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List the three most prevalent pathogenic species of Borrelia in Europe.

[' The Borrelia species causing Lyme borreliosis in Europe express different OspA serotypes on their surface, B. burgdorferi (serotype 1), B. afzelii (serotype 2), B. garinii (serotypes, 3, 5 and 6) and B. bavariensis (serotype 4), while only B. burgdorferi is present in the US. ', 'Borrelia afzelii is the predominant Borrelia species causing Lyme borreliosis in Europe.', 'Moreover we detected Borrelia spielmanii, Borrelia miyamotoi, Babesia divergens, and Babesia venatorum for the first time in Danish ticks. ', 'We successfully determined the prevalence of expected (Borrelia burgdorferi sensu lato', 'Borrelia miyamotoi is a newly described emerging pathogen transmitted to people by Ixodes species ticks and found in temperate regions of North America, Europe, and Asia. There is limited understanding of large scale entomological risk patterns of B. miyamotoi and of Borreila burgdorferi sensu stricto (ss), the agent of Lyme disease, in western North America. ', 'In France as elsewhere in Europe the most prevalent TBD in humans is Lyme borreliosis, caused by different bacterial species belonging to Borrelia burgdorferi sensu lato complex', 'B. miyamotoi belonging to the relapsing fever group and transmitted by the same Ixodes species has been involved in human disease in Russia, the USA and the Netherlands. ', 'Laboratory diagnosis of Lyme disease is based on the serological detection of antibodies against the etiologic agent Borrelia burgdorferi.', 'B. burgdorferi sl complex, currently comprising at least 19 genospecies, includes the main pathogenic species responsible for human disease in Europe: B. burgdorferi sensu stricto (ss), B. afzelii, and B. garinii. ', 'The European red squirrel (Sciurus vulgaris) has long been suspected to be a reservoir host of the agents of Lyme borreliosis, in particular B. burgdorferi sensu stricto (s.s.).', 'n adults (n = 227), the prevalence of infection with B. burgdorferi s.l. was 27.3%, with 18.9% B. burgdorferi s.s., 11.9% B. afzelii, and 3.5% B. garinii. ', ': The overall estimated prevalence of B. burgdorferi s.l was 9.7% ', '. The most prevalent genospecies was B. afzelii which was detected in 53.5% of Borrelia-positive ticks, followed by B. garinii and B. valaisiana with 26.2% and 5.5%, respectively. Also, B. bavariensis and B. burgdorferi s.s. DNA in single I. ricinus ti', ' Among all the analysed antigens those of B. burgdorferi s.s. were the most frequent cause of immunological reaction, followed by antigens of B. afzelii and B. garinii. Reaction to antigens of B. spielmanii was rarely detected.', 'Overall, 15.8% ticks were infected with B. burgdorferi s. I. Borrelia afzelii (43.1%) was the predominant genospecies, followed by Borrelia valaisiana (14.7%), Borrelia garinii (13.7%) and Borrelia burgdorferi sensu stricto (6.3%). ', 'In cases where the genospecies could be identified, B. garinii was most frequently found (8x), followed with B. burgdorferi s.s. (4×) and B. afzelii (3×).', 'In Europe, Ixodes ricinus is the vector of many pathogens of medical and veterinary relevance, among them Borrelia burgdorferi sensu lato and tick-borne encephalitis virus, which have been the subject of numerous investigations', 'The minimum prevalence of Borrelia burgdorferi sensu lato was 2.5%. Borr. afzelii, Borr. burgdorferi sensu stricto, Borr. garinii, Borr. lusitaniae, and Borr. valaisiana were identified by hybridization.']

['The most prevalent pathogenic species of Borrelia in Europe are: B. afzelii, B. garinii and B. burgdorferi ss.']

['B. afzelii', 'B. garinii', 'B. burgdorferi ss.']

Can Preimplantation Genetic Diagnosis (PGD) be used for gender selection?

['This testing is used for identifying singlegene disorders, chromosomal abnormalities, mitochondrial disorders, gender selection in non-mendelian disorders with unequal gender distribution, aneuploidy screening, and other preconceptually identified genetic abnormalities in prospective parents. ', ' Although many clinics offer PGD for HA by gender selection, an approach that detects the presence of the underlying F8 mutation has several advantages. ', 'Preimplantation genetic diagnosis (PGD) for gender selection for non-medical reasons has been considered an unethical procedure by several authors and agencies in the Western society on the basis that it could disrupt the sex ratio, that it discriminates against women and that it leads to disposal of normal embryos of the non-desired gender. In this study, the analysis of a large series of PGD procedures for gender selection from a wide geographical area in the USA shows that, in general, there is no deviation in preference towards any specific gender except for a preference of males in some ethnic populations of Chinese, Indian and Middle Eastern origin that represent a small percentage of the US population. ', ' In response to one specific question, one-third of the couples agreed to use the donor child as a lifetime organ donor and supported the use of PGD for non-medical gender selection. ', 'More specifically, I illustrate how the prescriptions of deliberative democracy can be applied to the issue of regulating non-medical uses of pre-implantation genetic diagnosis (PGD), such as gender selection. ', 'Private clinics were more likely than other programs to be on either the East or West Coast, list certain PGD risks (e.g., diagnostic error), note that PGD was new or controversial, reference source of PGD information, provide accuracy rates of genetic testing of embryos, and offer gender selection for social reasons.', 'The purpose of this article is to ascertain and appraise the ethical issues inherent to the utilisation of preimplantation genetic diagnosis for gender selection in infertile patients anticipating undergoing a medically indicated assisted reproductive technique procedure. Performance of preimplantation genetic diagnosis per request specifically for gender selection by an infertile couple undergoing medically indicated assisted reproductive technique may not breach the principles of ethics, and is unlikely to alter the population balance of sexes.', 'One possible use of PGD is to perform gender selection for couples whose offspring are at increased risk of disorders that do not follow Mendelian inheritance, but which are substantially more common in one sex than another (unequal sex incidence). Here, we examine the clinical and ethical issues to be considered prior to offering PGD gender selection to reduce the risk of a child being affected by a non-Mendelian condition with unequal sex incidence. ', 'New uses of PGD have been reported in the past year for screening embryos for susceptibility to cancer, for late-onset diseases, for HLA-matching for existing children, and for gender. ', 'This article describes current and likely future uses of PGD, and then analyses the ethical issues posed by new uses of PGD to screen embryos for susceptibility and late-onset conditions, for HLA-matching for tissue donation to an existing child, and for gender selection.', 'The use of PGD for sex selection arouses considerable debate, especially in countries like India that have a marked cultural preference for boys. It is argued that using PGD for sex selection is a treatment option that can be ethically offered to couples who desire to use this technology to plan their families.', 'Another concern is the use of this technology for nongenetic disorders such as gender selection. ']

['Preimplantation Genetic Diagnosis can be used for gender selection.']

['yes']

Is Alpers disease inherited in an autosomal recessive mode?

['Alpers-Huttenlocher syndrome (AHS) is a very rare autosomal recessive disorder', 'Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder that affects children and young adults', "Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease", 'Histopathological findings in both patients ((a) chronic hepatitis with prominent bile duct proliferation, fatty change, and fibrosis; (b) in the brain a patchy destruction of the cerebral cortex, predominantly involving striate cortex) were characteristic of progressive neuronal degeneration of childhood with liver disease--Alpers-Huttenlocher syndrome--a rare autosomal recessive disorder usually seen in infants and young children', 'Histopathological findings in both patients ((a) chronic hepatitis with prominent bile duct proliferation, fatty change, and fibrosis; (b) in the brain a patchy destruction of the cerebral cortex, predominantly involving striate cortex) were characteristic of progressive neuronal degeneration of childhood with liver disease--Alpers-Huttenlocher syndrome--a rare autosomal recessive disorder usually seen in infants and young children.', 'Alpers syndrome is a rare autosomal recessive hepatocerebral degenerative disorder.', 'Alpers disease is a recessive mitochondrial disorder caused by mutations in POLG1 and characterized primarily by progressive neurological and hepatic degeneration.', 'Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder that affects children and young adults.', 'We conclude that Alpers disease can be a cause of rapidly progressive liver failure in early childhood. Although the cause of this autosomal recessive disease is not known, it does not appear to be related to peroxisomal dysfunction.']

['Alpers disease is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease.', 'Alpers-Huttenlocher syndrome (AHS) is a very rare autosomal recessive disorder']

['yes']

Is RANKL secreted from the cells?

['Osteoprotegerin (OPG) is a soluble secreted factor that acts as a decoy receptor for receptor activator of NF-κB ligand (RANKL) ', 'Osteoprotegerin (OPG) is a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily. It usually functions in bone remodeling, by inhibiting osteoclastogenesis through interaction with a receptor activator of the nuclear factor κB (RANKL).', 'e RANKL/OPG ratio secreted by osteoblasts increased and RANK expression by osteoclasts increased, leading to increased osteoclastogenesis', 'Osteoprotegerin (OPG) is an essential secreted protein in bone turnover due to its role as a decoy receptor for the Receptor Activator of Nuclear Factor-kB ligand (RANKL) in the osteoclasts, thus inhibiting their differentiation', 'We identify a TNFSF11 transcript variant that extends the originally identified transcript encoding secreted RANKL.', 'Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL.', 'OPG, on the other hand, is secreted by osteoblast as a decoy receptor for RANKL, prevents RANKL from binding to RANK and thus prevents bone resorption', 'Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) are cytokines predominantly secreted by osteoblasts and play a central role in differentiation and functional activation of osteoclasts', 'Although B. abortus-activated T cells actively secreted the pro-osteoclastogenic cytokines RANKL and IL-17, osteoclastogenesis depended on IL-17, because osteoclast generation induced by Brucella-activated T cells was completely abrogated when these cells were cultured with BMMs from IL-17 receptor knockout mice. ', ' osteoclastogenesis and bone destruction in autoimmune arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression profile and the capacity of their secreted factors to induce osteoclastogenesis.', 'Osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) are cytokines predominantly secreted by osteoblasts and play critical roles in the differentiation and function of osteoclasts. ']

['Receptor activator of nuclear factor κB ligand (RANKL) is a cytokine predominantly secreted by osteoblasts.']

['yes']

What does mTOR stands for?

[' mammalian target of rapamycin (mTOR)', 'mammalian target of rapamycin (mTOR)', 'mammalian target of rapamycin (mTOR)', 'mammalian target or rapamycin (mTOR)', 'mammalian target of rapamycin (mTOR)', 'mammalian target of rapamycin (mTOR) ', ' mammalian target of rapamycin (mTOR)', ' mammal target of rapamycin (mTOR)', ' mammalian target of rapamycin (mTOR)', 'mammalian Target of Rapamycin (mTOR)', ' mammalian target of rapamycin (mTOR) ']

['mTOR stands for: mammalian target of rapamycin.']

['mammalian target of rapamycin']

In which types of DNA repair is the UvrAB complex involved?

['illegitimate recombination is mostly suppressed by UvrA and UvrB.', 'UvrAB complex suppresses illegitimate recombination', 'Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) that acts specifically on lesions in the transcribed strand of expressed genes.', 'the transcription repair coupling factor, Mfd. This protein recruits the NER lesion-recognition factor UvrA, and then dissociates from the DNA. UvrA binds UvrB, and the assembled UvrAB* complex initiates repair.', 'UvrB plays a key role in bacterial nucleotide excision repair. It is the ultimate damage-binding protein that interacts with both UvrA and UvrC.', 'UvrB subunits bind to UvrA, most likely as part of a UvrA2B2 complex', 'Escherichia coli nucleotide excision repair (NER) is responsible for removing bulky DNA adducts by dual incisions of the UvrABC endonuclease.', 'the activity of the UvrAB complex which can induce DNA conformational change is employed in NER', 'The recognition by Escherichia coli Uvr nucleotide excision repair proteins of a variety of lesions with diverse chemical structures and the presence of helicase activity in the UvrAB complex which can displace short oligonucleotides annealed to single-stranded DNA led to a model in which this activity moves UvrAB along undamaged DNA to damaged sites where the lesion blocks further translocation and the protein-DNA pre-incision complex is formed.', 'Transcription when coupled to nucleotide excision repair specifies the location in active genes where preferential DNA repair is to take place.', 'Transcription when coupled to nucleotide excision repair specifies the location in active genes where preferential DNA repair is to take place', 'The recognition by Escherichia coli Uvr nucleotide excision repair proteins of a variety of lesions with diverse chemical structures and the presence of helicase activity in the UvrAB complex which can displace short oligonucleotides annealed to single-stranded DNA led to a model in which this activity moves UvrAB along undamaged DNA to damaged sites where the lesion blocks further translocation and the protein-DNA pre-incision complex is formed', 'Transcription-coupled DNA repair in prokaryotes.']

['UvrB and the lesion-recognition factor UvrA form the UvrAB complex, which plays a key role in bacterial nucleotide excision repair (NER). In transcription-coupled repair (TCR), the transcription repair coupling factor Mfd recruits uvrA, and the assembled UvrAB complex initiates repair. UvrAB complex also suppresses illegitimate recombination.']

['nucleotide excision repair (NER)', 'transcription-coupled repair (TCR)', 'suppression of illegitimate recombination']

What causes Katayama Fever?

['The laboratory diagnosis of schistosomiasis and Katayama syndrome in returning travellers is difficult because the number of excreted eggs is often very limited.', 'Eosinophilia (sometimes exceeding 50%) is often present in patients with acute schistosomiasis (Katayama fever), but may be limited or absent in late fibrotic manifestations of the disease.', 'Laboratory diagnosis of schistosomiasis and Katayama syndrome in returning travellers', 'The specific diagnosis of early schistosomiasis and Katayama fever relies essentially on serologic tests or preferably on PCR (if available). ', 'BACKGROUND: Katayama fever is an acute clinical condition characterised by high fever, dry cough and general malaise occurring during early Schistosoma spp. infection.', 'Schistosomiasis is a helminthic infection that is endemic in tropical and subtropical regions.', 'In Africa, it predominantly manifests as urogenital disease, and the main infective agent is Schistosoma hematobium.', 'His symptoms were caused by acute invasive schistosomiasis, also known as Katayama fever.', 'OBJECTIVES: To investigate the characteristics of imported Katayama fever (acute schistosomiasis) as well as evolution and outcome under treatment.', 'RESULTS: Twenty-three patients were diagnosed with Katayama fever by Schistosoma egg detection and/or by seroconversion. ', 'The best therapeutic approach to acute schistosomiasis (Katayama fever) is still unsettled.', 'Katayama fever is an acute clinical condition characterised by high fever, dry cough and general malaise occurring during early Schistosoma spp.', "Acute schistosomiasis, called safari's fever in Africa and Katayama fever in Japan, is an immunoallergic reaction due to transcutaneous penetration of infective cercaria.", '[Acute schistosomiasis (Katayama fever)].', 'Acute schistosomiasis (Katayama fever): corticosteroid as adjunct therapy.', 'Katayama fever or acute schistosomiasis probably occurs more commonly than is recorded.', 'His symptoms were caused by acute invasive schistosomiasis, also known as Katayama fever.', "Three distinct syndromes caused by schistosomiasis have been described: cercarial dermatitis or swimmer's itch, acute schistosomiasis or Katayama fever, and chronic schistosomiasis.", 'Three well-defined syndromes caused by schistosomiasis mansoni have been described: the stage of invasion, acute schistosomiasis (Katayama fever), and chronic schistosomiasis.', 'Early detection of circulating anodic antigen (CAA) in a case of acute schistosomiasis mansoni with Katayama fever.', ' A 35-year-old man presented with fever and severe urticaria after visiting Uganda. His symptoms were caused by acute invasive schistosomiasis, also known as Katayama fever.', 'His symptoms were caused by acute invasive schistosomiasis, also known as Katayama fever. .', 'Three well-defined syndromes caused by schistosomiasis mansoni have been described: the stage of invasion, acute schistosomiasis (Katayama fever), and chronic schistosomiasis.', 'Three distinct syndromes caused by schistosomiasis have been described: cercarial dermatitis or swimmer's itch, acute schistosomiasis or Katayama fever, and chronic schistosomiasis.', ' To investigate the characteristics of imported Katayama fever (acute schistosomiasis) as well as evolution and outcome under treatment. Between April 2000 and September 2004, we included prospectively all patients with confirmed diagnosis of Katayama fever.', 'A 35-year-old man presented with fever and severe urticaria after visiting Uganda. His symptoms were caused by acute invasive schistosomiasis, also known as Katayama fever.', 'To investigate the characteristics of imported Katayama fever (acute schistosomiasis) as well as evolution and outcome under treatment. Between April 2000 and September 2004, we included prospectively all patients with confirmed diagnosis of Katayama fever.']

['Katayama fever is an acute clinical condition characterised by high fever, dry cough and general malaise occurring during early Schistosoma spp. infection.']

['Schistosoma spp']

What type of arrhythmia is known as bidirectional ventricular tachycardia (BDVT)?

['Bidirectional ventricular tachycardia (BVT) is an uncommon type of polymorphic ventricular tachycardia (PVT) with alternating polarity of the QRS complex most commonly described digitalis toxicity. ', 'Bidirectional ventricular tachycardia (BVT), which is characterized by an alternating beat-to-beat ECG QRS axis, is a rare but intriguing arrhythmia associated with digitalis toxicity, familial catecholaminergic polymorphic ventricular tachycardia (CPVT), and several other conditions that predispose cardiac myocytes to delayed afterdepolarizations (DADs) and triggered activity. Evidence from human and animal studies attributes BVT to alternating ectopic foci originating from the distal His-Purkinje system in the left and/or right ventricle, respectively.', 'When the heart rate exceeded the threshold for bigeminy at the first site in the His-Purkinje system, ventricular bigeminy developed, causing the heart rate to accelerate and exceed the threshold for bigeminy at the second site. Thus, the triggered beat from the first site induced a triggered beat from the second site. The triggered beat from the second site next reciprocated by inducing a triggered beat from the first site, and so forth. Bigeminy from two sites produced BVT, and that from three or more sites produced polymorphic VT.', 'This "ping pong" mechanism of reciprocating bigeminy readily produces the characteristic ECG pattern of BVT and its degeneration to polymorphic VT if additional sites develop bigeminy.', 'The BVT, in this case, was most likely due to myocardial ischema. The ethiology of published BVT cases are most commonly digitalis toxicity and rarely herbal aconitine poisoning, hypokalemic periodic paralysis, cathecolaminergic VT, myocarditis, and Anderson-Tawil syndrome.', 'Bidirectional ventricular tachycardia (BVT), although a rare arrhythmia in the general population, is frequently observed in patients with Andersen-Tawil syndrome and long QT interval. However, the pharmacologic treatment of this arrhythmia remains unknown.', 'This report suggests that flecainide can be effective in controlling BVT associated with Andersen-Tawil syndrome and indicates that the left ventricular dysfunction is secondary to the arrhythmia and not due to an associated phenotypic manifestation of the disorder.', 'Based on similarity of electrocardiographic features, bidirectional ventricular tachycardia has been considered a variant of long QT syndrome.', 'Double ventricular ectopic rhythms had bizarre abnormal QRS complexes of two different morphologies and were inscribed in opposite directions. Ectopic rhythms in each case had parasystolic characteristics. These observations suggest bifocal automaticity as a mechanism for bidirectional ventricular tachycardia.', 'Bidirectional ventricular tachycardia, defined as the rapid alternation of the QRS complexes with successive opposing axial deviation, is a rare arrhythmia. In the rare cases which have undergone endocavitary investigations, an infrahisian origin has generally been proved. However, the mechanism of these tachycardias remains poorly understood and is discussed with respect to a new case.', 'In the light of previously reported cases with documented endocavitary investigation and this new case, it seems possible to talk in terms of true "bidirectional ventricular tachycardia", a tachycardia whose mechanism is obscure but certainly not univocal.', 'Bidirectional ventricular tachycardia (BVT) is an uncommon type of polymorphic ventricular tachycardia (PVT) with alternating polarity of the QRS complex most commonly described digitalis toxicity.', 'BACKGROUND: Bidirectional ventricular tachycardia (BVT), which is characterized by an alternating beat-to-beat ECG QRS axis, is a rare but intriguing arrhythmia associated with digitalis toxicity, familial catecholaminergic polymorphic ventricular tachycardia (CPVT), and several other conditions that predispose cardiac myocytes to delayed afterdepolarizations (DADs) and triggered activity.', 'Bidirectional ventricular tachycardia (BVT) is an uncommon type of polymorphic ventricular tachycardia (PVT) with alternating polarity of the QRS complex most commonly described digitalis toxicity', 'Bidirectional ventricular tachycardia, defined as the rapid alternation of the QRS complexes with successive opposing axial deviation, is a rare arrhythmia', 'Bidirectional ventricular tachycardia (BVT) is an uncommon type of polymorphic ventricular tachycardia (PVT) with alternating polarity of the QRS complex most commonly described digitalis toxicity']

['Bidirectional ventricular tachycardia (BVT), which is characterized by an alternating beat-to-beat ECG QRS axis, is a rare but intriguing arrhythmia associated with digitalis toxicity, familial catecholaminergic polymorphic ventricular tachycardia (CPVT), and several other conditions that predispose cardiac myocytes to delayed afterdepolarizations (DADs) and triggered activity. Bidirectional ventricular tachycardia (BVT) is an uncommon type of polymorphic ventricular tachycardia (PVT). Based on similarity of electrocardiographic features, bidirectional ventricular tachycardia has been considered a variant of long QT syndrome. Evidence from human and animal studies attributes BVT to alternating ectopic foci originating from the distal His-Purkinje system in the left and/or right ventricle, respectively. This "ping pong" mechanism of reciprocating bigeminy readily produces the characteristic ECG pattern of BVT and its degeneration to polymorphic VT if additional sites develop bigeminy.']

[]

Which are the subtypes of Pfeiffer syndrome?

['Of 802 patients treated for craniosynostosis, 28 were identified with Pfeiffer syndrome: 17 were classified as type I (61 percent), seven were classified as type II (25 percent), and four were classified as type III (14 percent). ', 'Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull. ', 'Recently, based on clinical findings, the disorder has been divided into three subtypes: type 1, characterized by mild expression; type 2, in which clover leaf skull deformity and multiple congenital anomalies are present at birth; and type 3, which is similar to type 2, but lacks the presence of the clover leaf skull at birth. ', 'It is a clinically variable disorder and has been divided into three subtypes [Cohen, 1993: Am J Med Genet 45:300-307]. Type 1 represents the less severe cases, while types 2 and 3 are the more severe cases. These latter types tend to have a higher risk for neurodevelopmental problems and a reduced life expectancy.', 'Classic Pfeiffer syndrome is designated type I. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet together with ankylosis of the elbows. Such patients do poorly with an early death. All reported instances to date have been sporadic. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe in degree and the anterior cranial base is markedly short. These patients also do poorly and tend to have an early death. To date all cases have occurred sporadically. Although these 3 clinical subtypes do not have status as separate entities, their diagnostic and prognostic implications are important. Type 1 is commonly associated with normal intelligence, generally good outcome, and can be found dominantly inherited in some families. Types 2 and 3 generally have severe neurological compromise, poor prognosis, early death, and sporadic occurrence. ']

['Pfeiffer syndrome is divided into three clinical subtypes.', 'Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull.']

