 'Not unexpectedly, the groups differed with baseball/softball and football predominant in the United States (55% of events) and soccer, cricket, and hockey most common internationally (47% of events). ', 'The authors reviewed 41 incidents of baseball injuries reported to the National Center for Catastrophic Sports Injury Research from 1982 until 2002.', 'Catastrophic injuries included 23 severe head injuries, 8 cervical injuries, 3 cases of commotio cordis, and 2 cases each of a collapsed trachea and facial fractures.', 'Commotio cordis events occurred most commonly during organized sporting events (79 [62%]), such as baseball, but 49 (38%) occurred as part of daily routine and recreational activities.', 'Twenty-two (28%) participants were wearing commercially available chest barriers, including 7 in whom the projectile made direct contact with protective padding (baseball catchers and lacrosse/hockey goalies), and 2 in whom the projectile was a baseball specifically designed to reduce risk.', 'In a recent study of fatal chest impacts by baseballs, 28% of the children were wearing a chest protector. This study evaluates the effectiveness of chest protectors in reducing the risk of commotio cordis. ', 'It has been described after blows to the chest from baseballs, softballs, hockey pucks, and other objects.', 'Commotio cordis due to blunt trauma to the precordium is a rare cause of death in young athletes, occurring less frequently than all of the other athletics-related deaths. Several measures, such as the use of safety baseballs and the use of chest protectors, can help protect young athletes from commotio cordis. ']

['Participation in sports such as baseball, football, soccer, cricket, hockey and lacrosse has a risk for commotio cordis.']

['baseball', 'football', 'soccer', 'cricket', 'hockey', 'lacrosse']

Which genetic defects are observed in Prader-Willi syndrome?

['Prader-Willi syndrome is a complex genetic disease caused by lack of expression of paternally inherited genes on chromosome 15q11-q13.', 'Prader-Willi syndrome (PWS) is caused by the disturbed expression of genes from the imprinted region of 15q11-q13, but the specific contributions of individual genes remain unknown.', 'Prader-Willi syndrome (PWS) is a rare disorder caused by genetic defects in certain regions of chromosome 15q11-13.', 'Prader-Willi syndrome (PWS) is an example of a human genetic disorder that involves imprinting genes on the proximal long arm of chromosome 15 and SNRPN gene as a candidate gene for this syndrome.', 'Genomic imprinting plays an important role in the molecular pathogenesis of PWS that caused by paternal microdeletions of 15q11-q13 or maternal UPD of chromosome 15. The basic defect seemed to be an absence of function of PWS genes that are normally expressed only from the paternal chromosome 15.', 'Abnormalities in imprinted inheritance occur in several genetic diseases and cancer, and are exemplified by the diverse genetic defects involving chromosome 15q11-q13 in Prader-Willi (PWS) and Angelman (AS) syndromes.', 'The predominant genetic defects in PW are 15q11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy.', 'In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q11-13 loci.', 'Prader-Willi syndrome (PWS) is caused by absence of a paternal contribution of the chromosome region 15q11-q13, resulting from paternal deletions, maternal uniparental disomy, or rare imprinting mutations.', 'Because methylation analysis can detect all three major classes of genetic defects associated with PWS (deletion, UPD, or imprinting mutations), methylation analysis with either PW71 or SNRPN is an efficient primary screening test to rule out a diagnosis of PWS.', 'The predominant genetic defects in Prader-Willi syndrome (PWS) are 15q11-q13 deletions of paternal origin and maternal chromosome 15 uniparental disomy (UPD).', 'In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q11-q13 loci. The critical PWS region has been narrowed to a approximately 320-kb region between D15S63 and D15S174, encoding several imprinted transcripts, including PAR5, IPW, PAR1 (refs 7,8) and SNRPN, which has so far been considered a strong candidate for the PWS gene.', 'The genetic defects in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) map to 15q11-13.']

['The predominant genetic defects in Prader-Willi syndrome are 15q11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy, or rare imprinting mutations, combined with monoallelic expression of the paternal alleles.']

['15q11-13 deletions of paternal origin', 'maternal chromosome 15 uniparental disomy', 'rare imprinting mutations', 'monoallelic expression of the paternal alleles']

Describe the usefulness of CAMUR in The Cancer Genome Atlas (TCGA)

['CAMUR: Knowledge extraction from RNA-seq cancer data through equivalent classification rules', 'CAMUR, a new method that extracts multiple and equivalent classification models. CAMUR iteratively computes a rule-based classification model, calculates the power set of the genes present in the rules, iteratively eliminates those combinations from the data set, and performs again the classification procedure until a stopping criterion is verified. CAMUR includes an ad-hoc knowledge repository (database) and a querying tool.We analyze three different types of RNA-seq data sets (Breast, Head and Neck, and Stomach Cancer) from The Cancer Genome Atlas (TCGA) and we validate CAMUR and its models also on non-TCGA data. Our experimental results show the efficacy of CAMUR: we obtain several reliable equivalent classification models, from which the most frequent genes, their relationships, and the relation with a particular cancer are deduced', 'CAMUR includes an ad-hoc knowledge repository (database) and a querying tool.We analyze three different types of RNA-seq data sets (Breast, Head and Neck, and Stomach Cancer) from The Cancer Genome Atlas (TCGA) and we validate CAMUR and its models also on non-TCGA data.', 'CAMUR: Knowledge extraction from RNA-seq cancer data through equivalent classification rules.', 'We propose CAMUR, a new method that extracts multiple and equivalent classification models.']

['CAMUR is a new method that extracts multiple and equivalent classification models. CAMUR iteratively computes a rule-based classification model, calculates the power set of the genes present in the rules, iteratively eliminates those combinations from the data set, and performs again the classification procedure until a stopping criterion is verified. CAMUR includes an ad-hoc knowledge repository (database) and a querying tool. Three different types of RNA-seq data sets (Breast, Head and Neck, and Stomach Cancer) were analyzed from The Cancer Genome Atlas (TCGA) and CAMUR and its models were validated also on non-TCGA data. Experimental results show the efficacy of CAMUR by obtaining several reliable equivalent classification models, from which the most frequent genes, their relationships, and the relation with a particular cancer are deduced.']

[]

Are Sidekick proteins members of the immunoglobulin superfamily?

["Here we show that four closely related immunoglobulin superfamily (IgSF) adhesion molecules--Dscam (Down's syndrome cell adhesion molecule), DscamL (refs 6-9), Sidekick-1 and Sidekick-2", 'Sidekick-1, a cell adhesion molecule of the immunoglobulin superfamily, is up-regulated in glomerular podocytes in the collapsing glomerulopathy of HIV-associated nephropathy (HIVAN).']

['Yes, sidekick are cell adhesion molecules of the immunoglobulin superfamily.']

['yes']

Is the ACE inhibitor indicated for lung cancer treatment?

['The angiotensin converting enzyme (ACE) inhibitors are used widely as antihypertensive agents, and it has been suggested that they decrease the risk of some cancers, although available data are conflicting. ', 'Using cell viability and fluorescent activated cell sorting analysis tests, we demonstrated that captopril inhibited the viability of LNM35 cells by inducing apoptosis, providing insight about the mechanisms underlying its antitumorigenic activities. In view of these experimental findings, we conclude that captopril could be a promising option for the treatment of lung cancer.', 'In order to determine the mechanism by which captopril inhibited tumor growth, we investigated the impact of this drug on cell proliferation, apoptosis, and angiogenesis. Immunohistochemical analysis demonstrated that captopril treatment significantly reduced the number of proliferating cells (Ki-67) in the tumor samples but was not associated with inhibition of tumor angiogenesis (CD31).', 'Using this model, we demonstrated that daily IP administration of captopril (2.8 mg/mouse) for 3 weeks resulted in a remarkable reduction of tumor growth (58%, P < 0.01) and lymph node metastasis (50%, P= 0.088). ', 'Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models', 'ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer.']