['Type I', 'Type I (1)', 'Type II', 'Type II (2)', 'Type III', 'Type III (3)']

How many genes outside of the MHC locus have been genetically associated to Rheumatoid Arthritis through GWAS?

['Genome-Wide Association Studies (GWAS) have allowed the characterization of more than 40 new susceptibility genes and the confirmation of a marked differential genetic background between patients expressing anti-cyclic citrullinated peptide antibodies (ACPA, approximately 80% of all RA patients) and ACPA negative RA patients', 'Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. ', 'The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis.', 'The meta-analysis results showed that: (1) 30, 28 and 26 SNPs were significantly associated with RA (P<0.01) for the allele, dominant, and recessive models, respectively.', 'This paper compares corresponding non-MHC genomic regions identified in rodent and human genome-wide association studies (GWAS). To date, over 30 non-MHC RA-associated loci have been identified in humans, and over 100 arthritis-associated loci have been identified in rodent models of RA', 'Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease', 'Among these genes, PTPN22 plays an outstanding role. CD40, STAT4, PRM1, and TNFAIP3 also seem to be of relevance', 'Genome-wide association studies (GWASs) added about 10 new loci to the list of already more than 20 loci associated with RA, so the list is now over 30', 'Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases.', 'These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry', 'An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.', 'Genome-wide association studies have expanded the number of validated RA risk loci beyond HLA-DRB1 "shared epitope" alleles to include additional major histocompatibility complex (MHC) risk alleles and more than 10 regions outside the MHC.', 'We successfully identified 41 significant SNPs relevant to RA, 25 associated genes and a number of important SNP-SNP interactions (SNP patterns)', 'A total of 47 candidate regions were identified. ']

['Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. To date, over 30 non-MHC RA-associated loci have been identified in humans, and over 100 arthritis-associated loci have been identified in rodent models of RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases.']

['more than 30']

Which disease the London mutation involved in?

['In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). ', "The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimer's disease mouse model.", "One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation.", "The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease.", 'We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation.', 'In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation.', 'A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The "Swedish" mutations (APP(SW)) and the "London" mutation (APP(LON)) are examples of these mutants. ', 'The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.', "Here, we show ASP-RNAi against the Swedish- and London-type amyloid precursor protein (APP) variants related to familial Alzheimer's disease using two reporter alleles encoding the Photinus and Renilla luciferase genes and carrying mutant and wild-type allelic sequences in their 3'-untranslated regions. ", "Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimer's disease (V642I, so-called London mutation, hereafter APPLd2) and wild-type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques.", 'The "Swedish" mutations (APP(SW)) and the "London" mutation (APP(LON)) are examples of these mutants.', "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations.", 'Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimers disease (AD).We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation.In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far', 'The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimers disease', 'We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system.', 'We demonstrate that the APP-London and PS1 mutations have additive effects on the increased secretion of betaA4(1-42) relative to betaA4(1-40), indicating that both mutations operate independently.', 'Pathogenic mutations in APP at codon 717 (APP "London") lead to an increased proportion of Abeta 1-42 being produced and secreted.', 'The "Swedish" mutations (APP(SW)) and the "London" mutation (APP(LON)) are examples of these mutants.', "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations.", 'We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation.', "The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease.", 'Such cleavage is promoted by the Swedish and London mutations (APPSwe/Lon) inside the APP gene.', 'We also show that the Swedish and London mutations reduce the amount of APP in the lysosome.', 'This rapid transit to the lysosome is blocked by the presence of either the London or Swedish mutations.']

["London mutation that is the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile) is involved in Alzheimer's Disease."]

["Alzheimer's Disease", 'AD']

What is the effect of the direct interaction of Ikaros and Foxp1 in B-lymphocytes?

['Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia.', 'We describe a novel physical and functional interaction between the proteins, which requires the central zinc finger domain of Ikaros. The Ikaros-Foxp1 interaction is abolished by deletion of this region, which corresponds to the IK6 isoform that is commonly associated with high-risk acute lymphoblastic leukemia (ALL). We also identify the Gpr132 gene, which encodes the orphan G protein-coupled receptor G2A, as a novel target for Foxp1. ', 'Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL.', 'Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL.', 'Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia.', 'Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL..']

['Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia.', 'The effect of the direct interaction of Ikaros and Foxp1 in B-lymphocytesis is modulation of expression of the G protein-coupled receptor G2A.']

['Modulation of expression of the G protein-coupled receptor G2A.']

What is the role of lysine-specific demethylase 1 (LSD1) in hematopoiesis?

['Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells', 'we demonstrate that LSD1, a histone lysine demethylase, also participates in the trans-repressive effects of SALL4. Based on luciferase assays, the amine oxidase domain of LSD1 is important in suppressing SALL4-mediated reporter transcription. In freshly isolated adult mouse bone marrows, both SALL4 and LSD1 proteins are preferentially expressed in undifferentiated progenitor cells and co-localize in the nuclei', 'Further sequential chromatin immunoprecipitation assay confirmed that these two factors share the same binding sites at the promoter regions of important hematopoietic regulatory genes including EBF1, GATA1, and TNF', 'our data revealed that histone demethylase LSD1 may negatively regulate SALL4-mediated transcription, and the dynamic regulation of SALL4-associated epigenetic factors cooperatively modulates early hematopoietic precursor proliferation', 'RUNX1 has been shown to be part of a large transcription factor complex, together with LDB1, GATA1, TAL1, and ETO2 (N. Meier et al., Development 133:4913-4923, 2006) in erythroid cells. We used a tagging strategy to show that RUNX1 interacts with two novel protein partners, LSD1 and MYEF2, in erythroid cells. MYEF2 is bound in undifferentiated cells and is lost upon differentiation, whereas LSD1 is bound in differentiated cells', 'Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation', 'LSD1 represents a central regulator of hematopoietic stem and progenitor cells. LSD1 knockdown (LSD1-kd) expanded progenitor numbers by enhancing their proliferative behavior. LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors. In contrast, terminal granulopoiesis, erythropoiesis and platelet production were severely inhibited. The only exception was monopoiesis, which was promoted by LSD1 deficiency. Importantly, we showed that peripheral blood granulocytopenia, monocytosis, anemia and thrombocytopenia were reversible after LSD1-kd termination. Extramedullary splenic hematopoiesis contributed to the phenotypic reversion, and progenitor populations remained expanded. LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b, Hoxa9 and Meis1, which are known regulators of the HSC/progenitor compartment. We also demonstrated that LSD1-kd abrogated Gfi1b-negative autoregulation by crossing LSD1-kd with Gfi1b:GFP mice. Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy', 'A short Gfi-1B isoform controls erythroid differentiation by recruiting the LSD1-CoREST complex through the dimethylation of its SNAG domain', 'Gfi-1B p32 isoform binds to Gfi-1B target gene promoters and associates with the LSD1-CoREST repressor complex more efficiently than the major Gfi-1B p37 isoform', 'Furthermore, we show that Gfi-1B includes a KSKK motif in its SNAG domain, which recruits the repressor complex only when dimethylated on lysine 8. Mutation of lysine 8 prevents Gfi-1B p32-induced erythroid development. Our results thus highlight a key role for the alternatively spliced Gfi-1B p32 isoform in erythroid development', 'Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis', 'we reported that protein kinase A (PKA)-mediated phosphorylation regulates TAL1 interaction with the lysine-specific demethylase (LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails. Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 interaction leading to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis. Knockdown of TAL1 or LSD1 led to a derepression of the TAL1 target genes in T-cell acute lymphoblast leukemia (T-ALL) Jurkat cells, which is accompanied by elevating promoter H3K4 methylation. Similarly, treatment of PKA activator forskolin resulted in derepression of target genes by reducing its interaction with LSD1 while PKA inhibitor H89 represses them by suppressing H3K4 methylation levels. Consistent with the dual roles of TAL1 in transcription, TAL1-associated LSD1 is decreased while recruitment of hSET1 is increased at the TAL1 targets during erythroid differentiation', 'TAL1 has recently been shown to differentially recruit LSD1 and other histone modifying complexes to regulate its target genes', 'LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis', 'we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells', 'The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. Finally, shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs.', 'Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1', 'To elucidate the function of Gfi proteins, we purified Gfi-1b complexes and identified interacting proteins. Prominent among these is the corepressor CoREST, the histone demethylase LSD1, and HDACs 1 and 2. CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain. Gfi-1b further recruits these cofactors to the majority of target gene promoters in vivo', 'Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy.', 'LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis.', 'Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis.', 'Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 interaction leading to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis.', 'Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells.', 'Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy.']

['LSD1 represents a central regulator of hematopoietic stem and progenitor cells. LSD1 knockdown (LSD1-kd) expanded progenitor numbers by enhancing their proliferative behavior. LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors. In contrast, terminal granulopoiesis, erythropoiesis and platelet production were severely inhibited. The only exception was monopoiesis, which was promoted by LSD1 deficiency. Importantly, we showed that peripheral blood granulocytopenia, monocytosis, anemia and thrombocytopenia were reversible after LSD1-kd termination. Extramedullary splenic hematopoiesis contributed to the phenotypic reversion, and progenitor populations remained expanded. LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b, Hoxa9 and Meis1, which are known regulators of the HSC/progenitor compartment. We also demonstrated that LSD1-kd abrogated Gfi1b-negative autoregulation by crossing LSD1-kd with Gfi1b:GFP mice. There is also epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b that is mediated by the cofactors CoREST and LSD1. A short Gfi-1B isoform controls erythroid differentiation by recruiting the LSD1-CoREST complex through the dimethylation of its SNAG domain. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. ShRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, it appears that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs. Furthermore, RUNX1 has been shown to be part of a large transcription factor complex, together with LDB1, GATA1, TAL1, and ETO2 in erythroid cells. RUNX1 interacts with LSD1 and MYEF2 in erythroid cells. MYEF2 is bound in undifferentiated cells and is lost upon differentiation, whereas LSD1 is bound in differentiated cells. Finally, LSD1 also participates in the trans-repressive effects of SALL4. Based on luciferase assays, the amine oxidase domain of LSD1 is important in suppressing SALL4-mediated reporter transcription. In freshly isolated adult mouse bone marrows, both SALL4 and LSD1 proteins are preferentially expressed in undifferentiated progenitor cells and co-localize in the nuclei. Further sequential chromatin immunoprecipitation assay confirmed that these two factors share the same binding sites at the promoter regions of important hematopoietic regulatory genes including EBF1, GATA1, and TNF.']

[]

Which proteins constitute the methyl-directed mismatch repair system (MMR) in bacteria?

['MutY and MutSL (mismatch repair system [MMR])', 'Escherichia coli DNA Mismatch Repair (MMR) protein MutS ', 'We have characterized the mismatch repair system (MMR) of the highly radiation-resistant type strain of Deinococcus radiodurans, ATCC 13939. We show that the MMR system is functional in this organism, where it participates in ensuring the fidelity of DNA replication and recombination. The system relies on the activity of two key proteins, MutS1 and MutL, which constitute a conserved core involved in mismatch recognition.', 'the mutS/L operon essential for methyldirected mismatch repair (MMR) activity', 'The mismatch repair system (mutS, mutL and uvrD genes) in Pseudomonas aeruginosa', 'The mismatch repair system (MMR) recognizes and corrects mismatched or unpaired bases caused mainly by DNA polymerase, and contributes to the fidelity of DNA replication in living cells. In Escherichia coli, the MutHLS system is known to function in MMR, and homologues of MutS and MutL are widely conserved in almost all organisms.', 'A simple genetic system has been developed to test the effect of over-expression of wild-type or mutated human MutL homologue 1 (hMLH1) proteins on methyl-directed mismatch repair (MMR) in Escherichia coli.', 'Among these six mutated genes was mutS, which encodes a component of the methyl-directed mismatch repair (MMR) system.', 'The majority of naturally occurring, strong mutators contain defects in the methyl-directed mismatch repair (MMR) system, with mutations in mutS predominating.', 'The picture of MutH-independent MMR in other bacteria is less clear, as MMR components other than MutS and MutL have not been identified in the majority of bacteria.', 'The methyl-directed mismatch repair (MMR) mechanism has been extensively studied in vitro and in vivo, but one of the difficulties in determining the biological relationships between the MMR-related proteins is the tendency of MutL to self-aggregate.', 'Among these six mutated genes was mutS, which encodes a component of the methyl-directed mismatch repair (MMR) system.', 'MutL is required to assist the mismatch repair protein MutS during initiation of the methyl-directed mismatch repair (MMR) response in various organisms ranging from prokaryotes to eukaryotes.', 'Moreover, methyl-directed mismatch repair (MMR) is known to trigger sensitivity to methylating agents via a mechanism that involves recognition by MutS of the O(6)-mG:T replication intermediates.', 'The system relies on the activity of two key proteins, MutS1 and MutL, which constitute a conserved core involved in mismatch recognition.', 'In Escherichia coli, the best studied mismatch repair (MMR) pathway is the methyl-directed long patch repair system which is mediated by three gene products; MutS, MutL and MutH.', 'Cells devoid of MutS1 or MutL proteins were as resistant to gamma-rays, mitomycin C and UV-irradiation as wild-type bacteria, suggesting that the mismatch repair system is not essential for the reconstitution of a functional genome after DNA damage.', 'The system relies on the activity of two key proteins, MutS1 and MutL, which constitute a conserved core involved in mismatch recognition']

['The mismatch repair system (MMR) recognizes and corrects mismatched or unpaired bases caused mainly by DNA polymerase, and contributes to the fidelity of DNA replication in living cells. In bacteria, the methyldirected mismatch repair (MMR) is comprised of MutS and MutL proteins, encoded by the mutS/L operon.']

['mutS', 'mutL', 'mutH']

Which is the target protein of the drug nivolumab?

['nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody', ' Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor)', 'Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, ', ' programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma', 'Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. ', 'Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor,']

['Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation.']

['programmed death receptor-1']

Is exonuclease Xrn1 a component of the P-bodies?

["PBs are associated with mRNA decay and contain the decapping enzymes DCP1/2, the 5' to 3' exonuclease Xrn1, the Lsm proteins (1-7), and the scaffolding proteins hedls/GE-1 and GW182. Both SGs and PBs contain mRNA, eIF4E, microRNAs and argonaute proteins, and various regulators of mRNA stability and translation (TTP, RCK/p54, and CPEB).", "An alternative pathway of mRNA degradation occurs at processing bodies, cytoplasmic foci that contain decapping enzymes, the 5'-3' exonuclease Xrn1 and the Lsm1-7 heptamer. ", "n eukaryotic cells degradation of bulk mRNA in the 5' to 3' direction requires the consecutive action of the decapping complex (consisting of DCP1 and DCP2) and the 5' to 3' exonuclease XRN1. These enzymes are found in discrete cytoplasmic foci known as P-bodies or GW-bodies (because of the accumulation of the GW182 antigen).", "Several proteins that stimulate mRNA decapping by the Dcp1:Dcp2 complex co-localize with Dcp1 and Dcp2, together with Xrn1, a 5'-to-3' exonuclease, to structures in the cytoplasm called processing bodies. ", ' On the other hand, many P-body components including LSM1, GW182, DDX3, DDX6 and XRN1, but not others like DCP1a and EDC4 are recruited to the viral replication sites, as evidenced by their colocalization at perinuclear region with viral NS3.', 'We identified the Pab 1801 cytoplasmic puncta as P Bodies (PBs), which are involved in mRNA regulation. We found that, in several cell lines, including U2OS, WI38, SK-N-SH and HCT116, the Pab 1801 puncta strictly colocalize with PBs identified with specific antibodies against the PB components Hedls, Dcp1a, Xrn1 or Rck/p54.', "The core components of P-bodies, including the decapping machinery (Dcp2 and Dhh1), 5'-3' exoribonuclease (Kem1/Xrn1), and the P-body scaffolding protein (Edc3), were identified and their localizations with respect to P-bodies were demonstrated.", 'The second type of granules, piP-bodies, harbors the MIWI2-TDRD9-MAEL module of the piRNA pathway and signature components of P-bodies, GW182, DCP1a, DDX6/p54, and XRN1 proteins.', 'In yeast and human tissue culture cells, Xrn1 has been shown to be a component of P-bodies (processing bodies), dynamic cytoplasmic granules where RNA degradation can take place.', 'Here, we show that staufen- and FMRP-containing RNPs in Drosophila neurons contain proteins also present in somatic "P bodies," including the RNA-degradative enzymes Dcp1p and Xrn1p/Pacman and crucial components of miRNA (argonaute), NMD (Upf1p), and general translational repression (Dhh1p/Me31B) pathways.', " In eukaryotic cells, XRN1 is often found in particles known as processing bodies (P bodies) together with other proteins involved in the 5' → 3' degradation pathway, such as DCP2 and the helicase DHH1 (Me31B). ", 'In yeast and human tissue culture cells, Xrn1 has been shown to be a component of P-bodies (processing bodies), dynamic cytoplasmic granules where RNA degradation can take place', 'Owing to the essential functions of P bodies in mRNA regulation, we explored computationally the functional significance of SNPs in 7 P body components such as XRN1, DCP2, EDC3, CPEB1, GEMIN5, STAU1 and TRIM71', 'The core components of P-bodies, including the decapping machinery (Dcp2 and Dhh1), 5&apos;-3&apos; exoribonuclease (Kem1/Xrn1), and the P-body scaffolding protein (Edc3), were identified and their localizations with respect to P-bodies were demonstrated', 'Here, we show that staufen- and FMRP-containing RNPs in Drosophila neurons contain proteins also present in somatic &quot;P bodies,&quot; including the RNA-degradative enzymes Dcp1p and Xrn1p/Pacman and crucial components of miRNA (argonaute), NMD (Upf1p), and general translational repression (Dhh1p/Me31B) pathways', 'P-body components LSM1, GW182, DDX3, DDX6 and XRN1 are recruited to WNV replication sites and positively regulate viral replication.', 'The core components of P-bodies, including the decapping machinery (Dcp2 and Dhh1), 5&apos;-3&apos; exoribonuclease (Kem1/Xrn1), and the P-body scaffolding protein (Edc3), were identified and their localizations with respect to P-bodies were demonstrated. Various growth conditions, including glucose deprivation, hyperosmotic stress, and heat stress, stimulated the accumulation of P-bodies.', 'Here we show that microscopically visible P-bodies are greatly diminished following West Nile viral infection, but the component proteins are not depleted. On the other hand, many P-body components including LSM1, GW182, DDX3, DDX6 and XRN1, but not others like DCP1a and EDC4 are recruited to the viral replication sites, as evidenced by their colocalization at perinuclear region with viral NS3.', 'Owing to the essential functions of P bodies in mRNA regulation, we explored computationally the functional significance of SNPs in 7 P body components such as XRN1, DCP2, EDC3, CPEB1, GEMIN5, STAU1 and TRIM71. Computational analyses of non-synonymous SNPs of these components was initiated using well utilized publicly available software programs such as the SIFT, followed by PolyPhen, PANTHER, MutPred, I-Mutant-2.', 'Xrn1 has been shown to be a component of P-bodies (processing bodies),', "Here, we show that hDIS3L2 is an exosome-independent cytoplasmic mRNA 3'-5' exonuclease, which exhibits processive activity on structured RNA substrates in vitro. hDIS3L2 associates with hXRN1 in an RNA-dependent manner and can, like hXRN1, be found on polysomes", 'Inhibition of TAK1-JNK signaling also affected the number and size of P bodies and the localization of DCP1a, Xrn1, and Edc4.', " The organizing mechanism that forms P body foci in cells is unknown; however, potential scaffolding, aggregating, or other regulatory proteins found in P bodies were investigated for degradation. Two factors involved in 5'-end mRNA decapping and degradation, Xrn1 and Dcp1a, and the 3' deadenylase complex component Pan3 underwent accelerated degradation during infection, and Dcp1a may be a direct substrate of PV 3C proteinase.", 'Secondly, P-bodies recruit mRNAs that are targeted for deadenylation and degradation by the decapping/Xrn1 pathway. ', "Depletion of TRN increased the number of P-bodies and stabilized ARE-containing mRNAs, as observed with knockdown of the 5'-3' exonuclease Xrn1.", 'In this paper we show for the first time that Pacman, the Drosophila homologue of Xrn1, is localized in cytoplasmic particles in Drosophila testis cells. ', 'Depletion of TRN increased the number of P-bodies and stabilized ARE-containing mRNAs, as observed with knockdown of the 5&apos;-3&apos; exonuclease Xrn1', 'These structures stain positively for a number of P-body and microRNP components, a microRNA-repressed mRNA and some translational repressors. They appear more heterogeneous than P-bodies of HeLa cells, and they rarely contain the exonuclease Xrn1 but are positive for rRNA.']

["In eukaryotic cells, XRN1 is often found in particles known as processing bodies (P bodies) together with other proteins involved in the 5' → 3' degradation pathway, such as DCP2 and the helicase DHH1 (Me31B). In yeast and human tissue culture cells, Xrn1 has been shown to be a component of P-bodies (processing bodies), dynamic cytoplasmic granules where RNA degradation can take place. Many P-body components including LSM1, GW182, DDX3, DDX6 and XRN1, but not others like DCP1a and EDC4 are recruited to the viral replication sites, as evidenced by their colocalization at perinuclear region with viral NS3.", "In eukaryotic cells, degradation of bulk mRNA in the 5' to 3' direction requires the consecutive action of the decapping complex (consisting of DCP1 and DCP2) and the 5' to 3' exonuclease XRN1. These enzymes are found in discrete cytoplasmic foci known as P-bodies.", "We show that the RNA-binding protein GW182 and the DCP1:DCP2 decapping complex are required for miRNA-mediated gene silencing, uncovering a crucial role for P-body components in the miRNA pathway. An alternative pathway of mRNA degradation occurs at processing bodies, cytoplasmic foci that contain decapping enzymes, the 5'-3' exonuclease Xrn1 and the Lsm1-7 heptamer. Our results show that mammalian cells, similar to yeast, require the 5'-3' Xrn1 pathway to degrade ARE-mRNAs. Recent evidence suggests that the processing bodies may constitute specialized cellular compartments of mRNA turnover, which suggests that mRNA and protein localization may be integral to mRNA decay."]