['No, the angiotensin converting enzyme (ACE) inhibitors are used widely as antihypertensive agents. On the contrary, it has been suggested that they decrease the risk of some cancers, although available data are conflicting. One study proposes that captopril could be a promising option for the treatment of lung cancer. Furthermore, angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models']

['no']

List genes that have been found mutated in CMT1A (Charcot-Marie-Tooth disease type 1 A).

['Most cases of CMT are caused by mutations in PMP22,', ' structural myelin protein PMP22', 'Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure.', '. Two patients showed rearrangements in the PMP22 gene, which is commonly associated with CMT1', 'Many PMP22 mutants accumulate in excess in the endoplasmic reticulum (ER) and lead to the inherited neuropathies of Charcot-Marie-Tooth (CMT) disease. ', 'The T118M mutation in PMP22 gene is associated with Charcot Marie Tooth, type 1A (CMT1A).', 'In CMT1, PMP22 duplication was the most common mutation while the second gene in order of frequency was MPZ in familial and SH3TC2 in isolated cases. ', 'CMT1A/PMP22 duplication', 'he most frequent subtype is type 1A (CMT1A) caused by duplication in chromosome 17p12 that includes PMP22.']

['PMP22 is the common gene found mutated through a duplication in CMT1A. Other genes are\nMPZ and SH3TC2']

['PMP22', 'MPZ', 'SH3TC2']

In which genomic regions are Alu enriched?

['There are regions such as the four homeobox gene clusters, which are nearly devoid of these repeats that contrast with repeat dense regions in other transcriptionally active regions of the genome.', 'These elements are more clustered in genes which are involved in metabolism, transport, and signaling processes. In contrast, they are significantly fewer in genes coding for information pathway components as well as structural proteins.', 'This bias in Alu distribution is independent of the effect of Alu density of the flanking genomic region and is also not affected by the GC content of the gene and its upstream and downstream regions.', 'The relative proportions of Alu subfamilies (Alu J, Alu S, and Alu Y) are not significantly different in genes with high Alu density belonging to the functional categories of transport, metabolism, and signaling.', 'We suggest that Alu elements might be involved in regulatory mechanisms and are therefore differentially selected in primate genomes.', 'Sequence analysis demonstrated these "young" Alu insertions represented gene conversion events of pre-existing ancient Alu elements or independent parallel insertions of older Alu elements in the same genomic region. ', 'This study suggests that the majority of Alu insertions in primate genomes are the products of unique evolutionary events.', 'Our screening of the Alu insertion loci also resulted in the recovery of several "young" Alu elements that resided at orthologous positions in nonhuman primate genomes.']

['There are regions such as the four homeobox gene clusters, which are nearly devoid of these repeats that contrast with repeat dense regions in other transcriptionally active regions of the genome. Alu elements are more clustered in genes which are involved in metabolism, transport, and signaling processes. In contrast, they are significantly fewer in genes coding for information pathway components as well as structural proteins.\nThis bias in Alu distribution is independent of the effect of Alu density of the flanking genomic region and is also not affected by the GC content of the gene and its upstream and downstream regions.', 'There are regions such as the four homeobox gene clusters, which are nearly devoid of these repeats that contrast with repeat dense regions in other transcriptionally active regions of the genome.']

['genes which are involved in metabolism, transport, and signaling processes', 'gene conversion-prone regions']

Which histone mutation is associated with gliomas?

['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', 'We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation.', 'Some of these molecular changes with clinicopathological utility have been used for the first time in the most recent edition of the World Health Organization (WHO) classification of CNS tumours to define entities like ependymoma, RELA fusion-positive or diffuse midline glioma, H3 K27M-mutant.', 'The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment.', 'Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation.', 'In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.', '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.', 'Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations.', 'Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation.', 'Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas.', 'Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B).', 'Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3', 'We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo', 'In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare.', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.', 'The role of the H3.3K27M mutation in tumorigenesis is not fully understood. ', 'The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.', 'In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10. <CopyrightInformation>© 2015 International Society of Neuropathology.</C', 'We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations.', 'Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation.', 'We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo.', 'In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas.CONCLUSION: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.', 'Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles.', 'Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas.', 'Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations.', 'In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.', 'The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.', '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.', 'Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3.']

['Pediatric central nervous system tumors are the most common solid tumor of childhood. 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.', '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. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes.', 'some of these molecular changes with clinicopathological utility have been used for the first time in the most recent edition of the world health organization (who) classification of cns tumours to define entities like ependymoma, rela fusion-positive or diffuse midline glioma, h3 k27m-mutant.', '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']

['K27M in H3.3']

What are the side effects of Nalmefene?

['Adverse experiences included nausea, dizziness, and insomnia.', 'Side effects to nalmefene were of greater duration and intensity in the subjects receiving 10 mg of nalmefene vs. those receiving 6 or 2 mg. These included most notably fatigue, lightheadedness, nausea and vomiting.', 'The nalmefene treated group ate 22% less, both in terms of absolute weight and caloric intake, of a standardised buffet-meal than did the placebo group. ', 'Thus the apparent nutrient specificity of nalmefene appeared to be an indirect consequence of its effect on palatability. Nalmefene also caused slight increases in self-rated alertness, and decreases in ratings of tiredness and elation, although it was thought unlikely that these accounted for observed changes in eating behaviour.', 'In the second study, six healthy men were initially administered a single 50-mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven-day administration period.', ' In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. ', 'Doses of nalmefene as large as 0.4 mg/kg, IV, produced only minor side effects. These side effects included some passage of semifluid fecal material, intermittent penile relaxation, and mild sedation. Treated horses responded normally to external stimuli, retained their appetites, and performed appropriately when ridden. Sedation wore off during the course of prolonged infusions. ', 'The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness.']

['Side effects of nalmefene include nausea, dizziness / lightheadedness, insomina, fatigue, vomiting, reduced caloric intake / apetite, increased self-rated alertness and decreased tiredness. In horses some passage of semifluid fecal material, intermittent penile relaxation, and mild sedation has been described. In some studies nalmefene was well tolerated by all subjects, and no clinically significant adverse effects were observed.']

['nausea', 'dizziness / lightheadedness', 'insomnia', 'fatigue', 'vomiting', 'reduced caloric intake / apetite', 'increased self-rated alertness', 'decreased tiredness', '(horses) some passage of semifluid fecal material', '(horses) intermittent penile relaxation', '(horses) mild sedation']

Is there any functional association during viral replication between flaviviridae viral RNA depended RNA polymerase and viral helicase?

['Several labs have obtained evidence for a protein complex that involves many of the nonstructural (NS) proteins encoded by the virus. NS3, NS4A, NS4B, NS5A, and NS5B appear to interact structurally and functionally. In this study, we investigated the interaction between the helicase, NS3, and the RNA polymerase, NS5B. Pull-down experiments and surface plasmon resonance data indicate a direct interaction between NS3 and NS5B that is primarily mediated through the protease domain of NS3. This interaction reduces the basal ATPase activity of NS3. However, NS5B stimulates product formation in RNA unwinding experiments under conditions of excess nucleic acid substrate. When the concentrations of NS3 and NS5B are in excess of nucleic acid substrate, NS5B reduces the rate of NS3-catalyzed unwinding. Under pre-steady-state conditions, in which NS3 and substrate concentrations are similar, product formation increased in the presence of NS5B. The increase was consistent with 1:1 complex formed between the two proteins. A fluorescently labeled form of NS3 was used to investigate this interaction through fluorescence polarization binding assays. Results from this assay support interactions that include a 1:1 complex formed between NS3 and NS5B.', 'Contradictory results have been reported regarding NS3 in RNA synthesis. To investigate the effect of NS3 on classical swine fever virus (CSFV) NS5B RNA-dependent RNA polymerase activity (RdRp) activity and NS3-NS5B interaction, RdRp reactions, GST-pull-down assays and co-immunoprecipitation analyses containing NS5B and either of NS3 protein and the different truncated NS3 mutants were performed, respectively. We found that NS3 stimulated NS5B RdRp activity in a dose-dependent manner by binding to NS5 through a NS3 protease domain. Furthermore, mapping important regions of the NS3 protease domain was carried out by deletion mutagenesis, associated with RdRp reactions, GST-pull-down assays and co-immunoprecipitation analyses. Results showed that stimulation of CSFV NS5B RdRp activity was obtained by NS3 binding to NS5B through a 31-amino acid fragment at the N-terminal end of NS3 protease domain, which mediated a specific NS3-NS5B interaction.', 'The protocols detailed in this unit are used to purify three recombinant enzymes that are widely used in HCV research: the HCV NS3 protease domain, the helicase domain as an NS3+NS4A complex, and the NS5B RNA-dependent RNA polymerase. The active enzymes are purified to homogeneity by two-column chromatography to support a screening program for HCV inhibitors.', 'Among potential targets are viral entry factors, including scavenger receptor type B1 (SR-B1) and CD81, as well as neutralizing antibodies against the viral glycoproteins. Popular targets related to translation and replication are the NS3/4A protease (inhibited by telaprevir and boceprevir) and the NS5B polymerase, as well as the NS2/3 autoprotease, the NS3 helicase, and nonenzymatic targets such as NS4B and NS5A proteins. ', 'The NS3 helicase domain competes with NS3 full-length for NS5 RdRp binding, with a K(d.) of 2.5μM. Since NS3 and NS5 are required for DENV replication, this fascile assay could be used to screen for non-nucleoside, allosteric inhibitors that disrupt the interaction between the two proteins.']

['Several labs have obtained evidence for a protein complex that involves many of the nonstructural (NS) proteins encoded by the virus. NS3, NS4A, NS4B, NS5A, and NS5B appear to interact structurally and functionally. The interaction between the helicase, NS3, and the RNA polymerase, NS5B play a key role in viral replication. Pull-down experiments and surface plasmon resonance data indicate a direct interaction between NS3 and NS5B that is primarily mediated through the protease domain of NS3. This interaction reduces the basal ATPase activity of NS3. However, NS5B stimulates product formation in RNA unwinding experiments under conditions of excess nucleic acid substrate. When the concentrations of NS3 and NS5B are in excess of nucleic acid substrate, NS5B reduces the rate of NS3-catalyzed unwinding. Under pre-steady-state conditions, in which NS3 and substrate concentrations are similar, product formation increased in the presence of NS5B. The increase was consistent with 1:1 complex formed between the two proteins.']

['yes']

What is the role of thymidine phosphorylase inhibitor in TAS-102, a novel nucleoside antitumor agent?

['["PURPOSE: Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor).", "TAS-102, a combination of trifluorothymidine and the thymidine phosphorylase inhibitor TPI in a 1:0.5 ratio, is a novel oral formulation, which is active in 5FU-resistant models, both in vitro and in xenograft models.", "TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5. ", "PURPOSE: TAS-102 is an orally administered anticancer agent composed of \\u03b1,\\u03b1,\\u03b1-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). ", "Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. ", "Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.", "TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI)."]']

The thymidine phosphorylase inhibitor in TAS-102, a novel nucleoside antitumor agent, is designed to inhibit the enzyme thymidine phosphorylase, which helps increase the concentration of trifluridine in the tumor cells by preventing its breakdown. This leads to enhanced antitumor activity.

[]

Are there studies representing the involvement of Notch mutations in neurodegenerative diseases such as Down syndrome, Pick's and Prion's disease, and cadasil syndrome?

['he Notch signaling pathway plays a critical role in maintaining the balance between cell proliferation, differentiation and apoptosis, and is a highly conserved signaling pathway that regulates normal development in a context- and dose-dependent manner. Dysregulation of Notch signaling has been suggested to be key events in a variety of hematological malignancies. Notch1 signaling appears to be the central oncogenic trigger in T cell acute lymphoblastic leukemia (T-ALL), in which the majority of human malignancies have acquired mutations that lead to constitutive activation of Notch1 signaling.', 'In a forward genetic screen for mutations that alter intracellular Notch receptor trafficking in Drosophila melanogaster, we recovered mutants that disrupt genes encoding serine palmitoyltransferase and acetyl-CoA carboxylase.', 'Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells.', "Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease", "(PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP", 'As beta-APP and Notch are both processed by gamma-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notch1, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notch1 and Dll1, indicating that enhanced beta-APP processing found in both DS and AD could be instrumental in these changes', 'A systems biology approach to Down syndrome: identification of Notch/Wnt dysregulation in a model of stem cells aging', 'Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)']

["The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in organisms as diverse as insects, nematodes, echinoderms and mammals. Disruptions in conserved developmental pathways frequently result in inherited congenital anomalies in humans. Mutations in genes encoding Notch pathway components underlie human disease such as Down syndrome, Pick's and Prion's disease, and cadasil syndrome."]

['yes']

What organism causes tularemia?

['Francisella tularensis, the agent of tularemia, is a Gram-negative coccobacillus primarily pathogen for animals and occasionally for humans. ', 'F. tularensis is the causative agent of zoonotic tularemia', 'Tularemia is a zoonosis caused by Francisella tularensis that can be transmitted by several ways to human being and cause different clinical manifestations', 'Tularemia is a bacterial zoonotic disease that is caused by Francisella tularensis and among the infectious reasons that cause fever of unknown origin (FUO) in children', 'The bacterium Francisella tularensis causes the vector-borne zoonotic disease tularemia, and may infect a wide range of hosts including invertebrates, mammals and birds', 'Francisella tularensis, the Gram-negative bacterium that causes tularemia, is considered a potential bioterrorism threat due to its low infectivity dose and the high morbidity and mortality from respiratory disease', 'Francisella tularensis causes disease (tularemia) in a large number of mammals, including man', 'The tularemia-causing bacterium Francisella tularensis is a facultative intracellular organism with a complex intracellular lifecycle that ensures its survival and proliferation in a variety of mammalian cell types, including professional phagocytes.', 'Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated.', 'Tularemia, caused by the gram-negative bacterium Francisella tularensis, is a severe, sometimes fatal disease.', 'Tularemia, caused by the bacterium Francisella tularensis, where F.']

['Francisella tularensis, the agent of tularemia, is a Gram-negative coccobacillus primarily pathogen for animals and occasionally for humans. F. tularensis is the causative agent of zoonotic tularemia. ', 'francisella tularensis, the agent of tularemia, is a gram-negative coccobacillus primarily pathogen for animals and occasionally for humans.', 'Francisella tularensis, the agent of tularemia, is a Gram-negative coccobacillus primarily pathogen for animals and occasionally for humans. ', 'Francisella tularensis, the agent of tularemia, is a Gram-negative coccobacillus primarily pathogen for animals and occasionally for humans.']

['Francisella tularensis']

Which mutated gene is associated with Waardenburg and Tietz syndromes?

['Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations.', 'Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. ', 'For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome.', 'For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. ', 'These disorders are represented by Waardenburg syndrome, piebaldism and Tietz syndrome, and are caused by different mutations of various or the same genes. ', 'Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). ', 'All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). ', 'MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation.', 'On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.', 'Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes.', 'A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. ', 'Mutations in microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome type 2 (WS2), a dominantly inherited disorder involving hearing loss and pigment disturbances caused by a lack of melanocytes. On rare occasions, mutations in MITF lead to Tietz syndrome (TS), which is characterized by a severe WS2 phenotype. ', 'In humans, haploinsufficiency of MITF causes Waardenburg syndrome type 2, while a dominant-negative mutation causes Tietz syndrome. ', 'Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF.', 'This family was reascertained and a missense mutation was found in the basic region of the MITF gene in family members with Tietz syndrome. Mutations in other regions of this gene have been found to produce Waardenburg syndrome type 2 (WS2), which also includes pigmentary changes and hearing loss, but in contrast to Tietz syndrome, depigmentation is patchy and hearing loss is variable in WS2.', 'In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation. ', 'Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).', 'MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. ', 'Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS).', 'The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss', 'Mutations of the MITF gene may lead to hereditary diseases: Waardenburg type II and Tietz syndromes.', 'The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF.', 'On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997)', 'Mutations of the MITF gene may lead to hereditary diseases: Waardenburg type II and Tietz syndromes.', 'Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS).', 'For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome.', 'For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997).', 'Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome.', 'By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2.', 'MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II.', 'Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS)', 'Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes', 'For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome', 'This family was reascertained and a missense mutation was found in the basic region of the MITF gene in family members with Tietz syndrome. ', 'On rare occasions, mutations in MITF lead to Tietz syndrome (TS), which is characterized by a severe WS2 phenotype. ', 'For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). ', 'For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997).', 'In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation.', 'In humans, haploinsufficiency of MITF causes Waardenburg syndrome type 2, while a dominant-negative mutation causes Tietz syndrome.', 'Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations.', 'Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations.', 'Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome.', 'For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV.', 'Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).']