['yes']

Which hormone abnormalities are characteristic to Pendred syndrome?

['Loss or reduction of function mutations of SLC26A4 underlie Pendred syndrome, a disorder invariably leading to hearing loss with enlarged vestibular aqueducts and in some patients to hypothyroidism and goiter.', 'Goiter development and hypothyroidism vary among affected individuals and seem to be partially dependent on nutritional iodide intake.', 'Elucidation of the molecular basis of Pendred syndrome and the function of pendrin has provided unexpected novel insights into the pathophysiology of the inner ear, thyroid hormone synthesis, and chloride/bicarbonate exchange in the kidney.', 'Thyroid goiter was found in 46.5% of cases.', 'Biallelic mutations of SLC26A4 (encoding pendrin) cause Pendred syndrome (PS), an autosomal recessive genetic disorder with deafness and goiter.', 'From age 15 years, her thyroid gland showed progressive enlargement accompanied by elevation of serum thyroglobulin reaching 10-fold the normal amount. ', 'In summary, a molecularly confirmed PS patient showed goiter progression accompanied by elevated serum thyroglobulin and increased thyroidal iodine uptake, but normal serum TSH levels and normal iodine organification.', 'A coherent organization of differentiation proteins is required to maintain an appropriate thyroid function in the Pendred thyroid.', 'Pendred syndrome is an autosomal recessive disorder defined by sensorineural deafness, goiter and a partial organification defect of iodide. ', 'The clinical phenotype of patients with Pendred syndrome and the fact that pendrin can mediate iodide efflux in transfected cells suggest that this anion exchanger may be involved in mediating iodide efflux into the follicular lumen, a key step in thyroid hormone biosynthesis. ', 'Results of immunoblot and immunofluorescence experiments reveal that TSH and forskolin rapidly increase pendrin abundance at the plasma membrane through the protein kinase A pathway in PCCL-3 rat thyroid cells. ', 'These results demonstrate that pendrin translocates to the membrane in response to TSH and suggest that it may have a physiological role in apical iodide transport and thyroid hormone synthesis.', 'Mutations in the SLC26A4 gene, coding for the anion transporter pendrin, are responsible for Pendred syndrome, characterized by congenital sensorineural deafness and dyshormonogenic goiter. ', 'Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter and a partial defect in iodide organification. Goiter development and hypothyroidism vary and appear to depend on nutritional iodide intake. ', 'Pendrin is mainly expressed in the thyroid, the inner ear, and the kidney. In the thyroid, pendrin localizes to the apical membrane of thyrocytes, where it may be involved in mediating iodide efflux. ', 'Mutations of SLC26A4 cause an enlarged vestibular aqueduct, nonsyndromic deafness, and deafness as part of Pendred syndrome. SLC26A4 encodes pendrin, an anion exchanger located in the cochlea, thyroid, and kidney. ', 'Genetic causes of goiter and deafness: Pendred syndrome in a girl and cooccurrence of Pendred syndrome and resistance to thyroid hormone in her sister.', 'Goiter and deafness can be associated in some genetic syndromes, e.g. Pendred syndrome (PS) and resistance to thyroid hormone (RTH). PS is an autosomal recessive disorder characterized by goiter and sensorineural hearing impairment with an enlarged vestibular aqueduct bilaterally.', 'The elder sister had an elevated TSH level at newborn screening followed by subclinical hypothyroidism, childhood-onset goiter, and bilateral progressive sensorineural hearing impairment with enlarged vestibular aqueducts, consistent with a diagnosis of PS.', 'This is the first report of the cooccurrence, in the same individual, of PS and RTH, two genetic syndromes both associated with goiter and hearing impairment.', 'Its diagnosis requires identification of the classical triad of symptoms, including hypoacusis, thyroid goitre and iodine organification defect in the thyroid, which may lead to thyroid functional disorders of hypothyroidism.', 'Endocrine examination showed hypothyroidism in 5, its subclinical form in 1, diffuse thyroid goitre in 4 and nodular thyroid goiter in 2 cases.', 'Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. ', 'Thyroidectomy in a patient with multinodular dyshormonogenetic goitre--a case of Pendred syndrome confirmed by mutations in the PDS/SLC26A4 gene.', 'We report a young woman with genetically confirmed Pendred syndrome and discuss the current therapeutic strategies of dyshormonogenetic goitre.', 'Management of a patient with Pendred syndrome requires careful follow-up and regular imaging of the thyroid. ', 'Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing impairment, presence of goiter, and a partial defect in iodide organification, which may be associated with insufficient thyroid hormone synthesis. Goiter development and development of hypothyroidism are variable and depend on nutritional iodide intake.', 'Pendred syndrome (PS) is an autosomal recessive disease that is characterized by congenital sensorineural hearing loss, goiter, and a partial iodine organification defect. ', 'Levels of thyroid hormones were essentially normal in all patients: 2 patients had goiters and/or elevated serum thyroglobulin levels, whereas 2 other patients had positive thyroid antibodies and a positive perchlorate discharge test. ', 'Pendred syndrome, defined as the constellation of goiter, sensori-neural hearing loss, and positive perchlorate discharge test, is the most frequent cause of congenital deafness. ', 'Presuming the classic triad as the gold standard, we compared MRI findings in six such defined patients with six cases having goiter, hearing loss, and normal perchlorate discharge test. ', 'For over 100 years after the first description of the disorder, the molecular pathology underlying the deafness and thyroid pathology in Pendred syndrome (PS) remained unknown. ', 'We review the literature to identify genetic defects involved in the iodination process of the thyroid hormone synthesis, particularly defects in iodide transport from circulation into the thyroid cell, defects in iodide transport from the thyroid cell to the follicular lumen (Pendred syndrome), and defects of iodide organification.', 'Among those causing dyshormonogenesis, the thyroid peroxidase and thyroglobulin genes were initially described, and more recently PDS (Pendred syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene defects. ', 'Among permanent CH cases, those with a goitre (n = 27) had an iodine organification defect (n = 10), Pendred syndrome (n = 1), a defect of thyroglobulin synthesis (n = 8), or a defect of sodium iodine symporter (n = 1), and in seven patients no aetiology could be determined.', 'Pendred syndrome consists in sensorineural deafness, goiter and impaired thyroid hormone synthesis while in EVA thyroid function seems to be preserved.', 'All patients harbouring mutations in the SLC26A4 gene had goiter and a positive perchlorate discharge test: 3 were slightly hypothyroid and 2 euthyroid. ', 'Patients with mutations in the SLC26A4 gene had larger thyroid volume (p<0.002), higher serum thyroglobulin (Tg) levels (p<0.002) and greater radioiodine discharge after perchlorate (p=0.09) than patients without mutations. ', "The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. ", 'Two patients were hypothyroid, two individuals were euthyroid.', 'Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and thyroid goiter. ', 'Pendred syndrome is an autosomal recessive disorder characterized by the association between sensorineural hearing loss and thyroid swelling or goitre and is likely to be the most common form of syndromic deafness. ', 'Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter).', 'Pendred syndrome consists in sensorineural deafness, goiter and impaired thyroid hormone synthesis while in EVA thyroid function seems to be preserved', 'Biallelic mutations of SLC26A4 (encoding pendrin) cause Pendred syndrome (PS), an autosomal recessive genetic disorder with deafness and goiter', 'Pendred syndrome (PS) is an autosomal recessive disease that is characterized by congenital sensorineural hearing loss, goiter, and a partial iodine organification defect', "Individuals were assigned affected status based on the characteristic clinical features of Pendred's syndrome, namely the presence of congenital sensorineural hearing loss and the appearance in early life of a goitre"]

['Thyroid hormone abnormalities are characteristic to Pendred syndrome. Hypothyroidism is the most common thyroid hormone abnormality in Pendred syndrome. Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter and a partial defect in iodide organification.']

['thyroid hormone abnormalities']

What is the Genomic Regions Enrichment of Annotations Tool (GREAT)?

['We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions', ' GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets', 'We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome.', 'We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome', 'We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. ', ' We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions.', 'We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions.']

['Genomic Regions Enrichment of Annotations Tool (GREAT) is a tool to analyse the functional significance of cis-regulatory regions identified by localised measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, many functions of these factors are recovered that are missed by existing gene-based tools, and testable hypotheses are generated. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.']

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Which is the most typical peptide sequence responsible for retrieval of endoplasmic reticulum (ER) lumenal proteins from the Golgi apparatus?

['Retention of soluble proteins in the endoplasmic reticulum is dependent on their interaction with the KDEL (Lys-Asp-Glu-Leu) receptor in the Golgi apparatus and their subsequent retrieval back to the endoplasmic reticulum.', 'the retrieval system for lumenal ER proteins. These proteins carry a specific sorting signal, typically the tetrapeptide KDEL, which is bound by a receptor in the Golgi apparatus.', 'The carboxyl-terminal Lys-Asp-Glu-Leu (KDEL), or a closely-related sequence, is important for ER localization of both lumenal as well as type II membrane proteins. This sequence functions as a retrieval signal at post-ER compartment(s)', 'the KDEL receptor is concentrated in the intermediate compartment, as well as in the Golgi stack', 'retrieval of KDEL-containing proteins occurs at multiple post-ER compartments up to the TGN along the exocytotic pathway', 'The erd2 protein is the receptor responsible for recycling proteins bearing the carboxyl-terminal sequence KDEL (single-letter amino acid code) to the endoplasmic reticulum, following their loss from that organelle by the process of forward transport']

['The lumenal endoplasmic reticulum (ER) proteins carry a specific sorting signal which enables their retrieval from multiple post-ER compartments (up to the TGN along the exocytotic pathway), back to the ER. The most typical such signal is the carboxyl-terminal Lys-Asp-Glu-Leu (KDEL), which is bound by a KDEL receptor in the Golgi apparatus, as well as in the intermediate compartment. Thus KDEL functions as a retrieval signal of lumenal ER proteins from Golgi to ER.']

['the carboxyl-terminal Lys-Asp-Glu-Leu (KDEL)']

Are there conserved noncoding elements identified between genomes of human and teleosts?

['We report evidence for a mechanism for the maintenance of long-range conserved synteny across vertebrate genomes. We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes', 'After whole genome duplication in teleosts, GRBs, including HCNEs and target genes, were often maintained in both copies, while bystander genes were typically lost from one GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy GRBs of higher vertebrates intact. We show that loss of bystander genes and other mutational events suffered by duplicated GRBs in teleost genomes permits target gene identification and HCNE/target gene assignment', 'Vertebrate genomes contain thousands of conserved noncoding elements (CNEs) that often function as tissue-specific enhancers. In this study, we have identified CNEs in human, dog, chicken, Xenopus, and four teleost fishes (zebrafish, stickleback, medaka, and fugu) using elephant shark, a cartilaginous vertebrate, as the base genome and investigated the evolution of these ancient vertebrate CNEs (aCNEs) in bony vertebrate lineages', 'This implicates the "fish-specific" whole-genome duplication in the accelerated evolution and the loss of a large number of both copies of duplicated CNEs in teleost fishes', 'We found zebrafish conserved noncoding elements (CNEs) with pan-vertebrate as well as fish-specific orthologous sequences from across 200 kb of the zebrafish fgf8a genomic regulatory block to direct reporter expression in patterns consistent with the expression pattern of fgf8a', ' A significant number of conserved noncoding elements (CNEs) shared between cartilaginous fishes and tetrapods have diverged beyond recognition in teleost fishes. The divergence of CNEs seems to have been initiated in basal ray-finned fishes before the WGD. The fast evolving singleton and duplicated genes as well as the divergent CNEs might have contributed to the diversity of teleost fishes', 'We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes.', 'Ancient vertebrate conserved noncoding elements have been evolving rapidly in teleost fishes.', 'A significant number of conserved noncoding elements (CNEs) shared between cartilaginous fishes and tetrapods have diverged beyond recognition in teleost fishes.', 'We have used a transposon-based transgenic assay in zebrafish to evaluate noncoding sequences at the zebrafish ret locus, conserved among teleosts, and at the human RET locus, conserved among mammals.', 'Using computational analysis and exploiting the diversity of teleost genomes, we identified a cluster of highly conserved noncoding sequences surrounding the Six3 gene']

['Vertebrate genomes contain thousands of conserved noncoding elements (CNEs) that often function as tissue-specific enhancers. In this study, we have identified CNEs in human, dog, chicken, Xenopus, and four teleost fishes (zebrafish, stickleback, medaka, and fugu) using elephant shark, a cartilaginous vertebrate, as the base genome and investigated the evolution of these ancient vertebrate CNEs (aCNEs) in bony vertebrate lineages ', 'Yes. Vertebrate genomes contain thousands of conserved noncoding elements (CNEs) that often function as tissue-specific enhancers. CNEs have been identified, among others, in human, dog, chicken, Xenopus, and four teleost fishes (zebrafish, stickleback, medaka, and fugu).']

['yes']

What is the purpose of the Orpington Prognostic Scale?

['Stroke severity was determined using the Orpington Prognostic Scale.', 'Predicting response to rehabilitation in elderly patients with stroke using the Orpington Prognostic Scale and selected clinical variables.', ' The purpose of this study was to determine the ability of the Orpington Prognostic Scale (OPS) to predict outcome and response to subacute rehabilitation in older patients with stroke.', 'The OPS scores were strong predictors of response to subacute rehabilitation and discharge FIM motor subscale scores. The OPS may warrant a broader application as a prognostic indicator for patients with stroke.', 'PURPOSE: The aim of our study is to compare the Orpington Prognostic Scale (OPS) and the National Institutes of Health Stroke Scale (NIHSS) and to evaluate whether they help us estimate the future functional status of patients with stroke.', 'Comparison of the Orpington Prognostic Scale (OPS) and the National Institutes of Health Stroke Scale (NIHSS) for the prediction of the functional status of patients with stroke.', 'CONCLUSION: In patients with stroke, OPS and NIHSS had significant contribution to the estimation of the functional status and OPS was more effective than NIHSS.', 'The Orpington Prognostic Score (OPS) is a clinically derived stroke severity scale that can be used to stratify patients into different severity groups.', 'The OPS is a valid measure of stroke severity in Irish stroke in-patients.', 'CONCLUSIONS: Despite high inter-rater and test-retest reliability, the OPS has limited predictive accuracy for discharge destination and is a poor predictor of follow-up services.', 'PARTICIPANTS: Sixty-four patients with recent stroke admitted for inpatient rehabilitation were randomized within severity strata (Orpington Prognostic Scale) into 1 of 3 intervention groups.', 'Predicting final disposition after stroke using the Orpington Prognostic Score.', 'In Calgary, the Orpington Prognostic Score (OPS) has been used to predict outcome as an aid to rehabilitation triage. ', 'CONCLUSIONS: The first week OPS can be used to predict final outcome.', 'Predicting stroke recovery: three- and six-month rates of patient-centered functional outcomes based on the orpington prognostic scale.', 'CONCLUSION: OPS scores can predict widely differing rates of functional recovery in five important functional abilities. ', 'Prediction of functional outcome after stroke: comparison of the Orpington Prognostic Scale and the NIH Stroke Scale.', 'CONCLUSIONS: Our results demonstrate that in a sample of mostly mild and moderate strokes, the Orpington Prognostic Scale compared with the NIH Stroke Scale is simpler to use and is a slightly better predictor of ADL and higher levels of physical function.', 'CONCLUSIONS: The Orpington score when assessed at 2-weeks post-stroke is a useful prognostic indicator with special suitability for the elderly and may help to select patients most likely to benefit from stroke unit rehabilitation.', 'The OPS at 48 hours is a good predictor of outcome at 6 months and 2 years after ischemic stroke and allows early identification of 3 prognostic groups, which may help in identifying patients most likely to benefit from intensive rehabilitation.', 'The purpose of this study was to determine the ability of the Orpington Prognostic Scale (OPS) to predict outcome and response to subacute rehabilitation in older patients with stroke.', 'This study investigates the prognostic ability of the Orpington Prognostic Scale within 48 hours (OPS-1) after admission in predicting outcome at 6 months and 2 years in acute ischemic stroke and compares it with the 2 week OPS (OPS-2).', 'The aim of our study is to compare the Orpington Prognostic Scale (OPS) and the National Institutes of Health Stroke Scale (NIHSS) and to evaluate whether they help us estimate the future functional status of patients with stroke.', 'This study compared the ability of 2 stroke impairment scales, Orpington Prognostic Scale and National Institutes of Health (NIH) Stroke Scale, to predict disability as measured by the Barthel activities of daily living (ADL) Index and higher level of self-reported physical functioning as measured by the SF-36 physical functioning index (PFI) at 1, 3, and 6 months after stroke.', 'To provide recovery rates after stroke for specific functions using the Orpington Prognostic Scale (OPS).', 'To study the validity of the Orpington scale as a predictive instrument of functional prognosis in patients with stroke.', 'In Calgary, the Orpington Prognostic Score (OPS) has been used to predict outcome as an aid to rehabilitation triage.', 'The purpose of this study was to determine the ability of the Orpington Prognostic Scale (OPS) to predict outcome and response to subacute rehabilitation in older patients with stroke.Twenty-two subjects in the subacute care setting diagnosed with acute stroke were prospectively studied', 'This study investigates the prognostic ability of the Orpington Prognostic Scale within 48 hours (OPS-1) after admission in predicting outcome at 6 months and 2 years in acute ischemic stroke and compares it with the 2 week OPS (OPS-2)', 'Predicting response to rehabilitation in elderly patients with stroke using the Orpington Prognostic Scale and selected clinical variables', 'Comparison of the Orpington Prognostic Scale (OPS) and the National Institutes of Health Stroke Scale (NIHSS) for the prediction of the functional status of patients with stroke', 'Prediction of functional outcome after stroke: comparison of the Orpington Prognostic Scale and the NIH Stroke Scale', 'BACKGROUND AND PURPOSE: This study compared the ability of 2 stroke impairment scales, Orpington Prognostic Scale and National Institutes of Health (NIH) Stroke Scale, to predict disability as measured by the Barthel activities of daily living (ADL) Index and higher level of self-reported physical functioning as measured by the SF-36 physical functioning index (PFI) at 1, 3, and 6 months after stroke. ', 'The purpose of this study was to determine the ability of the Orpington Prognostic Scale (OPS) to predict outcome and response to subacute rehabilitation in older patients with stroke. ', 'PURPOSE: The aim of our study is to compare the Orpington Prognostic Scale (OPS) and the National Institutes of Health Stroke Scale (NIHSS) and to evaluate whether they help us estimate the future functional status of patients with stroke. ', 'The purpose of this study was to determine the ability of the Orpington Prognostic Scale (OPS) to predict outcome and response to subacute rehabilitation in older patients with stroke.Twenty-two subjects in the subacute care setting diagnosed with acute stroke were prospectively studied.', 'The purpose of this study was to determine the ability of the Orpington Prognostic Scale (OPS) to predict outcome and response to subacute rehabilitation in older patients with stroke.', 'Prediction of functional outcome after stroke: comparison of the Orpington Prognostic Scale and the NIH Stroke Scale.', 'Comparison of the Orpington Prognostic Scale (OPS) and the National Institutes of Health Stroke Scale (NIHSS) for the prediction of the functional status of patients with stroke.', 'Predicting response to rehabilitation in elderly patients with stroke using the Orpington Prognostic Scale and selected clinical variables.', 'The Orpington Prognostic Scale within the first 48 hours of admission as a predictor of outcome in ischemic stroke.']

['The Orpington Prognostic Scale (OPS) is used to predict futue functional status of stroke patients, to asses stroke severity, outcome and response to subacute rehabilitation. In patients with stroke, OPS and NIHSS had significant contribution to the estimation of the functional status and OPS was more effective than NIHSS. However, other reported that the OPS has limited predictive accuracy for discharge destination and is a poor predictor of follow-up services.']

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What is PANTHER-PSEP?

['PANTHER-PSEP: predicting disease-causing genetic variants using position-specific evolutionary preservation.', "PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease. Several previous variant pathogenicity prediction methods have been proposed that quantify evolutionary conservation among homologous proteins from different organisms. PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors. ", 'PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease.', "PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors.", 'PANTHER-PSEP: predicting disease-causing genetic variants using position-specific evolutionary preservation.', "PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors."]

["PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease. Several previous variant pathogenicity prediction methods have been proposed that quantify evolutionary conservation among homologous proteins from different organisms. PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors. ", "PANTHER-PSEP is a software tool for predicting non-synonymous genetic variants that may play a causal role in human disease. PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors.", 'PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease.']

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What is the color of the protein Ranasmurfin?

['Ranasmurfin, a blue protein from a different species of frog, displays a novel structure with a unique chromophoric crosslink.', 'Crystallization of Ranasmurfin, a blue-coloured protein from Polypedates leucomystax.', 'Ranasmurfin, a previously uncharacterized approximately 13 kDa blue protein found in the nests of the frog Polypedates leucomystax, has been purified and crystallized. The crystals are an intense blue colour ']

['Ranasmurfin is a blue protein.']

['Blue']

Is alternative splicing of apoptotic genes playing a role in the response to DNA or mitochondrial damage?

['Apoptosis promoted by UV in cells lacking p53 is prevented when the change in AS of the apoptotic gene bcl-x is reverted, confirming the relevance of this mechanism.', 'We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs.', 'This analysis revealed that DNA damage resulted in changes in splicing activity that modified the splicing pattern of Fas, a key pro-apoptotic, p53-inducible death receptor.', 'Bortezomib induces mitochondrial damage in native cells and also activates the UPR by splicing of Xbp-1 and induction of CHOP, which is significantly reduced by silencing of MUC4.', 'The tumour-suppressor protein p53 is an important activator of apoptosis. Although p53-deficient cancer cells are less responsive to chemotherapy, their resistance is not complete, which suggests that other apoptotic pathways may exist. A p53-related gene, p73, which encodes several proteins as a result of alternative splicing, can also induce apoptosis.', 'Induction of apoptosis was significantly reduced in P388/SPR cells, as indicated by minimal DNA fragmentation. Analysis of oncogenes regulating apoptotic cell death revealed a marked decrease of bcl-2 in combination with a moderate reduction of bax protein, but a striking overexpression of the long form of the bcl-X protein.']

['Yes, alternative splicing seem to play a key role in the response to DNA or mitocondrial damage as suggested by the number of apoptotic genes that are alternatively spliced, with often antagonistic roles of the isoforms generated.']

['yes']

Which translocation is the hallmark of Ewing sarcoma?

['Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant neoplasms that most often affect children and young adults in the first 2 decades of life. The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24; 12), is detected in 95% of ES patients', "Ewing's sarcoma is a malignancy characterized by a specific 11:22 chromosomal translocation which generates a novel EWS-FLI1 fusion protein functioning as an aberrant transcription factor", "The hallmark of Ewing's sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene", 'The chromosomal translocation t(11;22)(q24;q12) yields the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs)', 'Ewing sarcoma is extremely rare in people from East and Southeast Asia', 'The t(11;22)(q24:q12) translocation was present in all patients in our series', 'We confirmed that distant metastases is highly predictive of a poor outcome, and that the t(11;22)(q24:q12) translocation was present in all patients in our series', 'The genetic hallmark of the Ewing sarcoma family of tumours (ESFT) is the presence of the t(11;22)(q24;q12) translocation, present in up to 85% of cases of ESFT, which creates the EWS/FLI1 fusion gene and results in the expression of a chimeric protein regulating many other genes.', 'Ewing sarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) translocation that generates the Ewing sarcoma breakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible for the highly malignant phenotype of this tumor.', 'The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma.', 'Translocation of chromosomes 11 and 22 in choroidal metastatic Ewing sarcoma detected by fluorescent in situ hybridization.', 'Molecular detection of the t(11;22)(q24;q12) translocation in Ewing sarcoma is valuable in the differential diagnosis of small round cell tumors.', 'This patient illustrates the second reported occurrence of primary Ewing sarcoma in the stomach and the first reported with the t(11;22)(q24;q12) gene translocation.', 'Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma.', 'EWS-Fli1, a fusion gene resulting from a chromosomal translocation t(11;22, q24;q12) and found in Ewing sarcoma and primitive neuroectodermal tumors, encodes a transcriptional activator and promotes cellular transformation.', 'The presence of the t(11;22)(q24;ql2) translocation should probably not be considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor in the absence of supporting histological evidence.', 'Ewing sarcoma is the prototypical member of this group of sarcomas; it was the first to be recognized pathologically as a singular entity and to have its signature translocation defined cytogenetically, which led to the identification of its key driver alteration, the EWS-FLI1 gene fusion that encodes this aberrant, chimeric transcription factor.', 'The hallmark of Ewings sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene.', 'Ewing sarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) translocation that generates the Ewing sarcoma breakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible for the highly malignant phenotype of this tumor.', 'This patient illustrates the second reported occurrence of primary Ewing sarcoma in the stomach and the first reported with the t(11;22)(q24;q12) gene translocation.', "Diagnosis is based on history, immunostaining with at least 2 neural markers, ultrastructural examination, and evidence of an abnormal t(11;22)(q24;q12) translocation as the hallmark for the Ewing's sarcoma family.", 'The translocation results in the fusion of the EWS gene with the transcription factor gene FLI1 which has been considered a hallmark of ESFT.', "[Chromosomal translocation (11; 22) in cell lines of Ewing's sarcoma].", 'These results, associated with those obtained at the same time and independently from fresh tumor cells, suggest that the translocation t(11; 22)(q24; q12) may be a chromosomal marker characteristic of Ewing sarcoma cells.', 'Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma', "Diagnosis is based on history, immunostaining with at least 2 neural markers, ultrastructural examination, and evidence of an abnormal t(11;22)(q24;q12) translocation as the hallmark for the Ewing's sarcoma family", 'Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma', 'The genetic hallmark of the Ewing sarcoma family of tumours (ESFT) is the presence of the t(11;22)(q24;q12) translocation, present in up to 85% of cases of ESFT, which creates the EWS/FLI1 fusion gene and results in the expression of a chimeric protein regulating many other genes', 'The translocation results in the fusion of the EWS gene with the transcription factor gene FLI1 which has been considered a hallmark of ESFT']

['Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant neoplasms that most often affect children and young adults in the first 2 decades of life. The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24; 12), is detected in 95% of ES patients', 'The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24;12), is detected in 95% of Ewing sarcoma patients.', 'The hallmark of Ewing s sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene ']

['translocation t(11;22) (q24;12)']

Are reduced-nicotine cigarettes effective for smoking cessation?

['CONCLUSIONS: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. ', 'RESULTS: Significant reductions in nicotine intake were observed between usual brand smoking (∼1.2 mg nicotine) and the 0.3 and 0.05 mg nicotine emission cigarettes, but not the 0.6 mg cigarette.', 'CONCLUSIONS: The study adds to the evidence that cigarettes with markedly reduced nicotine content are not associated with increased smoking intensity or exposure to smoke toxicants.', 'BACKGROUND: When switching from usual brand cigarettes, very low nicotine content (VLNC) cigarettes lead to a reduction in the number of cigarettes smoked, toxicant exposure, withdrawal symptoms and dependence. ', 'Moreover, while nicotine patches were well tolerated when subjects smoked nicotine-containing cigarettes, the use of nicotine skin patches with reduced-nicotine cigarettes potentially offers the advantage of increased efficacy without introducing concern about toxic effects of excessive nicotine intake.', 'Results showed that Quest plus NRT was more effective than active control plus NRT in achieving 4 weeks of continuous abstinence (32.8% vs. 21.9%).', 'Quest plus NRT offers promise as a new smoking cessation treatment.', 'We identified three clinical trials (total n = 489) that suggest that smokers can dissociate nicotine delivery from the act of smoking if they use reduced-nicotine content cigarettes in combination with nicotine replacement therapy.', 'CONCLUSION: The 0.05 mg nicotine yield cigarettes may be a tobacco product that can facilitate cessation; however, future research is clearly needed to support these preliminary findings.', 'Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment.', 'Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation.', 'Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates.', 'The concept for a reduced-nicotine cigarette designed to progressively wean smokers from the smoking habit is based on research demonstrating that successful smoking cessation is not only dependent on withdrawal of nicotine, but also on weaning from the habitual sensory and behavioral reinforcement of smoking.', 'Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment', 'Specifically, standards that required substantially reduced nicotine content in cigarettes could enable cessation in smokers and prevent future smoking among current non-smokers', 'Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation', 'Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates', 'The concept for a reduced-nicotine cigarette designed to progressively wean smokers from the smoking habit is based on research demonstrating that successful smoking cessation is not only dependent on withdrawal of nicotine, but also on weaning from the habitual sensory and behavioral reinforcement of smoking', 'These results suggest that use of NRT before a target quit-smoking date deserves further evaluation as a possible smoking cessation treatment. Moreover, while nicotine patches were well tolerated when subjects smoked nicotine-containing cigarettes, the use of nicotine skin patches with reduced-nicotine cigarettes potentially offers the advantage of increased efficacy without introducing concern about toxic effects of excessive nicotine intake.', 'Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment.']

['Yes, reduced-nicotine cigarettes are effective for smoking cessation.']

['yes']

Is the HRC Ser96Ala variant associated with sudden cardiac death in patients with dilated cardiomyopathy?

['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.', 'The Ser96Ala (S96A) mutation within the histidine rich Ca(2+) binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca(2+) release events.', '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.', '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.', ' 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.', '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', '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.', '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', 'The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy.', '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.']

['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.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.', '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.The Ser96Ala (S96A) mutation within the histidine rich Ca(2+) binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca(2+) release events.', '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.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.', 'The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias and sudden death in idiopathic DCM.']

['yes']

What is the mode of action of everolimus?

['Target-of-Rapamycin Inhibitors (Sirolimus, Everolimus),', 'Although the mTOR inhibitor everolimus is effective for the treatment of patients who have failed TKI therapy, it is important to consider all available treatment options before switching therapy mode of action.', 'The mTOR pathway, and its upstream regulators in the PI3K/PTEN/AKT cascade, are altered in a variety of experimental and human malignancies.This has led to the prediction that mTOR inhibitors may be used as anticancer agents. With the recent approval of two mTOR-targeted drugs (temsirolimus and everolimus) for the treatment of renal cell carcinoma and mantle cell lymphoma, this paradigm has been effectively translated into the clinical setting.', 'mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex.', 'mTOR inhibitors act on the signaling pathway PI3K/AKT/mTOR, and key molecules are temsirolimus, everolimus, and deforolimus.', 'The introduction of the inhibitors of the mammalian target of rapamycin sirolimus and everolimus in renal transplantation has increased the repertoire of immunosuppressive protocols substantially.', 'Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway', 'RAD001 (everolimus) is a novel agent that is being trialled in the treatment of neuro-endocrine tumours, and is known to interact with mTOR.', 'In this cell model, octreotide and RAD001 appear to act through a similar pathway and inhibit the Akt-mTOR-p70S6 kinase pathway downstream of Akt.', 'Target of rapamycin inhibitors (sirolimus and everolimus)', 'Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus)', 'Target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus) are immunosuppressive agents with a novel mode of action', 'These three classes are tyrosine kinase inhibitors with sunitinib and sorafenib, the anti-VEGF antibodies (bevacizumab which is associated with alpha interferon in the treatment of advanced kidney cancer) and mTOR inhibitors with temsirolimus and everolimus.']

['Everolimus is a drug that binds to mTORC1 and inhibits activation of the mTOR signalling pathway. It is used in targeted cancer therapy protocols or after transplantation for maintenance immunosuppression, against allograft rejection.']

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Which is the most widely used model for the study of multiple sclerosis (MS)?

['experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis', 'Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE)', 'the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS', 'The aim of our study was to characterize the sensory abnormalities and in particular the clinical signs linked to persistent pain in two models of Experimental Autoimmune Encephalomyelitis (EAE) in the rat', 'Experimental autoimmune encephalomyelitis (EAE) is an animal model for studying multiple sclerosis (MS)', "Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS)", 'experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS)', 'In this study we investigated whether in an animal model for MS, namely in experimental autoimmune encephalomyelitis (EAE), similar changes occur', 'Experimental autoimmune encephalomyelitis (EAE), a widely recognized animal model of multiple sclerosis (MS)', "we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS", 'In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD)', 'experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis', "Theiler's murine encephalomyelitis virus (TMEV)", 'Inflammatory diseases of the CNS, such as MS and its animal model EAE', 'the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE)', 'an animal model of multiple sclerosis (MS): disease modifying activity on acute and chronic relapsing experimental allergic encephalomyelitis (EAE).', 'The immunology of multiple sclerosis and its animal model, experimental allergic encephalomyelitis', 'EAE is the best available model for the inflammatory processes that occur in MS, and for the disease process', 'The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE)', 'The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE)', 'To assess neurological impairments quantitatively in an animal model of multiple sclerosis (MS), we have used a targeted model of experimental autoimmune encephalomyelitis (EAE)', 'Experimental autoimmune encephalomyelitis (EAE) is a well-studied disease in rodents that mimics many clinical and pathological features of MS, including central nervous system inflammation and demyelination', 'Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter', 'both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE)', 'In the MS animal model experimental autoimmune encephalomyelitis (EAE)', 'multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis', 'inflammatory demyelination in multiple sclerosis (MS) lesions and experimental autoimmune encephalomyelitis (EAE)']

["Experimental autoimmune encephalomyelitis (EAE) is a classical, conventional and widely recognized animal model for studying multiple sclerosis (MS). EAE is the best available model for the inflammatory processes that occur in MS, and for the disease process. A less commonly used model is that of Theiler's murine encephalomyelitis virus (TMEV)."]

['Experimental autoimmune encephalomyelitis (EAE)']

What is the role of neurexins in forming transsynaptic interactions at the presynapse?

['["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"]']

Neurexins play a key role in forming transsynaptic interactions at the presynapse by binding to diverse postsynaptic ligands, making them the best-characterized transsynaptic interactions.

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What is the methodological principle of ChIA-PET?

['Overall we show that ChIA-PET is the cornerstone to explore the three-dimensional (3D) chromatin structure, and certainly will lead the forthcoming wave of 3D genomics studies.', 'Chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) is a new technology to study genome-wide long-range chromatin interactions bound by protein factors. ', 'Chromatin Interaction Analysis using Paired-End Tag sequencing (ChIA-PET) is a method which converts functional chromatin structure into millions of short tag sequences. Combining Chromatin Immunoprecipitation (ChIP), proximity ligation and high-throughput sequencing, ChIA-PET provides a global and unbiased interrogation of higher-order chromatin structures associated with specific protein factors.', 'Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) was developed to identify these higher-order chromatin structures', ' ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. ', 'Proximity ligation assays commonly known as chromosome conformation capture (3C) and 3C based methodologies (e.g., GCC, HiC and ChIA-Pet) are increasingly being incorporated into empirical studies to investigate the role that three-dimensional genome structure plays in the regulation of phenotype.']

['Chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) is a new technology to study genome-wide long-range chromatin interactions bound by protein factors. To minimize non-specific noise and reduce complexity, as well as to increase the specificity of the chromatin interaction analysis, chromatin immunoprecipitation (ChIP) is used against specific protein factors to enrich chromatin fragments of interest before proximity ligation. Combining Chromatin Immunoprecipitation (ChIP), proximity ligation and high-throughput sequencing, ChIA-PET provides a global and unbiased interrogation of higher-order chromatin structures associated with specific protein factors. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall.', 'Chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) is a new technology to study genome-wide long-range chromatin interactions bound by protein factors. It converts functional chromatin structure into millions of short tag sequences. By combining Chromatin Immunoprecipitation (ChIP), proximity ligation and high-throughput sequencing, ChIA-PET provides a global and unbiased interrogation of higher-order chromatin structures associated with specific protein factors.']

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Can PLN mutations lead to dilated cardiomyopathy?

['A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype.', 'PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients', 'The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC', 'Arg(9) → Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with lethal dilated cardiomyopathy in humans', 'We previously reported the deletion of the highly conserved amino acid residue arginine 14 (nucleic acids 39, 40 and 41) in DCM patients.', 'Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy;', 'Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology', 'A missense mutation in PLN cytoplasmic domain (R9C) triggers dilated cardiomyopathy in humans, leading to premature death.', 'Complete genetic and clinical analyses were performed in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation.', 'A candidate gene approach resulted in identification of a heterozygous deletion of arginine 14 in the gene encoding phospholamban (PLN-R14Del) segregating with dilated cardiomyopathy in the family pedigree. Mutation carriers suffered from familial dilated cardiomyopathy associated with cardiac death between the ages of 26 and 50 years.', 'a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation.', 'For the phospholamban (PLN) and titin cap (TTN) genes, a direct mutation screening approach was used. DNA sequence analysis of all exons showed no evidence that these genes are involved in DCM in the Newfoundland dog.', 'two human PLN mutations, associated with either absence or sustained dephosphorylation of PLN, were linked to dilated cardiomyopathy.', 'Mutations in the gene encoding PLN have been associated with dilated cardiomyopathy characterized by early onset and the presence of lethal ventricular arrhythmias.', 'The identical PLN mutation can be associated with both mild and severe forms of dilated cardiomyopathy. Additionally, PLN mutations should be considered in late onset cardiomyopathy', 'Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure.', 'No PLN gene mutation was found in patients with DCM in Chengdu. This result indicated that PLN gene mutation may not be a common cause for DCM in the Chinese population in Chengdu.', 'none in PLN', 'the recent discoveries of human PLN mutations leading to disease states.', 'Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27.', 'humans lacking PLN develop lethal dilated cardiomyopathy.', 'Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN)']

['Yes, PLN mutations can lead to dilated cardiomyopathy.']

['yes']

Which dediodinases are present in kidney?

['Iodothyronine deiodinase in vitro activity studies in the chicken showed the presence of type I and type III iodothyronine deiodinase activity in both liver and kidney.', 'Co-expression of the deiodinases was also found in the kidney.', 'high ID-I activities were found in liver, kidney', "the kidney microsome 5'-deiodinase is type I."]

['Type 1 and Type 3 deiodinases are both present in liver']

['Type 1 deiodinase', 'Tipe 3 deiodinase']

How do somatic mutations in patients with MDS relate to clinical features, considering the common occurrence of inactivating mutations in PcG genes like EZH2?

['["Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\\\\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML)", "We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH result", " Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure.", "Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome", "Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.", "EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined", "Weaver syndrome and EZH2 mutations", "In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome", "The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. ", "Mutations in EZH2 cause Weaver syndrome", "These data show that mutations in EZH2 cause Weaver syndrome", "The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies", "EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.", "Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL)", "The EZH2 gene was previously reported to be located on chromosome 21q22 and was proposed as a candidate gene for some characteristics of the Down syndrome phenotype", "Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN).", "EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.", "In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome.", "Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively.", "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.", "Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.", "The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.", "We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities.", "Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). ", "Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features. ", "Recently, the advent of next generation sequencing (NGS) techniques has helped identify somatic gene mutations in 75-']

Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). EZH2 mutations are associated with poor survival in MDS.

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List the types of the Cardiorenal syndrome (CRS) according to the five-part classification system.

['The general definition has been expanded into five subtypes: CRS type 1 = acute worsening of heart function (acute heart failure-acute coronary syndrome) leading to kidney injury and/or dysfunction; CRS type 2 = chronic abnormalities in heart function (chronic heart failure-chronic heart disease) leading to kidney injury or dysfunction; CRS type 3 = acute worsening of kidney function (acute kidney injury) leading to heart injury and/or dysfunction; CRS type 4 = chronic kidney disease (chronic kidney disease) leading to heart injury, disease and/or dysfunction; and CRS type 5 = systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. ', 'Cardiorenal syndromes (CRS) have been recently classified into five distinct entities, each with different major pathophysiologic mechanisms. CRS type 1 most commonly occurs in the setting of acutely decompensated heart failure where approximately 25% of patients develop a rise in serum creatinine and a reduction of urine output after the first several doses of intravenous diuretics. ', 'CRS type 2 is the hastened progression of chronic kidney disease (CKD) in the setting of chronic heart failure. ', 'CRS type 3 is acutely decompensated heart failure after acute kidney injury from inflammatory, toxic, or ischemic insults. ', "CRS type 4 is manifested by the acceleration of the progression of chronic heart failure in the setting of CKD. Cardiac myocyte dysfunction and fibrosis, so-called 'CKD cardiomyopathy', is believed to be the predominant pathophysiologic mechanism. Type 5 CRS is simultaneous acute cardiac and renal injury in the setting of an overwhelming systemic insult such as sepsis. ", 'CRS type I: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. CRS type II: chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction. CRS type III: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. CRS type IV: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. CRS type V: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. ', 'Acute CRS (type 1): acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. Chronic cardio-renal syndrome (type 2): chronic abnormalities in heart function (CHF-CHD) leading to kidney injury and/or dysfunction. Acute reno-cardiac syndrome (type 3): acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. Chronic reno-cardiac syndrome (type 4): chronic kidney disease leading to heart injury, disease, and/or dysfunction. Secondary CRS (type 5): systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. ', 'For mentioning the interaction of cardiovascular and renal diseases the cardiorenal syndrome (CRS) term was introduced, with its classification on 5 types, according to the presence of acute/chronic heart failure and primary/secondary origination of heart and kidney injury.', 'For mentioning the interaction of cardiovascular and renal diseases the cardiorenal syndrome (CRS) term was introduced, with its classification on 5 types, according to the presence of acute/chronic heart failure and primary/secondary origination of heart and kidney injury', 'The most recent classification recognizes five types of CRS: types I and II originate from heart failure (acute and chronic, respectively), type III and IV from kidney failure (again acute and chronic), while type V originates from a range of systemic diseases', 'The most recent classification recognizes five types of CRS: types I and II originate from heart failure (acute and chronic, respectively), type III and IV from kidney failure (again acute and chronic), while type V originates from a range of systemic diseases.', 'For mentioning the interaction of cardiovascular and renal diseases the cardiorenal syndrome (CRS) term was introduced, with its classification on 5 types, according to the presence of acute/chronic heart failure and primary/secondary origination of heart and kidney injury.', 'Based on the pathophysiological primum movens, the actual classification recognizes five CRS types: in type I and II CRS, the initiating event is heart failure (acute or chronic), while it is kidney failure in type III and IV CRS; type V is linked to systemic diseases.', 'An effective classification of CRS in 2008 essentially divides CRS in two main groups, cardiorenal and renocardiac CRS, based on primum movens of disease (cardiac or renal); both cardiorenal and renocardiac CRS are then divided into acute and chronic, according to onset of disease.', 'Of particular interest to the critical care specialist are CRS type 1 (acute cardiorenal syndrome) and type 3 (acute renocardiac syndrome).', 'At present, the classification of the syndrome includes five types of CRS: types I and II which are strictly related to initial heart failure (both acute and chronic), types III and IV which include initial kidney failure, and type V which includes several systemic diseases.', 'The general definition has been expanded into five subtypes: CRS type 1 = acute worsening of heart function (acute heart failure-acute coronary syndrome) leading to kidney injury and/or dysfunction; CRS type 2 = chronic abnormalities in heart function (chronic heart failure-chronic heart disease) leading to kidney injury or dysfunction; CRS type 3 = acute worsening of kidney function (acute kidney injury) leading to heart injury and/or dysfunction; CRS type 4 = chronic kidney disease (chronic kidney disease) leading to heart injury, disease and/or dysfunction; and CRS type 5 = systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney.', 'The general definition has been expanded into five subtypes reflecting the primacy of organ dysfunction and the time-frame of the syndrome: CRS type 1 = acute worsening of heart function leading to kidney injury and/or dysfunction; CRS type 2 = chronic abnormalities in heart function leading to kidney injury or dysfunction; CRS type 3 = acute worsening of kidney function leading to heart injury and/or dysfunction; CRS type 4 = chronic kidney disease leading to heart injury, disease and/or dysfunction, and CRS type 5 = systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney.']

['Cardiorenal syndromes (CRS) have been recently classified into five distinct entities, each with different major pathophysiologic mechanisms. \nCRS type 1: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. \nCRS type 2: chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction. \nCRS type 3: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. \nCRS type 4: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. \nCRS type 5: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney.']

['CRS type 1', 'CRS type 2', 'CRS type 3', 'CRS type 4', 'CRS type 5']

Where does CTCF colocalize with cohesin?