['Mutations in microphthalmia-associated transcription factor (MITF) gene cause Waardenburg and Tietz syndromes.']

['microphthalmia-associated transcription factor gene', 'MITF']

Describe clinical manifestation of the Mal de debarquement syndrome.

['Mal de debarquement (MdD) is a subjective perception of self-motion after exposure to passive motion, in most cases sea travel, hence the name. Mal de debarquement occurs quite frequently in otherwise healthy individuals for a short period of time (several hours). However, in some people symptoms remain for a longer period of time or even persist and this is then called mal de debarquement syndrome (MdDS).', 'OBJECTIVE: Mal de debarquement syndrome (MdDS) is a balance disorder that typically starts after an extended exposure to passive motion, such as a boat or plane ride. ', 'Mal de debarquement syndrome (MdDS) is a rare and poorly understood condition of perceived continual motion.', 'BACKGROUND: Mal de debarquement syndrome (MdDS) is a disorder of chronic self-motion perception that occurs though entrainment to rhythmic background motion, such as from sea voyage, and involves the perception of low-frequency rocking that can last for months or years. ', 'It is characterized by abnormal sensation of motion/balance reported after travel by air, land, and sea; being reexposed to motion/activity relieves it. Symptoms may last from minutes to years. ', 'Persistent mal de debarquement syndrome: a motion-induced subjective disorder of balance.', 'Mal de debarquement syndrome (MdDS) is a disorder of phantom perception of self-motion of unknown cause. ', 'Mal de debarquement (MDD) is a common, benign, and self-limited syndrome suffered by many people after disembarkation from an oceangoing vessel.', 'Persistent mal de debarquement syndrome: a motion-induced subjective disorder of balance.']

['Mal de debarquement syndrome (MdDS) is a disorder of chronic self-motion perception that occurs though entrainment to rhythmic background motion, such as from sea voyage, and involves the perception of low-frequency rocking that can last for months or years.']

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Which are the most widely reported side-effects in the treatment of Crohn's disease?

['Different cutaneous side effects have been described for anti-TNF-α therapy such as psoriasis', 'Anti-TNF drug-induced alopecia is a less well-known side effect of this class of drugs.', '3 patients who developed scalp alopecia', "Psoriasis and psoriatic arthritis induced in a patient treated with infliximab for Crohn's disease", 'side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity', "Persistent corneal endothelial deposits associated with rifabutin therapy for Crohn's disease", 'complained of alopecia 3 days after starting 6-mercaptopurine (6-MP) and then developed severe myelosuppression', 'Leucopoenia was the more frequent side effect observed, occurring in 36 (34%)', 'Nausea, vomit, although slight, occurred in 29 (27.4%)', "Nodular regenerative hyperplasia as a side effect of azathioprine in a patient with Crohn's disease", 'The whole blood count revealed a pancytopenia, hyperbilirubinemia and slightly elevated transaminases', 'Analysis of the liver histology was highly suggestive of an azathioprine-related, nodular regenerative hyperplasia', '3 serious adverse events (SAEs) known to be associated with CD treatment (progressive multifocal leukoencephalopathy (PML), serious infections, and lymphoma)', 'Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease', "A severe side effect is acute pancreatitis, which is specific for Crohn's disease", "Recurrent myopericarditis in association with Crohn's disease", 'Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine', 'Pancreatitis in a patient with Crohn disease treated with mesalazine and azathioprine', 'Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs', 'Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease.', 'resulted to watery stools, vomiting, and fever', 'Eosionophilia was present and the lymphocyte stimulation test with mesalazine was positive', 'Pericarditis as a side effect induced by sulfasalazine or 5-aminosalicylic acid', 'The commonest side-effect was hyperaesthesia, but one patient developed nephrotoxicity and one developed hepatotoxicity', 'The only troublesome side effect is paresthesia, which apparently is dose-related and not progressive', 'The only major side effect observed was paresthesias. These occurred in 50% of the patients and developed in the patients at a mean of 6.5 mo after the onset of treatment.', 'Hemolysis is not a rare side-effect of sulfasalazine therapy', '17 of 40 (43%) patients with inflammatory bowel disease receiving sulfasalazine had evidence of hemolysis as detected by starch gel electrophoresis']

['Leukopenia, paresthesia, psoriasis, alopecia and hemolysis are the most commonly reported side effects depending on the treatment. Severe adverse effects include myelosuppression, liver toxicity and hyperplasia, pancreatitis and pericarditis. The most severe but rare side-effects reported are progressive multifocal leukoencephalopathy (PML), serious infections, and lymphoma.']

['Leukopenia', 'paresthesia', 'psoriasis', 'alopecia', 'hemolysis', 'pancreatitis', 'liver toxicity', 'pericarditis']

Does amiodarone affect thyroid hormone receptors in the myocardium?

['AM and Dron affected TR expression in the RA similarly by decreasing TRalpha 1 and beta 1 expression by about 50%', 'In the LVW, AM and Dron decreased TRbeta 1 and, interestingly, AM increased TRalpha 1.', 'n the apex, AM also increased TRalpha 2.', 'Both in treated and untreated mice, TRalpha2 mRNA had the highest density in mouse heart, whereas TRbeta2 mRNA had the lowest density. Amiodarone dose-dependently downregulated the levels of TRalpha1 and beta1 mRNA in comparison to the control.', 'amiodarone subtype selectively downregulates the TR mRNA levels in mouse myocardium in a dose-dependent manner.', 'Western blot analysis revealed no change in the expression of the ThR protein.', 'Amiodarone and T3, respectively, downregulated T3R alpha 1, T3R beta 1, T3R beta 2 (p < 0.05), but did not affect the levels of T3R alpha 2. Amiodarone and T3, added together, upregulated T3R alpha 2 and T3R beta 1 (p < 0.05) as compared to amiodarone or T3 alone.']

['Yes']

['yes']

List two common features of Tay syndrome.

['TTD is part of a more broadly defined group of diseases identified as IBIDS (ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature). Photosensitive cases are also identified as PIBIDS (photosensitivity with IBIDS). Cases without manifest ichthyosis are also identified as PBIDS. These syndromes defy rigorous definition because of clinical variation between patients. The original two cases were described by Tay in oriental siblings, whose parents were first cousins; thus the disease is also known as Tay syndrome. ', 'Tay syndrome or IBIDS is a rare autosomal recessive genetic disorder characterized by congenital ichthyosis and abnormal brittle hair (trichothiodystrophy). Other features include photosensitivity, abnormal nails and multiple developmental defects affecting organs mainly derived from neuroectoderm. ', 'We report a case of trichothiodystrophy initially classified as Tay syndrome that based on clinical features, complementary exams as well as on the disease evolution was labelled as PIBIDS syndrome.', 'Tay-syndrome is a rare monogen-inherited ektodermal dysplastic syndrome with ichtyosis, fragility of the hair and physical and mental retardation. The congenital ichtyosis is ubiquitous. Only the skin on the flexion side of the extremity joints are not involved (orthocerathosis combined with paraceratotic strings).', 'In Tay syndrome, the trichothiodystrophy is accompanied by congenital ichthyosis, short stature, delayed physical and mental development and pyramidal tract signs with increase in muscular tone and brisk tendon reflexes. ', 'We present a case of Tay syndrome in which a cranial MRI revealed an almost total lack of myelin within the cerebral hemispheres and a patchy hypomyelination of the cerebellum. In accordance, a strongly prolonged visual evoked response pointed to a dysfunction of the white matter in Tay syndrome.', 'For example, the brittle hair due to sulphur deficiency (trichothiodystrophy) is nowadays regarded as genetically heterogeneous; three different syndromes can be distinguished: BIDS syndrome, Tay syndrome, and PIBIDS syndrome. ', 'The Tay syndrome (congenital ichthyosis with trichothiodystrophy).', 'The Tay syndrome is a distinct type of congenital ichthyosis characterized by a peculiar anomaly of hair growth which has been termed trichothiodystrophy. ', 'Other features of this syndrome are low birth weight, short stature, mental retardation, delayed neuromuscular development and other CNS anomalies, dysplasia of nails, hypoplasia of subcutaneous fatty tissue, prematurely aged facial appearance, hypogonadism, cataracts, osteosclerosis, dysphonia, and increased susceptibility to infections. ']

['Tay syndrome is a rare autosomal recessive genetic disorder characterized by congenital ichthyosis and trichothiodystrophy (abnormal brittle hair). Other less common features of this syndrome are photosensitivity, low birth weight, short stature, mental retardation, delayed neuromuscular development and other CNS anomalies, dysplasia of nails, hypoplasia of subcutaneous fatty tissue, prematurely aged facial appearance, hypogonadism, cataracts, osteosclerosis, dysphonia, and increased susceptibility to infections.']

['ichthyosis', 'trichothiodystrophy']

How does ranolazine affect kinase signaling activation in the heart?

['support of this view, CaMKII activity was also increased in hearts of transgenic mice overexpressing a gain-of-function Na(v)1.5 mutant (N(1325)S). The effects of both ATX-II and the N(1325)S mutation were reversed by either I(NaL) inhibition (with ranolazine or tetrodotoxin) or CaMKII inhibition (with KN93 or autocamtide 2-related inhibitory peptide).', 'Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function.']

['Ranolazine inhibits Ca(2+)/calmodulin kinase II (CaMKII) activity']

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What is the minimal genome build?

['As a key focus of synthetic biology, building a minimal artificial cell has given rise to many discussions. A synthetic minimal cell will provide an appropriate chassis to integrate functional synthetic parts, devices and systems with functions that cannot generally be found in nature. The design and construction of a functional minimal genome is a key step while building such a cell/chassis since all the cell functions can be traced back to the genome. ', 'The field of Synthetic Biology seeks to apply engineering principles to biology in order to produce novel biological systems. One approach to accomplish this goal is the genome-driven cell engineering approach, which searches for functioning minimal genomes in naturally occurring microorganisms, which can then be used as a template for future systems. Currently a prototypical minimal genome has not been discovered. ', 'The identification of the essential genes of bacteria and the minimal genome for the free-living cellular life could provide insights into the origin, evolution, and essence of life forms. ', 'Minimal bacterial gene set comprises the genetic elements needed for survival of engineered bacterium on a rich medium. This set is estimated to include 300-350 protein-coding genes. One way of simplifying an organism with such a minimal genome even further is to constrain the amino acid content of its proteins. ', "A central undertaking in synthetic biology (SB) is the quest for the 'minimal genome'. However, 'minimal sets' of essential genes are strongly context-dependent and, in all prokaryotic genomes sequenced to date, not a single protein-coding gene is entirely conserved. Furthermore, a lack of consensus in the field as to what attributes make a gene truly essential adds another aspect of variation. Thus, a universal minimal genome remains elusive.", 'The minimal cell concept represents a pragmatic approach to the question of how few genes are required to run a cell. This is a helpful way to build a parts-list, and has been more successful than attempts to deduce a minimal gene set for life by inferring the gene repertoire of the last universal common ancestor, as few genes trace back to this hypothetical ancestral state. ']

['The identification of the essential genes of bacteria and the minimal genome for the free-living cellular life could provide insights into the origin, evolution, and essence of life forms. The field of Synthetic Biology seeks to apply engineering principles to biology in order to produce novel biological systems. One approach to accomplish this goal is the genome-driven cell engineering approach, which searches for functioning minimal genomes in naturally occurring microorganisms, which can then be used as a template for future systems. Currently a prototypical minimal genome has not been discovered.']

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What is the indication of Daonil (Glibenclamide)?

['Metformin and glibenclamide are now increasingly viewed as a rational alternative to insulin therapy--a treatment both preferred by the women and a less expensive one, during pregnancy and breastfeeding.', 'The effect of TFG on blood glucose were studied and the levels of lipid peroxidation [MDA (Malondialdehyde)] and antioxidant enzymes [SOD (Superoxide dismutase), GPx (Reduced Glutathione peroxidase)] were estimated and compared with standard drugs glibenclamide and insulin.', 'Treatment with TFG, insulin and glibenclamide resulted in significantly reduced blood glucose in LM (8.71%) and HM (3.87%) in comparison with normal controls.', 'Potency of TFG in restoring several parameters to normal values is comparable to glibenclamide, though not as efficient as insulin, an indication of its antihyperglycemic and antioxidant effect.', 'However, dietary supplementation with PB (6 g/kg extract for 4 weeks administered orally using an intragastric tube) ameliorated the alloxan-induced diabetes in a manner comparable with that of the reference antidiabetic drug glibenclamide', 'Moreover, the potassium-specific effects of both diazoxide and nicorandil on oxidative phosphorylation in skeletal muscle mitochondria were completely abolished by the antidiabetic sulfonylurea derivative glibenclamide, a well-known inhibitor of ATP-regulated potassium channels (K(ATP) channels).', 'In mild NIDDM, gliclazide, tolbutamide or acetohexamide is used, and in more severe NIDDM glibenclamide is used.', 'An improvement of the glucose tolerance could be observed up to 3 years, whereas after a 5-year glibenclamide therapy no certain influence on the glucose tolerance and insulin secretion could be proved.', 'In general the improvement of the glucose tolerance was not associated with an increased secretion of insulin, so that an extrapancreatic effect of glibenclamide (improvement of the peripheral insulin sensitivity?) seems to be possible.', 'From clinical and practical point of view the findings would support the opinion that normal weight persons with IGT, particularly in already decreased insulin secretion, have an indication for a glibenclamide therapy.']

['Glibenclamide is an antidiabetic and antiglycemic, used in severe NIDDM, and increasingly viewed as a rational alternative to insulin therapy.']

['Diabetes mellitus']

Does ziconotide bind to N-type calcium channels?

['Since this region partially overlaps with residues previously implicated in block of the channel by omega-conotoxin GVIA, we assessed the effects of mutations in the putative EF hand domain on channel block by omega-conotoxin GVIA and the structurally related omega-conotoxin MVIIA. Both of the toxins irreversibly block the activity of wild type alpha(1B) N-type channels. ', 'Despite their high sequence homology, the peptide neurotoxins omega-conotoxin MVIIA and MVIIC selectively block N- and P/Q-type calcium channels, respectively. ', ' Binding assay for both N- and P/Q-type calcium channels showed that amino acid residues restricted to the N-terminal half are important for the recognition of N-type channels, whereas essential residues for P/Q-type channel recognition are widely spread over the whole omega-conotoxin molecule.', 'Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals.', 'Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs).', 'The therapeutic benefit of ziconotide derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels.', 'Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats.', 'Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain.', 'Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain.', 'Thus, ziconotide is the first of a new class of agents--N-type calcium channel blockers, or NCCBs.', 'Ziconotide, formerly known also as SNX- 111, represents a new class of agents, the N-type calcium channel blockers.', 'The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration.', 'A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain.', 'As the clinically available analgesics, pregabalin (alpha2delta-subunit calcium channel ligand), ziconotide (N-type calcium channel blocker), mexiletine (sodium channel blocker), and duloxetine (serotonin and norepinephrine reuptake inhibitors) were evaluated in these neurochemically-induced allodynia models.', 'The present investigation was designed to assess the safety and analgesic efficacy of ziconotide, a new N-type calcium channel blocker, when administered intrathecally to patients with acute postoperative pain.', 'Inhibition of the N-type calcium channel by intrathecal administration of the channel-specific blocker omega-conotoxin MVIIA (ziconotide) is efficacious in the treatment of severe chronic pain.', 'Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control neurotransmission at many synapses.', 'In conclusion, present findings provide implication that the spinal anti-nociceptive mechanistic site of pregabalin is different from that of ziconotide, mexiletine, and duloxetine, and pregabalin could have a broader anti-nociceptive mechanism other than N-type calcium channel blockade.', 'Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally.', 'Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain.', 'A state-dependent Ca(V)2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca(V)2.2 inhibitor used clinically. ', 'There is also human validation data from ziconotide, the CaV2.2-selective peptidyl inhibitor used clinically to treat refractory pain. ', 'A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. ', 'The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia.']