['In human cells, Pol III genes and transcription factors have also been shown to colocalize with cohesin and the transcription regulator and genome organizer CCCTC-binding factor (CTCF).', 'To investigate cohesin-non-CTCF (CNC) binding events in vivo we mapped cohesin and CTCF, as well as a collection of tissue-specific and ubiquitous transcriptional regulators using ChIP-seq in primary mouse liver.', ' In contrast to regions of the genome where cohesin and CTCF colocalize, CNC sites coincide with the binding of master regulators and enhancer-markers and are significantly associated with liver-specific expressed genes. ', 'Finally, we observe that the presence of mirrored CTCF binding events at promoters and their nearby cohesin-bound enhancers is associated with elevated expression levels.', 'Recently, cohesins have been implicated in transcriptional regulation and insulation through genome-wide colocalization with the insulator protein CTCF, including involvement at the imprinted H19/Igf2 locus.', 'Here we report that cohesins colocalize with CTCF at two additional imprinted loci, the Dlk1-Dio3 and the Kcnq1/Kcnq1ot1 loci. ', ' To determine the functional importance of the binding of CTCF and cohesins at the three imprinted loci, CTCF and cohesins were depleted in mouse embryonic fibroblast cells.', 'Results of these experiments demonstrate an unappreciated role for CTCF and cohesins in the repression of imprinted genes in somatic cells.', 'Here, we show in different cell types that cohesin functionally behaves as a tissue-specific transcriptional regulator, independent of CTCF binding.', 'By performing matched genome-wide binding assays (ChIP-seq) in human breast cancer cells (MCF-7), we discovered thousands of genomic sites that share cohesin and estrogen receptor alpha (ER) yet lack CTCF binding', 'By use of human hepatocellular carcinoma cells (HepG2), we found that liver-specific transcription factors colocalize with cohesin independently of CTCF at liver-specific targets that are distinct from those found in breast cancer cells', 'Together, our data show that cohesin cobinds across the genome with transcription factors independently of CTCF, plays a functional role in estrogen-regulated transcription, and may help to mediate tissue-specific transcriptional responses via long-range chromosomal interactions.', ' Because cohesin can colocalize with CTCF, we performed chromatin immunoprecipitation for the cohesin subunit Rad21 and found lineage and stage-specific Rad21 recruitment to CTCF in all Ig loci. The differential binding of cohesin to CTCF sites may promote multiple loop formation and thus effective V(D)J recombination', 'These numerous CTCF/cohesin sites potentially form the bases of the multiloop rosette structures at the Igh locus that compact during Ig heavy chain rearrangement.', 'We conclude that cohesins interact with CTCF in mid-S phase and repress CTCF-regulated genes in a cell cycle-dependent manner.', 'We propose that the CTCF-cohesin complex plays a critical role in regulating the cell cycle control of viral gene expression during latency and that failure to maintain cell cycle control of latent transcripts inhibits host cell proliferation and survival', 'We conclude that cohesin subunits associate with viral and cellular CTCF sites involved in complex gene regulation and chromatin organization.', 'Because cohesin can colocalize with CTCF, we performed chromatin immunoprecipitation for the cohesin subunit Rad21 and found lineage and stage-specific Rad21 recruitment to CTCF in all Ig loci.', 'In human cells, Pol III genes and transcription factors have also been shown to colocalize with cohesin and the transcription regulator and genome organizer CCCTC-binding factor (CTCF).', 'Here, we show that ATRX, MeCP2, and cohesin, chromatin regulators implicated in ATR-X, RTT, and CdLS syndromes, respectively, interact in the brain and colocalize at the H19 imprinting control region (ICR) with preferential binding on the maternal allele.', 'Subcellular distribution of CTCF and colocalization with cohesins also varied across the cell cycle. ', 'ChIP sequencing was performed on pro-B cells, revealing colocalization of CTCF and Rad21 binding at ~60 sites throughout the V(H) region and 2 other sites within the Igh locus. ', 'Recently, cohesins have been implicated in transcriptional regulation and insulation through genome-wide colocalization with the insulator protein CTCF, including involvement at the imprinted H19/Igf2 locus. ', 'CTCF colocalizes with cohesin but not RNA Polymerase II. ', 'Because cohesin can colocalize with CTCF, we performed chromatin immunoprecipitation for the cohesin subunit Rad21 and found lineage and stage-specific Rad21 recruitment to CTCF in all Ig loci. ', 'Because cohesin can colocalize with CTCF, we performed chromatin immunoprecipitation for the cohesin subunit Rad21 and found lineage and stage-specific Rad21 recruitment to CTCF in all Ig loci. The differential binding of cohesin to CTCF sites may promote multiple loop formation and thus effective V(D)J recombination.', 'Here we report that cohesins colocalize with CTCF at two additional imprinted loci,']

['Cohesin subunits associate with viral and cellular CTCF sites involved in complex gene regulation and chromatin organization. Cohesin cobinds across the genome with transcription factors independently of CTCF, plays a functional role in estrogen-regulated transcription, and may help to mediate tissue-specific transcriptional responses via long-range chromosomal interactions.\nNumerous CTCF/cohesin sites potentially form the bases of the multiloop rosette structures at the Igh locus that compact during Ig heavy chain rearrangement. Cohesins colocalize with CTCF at two additional imprinted loci, the Dlk1-Dio3 and the Kcnq1/Kcnq1ot1 loci.']

['In imprinted and repressed, highly compacted loci that are prone to recombination events.']

Is there any algorithm for enhancer identification from chromatin state?

['RFECS: a random-forest based algorithm for enhancer identification from chromatin state.', 'However, only a limited number of cell types or chromatin marks have previously been investigated for this purpose, leaving the question unanswered whether there exists an optimal set of histone modifications for enhancer prediction in different cell types. Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. We show that RFECS not only leads to more accurate and precise prediction of enhancers than previous methods, but also helps identify the most informative and robust set of three chromatin marks for enhancer prediction.', 'We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types.', 'Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. ', 'ChromaGenSVM selects optimum combinations of specific histone epigenetic marks to predict enhancers. ', 'We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types.']

['yes', 'Yes. RFECS is a random-forest based algorithm for enhancer identification from chromatin state. It integrates histone modification profiles for the identification of enhancers, and can be used to identify enhancers in a number of cell-types. RFECS not only leads to more accurate and precise prediction of enhancers than previous methods, but also helps identify the most informative and robust set of three chromatin marks for enhancer prediction.']

['yes']

What are the main characteristics/symptoms of the "Brugada" syndrome

['In 1992, Brugada and Brugada first described a new entity, which became known as Brugada syndrome, that is associated with a high risk of ventricular arrhythmias and sudden cardiac death in patients without structural heart disease. This syndrome is characterized by a distinct electrocardiographic phenotype, type 1 Brugada pattern, consisting of a coved ST-segment elevation (≥0.2 mV) followed by a negative T wave in more than one right precordial lead.', 'Brugada syndrome predisposes individuals to ventricular arrhythmias and sudden cardiac death, in the absence of structural heart disease. The typical Brugada electrocardiogram (ECG) phenotype is often concealed in affected population', 'Brugada syndrome is a rare cardiac arrhythmia characterized by electrocardiographic right bundle branch block and persistent ST-segment elevation in the right precordial leads.', 'Brugada syndrome is a genetically determined familial disease with autosomal dominant transmission and variable penetrance, conferring a predisposition to sudden cardiac death due to ventricular arrhythmias.', 'Brugada syndrome (BrS) ', 'BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. ', 'Brugada syndrome (BrS) primarily associates with the loss of sodium channel function.', 'PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.', 'Brugada syndrome is an inherited arrhythmia syndrome predisposing to sudden cardiac death. ', 'the first mutations in SCN5A encoding the cardiac sodium channel Nav1.5 were reported.', 'Brugada syndrome is characterized by typical ECG features, ventricular arrhythmias and sudden cardiac death (SCD), more frequent during nighttime.', 'Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in family members with isolated conduction disturbances.', 'Brugada syndrome (BrS), one of the most frequently diagnosed inherited arrhythmogenic syndromes, is responsible for more than 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts.', 'Brugada syndrome is a major cause of sudden death in young adults.', "Brugada's syndrome is one of the main causes of sudden death in young adults without a structural heart disease", 'The Brugada syndrome is a clinical-electrocardiographic diagnosis characterized by syncopal episodes or sudden death (caused by ventricular tachycardia and ventricular fibrillation) in patients with a structurally normal heart with a characteristic electrocardiographic pattern consisting of ST segment elevation in precordial leads (Vl-V3) and a morphology of the QRS complex resembling right bundle branch block (the latter can transiently disappear). Timely diagnosis and adequate treatment may essentially decrease mortality of this disease.', 'Brugada syndrome', 'In 1992 we described a new syndrome consisting of syncopal episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram displaying a pattern resembling right bundle branch block with an ST segment elevation in leads V1 to V3. In 1998 it was described that the disease is genetically determined with an autosomal dominant pattern of transmission. Three different mutations have been identified. All three mutations affect the structure and the function of the sodium channel SCN5A.', 'The diagnosis is easily made by means of the electrocardiogram (ECG). The presence of concealed and intermittent forms, however, makes the diagnosis difficult in some patients.', 'The Brugada syndrome is a clinical-electrocardiographic diagnosis characterised by syncopal or sudden death episodes in patients with a structurally normal heart with a characteristic electrocardiographic pattern consisting of ST segment elevation in the precordial leads V1 to V3 and a morphology of the QRS complex resembling a right bundle branch block. In many patients with the Brugada syndrome, the electrocardiographic manifestations transiently normalize; leading to underdiagnosis of the syndrome. ', 'The incidence of sudden death in this syndrome is very high and can only be prevented by implanting a cardioverter-defibrillator. ']

['In 1992, Brugada and Brugada first described a new entity, which became known as Brugada syndrome, that is associated with a high risk of ventricular arrhythmias and sudden cardiac death in patients without structural heart disease. This syndrome is characterized by a distinct electrocardiographic phenotype, type 1 Brugada pattern, consisting of a coved ST-segment elevation (≥0.2 mV) followed by a negative T wave in more than one right precordial lead. The typical Brugada electrocardiogram (ECG) phenotype is often concealed in affected population. Brugada syndrome is a genetically determined familial disease with autosomal dominant transmission and variable penetrance, conferring a predisposition to sudden cardiac death due to ventricular arrhythmias. Brugada syndrome (BrS)is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in family members with isolated conduction disturbances.']

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Are mutations in the C9orf72 gene associated with macular degeneration?

['Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene C9orf72.', 'Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death. 5-10% are caused by inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS.', 'In this article, we will review the brief characterizations of the C9ORF72 gene, the expansion mutations, the related disorders, and their features, followed by a discussion of the deficiency knowledge of C9ORF72 mutations.', 'Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.', 'Frontotemporal lobar degeneration (FTLD) is a genetically heterogenous syndrome and has been associated most recently with a hexanucleotide repeat expansion within the C9ORF72 gene.', 'An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration associated with TDP-43 pathology (FTLD-TDP).', 'Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia.', 'There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease.', 'Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis.', 'C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study.', 'Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases.', 'studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).', 'GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene was recently identified as an important cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations.']

['Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death. 5-10% are caused by inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS.']

['no']

Which proteins form part of the NRD complex in S. cerevisiae?

['This activity is derived from the CHD3 and CHD4 proteins which contain helicase/ATPase domains found in SWI2-related chromatin remodelling factors, and facilitates the deacetylation of oligonucleosomal histones in vitro. We refer to this complex as the nucleosome remodelling and deacetylating (NRD) complex', 'Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4', 'The purification of an ATR complex allowed identification of chromodomain-helicase-DNA-binding protein 4 (CHD4) as an ATR-associated protein by tandem mass spectrometric sequencing. CHD4 (also called Mi-2beta) is a component of a histone-deacetylase-2 (HDAC2)-containing complex, the nucleosome remodeling and deacetylating (NRD) complex', 'Endogenous ATR, CHD4, and HDAC2 are shown to coimmunoprecipitate, and ATR and HDAC2 coelute through two biochemical purification steps. Other members of the NRD complex, HDAC1, MTA1, and MTA2, are also detectable in ATR immunoprecipitates.', 'Sen1 of S. cerevisiae is a known component of the NRD complex implicated in transcription termination of nonpolyadenylated as well as some polyadenylated RNA polymerase II transcripts. ', 'We now show that Pcf11, a component of the cleavage and polyadenylation complex (CPAC), is also generally required for NRD-dependent transcription termination through the action of its C-terminal domain (CTD)-interacting domain (CID).', 'In Saccharomyces cerevisiae, short noncoding RNA (ncRNA) generated by RNA polymerase II (Pol II) are terminated by the NRD complex consisting of Nrd1, Nab3, and Sen1.', 'Sen1 of S. cerevisiae is a known component of the NRD complex implicated in transcription termination of nonpolyadenylated as well as some polyadenylated RNA polymerase II transcripts.', 'CHD4 (also called Mi-2beta) is a component of a histone-deacetylase-2 (HDAC2)-containing complex, the nucleosome remodeling and deacetylating (NRD) complex.', 'Other members of the NRD complex, HDAC1, MTA1, and MTA2, are also detectable in ATR immunoprecipitates.', 'In Saccharomyces cerevisiae, short noncoding RNA (ncRNA) generated by RNA polymerase II (Pol II) are terminated by the NRD complex consisting of Nrd1, Nab3, and Sen1. ']

['The purification of an ATR complex allowed identification of chromodomain-helicase-DNA-binding protein 4 (CHD4) as an ATR-associated protein by tandem mass spectrometric sequencing. CHD4 (also called Mi-2beta) is a component of a histone-deacetylase-2 (HDAC2)-containing complex, the nucleosome remodeling and deacetylating (NRD) complex. Endogenous ATR, CHD4, and HDAC2 are shown to coimmunoprecipitate, and ATR and HDAC2 coelute through two biochemical purification steps. Other members of the NRD complex, HDAC1, MTA1, and MTA2, are also detectable in ATR immunoprecipitates. Sen1 of S. cerevisiae is a known component of the NRD complex implicated in transcription termination of nonpolyadenylated as well as some polyadenylated RNA polymerase II transcripts. We now show that Pcf11, a component of the cleavage and polyadenylation complex (CPAC), is also generally required for NRD-dependent transcription termination through the action of its C-terminal domain (CTD)-interacting domain (CID).']

['Chd2', 'Chd4', 'Hdac2', 'Mta1', 'Mta2', 'Sen1', 'Pcf11']

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

["Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs. 10.5 months; P = 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01-1.88, P = 0.041). However, TERT mutations had no significant impact on patients' survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas.", 'Patients with tumors lacking hTERT expression/TA showed a significant survival benefit (Kaplan-Meier test, both P < .01), which, however, was based exclusively on the younger patient subgroup (≤60 y, both P < .005; >60 y, both ns). ', 'Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs']

['Telomerase reverse transcriptase (TERT) promoter are associated with shorter survival of glioblastoma patients. Prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations.']

['yes']

What is the biological role of expansins in fungi?

['interactions with alpha-expansin in cell wall extension and polysaccharide degradation', 'cell wall swelling may not be a significant event during the action of expansin and hydrolases', 'To evaluate a putative implication of three newly identified expansin/family 45 endoglucanase-like (EEL) proteins in lignocellulose degradation', 'Our results show that EglD is a conidial cell wall localized expansin-like protein, which could be involved in cell wall remodeling during germination', 'Swollenin, a protein first characterized in the saprophytic fungus Trichoderma reesei, contains an N-terminal carbohydrate-binding module family 1 domain (CBD) with cellulose-binding function and a C-terminal expansin-like domain', 'alpha-Expansins are extracellular proteins that increase plant cell-wall extensibility', 'these wall-loosening proteins are directly involved in the accommodation of the fungus by infected cortical cells']

['Expansins are extracellular proteins that increase plant cell-wall extensibility. These wall-loosening proteins are involved in cell wall extension and polysaccharide degradation. In fungi expansins and expansin-like proteins have been found to localize in the conidial cell wall and are probably involved in cell wall remodeling during germination.']

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How does miR-1 overexpression worsen arrhythmias in coronary artery disease patients and what are the implications for antiarrhythmic treatments?

['["Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT).", "miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias.", "The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. ", "As miR-1 has been shown in animal models and clinical studies to contribute to arrhythmogenesis by regulating pacemaker channel genes, our finding of miR-1 up-regulation in patients with myocardial infarction indicates that it might be responsible for the higher risk for arrhythmias in these patients. ", "Lately, some highlight articles revealed that the altered expression of miRNAs such as miR-1, miR-133, miR-21, miR-208 etc in hearts also contributed to cardiovascular diseases, such as heart ischemia, cardiac hypertrophy, and arrhythmias.", "MicroRNA-1 (miR-1) reciprocally regulates inwardly rectifying potassium channel (Kir)2.1 expression in coronary disease, contributing to arrhythmogenesis. ", "miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased I(K1). Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.", "The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. ", "We conclude that the beta-adrenergic pathway can stimulate expression of arrhythmogenic miR-1, contributing to ischaemic arrhythmogenesis, and beta-blockers produce their beneficial effects partially by down-regulating miR-1, which might be a novel strategy for ischaemic cardioprotection.", "MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction.", "Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure.", "In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca(2+), events that occurred rarely in control myocytes under the same conditions.", "Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis.", " Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.", "MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction", "The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins", "Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure", "Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure"]']

miR-1 overexpression worsens arrhythmias in coronary artery disease patients by regulating pacemaker channel genes and contributing to arrhythmogenesis. This up-regulation of miR-1 in patients with myocardial infarction indicates a higher risk for arrhythmias. Antiarrhythmic treatments could potentially target miR-1 to alleviate arrhythmogenesis in these patients.

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What is the association between proBNP serum concentrations and stroke outcomes?

['N-terminal probrain natriuretic peptide levels as a predictor of functional outcomes in patients with ischemic stroke.', 'There was a strong positive correlation between the plasma level of NT-proBNP and the National Institutes of Health Stroke Scale score (r=0.415, P=0.000). Plasma levels of NT-proBNP in patients with an unfavorable outcome were significantly higher than those in patients with a favorable outcome [3432 (interquartile range, 1100-54991) vs. 978 (interquartile range, 123-1705) pg/ml; P=0.000]. In multivariate analyses, after adjusting for all other significant outcome predictors, the NT-proBNP level that remained can be seen as an independent unfavorable outcome predictor, with an adjusted odds ratios of 4.14 (95% confidence interval, 2.72-7.99; P=0.000). Our results show that plasma NT-proBNP levels were significantly elevated in patients with an unfavorable outcome and might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with AIS.', 'Plasma levels of BNP, NT-proBNP, cortisol and copeptin were associated with stroke severity, as well as short-term functional outcomes. After adjusting for all other significant outcome predictors, NT-proBNP, cortisol and copeptin remained as independent outcome predictors. In the receiver operating characteristic curve analysis, the biomarker panel (including BNP, NT-proBNP, cortisol and copeptin) predicted functional outcome and death within 90 days significantly more efficiently than the National Institute of Health Stroke Scale (NIHSS) or the biomarker alone.', 'The NT-proBNP levels were significantly higher at 4 intervals after ischemic stroke than in healthy and at-risk control subjects (all p<0.001). ', 'Multivariate analysis demonstrated that age and NIH Stroke Scale were the 2 strongest independent predictors of increased NT-proBNP levels (all p<0.01). Furthermore, increased NT-proBNP (> or = 150 pg/ml) was the strongest independent predictor of long-term (mean follow-up: 24 months) UFCO (26 patients) (all p<0.05). CONCLUSIONS: The NT-proBNP level was markedly elevated after acute ischemic stroke and declined substantially thereafter. An increased NT-proBNP level was strongly and independently correlated with UFCO in patients after ischemic stroke.']

['ProBNP serum concentrations are elevated in stroke patients relative to healthy controls. Greater proBNP serum concentrations are associated with greater stroke severity and with increased risk for unfvorable functional outcomes.']

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In which fields of DNA sequencing are Bloom filters applied?

['A novel algorithm, fast and accurate classification of sequences (FACSs), is introduced that can accurately and rapidly classify sequences as belonging or not belonging to a reference sequence. ', 'Classification of DNA sequences using Bloom filters', 'Lighter is a fast, memory-efficient tool for correcting sequencing errors. Lighter avoids counting k-mers. Instead, it uses a pair of Bloom filters, one holding a sample of the input k-mers and the other holding k-mers likely to be correct.', 'Fast lossless compression via cascading Bloom filters', 'In contrast to reference-based methods that first align reads to the genome, we hash all reads into Bloom filters to encode, and decode by querying the same Bloom filters using read-length subsequences of the reference genome. Further compression is achieved by using a cascade of such filters', 'Using cascading Bloom filters to improve the memory usage for de Brujin graphs', "In this work, we show how to reduce the memory required by the data structure of Chikhi and Rizk (WABI'12) that represents de Brujin graphs using Bloom filters.", 'We introduce a novel hash-based method for constructing the string graph. We use incremental hashing, and specifically a modification of the Karp-Rabin fingerprint, and Bloom filters', 'Further, we note that Bloom filters would be suitable to implicitly store spaced seeds and be tolerant to sequencing errors.', ' It uses a pair of cache oblivious Bloom filters, one holding a uniform sample of [Formula: see text]-spaced sequenced [Formula: see text]-mers and the other holding [Formula: see text]-mers classified as likely correct, using a simple statistical test.', 'Improving Bloom Filter Performance on Sequence Data Using k-mer Bloom Filters', 'BFs reduce the memory footprint required to store millions of k-mers while allowing for fast set containment queries, at the cost of a low false positive rate (FPR).', 'We consider several variants of such k-mer Bloom filters (kBFs), derive theoretical upper bounds for their FPR, and discuss their range of applications and limitations.', 'Fast lossless compression via cascading Bloom filters.', 'Fast lossless compression via cascading Bloom filters.']

['A novel algorithm, fast and accurate classification of sequences (FACSs), is introduced that can accurately and rapidly classify sequences as belonging or not belonging to a reference sequence. Classification of DNA sequences using Bloom filters Lighter is a fast, memory-efficient tool for correcting sequencing errors.', 'A novel algorithm, fast and accurate classification of sequences (FACSs), is introduced that can accurately and rapidly classify sequences as belonging or not belonging to a reference sequence. Classification of DNA sequences using Bloom filters. Further, we note that Bloom filters would be suitable to implicitly store spaced seeds and be tolerant to sequencing errors. Lighter avoids counting k-mers. Fast lossless compression via cascading Bloom filters. ', 'A novel algorithm, fast and accurate classification of sequences (FACSs), is introduced that can accurately and rapidly classify sequences as belonging or not belonging to a reference sequence. Classification of DNA sequences using Bloom filters. Instead, it uses a pair of Bloom filters, one holding a sample of the input k-mers and the other holding k-mers likely to be correct. Fast lossless compression via cascading Bloom filters. Lighter is a fast, memory-efficient tool for correcting sequencing errors. ', 'A novel algorithm, fast and accurate classification of sequences (FACSs), is introduced that can accurately and rapidly classify sequences as belonging or not belonging to a reference sequence. Classification of DNA sequences using Bloom filters. Instead, it uses a pair of Bloom filters, one holding a sample of the input k-mers and the other holding k-mers likely to be correct. Lighter is a fast, memory-efficient tool for correcting sequencing errors. Lighter avoids counting k-mers. ', 'Bloom Filters (BFs) reduce the memory footprint required to store millions of k-mers while allowing for fast set containment queries, at the cost of a low false positive rate (FPR). Cascading Bloom filters have been used to improve the memory usage and speed of DNA sequence compression.', 'Further, we note that Bloom filters would be suitable to implicitly store spaced seeds and be tolerant to sequencing errors. It uses a pair of cache oblivious Bloom filters, one holding a uniform sample of [Formula: see text]-spaced sequenced [Formula: see text]-mers and the other holding [Formula: see text]-mers classified as likely correct, using a simple statistical test.']