['Yes, ziconotide/omega-conotoxin MVIIA blocks N-type calcium channels.']

['yes']

What is known about efficacy of the high dose intravenous ascorbate in the treatment of cancer patients?

['Evidence suggests that IVC may be able to modulate inflammation, which in turn might improve outcomes for cancer patients. IVC may serve as a safe, adjunctive therapy in clinical cancer care.', 'SIGNIFICANCE: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10\u2009g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. ', 'RECENT ADVANCES: High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H2O2). ', ' CRITICAL ISSUES: Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H2O2-mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. ', 'BACKGROUND: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models.', 'CONCLUSIONS: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy.', ' IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.', 'CONCLUSIONS: The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients.', 'Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models.', 'Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer.', 'Two popular complementary, alternative, and integrative medicine therapies, high-dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are often coadministered to cancer patients with unclear efficacy and drug-drug interaction.', 'Ascorbate (ascorbic acid, vitamin C) is one of the early, unorthodox treatments for cancer. The evidence upon which people base the use of ascorbate in cancer treatment falls into two categories: clinical data on dose concentration relationships, and laboratory data describing potential cell toxicity with high concentrations of ascorbate in vitro.', 'Recently, high dose of ascorbate in cancer treatment has been reexamined.', 'These data suggest that ascorbic acid may have benefits for patients with mesothelioma.', 'Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously.', 'Both these regressions coincided exactly in time with intravenous high-dose ascorbate administration, and it seemed reasonable to conclude that this unconventional therapy must have been responsible for his excellent responses.', 'In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients.', 'In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid).', 'In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients.', 'The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients.', 'In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients.', 'In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients', 'In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid)', 'Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated']

['It was reported that ascorbate, given orally and intravenously at doses of up to 10\u2009g/day, was effective in the treatment of cancer. However, double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. Pharmacologic actions of ascorbate against cancer cells remain to be fully understood. It is thought that high dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide. High dose intravenous ascorbate (IVC) may be able to modulate inflammation, which in turn might improve outcomes for cancer patients. IVC may serve as a safe, adjunctive therapy in clinical cancer care']

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Where is the protein slitrk1 localized?

['Slitrk1 is localized to excitatory synapses', ' Slitrk1 is enriched in postsynaptic fractions and is localized to excitatory synapses.', ' The porcine SLITRK1 gene is expressed exclusively in brain tissues.', 'Six family members exist (Slitrk1-6) and all are highly expressed in the central nervous system (CNS).']

['Slitrk1 is enriched in postsynaptic fractions and is localized to excitatory synapses. ']

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What is the oldest human sample analysed by paleontology proteomics?

["Paleoproteomic study of the Iceman's brain tissue.", 'We report the first use of shotgun proteomics to detect the protein expression profile of buccal swabs and cloth samples from two 500-year-old Andean mummies.', 'Identification of ancient biological samples from the 1991-discovered and more than 5300-year-old Tyrolean mummy, also called iceman or Oetzi, is very difficult. T', 'To determine whether a 2,700-year-old tumor can be reliably diagnosed using microscopic and proteomic techniques ']

["The Tyrolean Iceman's brain is the oldest (5300 years old) human sample that has been studied by paleoproteomics."]

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How do protein misfolding and aggregation contribute to neurodegenerative disorders like ALS, PD, and AD?

['["Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson\'s disease (PD), and Alzheimer\'s disease (AD).", "Human Hsp70 Disaggregase Reverses Parkinson\'s-Linked \\u03b1-Synuclein Amyloid Fibrils.", "Disaggregases, molecular chaperones that resolubilize protein aggregates.", "The structural basis by which Hsp104 dissolves disordered aggregates and prions is unknown."]']

Protein misfolding and aggregation contribute to neurodegenerative disorders like ALS, PD, and AD by causing common and fatal conditions that urgently require therapeutic agents. These disorders are linked to the misfolding and aggregation of proteins, leading to issues such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).

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List scaffold proteins of the ERK signaling pathway.