['storage', 'compression', 'alignment-free comparisons']

Where are the unipolar brush cells localized?

['Cerebellar unipolar brush cells (UBCs) are glutamatergic interneurons that receive direct input from vestibular afferents in the form of a unique excitatory synapse on their dendritic brush. ', 'Immunostained unipolar brush cells were observed in granule cell regions of the cochlear nucleus and the vestibulocerebellum.', 'Postsynaptic enrichment of Eps8 at dendritic shaft synapses of unipolar brush cells in rat cerebellum.', 'In cerebellum, unipolar brush cells (UBCs) were densely Eps8 immunopositive and granule cells were moderately immunostained. ', 'Postnatal differentiation of unipolar brush cells and mossy fiber-unipolar brush cell synapses in rat cerebellum.', 'Knowledge of the ultrastructure of the unipolar brush cell terminals and of the cellular identity of its postsynaptic targets is required to understand how unipolar brush cells contribute to information processing in the cerebellar circuit.', 'To investigate the unipolar brush cell axon and its targets, unipolar brush cells were patch-clamped in fresh parasagittal slices from rat cerebellar vermis with electrodes filled with Lucifer Yellow and Biocytin, and examined by confocal fluorescence and electron microscopy.', 'Calretinin-immunoreactive unipolar brush cells in the developing human cerebellum.', 'Unipolar brush cell: a potential feedforward excitatory interneuron of the cerebellum.', 'Unipolar brush cells are also found in the cochlear nucleus.', 'The unipolar brush cells reside nearly exclusively in the granular layer.', 'In the monkey cerebellum, unipolar brush cells, localized in the granular layer, were heavily labeled, whereas Golgi cells were devoid of NG', 'Unipolar brush cells (UBC) are small, glutamatergic neurons residing in the granular layer of the cerebellar cortex and the granule cell domain of the cochlear nuclear complex', 'Knowledge of the ultrastructure of the unipolar brush cell terminals and of the cellular identity of its postsynaptic targets is required to understand how unipolar brush cells contribute to information processing in the cerebellar circuit', 'To investigate the unipolar brush cell axon and its targets, unipolar brush cells were patch-clamped in fresh parasagittal slices from rat cerebellar vermis with electrodes filled with Lucifer Yellow and Biocytin, and examined by confocal fluorescence and electron microscopy', 'While granule cells express solely VGLUT1, there is no report about the VGLUT(s) of the unipolar brush cell (UBC), the second type of glutamatergic interneuron residing in the cerebellar granular layer', 'Large clusters of labeled nuclei consisting mainly of granule cells and calretinin-positive unipolar brush cells were present in the granular layer, whereas Purkinje cell nuclei were unlabeled, and labeled basket and stellate cell nuclei were scattered in the molecular layer', 'Unipolar brush cells (UBCs) are a class of excitatory interneuron found in the granule cell layer of the vestibulocerebellum', 'TBR2-immunopsitive unipolar brush cells are associated with ectopic zebrin II-immunoreactive Purkinje cell clusters in the cerebellum of scrambler mice', 'Glutamate receptor subunits at mossy fiber-unipolar brush cell synapses: light and electron microscopic immunocytochemical study in cerebellar cortex of rat and cat.', 'Properties of transmission at a giant glutamatergic synapse in cerebellum: the mossy fiber-unipolar brush cell synapse.', 'Metabotropic glutamate receptors are associated with non-synaptic appendages of unipolar brush cells in rat cerebellar cortex and cochlear nuclear complex.', 'The unipolar brush cells of the rat cerebellar cortex and cochlear nucleus are calretinin-positive: a study by light and electron microscopic immunocytochemistry.', 'Cerebellar choline acetyltransferase positive mossy fibres and their granule and unipolar brush cell targets: a model for central cholinergic nicotinic neurotransmission.', 'In cerebellum, unipolar brush cells (UBCs) were densely Eps8 immunopositive and granule cells were moderately immunostained.', 'In the monkey cerebellum, unipolar brush cells, localized in the granular layer, were heavily labeled, whereas Golgi cells were devoid of NG.', 'The results indicate that synaptic excitation of unipolar brush cells by mossy fibers will drive a large population of granule cells, and thus will contribute a powerful form of distributed excitation within the basic circuit of the cerebellar cortex.', 'These neurons, here termed unipolar brush cells, are intermediate in size between granule cells and Golgi cells.', 'Extraordinary synapses of the unipolar brush cell: an electron microscopic study in the rat cerebellum.', 'Knowledge of the ultrastructure of the unipolar brush cell terminals and of the cellular identity of its postsynaptic targets is required to understand how unipolar brush cells contribute to information processing in the cerebellar circuit.', 'The unipolar brush cell: a neglected neuron of the mammalian cerebellar cortex.', 'Postnatal differentiation of unipolar brush cells and mossy fiber-unipolar brush cell synapses in rat cerebellum.', 'To investigate the unipolar brush cell axon and its targets, unipolar brush cells were patch-clamped in fresh parasagittal slices from rat cerebellar vermis with electrodes filled with Lucifer Yellow and Biocytin, and examined by confocal fluorescence and electron microscopy.']

['Unipolar brush cells (UBCs) are glutamatergic interneurons localized in granule cell regions of the cochlear nucleus and the vestibulocerebellum of cerebellum.']

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Is CD84 genetically associated with arthritis?

["The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients)", 'Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity', ' Three members of this gene family, Ly108, Ly9, and CD84, exhibit polymorphisms that strongly influence susceptibility to systemic autoimmunity, notably in mice, but also in some human populations']

['Three members of this gene family, Ly108, Ly9, and CD84, exhibit polymorphisms that strongly influence susceptibility to systemic autoimmunity, notably in mice, but also in some human populations. Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with Rheumatoid Arthritis disease activity.']

['yes']

Which is the receptor for substrates of Chaperone Mediated Autophagy?

['These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A)', 'Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor.', 'CMA activity has been shown to be proportional to levels of the CMA receptor Lamp-2a.', 'Lysosomes from livers of lipid-challenged mice had a marked decrease in the levels of the CMA receptor, the lysosome-associated membrane protein type 2A,', 'We report that Bcl-2-related early rod apoptosis was associated with the upregulation of autophagy markers including chaperone-mediated autophagy (CMA) substrate receptor LAMP-2', 'we examined gene expression levels of lysosome-associated membrane 2 (LAMP-2), a CMA receptor', 'The lysosomal-membrane protein type 2A (LAMP-2A) acts as the receptor for the substrates of chaperone-mediated autophagy (CMA)', 'Chaperone-mediated autophagy (CMA) is a selective type of autophagy by which specific cytosolic proteins are sent to lysosomes for degradation. Substrate proteins bind to the lysosomal membrane through the lysosome-associated membrane protein type 2A (LAMP-2A), one of the three splice variants of the lamp2 gene, and this binding is limiting for their degradation via CMA.', 'Substrate proteins only bind to monomeric LAMP-2A, while the efficient translocation of substrates requires the formation of a particular high-molecular-weight LAMP-2A complex', 'We recently reported that UCH-L1 physically interacts with LAMP-2A, the lysosomal receptor for chaperone-mediated autophagy (CMA', 'In this study, we found that UCH-L1 physically interacts with LAMP-2A, the lysosomal receptor for CMA,', 'We have previously described an age-related decline in chaperone-mediated autophagy (CMA), a selective form of autophagy, by which particular cytosolic proteins are delivered to lysosomes after binding to the lysosome-associated membrane protein type 2A (LAMP-2A), a receptor for this pathway.', 'Chaperone-mediated autophagy (CMA) is a selective pathway for the degradation of cytosolic proteins in lysosomes. CMA declines with age because of a decrease in the levels of lysosome-associated membrane protein (LAMP) type 2A, a lysosomal receptor for this pathway.', 'Oxidation-induced activation of CMA correlates with higher levels of several components of the lysosomal translocation complex, but in particular of the lumenal chaperone, required for substrate uptake, and of the lysosomal membrane protein (lamp) type 2a, previously identified as a receptor for this pathway.', 'We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA).', 'We have previously identified this receptor as the lysosome-associated membrane protein type 2a (lamp2a)', 'Lamp2a acts as a receptor in the lysosomal membrane for substrate proteins of chaperone-mediated autophagy.', 'These characteristics may be important for lamp2a to act as a receptor for chaperone-mediated autophagy.', 'A progressive age-related decrease in the levels of the lysosome-associated membrane protein type 2a that acts as a receptor for chaperone-mediated autophagy', 'Hsc70 and Hsp40 are members of a molecular chaperone complex required for protein transport into the lysosome during chaperone-mediated autophagy (CMA).', 'Once there, substrate proteins bind to the lysosome-associated membrane protein type 2 isoform A (LAMP2A), inducing assembly of this receptor protein into a higher molecular weight protein complex that is used by the substrate proteins to reach the lysosomal lumen. ', 'Protein substrates bind to a receptor in the lysosomal membrane, the lysosome-associated membrane protein (lamp) type 2a.']

['Chaperone-mediated autophagy (CMA) is a lysosomal pathway for selective removal of damaged cytosolic proteins. The LAMP2A (Lysosome-associated membrane protein 2 isoform A) functions as a receptor for cytosolic proteins and also as essential component of the CMA translocation complex [28]. Cytosolic substrate proteins bind to monomers of LAMP-2A, which then multimerizes to form the complex required for substrate transmembrane import.']

['LAMP2A', 'Lysosome-associated membrane protein 2 isoform A']

Which R package is used for the analysis of genome-wide DNA methylation profiles?

['methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles.', ' Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation.', 'Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments.', 'methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles', 'Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation', 'Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation.', 'methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles.']

['MethylKit is a comprehensive R package for the analysis of genome-wide DNA methylation profiles. MethylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation.']

['methylKit']

Which genes were found to be methylated in bladder cancer cells?

['CpG island in promoter of hepaCAM gene was hyper-methylated both in bladder carcinoma tissues and cell lines (T24 and BIU-87). Otherwise, aberrant methylation of its promoter was associated with its decreased expression.', 'Abnormal hypermethylation in CpG island of hepaCAM promoter is involved in absence of hepaCAM gene expression when bladder cancer occurs.', 'Methylated RARβ(2) and APC were significantly higher in bladder cancer patients (62.8%, 59.5%) than benign (16.4%, 5%) but not detected in healthy volunteers (0%) at (P < 0.0001).', 'Among the 128 patients with bilharzial bladder cancer, 94 (73.4%) showed methylated RARβ(2) and 86 (67.2%) showed methylated APC.', 'Thus, methylated RARβ(2) and APC genes might be valuable urinary molecular markers for early detection of bilharzial and nonbilharzial bladder cancer.', 'Exon 2 methylation inhibits hepaCAM expression in transitional cell carcinoma of the bladder', 'the expression of hepaCAM was absent in T24 and BIU-87 cells, and we found that exon 2 of hepaCAM was methylated in the 2 cells.', 'hepaCAM mRNA was re-expressed and the methylation status of hepaCAM exon 2 was reversed after treatment with 5-Aza-CdR.', 'The methylation rate of hepaCAM exon 2 was significantly higher in bladder cancer tissues than in adjacent tissues.', 'Recently, methylation of the TPEF (transmembrane protein containing epidermal growth factor and follistatin domain) gene was reported in human colon, gastric, and bladder cancer cells.', 'Hypermethylation of at least one of three suppressor genes (APC, RASSF1A, and p14(ARF)) was found in all 45 tumor DNAs (100% diagnostic coverage).', 'Methylation of the CpG island in the promoter of the p16 gene in human bladder cancer cells did not stop the formation of a transcript initiated 20 kb upstream by the p19 promoter but did prevent the expression of a p16 transcript.', 'We also present the first functional evidence that methylation of only a small number of CpG sites can significantly down-regulate p16 promoter activity, thus providing support for the model of progressive inactivation of this tumor suppressor gene by DNA methylation.', 'Hypermethylation of hepaCAM gene was reversed and expression of its mRNA and protein were re-activated in two cell lines by DNA methyltransferases inhibitor 5-aza-CdR']

['In bladder cancer, hepaCAM (hepatocyte cell adhesion molecule), RARβ(2), APC, TPEF (transmembrane protein containing epidermal growth factor and follistatin domain), RASSF1A, p14(ARF) and p16 genes were found to be methylated. These methylation events were demostrated to associate with downregulation of gene expression.']

['hepaCAM (hepatocyte cell adhesion molecule)', 'RARβ(2)', 'APC', 'TPEF (transmembrane protein containing epidermal growth factor and follistatin domain)', 'RASSF1A', 'p14(ARF)', 'p16']

Which signaling pathway is activating the dishevelled proteins?

['Wnt signaling is known to be important for diverse embryonic and post-natal cellular events and be regulated by the proteins Dishevelled and Axin. Although Dishevelled is activated by Wnt and involved in signal transduction, it is not clear how Dishevelled-mediated signaling is turned off. ', 'The Dishevelled protein mediates several diverse biological processes. Intriguingly, within the same tissues where Xenopus Dishevelled (Xdsh) controls cell fate via canonical Wnt signaling,', 'Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways.']

['Dishevelled (Xdsh) controls cell fate via canonical Wnt signaling']

['Wnt signaling']

Which is the physiological target for LeuRS translational quality control?

['The physiological target for LeuRS translational quality control is norvaline.', 'The physiological target for LeuRS translational quality control is norvaline', 'Rather, as shown by kinetic, structural and in vivo approaches, the prime biological function of LeuRS editing is to prevent mis-incorporation of the non-standard amino acid norvaline']

['QUALITY CONTROL', 'The physiological target for LeuRS translational quality control is norvaline.', 'The fidelity of protein synthesis depends on the capacity of aminoacyl-tRNA synthetases (AARSs) to couple only cognate amino acid-tRNA pairs. If amino acid selectivity is compromised, fidelity can be ensured by an inherent AARS editing activity that hydrolyses mischarged tRNAs. Rather, as shown by kinetic, structural and in vivo approaches, the prime biological function of LeuRS editing is to prevent mis-incorporation of the non-standard amino acid norvaline.']

['Norvaline']

Which cell types are known to be driving Rheumatoid Arthritis?

['Integration of GWAS results with cell-type specific gene expression or epigenetic marks have highlighted regulatory T cells and CD4 memory T cells as critical cell types in RA', 'A subset of synovial DCs is important in the response to cigarette smoke', ' we demonstrate that autoimmune patient (systemic lupus erythematosus and rheumatoid arthritis) serum activates both pDC and B cells, but IRAK1/4 kinase inhibition affects only the pDC response, underscoring the differential IRAK1/4 functional requirements in human immune cell', 'In rheumatoid arthritis (RA), activated synovial fibroblasts (SFs) have the ability to invade joint cartilage, actively contributing to joint destruction in RA', 'Recently, RASFs have been shown to be able to migrate to non-affected areas and joints through the blood stream and to invade distant cartilage', 'MSC interaction with B cells provides stimuli for B-cell survival and therefore may contribute to the pathogenesis of rheumatoid arthritis', 'Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells of synovial joints that have been recognized to play an increasingly important role in the pathogenesis of rheumatoid arthritis (RA)', 'This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF)', 'In this regard, macrophages, T cells and their respective cytokines play a pivotal role in RA', 'it has been understood that resident, fibroblast-like cells contribute significantly to the perpetuation of disease, and that they may even play a role in its initiation', 'RASFs are no longer considered passive bystanders but active players in the complex intercellular network of RA', 'These rheumatoid arthritis synovial fibroblasts (RASFs) constitute a quite unique cell type that distinguishes RA from other inflammatory conditions of the joints', 'The molecular feature that defines the myofibroblast-like phenotype was reflected as an increased proportion of myofibroblast-like cells in the heterogeneous FLS population', 'ur findings support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence of a possible link between the behavior of FLS and the inflammation status of RA synovium', 'This change was accompanied by a significant decrease in the synovial monocyte/macrophage population', 'In RA patients, both etanercept and infliximab are able to induce cell type-specific apoptosis in the monocyte/macrophage population', 'Furthermore, fluorescent double-staining showed that the HOXD9 protein was expressed in fibroblast-like synoviocytes (FLS)', 'AHR gene expression was demonstrated in rheumatoid synovial tissues and nodules with significantly greater expression in synovia.', 'Twenty synovial and eighteen subcutaneous nodule tissue samples from 31 patients with RA were studied. Patient smoking status at the time of tissue collection was established', 'Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells']

['Macrophages, T cells and their respective cytokines play a pivotal role in RA. Rheumatoid arthritis synovial fibroblasts (RASFs) constitute a quite unique cell type that distinguishes RA from other inflammatory conditions of the joints. Activated synovial fibroblasts (SFs) have the ability to invade joint cartilage, actively contributing to joint destruction in RA.']

['Macrophages', 'T-cells', 'Fibroblast-like synoviocytes (FLS)', 'Dendritic cells', 'synovial fibroblasts']

What is the mode of inheritance of Romano Ward long QT syndrome?

['KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias.', 'The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance.', 'The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions.', 'The Jervell and Lange-Nielsen syndrome (JLNS) is characterized by prolongation of the QT interval, deafness, and autosomal-recessive inheritance, and the Romano-Ward syndrome is characterized by a prolonged QT interval, autosomal-dominant inheritance, and no deafness. ', 'Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. ', 'The Romano-Ward syndrome shows an autosomal dominant pattern of inheritance and normal hearing. ', 'The Romano-Ward syndrome is of autosomal dominant inheritance, and the Jervell and Lange-Nielson syndrome, with associated deafness, of autosomal recessive inheritance. ', 'Romano-Ward syndrome is a subtype of prolonged QT syndrome with autosomal dominant inheritance. ', 'A family with the Romano-Ward syndrome is presented. This family showed typical features of this syndrome with QT prolongation, torsades de pointes ventricular tachycardia, sudden death and an autosomal dominant inheritance pattern. ']

['The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance.']

['autosomal dominant']

What is the role of the Tsix gene during X chromosome inactivation?

['A conservation of Tsix expression pattern in voles, rat and mice suggests a crucial role of the antisense transcription in regulation of Xist and XIC in rodents.', 'the Tsix gene (antisense counterpart of Xist)', 'One of the two X chromosomes in female mammalian cells is subject to inactivation (XCI) initiated by the Xist gene.', 'One example for antisense regulation is the Xist (X-inactive specific transcript) and Tsix gene pair, which is pivotal in X-inactivation. Xist works as a functional RNA molecule that recruits repressive chromatin factors towards one of the female Xs for inactivation. Antisense Tsix transcription negatively regulates Xist and protects one X-chromosome in cis from inactivation by Xist. Albeit, the precise molecular mechanism is still obscure it has been shown that Tsix transcription regulates the chromatin structure by altering histone tail modifications and DNA methylation at the Xist promoter. In addition, Xist and Tsix RNA form an RNA duplexes in vivo and are processed to small RNAs, which have a potential regulatory function.', "In eutherian mammals, random XCI of the soma requires a master regulatory locus known as the 'X-inactivation center' (XIC/Xic), wherein lies the noncoding XIST/Xist silencer RNA and its regulatory antisense Tsix gene.", "A counting process senses the X chromosome/autosome ratio and ensures that X chromosome inactivation (XCI) initiates in the early female (XX) embryo and in differentiating female ES cells but not in their male (XY) counterparts. Counting depends on the X inactivation center (Xic), which contains the Xist gene encoding a nuclear RNA, which coats the inactive X chromosome and induces gene silencing. A 37-kb sequence lying 3' to the Xist gene is known to prevent initiation of XCI in male differentiating ES cells. This region contains the major and minor promoters of the Tsix gene, which runs antisense to Xist", 'Our results identify a function for DXPas34 in murine XCI and demonstrate the critical role of Tsix transcription in preventing XCI in differentiating male ES cells and in normal functioning of the counting pathway.', 'Transcriptional silencing of the human inactive X chromosome is induced by the XIST gene within the human X-inactivation center. The XIST allele must be turned off on one X chromosome to maintain its activity in cells of both sexes. In the mouse placenta, where X inactivation is imprinted (the paternal X chromosome is always inactive), the maternal Xist allele is repressed by a cis-acting antisense transcript, encoded by the Tsix gene.']

['One of the two X chromosomes in female mammalian cells is subject to inactivation (XCI) initiated by the Xist gene. Xist works as a functional RNA molecule that recruits repressive chromatin factors towards one of the female Xs for inactivation. The Tsix gene, antisense of Xist, through transcription negatively regulates Xist and protects one X-chromosome in cis from inactivation by Xist. Although, the precise molecular mechanism is still unclear it has been shown that Tsix transcription regulates the chromatin structure by altering histone tail modifications and DNA methylation at the Xist promoter. In addition, Xist and Tsix RNAs form duplexes in vivo and are processed to small RNAs, which have a potential regulatory function.']

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Is the Prostate- Specific Antigen (PSA) test relevant only for prostate cancer?

['rostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death in men', 'PSA is known to be prostate specific, but not PCa specific', 'deficiencies of serum PSA as a prostate-cancer-specific diagnostic test are well recognized.', 'medical debate surrounding the use of the prostate-specific antigen (PSA) test for prostate cancer screening', 'The clinical relevance of this surprisingly high rate of prostate cancer in men with a normal PSA is yet to be determined ', 'Rapid uptake of prostate-specific antigen (PSA) testing has occurred in the United States despite inconclusive evidence regarding mortality benefit', 'Routine cancer screening with prostate-specific antigen (PSA) is controversial, and practice guidelines recommend that men be counseled about its risks and benefits', 'Prostate carcinoma was histologically confirmed in 14 (0.66%) of the men, nine times in the early stage (T2) and five times in the clinical stage (T3), corresponding to an incidence of circa 650 cases per 100,000 men in the target age group', 'This newly developed PSA test system can enhance the acceptance rate and effectiveness of medical check-ups for prostate cancer,', 'PSA can be used reliably as a unique tool in the follow-up of patients for the early detection of progressive disease', 'PSA showed negative predictive values of 82 and 77%, respectively, using 4 and 10 ng/ml as cutoff points', 'have assessed the feasibility of using fixed-limit criteria based on medical relevance and biological variation for evaluating the analytical performance of the prostate-specific antigen (PSA) test']

['No, although the PSA test can detect high levels of PSA that may indicate the presence of prostate cancer, many other conditions, such as an enlarged or inflamed prostate, can also increase PSA levels.']