['Human disc-large homolog (hDlg), also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family, implicated in neuronal synapses and epithelial-epithelial cell junctions whose expression and function remains poorly characterized in most tissues, particularly in the vasculature. ', 'Using the yeast two-hybrid system to screen a human aorta cDNA library, we identified mitogen-activated protein/extracellular signal-responsive kinase (ERK) kinase (MEK)2, a member of the ERK cascade, as an hDlg binding partner.', 'Taken together, these findings allow us to hypothesize that hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway, and may improve our understanding of how scaffold proteins, such as hDlg, differentially tune MEK1/MEK2 signaling and cell responses.', 'Here, we show that two scaffold proteins, caveolin-1 and IQGAP1, are required for phosphorylation of the actin associated pool of extracellular signal regulated kinase 1 and 2 (ERK1/2) in response to protein kinase C activation.', 'ERK activation is enhanced by the scaffolding proteins KSR and MP1, localized near the cell membrane and late endosomes respectively, but little is known about their dynamic interplay.', ' Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), beta-arrestin, MEK partner-1, Sef and IQGAP1.', 'Here we analyze a potential scaffold of the Ras/mitogen-activated protein kinase (MAPK) pathway, kinase suppressor of Ras (KSR), by generating KSR-deficient mice. ', 'This demonstrates that KSR is a bona fide scaffold that is not required for but enhances signaling via the Ras/MAPK signaling pathway.', 'We reported previously that several 14-3-3 isotypes bind to protein kinase C (PKC)-zeta and facilitate coupling of PKC-zeta to Raf-1 [van der Hoeven, van der Wal, Ruurs, van Dijk and van Blitterswijk (2000) Biochem. J. 345, 297-306], an event that boosts the mitogen-activated protein kinase (ERK) pathway in Rat-1 fibroblasts. ', 'In this study, IQGAP1 (IQ motif-containing GTPase-activating protein 1), a new Nrf2 interaction partner that we have published previously, was found to modulate MEK-ERK-mediated Nrf2 activation and induction of phase II detoxifying/antioxidant genes.', 'In the aggregate, these results suggest that IQGAP1 may play an important role in the MEK-ERK-Nrf2 signaling pathway.', ' Taken together, these findings allow us to hypothesize that hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway, and may improve our understanding of how scaffold proteins, such as hDlg, differentially tune MEK1/MEK2 signaling and cell responses.', 'The MAP kinase ERK and its scaffold protein MP1 interact with the chromatin regulator Corto during Drosophila wing tissue development.', 'KSR-1 is a scaffold protein that is essential for Ras-induced activation of the highly conserved RAF-MEK-ERK kinase module. Previously, we identified a close homolog of KSR-1, called KSR-2, through structural homology-based data mining', 'The scaffold protein beta-arrestin2 interacted with both p-ERK and D1 DA receptor, triggering the cytosolic retention of p-ERK and inducing striatal neuronal apoptotic death. ', 'Involvement of the MP1 scaffold protein in ERK signaling regulation during Drosophila wing development.', 'Beta-arrestin mediates desensitization and internalization of beta-adrenergic receptors (betaARs), but also acts as a scaffold protein in extracellular signal-regulated kinase (ERK) cascade.', 'Recent studies indicate that kinase suppressor of Ras (KSR)is a scaffold protein for the Ras/Raf/MEK/ERK signaling cascade in mammals. ', 'The scaffold protein IQGAP1 regulates cell signaling through the RAF/MEK/ERK pathway.', 'Kinase suppressor of Ras (KSR) is a molecular scaffold that interacts with the components of the Raf/MEK/ERK kinase cascade and positively regulates ERK signaling.', 'Our results indicate that KSR-2 may act as a scaffold protein similar as KSR-1 to mediate the MAPK core (RAF-MEK-ERK) signaling but with a distinct RAF isoform specificity, namely KSR-2 may only mediate the A-RAF signaling while KSR-1 is responsible for transducing signals only from c-RAF.', 'Kinase Suppressor of Ras (KSR) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Raf, MEK, ERK to provide spatial and temporal regulation of Ras-dependent ERK cascade signaling.', 'These findings identify KSR2 as a Ca2+-regulated ERK scaffold and reveal a new mechanism whereby Ca2+ impacts Ras to ERK pathway signaling.', 'MEK Partner-1 (MP1) was identified as a potential "scaffold" protein for the mammalian extracellular signal-regulated kinase (ERK) pathway', 'The scaffold protein MP1 (MEK1 partner) assembles a scaffold complex in the ERK cascade', 'IQGAP1 scaffold-MAP kinase (ERK) interaction was noted in the human myeloma RPMI8226 cell lines. In conclusion, IQGAP1 plays an important role in the cell proliferation of MM via the MAP kinase (ERK) pathway.', 'ERK-regulated, metastasis-associated scaffold protein Ezrin', 'bsence of kinase suppressor of Ras 1 (KSR1), a scaffold protein of the ERK signaling pathway', 'GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2.', 'In Drosophila, dMP1, that encodes an ERK scaffold protein, regulates ERK signaling during wing development and contributes to intervein and vein cell differentiation.', 'Scaffold proteins regulate intracellular MAP kinase signaling by providing critical spatial and temporal specificities. We have shown previously that the scaffold protein MEK1 partner (MP1) is localized to late endosomes by the adaptor protein p14.', 'The scaffold protein Shoc2/SUR-8 accelerates the interaction of Ras and Raf.', 'We propose that Shoc2 regulates the spatio-temporal patterns of the Ras-ERK signaling pathway primarily by accelerating the Ras-Raf interaction.', 'Proteomic characterization of the dynamic KSR-2 interactome, a signaling scaffold complex in MAPK pathway.', 'Kinase modules are associated with scaffold proteins that regulate signaling by providing critical spatial and temporal specificities. Some of these scaffold proteins have been shown to be conserved, both in sequence and function. In mouse, the scaffold MP1 (MEK Partner 1) forms a signaling complex with MEK1 and ERK1. ', ' extracellular signal-regulated kinase (ERK) pathway scaffold protein MP1. ', 'We propose that MORG1 is a component of a modular scaffold system that participates in the regulation of agonist-specific ERK signaling.', ' IQGAP1, a scaffold protein linking cadherin-mediated cell adhesion to the cytoskeleton. This effect was accompanied by reduction of N-cadherin/IQGAP1/Erk-2 interactions.', 'G protein-coupled receptor kinase 2 (GRK2) is a Rho-activated scaffold protein for the ERK MAP kinase cascade.', 'GRK2 is a RhoA effector that serves as a RhoA-activated scaffold protein for the ERK MAP kinase cascade.']

['Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include kinase suppressor of Ras (KSR), beta-arrestin, MEK partner-1 (MP-1), Sef and IQ motif-containing GTPase-activating protein 1(IQGAP1). Human disc-large homolog (hDlg) acts as a MEK2-specific scaffold protein for the ERK signaling pathway. Two scaffold proteins, caveolin-1 and IQGAP1, are required for phosphorylation of the actin associated pool of extracellular signal regulated kinase 1 and 2 (ERK1/2). Several 14-3-3 isotypes bind to protein kinase C (PKC)-zeta and facilitate coupling of PKC-zeta to Raf-1 an event that boosts the mitogen-activated protein kinase (ERK) pathway.', 'kinase suppressor of Ras 1\nMEK Partner 1\nBeta-arrestin\nIQ motif containing GTPase-activating protein 1\nkinase suppressor of Ras 2\nmitogen-activated protein kinase organizer 1']

['Human disc-large homolog', 'hDlg', 'caveolin-1', 'IQ motif-containing GTPase-activating protein 1', 'IQGAP1', 'kinase suppressor of Ras', 'KSR', 'MEK partner-1', 'MP-1', 'beta-arrestin', 'Sef', '14-3-3', 'mitogen-activated protein kinase organizer 1']

Is the Histidine-Rich Calcium Binding protein (HRC) related to arrhythmias and cardiac disease?

['A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. ', 'These findings suggest that aberrant SR Ca2+ release and increased susceptibility to delayed afterdepolarizations underlie triggered arrhythmic activity in human Ala96 HRC carriers.', 'The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers.', 'These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers.', 'HRC plays an important role in myocyte differentiation and in antiapoptotic cardioprotection against ischemia/reperfusion induced cardiac injury. Interestingly, HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy.', 'This review summarizes studies, which have established the critical role of HRC in Ca(2+)-homeostasis, suggesting its importance in cardiac physiology and pathophysiology.', 'HRC is a SR luminal Ca(2+) binding protein known to associate with both triadin and the sarcoplasmic reticulum Ca(2+)-ATPase, and may thus mediate the crosstalk between SR Ca(2+) uptake and release. Indeed, evidence from genetic models of JCN and HRC indicate that they are important in cardiophysiology as alterations in these proteins affect SR Ca(2+) handling and cardiac function. In addition, downregulation of JCN and HRC may contribute to Ca(2+) cycling perturbations manifest in the failing heart, where their protein levels are significantly reduced.', 'The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.', 'AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure.', 'Chronic overexpression of HRC that may disrupt intracellular Ca(2+) homeostasis is implicated in pathogenesis of cardiac hypertrophy', 'Ablation of HRC showed relatively normal phenotypes under basal condition, but exhibited a significantly increased susceptibility to isoproterenol-induced cardiac hypertrophy', 'Our results present evidence that down-regulation of HRC could deteriorate cardiac function in TAC-FH through perturbed SR-mediated Ca(2+) cycling', 'However, AAV9-mediated HRC-KD in TAC-FH was associated with decreased fractional shortening and increased cardiac fibrosis compared with control.', 'Histidine-rich calcium binding protein (HRC) is a high capacity, low affinity Ca(2+) binding protein, specifically expressed in striated muscles of mammals. In rabbit skeletal and cardiac muscles, HRC binds to sarcoplasmic reticulum (SR) membranes via triadin, a junctional SR protein. Recently, a potential role in heart failure and arrhythmogenesis has been assigned to HRC due to its activity as regulator of SR Ca(2+) uptake and Ca(2+) release.', 'In addition, HRC null mice displayed a significantly exaggerated response to the induction of cardiac hypertrophy by isoproterenol compared to their wild-type littermates. The exaggerated response of HRC knockout mice to the induction of cardiac hypertrophy is consistent with a regulatory role for HRCBP in calcium handling in vivo and suggests that mutations in HRC, in combination with other genetic or environmental factors, might contribute to pathological hypertrophy and heart failure.', 'We observed that the levels of HRC were reduced in animal models and human heart failure.', 'Collectively, these data indicate that alterations in expression levels of HRC are associated with impaired cardiac SR Ca homeostasis and contractile function.', 'Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein.', 'The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy.', 'Interestingly, HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy']

['Histidine-rich calcium binding protein (HRC) is a high capacity, low affinity Ca(2+) binding protein with a potential role in heart failure and arrhythmogenesis due to its activity as regulator of SR Ca(2+) uptake and Ca(2+) release.In addition, HRC null mice displayed a significantly exaggerated response to the induction of cardiac hypertrophy by isoproterenol compared to their wild-type littermates. A human genetic variant (Ser96Ala) in HRC has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy.']