['no']

Is Cri Du Chat associated with an expansion of a repeat with in the gene found on chromosome 5?

['Cri-du-chat syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5', 'The typical cri du chat syndrome, due to 5p15.2 deletion, includes severe intellectual disability, facial dysmorphisms, neonatal hypotonia and pre- and post-natal growth retardation, whereas more distal deletions in 5p15.3 lead to cat-like cry and speech delay and produce the clinical picture of the atypical cri du chat syndrome, with minimal or absent intellectual impairment.', 'Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p.', 'Cri-du-chat is a chromosomal deletion syndrome characterized by partial deletion of the short arm of chromosome 5.', 'The karyotype showed a terminal deletion of the short arm of chromosome 5 including the critical region 5p15 for cri du chat syndrome.', 'Fewer than 1 in 200 of cri du chat syndrome cases are due to recombination aneusomy arising from a parental inversion of chromosome 5.', 'Molecular approach to analyzing the human 5p deletion syndrome, cri du chat.', 'Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p', 'The cri du chat syndrome (CdCS) is a chromosomal deletion syndrome associated with a partial deletion of the short (p) arm of chromosome 5', 'The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p).', 'Cri-du-chat syndrome is associated with a deletion of the short arm of chromosome 5.', 'The deletion of the short arm of chromosome 5 is associated with the cri-du-chat syndrome.', 'The Cri du Chat syndrome (CdCS) is a genetic disease resulting from a deletion of variable size occurring on the short arm of chromosome 5 (5p-).', 'Cri-du-chat is a well described partial aneusomy resulting from deletion of the short arm of chromosome 5.', 'Cri-du-chat syndrome is caused by haploinsufficiency of the genes on the distal part of the short arm of chromosome 5, and characteristic features include microcephaly, developmental delays, and a distinctive high-pitched mewing cry.', 'The pathological condition of cri du chat syndrome is due to the cytogenetic deletion of band p15.2 of chromosome 5. ', ' Karyotype analysis indicated that the patient has carried a terminal deletion in 5p. FISH with Cri du Chat syndrome region probe confirmed that D5S23 and D5S721 loci are deleted. ']

['Cri-du-chat syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5', 'Cri-du-chat syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5. ', 'syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5 . ', 'cri-du-chat syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5.', 'Cri-du-chat syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5.']

['no']

What is the function of the exosome?

['Exosomes-secreted microRNAs play an important role in metastatic spread', 'Exosome-mediated communication', 'Cells are able to produce and release different types of vesicles, such as microvesicles and exosomes, in the extracellular microenvironment. According to the scientific community, both microvesicles and exosomes are able to take on and transfer different macromolecules from and to other cells, and in this way, they can influence the recipient cell function', ' Exosomes are 40-100-nm vesicles released by most cell types after fusion of multivesicular endosomes with the plasma membrane. Exosomes, ubiquitary in body fluids including urines, contain proteins and RNA species specific of the tissue of origin.', ' Exosomes, small membrane vesicles secreted into the extracellular environment, are emerging as another important intercellular messenger in immune responses. ', "the exosome is a complex of 3' -->5' exoribonucleases that plays a key role in the processing and degradation of a wide variety of RNA substrates", 'RNA exosome is responsible for a wide variety of RNA processing and degradation reactions', 'ability of exosomes to carry and selectively deliver bioactive molecules (e.g., lipids, proteins, and nucleic acids) confers on them the capacity to modulate the activity of receptor cells, even if these cells are located in distant tissues or organs. ', 'Our data show that NKG2D is a likely physiological target for exosome-mediated immune evasion in cancer.', 'Exosomes, a key component of cell paracrine secretion, can exert protective effects in various disease models', 'Exosome secretion participates in the eradication of obsolete proteins but several findings, essentially in the immune system, indicate that exosomes constitute a potential mode of intercellular communication', 'Exosomes, nano-sized extracellular vesicles, are believed to play important roles in intercellular communications. This study demonstrates that exosomes released from human macrophages negatively regulate endothelial cell migration through control of integrin trafficking. ', 'We found that the majority of extracellular vesicles in the AH were in the exosome size range, suggesting that miRNAs housed within exosomes may function in communication between AH inflow and outflow tissues.', 'umor cell-derived exosomes (TEX) suppress functions of immune cells. ']

['Exosomes are 40-100-nm vesicles released by most cell types after fusion of multivesicular endosomes with the plasma membrane. Exosomes contain proteins and RNA species and can mediate communication and immune responses.']

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In which phase of the cell cycle arrest is impaired in Fanconi anemia?

['We found that ICLs activate a branched pathway downstream of the ATR kinase: one branch depending on CHK1 activity and the other on the FANCs-RMN complex. The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or FA cells showed partial S-phase arrest', 'Arrest of S-phase progression is impaired in Fanconi anemia cells', 'Fanconi anemia (FA) is an inherited cancer-susceptibility disorder, characterized by genomic instability, hypersensitivity to DNA cross-linking agents, and a prolonged G2 phase of the cell cycle', "We observed a marked dose-dependent accumulation of FA cells in the G2 compartment after treatment with 4,5',8-trimethylpsoralen (Me(3)Pso) in combination with 365 nm irradiation", 'Taken together, the above data suggest that, in response to damage induced by DNA cross-linking agents, the S-phase checkpoint is inefficient in FA cells. This would lead to accumulation of secondary lesions, such as single- and double-strand breaks and gaps. The prolonged time in G2 phase seen in FA cells therefore exists in order to allow the cells to remove lesions which accumulated during the preceding abnormal S phase', 'Fanconi anemia (FA) is a genetic disorder defined by cellular hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). MMC causes increased FA cell death, chromosome breakage, and accumulation in the G2 phase of the cell cycle', 'DNA cross-linker-induced G2/M arrest in group C Fanconi anemia lymphoblasts reflects normal checkpoint function', 'Cells from individuals with Fanconi anemia (FA) arrest excessively in the G2/M cell cycle compartment after exposure to low doses of DNA cross-linking agents', 'Based on these studies we conclude that the aberrant G2/M arrest that typifies the response of FA(C) cells to low doses of cross-linking agents does not represent an abnormal cell cycle response but instead represents a normal cellular response to the excessive DNA damage that results in FA(C) cells following exposure to low doses of cross-linking agents', 'Arrest of S-phase progression is impaired in Fanconi anemia cells.', 'The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S phase.']

['In response to damage induced by DNA cross-linking agents, the S-phase checkpoint is inefficient in Fanconi anemia (FA) cells, leading to accumulation of secondary lesions, such as single- and double-strand breaks and gaps. The prolonged time in G2 phase seen in FA cells therefore exists in order to allow the cells to remove lesions which accumulated during the preceding abnormal S phase.']

['In Fanconi anemia cells, the S-phase checkpoint is inefficient.']

What distinguishes lantibiotics from antibiotics?

['One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides.', 'low levels of resistance have been reported for lantibiotics compared with commercial antibiotics', 'Mechanisms that hinder the action of lantibiotics are often innate systems that react to the presence of any cationic peptides/proteins or ones which result from cell well damage, rather than being lantibiotic specific.', 'Lantibiotics are biologically active peptides produced by Gram-positive bacteria. ', 'Lantibiotics are post-translationally modified, ribosomally synthesised antimicrobial peptides with a broad spectrum antimicrobial activity.', 'Lantibiotic compounds are ribosomally synthesized antimicrobial peptides against which bacteria are not able to produce resistance, hence making them a good alternative to antibiotics.', 'Lantibiotics are ribosomally synthesized peptide antibiotics that are posttranslationally modified to introduce (methyl)lanthionine bridges.', 'Lantibiotics are defined as peptide antibiotics containing the unusual amino acids mesolanthionine, 3-methyllanthionine, dehydroalanine, and dehydrobutyrine.', 'Lantibiotics are antibiotic peptides distinguished by the presence of the rare thioether amino acids lanthionine and/or methyllanthionine.', 'Lantibiotics are ribosomally synthesized, post-translationally modified, peptide antibiotics containing unusual amino acids such as dehydrated amino acids and lanthionine.', 'Lantibiotics are peptide antibiotics, realizing their unique secondary structure by posttranslational modifications, the most important one being the formation of the characteristic amino acid lanthionine.', 'Lantibiotics are lanthionine-containing peptide antibiotics. ', 'Lantibiotics, a group of lanthionine-containing peptides, display their antibiotic activity by combining different killing mechanisms within one molecule. ', 'Lantibiotics are ribosomally synthesized as prepeptides, which are posttranslationally modified.']

['Lantibiotic compounds are ribosomally synthesized antimicrobial peptides against which bacteria are not able to produce resistance, hence making them a good alternative to antibiotics. It is interesting that low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Given that there are very few examples of naturally occurring lantibiotic resistance, attempts have been made to deliberately induce resistance phenotypes in order to investigate this phenomenon. Other general forms of resistance include the formation of spores or biofilms, which are a common mechanistic response to many classes of antimicrobials.', 'One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides. Low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Nisin is the oldest and the most widely used lantibiotic, in food preservation, without having developed any significant resistance against it.', 'One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides.']

['Lantibiotics are post-translationally modified natural peptides containing lanthionine']

What molecule is targeted by Avelumab?

['Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development.', 'We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. ', 'Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab).', 'In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques.', 'We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy.', 'Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody.', 'Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung.', 'In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.', 'Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells.', 'MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb.', 'These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.', 'We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction.', 'In addition, mesothelioma tumor cells are susceptible to ADCC by the anti-PD-L1 antibody avelumab..', 'Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.', 'In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques.', 'Different mechanisms to prevent immunologic escape have been characterized during the last years; in particular the PD-1/PD-L1 inhibitors pembrolizumab, avelumab, durvalumab and atezolizumab have shown early sign of efficacy.']

['Avelumab is a monoclonal antibody that binds programmed death-ligand 1 (PD-L1).']

['programmed death-ligand 1', 'PD-L1']

Describe the applicability of Basset in the context of deep learning

['Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks.', "We introduce the open source package Basset to apply CNNs to learn the functional activity of DNA sequences from genomics data. We trained Basset on a compendium of accessible genomic sites mapped in 164 cell types by DNase-seq, and demonstrate greater predictive accuracy than previous methods. Basset predictions for the change in accessibility between variant alleles were far greater for Genome-wide association study (GWAS) SNPs that are likely to be causal relative to nearby SNPs in linkage disequilibrium with them. With Basset, a researcher can perform a single sequencing assay in their cell type of interest and simultaneously learn that cell's chromatin accessibility code and annotate every mutation in the genome with its influence on present accessibility and latent potential for accessibility. Thus, Basset offers a powerful computational approach to annotate and interpret the noncoding genome.", 'Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks.']

["Basset is an open source package which applies CNNs to learn the functional activity of DNA sequences from genomics data. Basset was trained on a compendium of accessible genomic sites mapped in 164 cell types by DNase-seq, and demonstrated greater predictive accuracy than previous methods. Basset predictions for the change in accessibility between variant alleles were far greater for Genome-wide association study (GWAS) SNPs that are likely to be causal relative to nearby SNPs in linkage disequilibrium with them. With Basset, a researcher can perform a single sequencing assay in their cell type of interest and simultaneously learn that cell's chromatin accessibility code and annotate every mutation in the genome with its influence on present accessibility and latent potential for accessibility. Thus, Basset offers a powerful computational approach to annotate and interpret the noncoding genome."]

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What is considered a reliable technique for the definitive cytogenetic diagnosis of Fanconi anemia homozygosity?

["The in vitro enhancement of chromosome breakage by diepoxybutane (DEB) and mitomycin C (MMC) was studied in 24 Fanconi's anemia (FA) homozygotes and 28 heterozygotes. Both drugs were shown to enhance chromosome breakage significantly in the homozygotes", 'In the great majority of cases, DEB and MMC stressing are reliable techniques for the definitive cytogenetic diagnosis of FA homozygosity', ' In the great majority of cases, DEB and MMC stressing are reliable techniques for the definitive cytogenetic diagnosis of FA homozygosity.', 'The diagnosis of Fanconi anemia was confirmed by increased chromosomal breakage abnormalities observed in cultured cells that were treated with cross-linking agents.', 'In the great majority of cases, DEB and MMC stressing are reliable techniques for the definitive cytogenetic diagnosis of FA homozygosity.', 'The cytogenetic test was shown to be reliable in ascertaining the diagnosis of FA', 'For that purpose, the flow-based mitomycin C sensitivity test here described proved to be a reliable alternative method to evaluate Fanconi anemia phenotype in fibroblasts']

['In vitro enhancement of chromosome breakage by diepoxybutane (DEB) and mitomycin C (MMC) are reliable techniques for the definitive cytogenetic diagnosis of Fanconi anemia homozygosity.', 'In the great majority of cases, DEB and MMC stressing are reliable techniques for the definitive cytogenetic diagnosis of FA homozygosity']

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What species is associated with Tetrodotoxin?

['The selling and importing of puffer fish species and their products was banned in Thailand in 2002, because of possible neurotoxic effects.', 'Efficiency of a rapid test for detection of tetrodotoxin in puffer fish.', 'Marine pufferfish contain tetrodotoxin (TTX), an extremely potent neurotoxin', 'Tetrodotoxin is a potent low weight marine toxin found in warm waters, especially of the Indian and Pacific Oceans. Intoxications are usually linked to the consumption of the puffer fish, although TTX was already detected in several different edible taxa.', 'Food poisoning due to ingestion of a puffer fish occurred in Nagasaki Prefecture, Japan, in October 2008, causing neurotoxic symptoms similar to those of tetrodotoxin (TTX) poisoning.', ' Our findings raised a concern for people, not only Thais but also inhabitants of other countries situated on the Andaman coast; consuming puffers of the Andaman seas is risky due to potential TTX intoxication.', 'Toxic marine puffer fish in Thailand seas and tetrodotoxin they contained.', 'Puffer fish, Takifugu niphobles, collected from the Hong Kong coastal waters were screened for tetrodotoxin-producing bacteria. A Gram-negative, non-acid-fast, non-sporing and rod shaped bacterial strain (designated as gutB01) was isolated from the intestine of the puffer fish and was shown to produce tetrodotoxin (TTX)', 'Isolation and identification of a new tetrodotoxin-producing bacterial species, Raoultella terrigena, from Hong Kong marine puffer fish Takifugu niphobles.', 'Green toadfish Lagocephalus lunaris inhabits tropical and subtropical seas and contains high tetrodotoxin (TTX) levels in the muscle as well as liver and gonad', 'Tetrodotoxin (TTX) is a highly potent neurotoxin that blocks the action potential by selectively binding to voltage-gated sodium channels (Na(v))', 'Suspected tetrodotoxin (TTX) poisoning was associated with eating unknown fish in April 2009 in Taiwan', 'Marine pufferfish generally contain a large amount of tetrodotoxin (TTX) in their skin and viscera, and have caused many incidences of food poisoning, especially in Japan.', ' TTX is originally produced by marine bacteria, and pufferfish are intoxicated through the food chain that starts with the bacteria. ', ', TTX poisoning due to marine snails has recently spread through Japan, China, Taiwan, and Europe.', 'The inhibitory effects of toxin extracted from muscle or liver of five different puffer fishes (hereafter referred as puffer(s)) captured on the Japanese sea coast ', 'LC/MS analysis of tetrodotoxin and its deoxy analogs in the marine puffer fish Fugu niphobles from the southern coast of Korea, and in the brackishwater puffer fishes Tetraodon nigroviridis and Tetraodon biocellatus from Southeast Asia.', 'Toxins such as saxitoxins, tetrodotoxin, palytoxin, nodularin, okadaic acid, domoic acid, may be produced in large amounts by dinoflagellates, cyanobacteria, bacteria and diatoms and accumulate in vectors that transfer the toxin along food chains', 'Tetrodotoxin (TTX) is a low molecular weight (approximately 319 Da) neurotoxin found in a number of animal species, including pufferfish.']

['Tetrodotoxin (TTX) is a low molecular weight (approximately 319 Da) neurotoxin found in a number of animal species, including pufferfish. TTX is originally produced by marine bacteria, and pufferfish are intoxicated through the food chain that starts with the bacteria. TTX is found in warm waters, especially of the Indian and Pacific Oceans. TTX poisoning due to marine snails has recently spread through Japan, China, Taiwan, and Europe.']

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Is the Snord116 cluster associated with the Prader-Willi syndrome?

['All three deletions included SNORD116, but only two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major contributor to the Prader-Willi phenotype. Our case adds further information about genotype-phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader-Willi syndrome', 'These results demonstrate that the AS candidate drug topotecan acts predominantly through stabilizing R loops and chromatin decondensation at the paternally expressed PWS Snord116 locus. Our study holds promise for targeted therapies to the Snord116 locus for both AS and PWS.', 'Prader-Willi syndrome (PWS) is caused by the loss of RNA expression from an imprinted region on chromosome 15 that includes SNRPN, SNORD115, and SNORD116. ', 'Recently published data strongly suggest a role for the paternally expressed small nucleolar RNA (snoRNA) cluster, SNORD116, in PWS etiology.', 'Whereas loss of function of the SNORD116 genes appears to be responsible for the major features of PWS, the role of the other genes is less clear. ', 'Recent data suggest that snoRNA Snord116 is important for the pathogenesis of Prader-Willi syndrome (PWS) characterized by hyperphagia and obesity. The current study was conducted to assess a potential cellular link between Snord116 and phenotypes of PWS. ', 'The imprinted Snurf-Snrpn chromosomal domain contains two large arrays of tandemly repeated, paternally expressed box C/D small-nucleolar RNA (snoRNA) genes: the SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters believed to play key roles in the fine-tuning of serotonin receptor (5-HT2C) pre-mRNA processing and in the etiology of the Prader-Willi Syndrome (PWS), respectively', 'There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features.', 'Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions.', 'There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. ', 'Although the SNORD116 gene cluster has become a prime candidate for PWS, it cannot be excluded that other paternally expressed genes in the chromosomal region 15q11q13 contribute to the full phenotype.', 'In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology.', 'Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. ']

['Yes, SNORD116 has a major role in Prader-Willi syndrome etiology.']

['yes']

Is Achondroplasia associated with hearing loss?

['A hearing screening program was performed to determine the prevalence of hearing loss and abnormal tympanometry in individuals with short-stature skeletal dysplasias attending a national meeting. Behavioral audiometry, otoacoustic emission testing, and tympanometry were used to assess hearing. Failed hearing screen was defined as hearing ≥ 35 dB at one or more frequencies or by "fail" on otoacoustic emissions. One hundred ten of 112 subjects completed the screening. 58 (51.8%) were children. Seventy-three (65.2%) had achondroplasia, 34 (30.4%) had one of 11 other diagnoses, and 5(4.4%) were undiagnosed. 25.8% of children failed hearing screening in one or both ears, while 46.3% of adults failed in one or both ears. 55.1% of adults and 25.0% of children with achondroplasia failed screening.', 'Forty-four children had achondroplasia, and 31 had normal hearing in both ears (71%); 8 failed hearing screening in 1 ear (18%), and 3 in both ears (7%). Tympanometry was performed in 45 children, with normal tympanograms found in 21 (47%), bilateral abnormal tympanograms in 15 (33%), and unilateral abnormal tympanograms in 9 (20%). Fourteen children with achondroplasia had normal tympanograms (42%); 11 had bilateral abnormal tympanograms (33%); and 8 had unilateral abnormal tympanograms (24%). For those children without functioning tympanostomy tubes, there was a 9.5 times greater odds of hearing loss if there was abnormal tympanometry (P\xa0=\xa0.03).', 'Achondroplasia (MIM 100800) is the most common non-lethal skeletal dysplasia. Its incidence is between one in 10,000 and one in 30,000. The phenotype is characterized by rhizomelic disproportionate short stature, enlarged head, midface hypoplasia, short hands and lordotic lumbar spine, associated with normal cognitive development. This autosomal-dominant disorder is caused by a gain-of-function mutation in the gene encoding the type 3 receptor for fibroblast growth factor (FGFR3); in more than 95% of cases, the mutation is G380R. The diagnosis is suspected on physical examination and confirmed by different age-related radiological features. Anticipatory and management care by a multidisciplinary team will prevent and treat complications, including cervical cord compression, conductive hearing loss and thoracolumbar gibbosity.', 'The report includes information on otitis media, ventilation tubes, hearing loss, tonsillectomy, speech problems, tibial bowing and osteotomy, ventricular shunting, apnoea, cervicomedullary decompression, and neurological signs attributable to spinal stenosis.', 'We conclude that verbal comprehension is significantly impaired in children with achondroplasia. This partial deficiency is probably related to frequent middle ear infections and resulting conductive hearing loss.', 'In order to determine whether these morphologic changes are the cause of the hearing deficit in achondroplasia, audiometric studies and ENT evaluation were performed in eight of the nine patients.', 'Audiograms were obtained in six of the nine achondroplastic subjects (two adults and four children). There was evidence of mixed hearing loss in the four children, but only of sensorineural hearing loss in the adults. We believe that the persistent hearing loss in achondroplasia is not due to sequelae of otitis media as some authors have suggested. ', 'The AA report a clinical and radiological study performed in 18 achondroplastic patients in order to achieve a nosological settlement of the otological impairments. ']

['Yes, there is hearing deficit in achondroplasia']

['yes']

Are conserved noncoding elements associated with the evolution of animal body plans?

['Here, we discuss the evidence that CNEs are part of the core gene regulatory networks (GRNs) that specify alternative animal body plans. The major animal groups arose>550 million years ago. We propose that the cis-regulatory inputs identified by CNEs arose during the "re-wiring" of regulatory interactions that occurred during early animal evolution. Consequently, different animal groups, with different core GRNs, contain alternative sets of CNEs. Due to the subsequent stability of animal body plans, these core regulatory sequences have been evolving in parallel under strong purifying selection in different animal groups.', 'Conserved noncoding elements and the evolution of animal body plans.', 'Conserved noncoding elements and the evolution of animal body plans']

['Yes. Cis-regulatory inputs identified by CNEs arose during the "re-wiring" of regulatory interactions that occurred during early animal evolution. Consequently, different animal groups, with different core GRNs, contain alternative sets of CNEs. Due to the subsequent stability of animal body plans, these core regulatory sequences have been evolving in parallel under strong purifying selection in different animal groups.']

['yes']

Which microRNAs are involved in exercise adaptation?