['yes']

Are defects in recombination repair involved in carcinogenesis?

['Inherited mutations in genes involved in HR are associated with gene rearrangement and may be a prerequisite for tumor development in some cancer-prone hereditary diseases like Bloom, Werner and Rothmund-Thomson syndromes. ', 'Variants in the XRCC3 gene might result in altered protein structure or function which may influence DSBR efficiency and lead to cancer. ', 'Although alcohol consumption is related to increased cancer risk, its molecular mechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol for 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde (AA), the first product of ethanol metabolism, is believed to be responsible for DNA damage induced by alcohol. ', 'Although efficiency of these repair processes substantially decrease the efficacy of cancer chemotherapies that target DNA, compromised DNA repair contributes to mutagenesis and genomic instability leading to carcinogenesis.', 'damage response and repair pathways are important barriers to carcinogenesis. ', 'olymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely documented. For colorectal cancer, the loss of mismatch repair gene activity is a key genetic determinant. Nucleotide excision repair (NER), recombination repair (RR) and base excision repair (BER) pathways have critical roles in protection against other cancers, and we wished to investigate their role in colorectal cancer. ']

['Yes. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in recombination repair.', 'Carcinogenesis or oncogenesis or tumorigenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells. It is characterized by a progression of changes at the cellular, genetic and epigenetic level that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass.\nCarcinogenesis is caused by mutation and epimutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. The uncontrolled and often rapid proliferation of cells can lead to benign tumors; some types of these may turn into malignant tumors (cancer). Based on studies, carcinogenesis also related with the defects in recombination repair.']

['yes']

How does Hst5 (histatin 5) affect infections by Candida glabrata?

['Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva', 'Histatin 5 (Hst 5) is a small cationic human salivary peptide with high fungicidal activity against C. albicans, however many strains of C. glabrata are resistant.', 'Since Hst 5 requires fungal binding to cell wall components prior to intracellular translocation, reduced Hst 5 binding to C. glabrata may be the reason for its insensitivity.', 'Hst 5 enters C. albicans cell through polyamine transporters Dur3p and Dur31p that are uncharacterized in C. glabrata. ', 'the crucial rate limiting step is reduced uptake that can be overcome by expression of C. albicans Dur proteins in C. glabrata.', 'Histatin 5, a human salivary protein with broad-spectrum antifungal activity, is remarkably ineffective against Candida glabrata.', 'Our results, taken together, demonstrated that histatin-5 possessed the fungicidal activity against Candida species other than C. glabrata.', 'The present study shows that a number of basic antifungal peptides, including human salivary histatin 5, a designed histatin analog designated dhvar4, and a peptide from frog skin, PGLa, are active against amphotericin B-resistant Candida albicans, Candida krusei, and Aspergillus fumigatus strains and against a fluconazole-resistant Candida glabrata isolate.', 'In addition, we tested azole-resistant C. albicans and Candida glabrata strains for their susceptibilities to Hsn-5.', 'Assessment of the candidacidal activity of Hsn-5 with the well-characterized azole-resistant strains of C. albicans and C. glabrata, however, suggested that the mode of action of histatins against Candida is distinct from that of azole-based antifungal agents because Hsn-5 kills both azole-sensitive and azole-resistant strains equally well.', 'Histatin 5 resistance of Candida glabrata can be reversed by insertion of Candida albicans polyamine transporter-encoding genes DUR3 and DUR31.', 'Roles of cellular respiration, CgCDR1, and CgCDR2 in Candida glabrata resistance to histatin 5.', 'Histatin 5 (Hst 5) is a small cationic human salivary peptide with high fungicidal activity against C. albicans, however many strains of C. glabrata are resistant. ', 'Biofilms of C. glabrata GDH1407 and 6115/06 were less susceptible to histatin 5, with 50% RMA of 31.2 +/- 4.8 and 62.5 +/- 0.7 microM, respectively. ', 'Thus, neither C. glabrata cell surface or biofilm matrix β-1,3-glucan levels affected Hst 5 toxicity; rather the crucial rate limiting step is reduced uptake that can be overcome by expression of C. albicans Dur proteins in C. glabrata.', 'These results indicate that histatin 5 exhibits antifungal activity against biofilms of C. albicans and C. glabrata developed on denture acrylic. ', 'Candida albicans and Candida glabrata are predominant fungi associated with oral candidiasis. ', 'C. glabrata is significantly less sensitive to histatin 5 than C. albicans.', 'We investigated whether the distinct resistance of C. glabrata to histatin 5 is related to similar mechanisms.', 'The authors report a case of disseminated candidiasis due to Candida glabrata with liver metastases.', 'We examined antifungal activities of histatin 5 against planktonic or biofilm Candida albicans and Candida glabrata.', 'Histatin 5 resistance of Candida glabrata can be reversed by insertion of Candida albicans polyamine transporter-encoding genes DUR3 and DUR31.', 'Roles of cellular respiration, CgCDR1, and CgCDR2 in Candida glabrata resistance to histatin 5.', 'Histatin 5, a human salivary protein with broad-spectrum antifungal activity, is remarkably ineffective against Candida glabrata.', 'Candida albicans and Candida glabrata are predominant fungi associated with oral candidiasis.']

['Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva', 'Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. We found that Hst 54-15-Spd was significantly more effective in killing C. albicans and Candida glabrata than Hst 5 alone in both planktonic and biofilm growth and that Hst 54-15-Spd retained high activity in both serum and saliva. Histatin 5 (Hst 5) is a small cationic human salivary peptide with high fungicidal activity against C. albicans, however many strains of C. glabrata are resistant. We constructed a conjugate peptide using spermidine (Spd) linked to the active fragment of Hst 5 (Hst 54-15), based upon our findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity.', 'Our results, taken together, demonstrated that histatin-5 possessed the fungicidal activity against Candida species other than C. glabrata. ', 'Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. Histatin 5, a human salivary protein with broad-spectrum antifungal activity, is remarkably ineffective against Candida glabrata. Histatin 5 (Hst 5) is a small cationic human salivary peptide with high fungicidal activity against C. albicans, however many strains of C. glabrata are resistant. Since Hst 5 requires fungal binding to cell wall components prior to intracellular translocation, reduced Hst 5 binding to C. glabrata may be the reason for its insensitivity. Hst 5 enters C. albicans cell through polyamine transporters Dur3p and Dur31p that are uncharacterized in C. glabrata. The crucial rate limiting step is reduced uptake that can be overcome by expression of C. albicans Dur proteins in C. glabrata.']

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Has the presence of delayed enhancement been documented in athletes performing strenuous exercise?

['Atypical findings such as marked cardiac dilation, reduced deformation, or small patches of delayed gadolinium enhancement may be commonly encountered in well-trained athletes, but, at present, the prognostic significance of such findings is unknown. ', 'On CMR, DGE localized to the interventricular septum was identified in 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF (47.1 ± 5.9 vs. 51.1 ± 3.7%, P = 0.042) than those with normal CMR.', 'Post-event cardiac MRI demonstrated the interval appearance of delayed enhancement of gadolinium at the inferior insertion of the right ventricle and in the interventricular septum-a novel finding that may represent subtle inflammation secondary to a combined exercise and altitude effect.', 'No evidence of delayed enhancement of the left ventricular myocardium was found on CMR imaging, suggesting that the increase in cardiac biomarkers after the marathon may not have be due to myocardial necrosis.', 'Of the 102 runners, five had a CAD pattern of LGE, and seven had a non-CAD pattern of LGE. The CAD pattern of LGE was located in the territory of the left anterior descending coronary artery more frequently than was the non-CAD pattern (P = .0027, Fisher exact test). The prevalence of LGE in runners was higher than that in age-matched control subjects (12% vs 4%; P = .077, McNemar exact test).']

['There are contrasting literature data on the presence of delayed enhancement, as a sign of myocardial fibrosis, in healthy athletes. More studies are necessary to define the presence, incidence and severity, as well clinical and prognostic meaning, of delayed enhancement magnetic resonance in healthy athletes.']

['yes']