['Some miRNAs as miR-1, miR-133 and miR-208a are highly expressed in the heart and strongly associated with the development of cardiac hypertrophy. Recent data indicate that these miRNAs as well as miR-206 change their expression quickly in response to physical activity.', 'the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise.', '1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a),', 'MicroRNA 1 expression was decreased independent of the training modality, and was paralleled by an increased expression of IGF-1 representing a potential target.', 'we investigated the expression of these myomiRs, including miR-1, miR-133a, miR-133b and miR-206 in muscle biopsies from vastus lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemic–euglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training.', 'In resting biopsies, endurance training for 12 weeks decreased basal expression of all four myomiRs (P < 0.05)', 'These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise.']

['miR-1, miR-133, miR-208a, miR-206, miR-494, miR-146a, miR-222, miR-21, miR-221, miR-20a, miR-133a, miR-133b, miR-23, miR-107 and miR-181 are involved in exercise adaptation']

['miR-1', 'miR-133', 'miR-208a', 'miR-206', 'miR-494', 'miR-146a', 'miR-222', 'miR-21', 'miR-221', 'miR-20a', 'miR-133a', 'miR-133b', 'miR-23', 'miR-107', 'miR-181']

What is the indication for valbenazine?

['VMAT2 inhibitors (e.g. deutetrabenazine and valbenazine) have been studied in the treatment of HD-related chorea, tardive dyskinesia and tics associated with Tourette syndrome.', 'Valbenazine granted breakthrough drug status for treating tardive dyskinesia.', 'The FDA lowered approval hurdles for valbenazine due to a successful Phase II trial, which showed a distinctive improvement in tardive dyskinesia symptoms during valbenazine administration. ']

['Valbenazine granted breakthrough drug status for treating tardive dyskinesia.']

['Valbenazine granted breakthrough drug status for treating tardive dyskinesia.']

What is Tn-seq?

[' Using Tn-seq, a genome-wide fitness profiling technique, we identified several functions required for fitness of Y.\xa0pestis in vivo that were not previously known to be important.', 'Tn-seq is a technique that allows for quantitative assessment of individual mutants within a transposon mutant library by sequencing the transposon-genome junctions and then compiling mutant presence by mapping to a base genome. Using Tn-seq, it is possible to quickly define all the insertional mutants in a library and thus identify nonessential genes under the conditions in which the library was produced. Identification of fitness of individual mutants under specific conditions can be performed by exposing the library to selective pressures.', 'Genome-wide fitness and genetic interactions determined by Tn-seq, a high-throughput massively parallel sequencing method for microorganisms.', 'Tn-seq: high-throughput parallel sequencing for fitness and genetic interaction studies in microorganisms.', 'Here we present the method Tn-seq, with which it has become possible to quantitatively determine fitness for most genes in a microorganism and to screen for quantitative genetic interactions on a genome-wide scale and in a high-throughput fashion. Tn-seq can thus direct studies in the annotation of genes and untangle complex phenotypes. ', 'Here we present a method (Tn-seq) for accurately determining quantitative genetic interactions on a genome-wide scale in microorganisms. Tn-seq is based on the assembly of a saturated Mariner transposon insertion library. After library selection, changes in frequency of each insertion mutant are determined by sequencing the flanking regions en masse. ', 'Whole-genome fitness analysis in microbes that uses saturating transposon mutagenesis combined with massively parallel sequencing (Tn-seq) is providing a measure of the contribution of each gene to a given growth condition. ', 'The procedure employs a new Tn-seq methodology based on the generation and amplification of single-strand circles carrying transposon junction sequences (the Tn-seq circle method),', 'Here we present a method (Tn-seq) for accurately determining quantitative genetic interactions on a genome-wide scale in microorganisms. Tn-seq is based on the assembly of a saturated Mariner transposon insertion library.', 'Here we present the method Tn-seq, with which it has become possible to quantitatively determine fitness for most genes in a microorganism and to screen for quantitative genetic interactions on a genome-wide scale and in a high-throughput fashion. Tn-seq can thus direct studies in the annotation of genes and untangle complex phenotypes.', 'Tn-seq measures the frequency of actual members of a heterogeneous mutant pool undergoing purifying selection to determine the contribution of every non-essential gene in the genome to the fitness of an organism under a given condition. Here we use Tn-seq to assess gene function in the Gram negative γ-proteobacterium Shewanella oneidensis strain MR-1.', 'Towards this goal, we utilized a quantitative genetic footprinting technique known as transposon insertion sequencing (Tn-seq) in conjunction with comparative pathogenomics to functionally dissect the genetic repertoire of a reference ExPEC isolate. Using Tn-seq and high-throughput zebrafish infection models, we tracked changes in the abundance of ExPEC variants within saturated transposon mutant libraries following selection within distinct host niches.']

['The transposon mutagenesis and high-throughput sequencing (Tn-seq) is a technique that allows for quantitative assessment of individual mutants within a transposon mutant library by sequencing the transposon-genome junctions and then compiling mutant presence by mapping to a base genome. Using Tn-seq, it is possible to quickly define all the insertional mutants in a library and thus identify nonessential genes under the conditions in which the library was produced. Identification of fitness of individual mutants under specific conditions can be performed by exposing the library to selective pressures.']

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Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue?

['ver the last few years, advances in methodology have made it possible to recover peptides from FFPE tissues that yield a reasonable representation of the proteins recovered from identical fresh or frozen specimens.', 'Thus, laser capture microdissection of FFPE tissue coupled with downstream proteomic analysis is a valid approach', 'Qualitative proteome profiling of formalin-fixed, paraffin-embedded (FFPE) tissue is advancing the field of clinical proteomics.', 'Recent improvements in proteomics technologies, from the 2D gel analysis of intact proteins to the "shotgun" quantification of peptides and the use of isobaric tags for absolute and relative quantification (iTRAQ) method, have made the analysis of FFPE tissues possible.', 'The ability to investigate the proteome of formalin-fixed, paraffin-embedded (FFPE) tissues can be considered a major recent achievement in the field of clinical proteomics.', 'The label-free approach enables the quantitative measurement of radiation-induced alterations in FFPE tissue and facilitates retrospective biomarker identification using clinical archives.', 'Proteomic analysis of formalin-fixed paraffin-embedded pancreatic tissue using liquid chromatography tandem mass spectrometry.', 'We report that differentially expressed proteins can be identified among FFPE tissue specimens originating from individuals with different pancreatic histologic findings.', 'Formalin-fixed paraffin-embedded (FFPE) proteome analysis using gel-free and gel-based proteomics.', 'This study will facilitate the development of future proteomic analysis of FFPE tissue and provide a tool for the validation in archival samples of biomarkers of exposure, prognosis and disease.', 'The CAAR method presented here complements previously described antigen-retrieval protocols and is an important step in being able to fully analyze the proteome of archived FFPE tissue.', 'Proteome, phosphoproteome, and N-glycoproteome are quantitatively preserved in formalin-fixed paraffin-embedded tissue and analyzable by high-resolution mass spectrometry.', 'It has only recently been shown that proteins in FFPE tissues can be identified by mass spectrometry-based proteomics but analysis of post-translational modifications is thought to be difficult or impossible', 'Results from the FFPE-FASP procedure do not indicate any discernible changes due to storage time, hematoxylin staining or laser capture microdissection.', 'Thus, FFPE biobank material can be analyzed by quantitative proteomics at the level of proteins and post-translational modifications.', 'A novel tissue microdissection technique has been developed and combined with a method to extract soluble peptides directly from FFPE tissue for mass spectral analysis of prostate cancer (PCa) and benign prostate hyperplasia (BPH). Hundreds of proteins from PCa and BPH tissue were identified,', 'espite using tissue blocks stored for as many as 28 years, high confidence and comparative proteome analysis between the leiomyomas and the sarcoma is achieved.', 'These findings demonstrate that formalin fixation, paraffin processing, and LCM do not negatively impact protein quality and quantity as determined by MS and that FFPE samples are amenable to global proteomic analysis.', 'Protein extraction of formalin-fixed, paraffin-embedded tissue enables robust proteomic profiles by mass spectrometry.']

['Yes, advances in sample preparation has enabled the proteomic analysis of formalin-fixed and paraffin-embedded tissues.']

['yes']

What is the effect of a defective CLN3 gene?

['Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative disorder caused by defective function of the lysosomal membrane glycoprotein CLN3. ', 'human CLN3 that is defective in Batten disease, localizes to the vacuole', 'JNCL results from mutations in CLN3 on chromosome 16p12.1.', 'Mutations in the CLN3 gene, which encodes a lysosomal membrane protein, are responsible for the neurodegenerative disorder juvenile Batten disease.', 'Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most common progressive encephalopathy of childhood, is caused by mutations in a novel lysosomal membrane protein (CLN3) with unknown function.', 'the human CLN3 gene that is defective in Batten disease,', 'ln3 was recently identified as the gene defective in juvenile Batten disease, an inherited neurodegenerative disease of childhood', 'Batten disease (juvenile-onset neuronal ceroid lipofuscinosis, JNCL), the most common neurodegenerative disorder of childhood, is caused by mutations in a recently identified gene ( CLN3 ) localized to chromosome 16p11.2-12.1. ']

['Mutations in the CLN3 gene, which encodes a lysosomal membrane protein, are responsible for the neurodegenerative disorder juvenile Batten disease.']

['Batten disease', 'juvenile-onset neuronal ceroid lipofuscinosis', 'JNCL']

List available genetic multicolor cell labeling techiniques in Drosophila

['Flybow: genetic multicolor cell labeling for neural circuit analysis in Drosophila melanogaster.', 'To facilitate studies of neural network architecture and formation, we generated three Drosophila melanogaster variants of the mouse Brainbow-2 system, called Flybow. Sequences encoding different membrane-tethered fluorescent proteins were arranged in pairs within cassettes flanked by recombination sites. Flybow combines the Gal4-upstream activating sequence binary system to regulate transgene expression and an inducible modified Flp-FRT system to drive inversions and excisions of cassettes. This provides spatial and temporal control over the stochastic expression of one of two or four reporters within one sample. Using the visual system, the embryonic nervous system and the wing imaginal disc, we show that Flybow in conjunction with specific Gal4 drivers can be used to visualize cell morphology with high resolution. Finally, we demonstrate that this labeling approach is compatible with available Flp-FRT-based techniques, such as mosaic analysis with a repressible cell marker; this could further support the genetic analysis of neural circuit assembly and function.', 'Drosophila Brainbow: a recombinase-based fluorescence labeling technique to subdivide neural expression patterns.', 'We developed a multicolor neuron labeling technique in Drosophila melanogaster that combines the power to specifically target different neural populations with the label diversity provided by stochastic color choice. This adaptation of vertebrate Brainbow uses recombination to select one of three epitope-tagged proteins detectable by immunofluorescence. Two copies of this construct yield six bright, separable colors. We used Drosophila Brainbow to study the innervation patterns of multiple antennal lobe projection neuron lineages in the same preparation and to observe the relative trajectories of individual aminergic neurons. Nerve bundles, and even individual neurites hundreds of micrometers long, can be followed with definitive color labeling. We traced motor neurons in the subesophageal ganglion and correlated them to neuromuscular junctions to identify their specific proboscis muscle targets. The ability to independently visualize multiple lineage or neuron projections in the same preparation greatly advances the goal of mapping how neurons connect into circuits.', 'Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis.']

['Flybow and Drosophila Brainbow.']

['Flybow', 'Drosophila Brainbow']

What is the role of peptide aptamers?

['Peptide aptamers: The versatile role of specific protein function inhibitors in plant biotechnology.', ' These artificial short peptides are able to specifically bind, track, and inhibit a given target molecule with high affinity, even molecules with poor immunogenicity or high toxicity, and represent a remarkable alternative to antibodies in many different applications. ', 'To inhibit the oncogenic action of Stat3 in tumor cells, we have selected short peptides, so-called peptide aptamers, which specifically interact with defined functional domains of this transcription factor. ', 'Aptasensors utilize aptamers as bioreceptors. Aptamers are highly efficient, have a high specificity and are reusable. Within the biosensor the aptamers are immobilized to maximize their access to target molecules. Knowledge of the orientation and location of the aptamer and peptide during binding could be gained through computational modeling. ', 'Understanding orientation and location of the binding region for a peptide-aptamer complex is critical in their biosensor applicability.', ' Our study clearly demonstrates the ability of MD simulations to obtain molecular insights for peptide-aptamer binding, and to provide details on the orientation and location of binding between the peptide-aptamer that can be instrumental in biosensor development.', 'Peptide aptamers are artificial short peptides that potentially interfere with the biological roles of their target proteins; however, this technology has not yet been applied to plant functional genomics.', 'To extend such strategies we selected peptide aptamers binding to PrP from a combinatorial peptide library presented on the Escherichia coli thioredoxin A (trxA) protein as a scaffold.', 'These peptide aptamers retained their binding properties to PrPc and, depending on peptide sequence and C-terminal modification, interfered with endogenous PrPSc conversion upon expression in prion-infected cells.', 'Binding to the nonfarnesylated peptide was at least 10-fold weaker, showing that the aptamers can recognize the hydrophobic farnesyl moiety.', 'Peptide aptamers: exchange of the thioredoxin-A scaffold by alternative platform proteins and its influence on target protein binding.', 'Typically, peptide aptamers are generated by screening a randomized peptide expression library, displayed from the Escherichia coli thioredoxin A (TrxA) protein.', 'Peptide aptamers define distinct EB1- and EB3-binding motifs and interfere with microtubule dynamics.', 'Reverse analysis with peptide aptamers involves isolating aptamers that interact with a specific protein and monitoring the resulting aptamer-induced phenotype.', 'Peptide aptamers are combinatorial protein reagents that bind to targets with a high specificity and a strong affinity thus providing a molecular tool kit for modulating the function of their targets in vivo.Here we report the isolation of a peptide aptamer named swiggle that interacts with the very short (21 amino acid long) intracellular domain of membrane type 1-metalloproteinase (MT1-MMP), a key cell surface protease involved in numerous and crucial physiological and pathological cellular events', 'Peptide aptamers are simple structures, often made up of a single-variable peptide loop constrained within a constant scaffold protein', 'Peptide aptamers are small peptide sequences that have been selected to recognise a predetermined target protein domain and are potentially able to interfere with its function', 'Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells', 'Aptamers are a group of molecules, which can specifically bind, track, and inhibit target molecules, comprising DNA aptamers, RNA aptamers, and peptide aptamers', 'Peptide aptamers: The versatile role of specific protein function inhibitors in plant biotechnology', 'Peptide aptamers are small proteins containing a randomized peptide sequence embedded into a stable protein scaffold, such as Thioredoxin', 'Peptide aptamers can subsequently be used to guide the discovery of small molecule drugs specific for these molecular surfaces.Here, we present a high-throughput screening assay that identifies small molecules that displace interactions between proteins and their cognate peptide aptamers', 'These peptide aptamers are target-specific peptides expressed within a protein scaffold engineered from the human protease inhibitor stefin A. The scaffold provides stability to the inserted peptides and increases their binding affinity owing to the resulting three-dimensional constraints', 'Isolation of Peptide aptamers to target protein function.', 'Peptide aptamers with binding specificity for the intracellular domain of the ErbB2 receptor interfere with AKT signaling and sensitize breast cancer cells to Taxol.', 'Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy.', 'Peptide aptamers targeting the hepatitis B virus core protein: a new class of molecules with antiviral activity.', 'These data highlight the utility of peptide aptamers to identify novel binding interfaces and highlight a role for MAP1B in DAPK-1-dependent signaling in autophagy and membrane blebbing.', 'Therapeutic application depends on binding specificities and affinities, as well as on the production and purification characteristics of the peptide aptamers and their delivery into cells.', 'While antibodies are known to recognize the sequence and conformation of protein surface features (epitopes), very little is known about the precise interactions between aptamers and their epitopes.', 'Monomeric recombinant peptide aptamers are required for efficient intracellular uptake and target inhibition.', 'The use of small peptide aptamers to competitively inhibit protein interaction and function is becoming increasingly recognized as a powerful technique.', 'For the first time, we show that trxA-based peptide aptamers can be targeted to the secretory pathway, thereby not losing the affinity for their target protein.', 'Moreover, the aptamers appeared to be able to bind peptides with different solution conformations, implying an induced fit mechanism for binding.', 'Peptide aptamers are small proteins containing a randomized peptide sequence embedded into a stable protein scaffold, such as Thioredoxin.', 'Peptide aptamers are the newest in the class of "genetic" agents that aid in the analysis of cellular processes.', 'Peptide aptamers: The versatile role of specific protein function inhibitors in plant biotechnology.', 'Here we present a detailed protocol for the creation of a peptide aptamer plasmid library, selection of peptide aptamers using the LiRP scaffold in a yeast two-hybrid system, and the screening of those peptide aptamers for a ligand-regulated interaction..']

['Peptide aptamers are artificial short peptides which are able to specifically bind to defined functional domains, track, and inhibit a given target molecule with high affinity, even molecules with poor immunogenicity or high toxicity. They represent a remarkable alternative to antibodies in many different applications.']

[]

Can we use platelet biomarkers to study Alzheimer's disease?

["Platelet biomarkers in Alzheimer's disease.", 'platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B.', 'Alternative plasma and platelet measures are described,', "The success of these studies led to the application of platelet proteomics to the study of several pathologies where platelets play a fundamental role. Those include platelet-related disorders, such as storage pool disease, gray platelet syndrome, and Quebec platelet disorder; diseases where unwanted platelet activation is highly relevant, such as thrombosis and cardiovascular disease; and other diseases, such as cystic fibrosis, uremia, or Alzheimer's disease. "]

["Yes, platelet biomarkers can be used to study Alzheimer's disease."]

['yes']

Is dichlorphenamide effective for periodic paralysis?

['BACKGROUND AND PURPOSE: Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP).', 'In one study dichlorphenamide (DCP) vs placebo was tested in two groups of participants: 42 with hypokalemic periodic paralysis (HypoPP) and 31 with hyperkalemic periodic paralysis (HyperPP), based on clinical criteria. Thirty-four of 42 participants with hypokalemic periodic paralysis completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. ', "AUTHORS' CONCLUSIONS: The largest included study that met our inclusion criteria suggested that DCP was effective in the prevention of episodic weakness in both hypokalemic and hyperkalemic periodic paralyses.", 'For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. ', 'Chronically, acetazolamide, dichlorphenamide, or potassium-sparing diuretics decrease attack frequency and severity but are of little value acutely. ', ' In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP.', 'Diclofenamid has now already been administered for 2 years. It is well tolerated and has suppressed further attacks.', 'Three patients with Hypokalemic Periodic Paralysis (HOPP)-associated progressive interattack muscle weakness, who became unresponsive or worsened by acetazolamide, responded favorably to dichlorophenamide, a more potent carbonic anhydrase inhibitor. Dichlorophenamide in single-blind placebo-controlled trials, considerably improved functional strength in two of the patients and had a moderate but definite effect in the third.', 'Dichlorophenamide should be considered as an alternate to acetazolamide in the treatment of patients with HOPP-associated interattack muscle weakness who have become unresponsive or worsened by acetazolamide.', 'Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP).', 'For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis.', 'BACKGROUND AND PURPOSE: Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). Whether these drugs prevent vacuolar myopathy, which is a pathogenic factor in hypoPP, is unknown. ', 'Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP).', 'For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. A second trial, comparing dichlorphenamide with acetazolamide versus placebo, is currently in progress.', 'Despite our better understanding of the pathogenesis of these disorders, current treatments are largely empirical and the evidence in favor of specific therapy largely anecdotal. For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis.']

['Yes, dichlorphenamide is effective for periodic paralysis. Dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis.']

['yes']

What is ChiRP-seq (Chromatin Isolation by RNA Purification sequencing)?

["Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous. Drosophila roX2 RNA occupies male X-linked gene bodies with increasing tendency toward the 3' end, peaking at CES sites. Human telomerase RNA TERC occupies telomeres and Wnt pathway genes. HOTAIR lncRNA preferentially occupies a GA-rich DNA motif to nucleate broad domains of Polycomb occupancy and histone H3 lysine 27 trimethylation. HOTAIR occupancy occurs independently of EZH2, suggesting the order of RNA guidance of Polycomb occupancy. ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.", 'ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.', 'ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous.', 'Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing.', 'Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ', 'ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.', 'Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous. ', 'HOTAIR occupancy occurs independently of EZH2, suggesting the order of RNA guidance of Polycomb occupancy. ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.', 'Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous.', 'Long noncoding RNAs (lncRNAs) are key regulators of chromatin state, yet the nature and sites of RNA-chromatin interaction are mostly unknown. Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing.', 'ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.', 'Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing.', 'ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous.']

['ChiRP-seq (Chromatin Isolation by RNA Purification sequencing) is a method where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous. ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.']

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Name the major classes of small non coding RNAs in mammalians?

['Some of these RNA classes, in particular microRNAs and snoRNAs, undergo maturation processes that lead to the production of shorter RNAs.']

['microRNAs (miRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs) are the major classes of small non coding RNAs. Recently, thanks mostly to massively parallel sequencing technologies, other classes of small RNAs have been discovered, such as piRNAs and scaRNAs.']

['miRNA', 'snRNA', 'snoRNAs', 'scaRNAs', 'piRNAS']

Which are the supplemental antioxidant in athletes?

['Although these supplementations are increasingly used by master athletes, very few data are available on their effects on oxidative stress, muscle recovery, and physical performance. The potential benefits of supplement use in athletes are thus questionable. Some studies indicate no benefits, while others highlight potential negative side effects of vitamin supplementation. ', 'These data indicate that RQ significantly reduces exercise-induced lipid peroxidation without associated changes in inflammation or plasma antioxidant status.', 'Cr supplementation inhibited the increase of inflammation markers TNF-α and CRP, but not oxidative stress markers, due to acute exercise.', 'Quercetin and vitamin C supplementation may not be beneficial in lipid profile improvement, although it may reduce induce muscle damage and body fat percent.', 'Vitamins C and E supplementation had no significant effect on any of the studied parameters.', 'Effects of the two treatments relative to placebo on mean performance in the incremental test and time trial were unclear, but runners faster by 1 SD of peak speed demonstrated a possible improvement on peak running speed with BC juice (1.9%; ±2.5%). ', 'Training status correlates more strongly with antioxidant status than diet does', 'Consequently, we can conclude that Biostimine supplementation reduces the postexercise level of TBARS by increasing the antioxidant activity of plasma but has no effect on inflammatory markers.', 'Supplementation with Asx could prevent exercise induced free radical production and depletion of non-enzymatic antioxidant defense in young soccer players.', 'In conclusion these results indicated that treatment with melatonin in acute sports exercise reversed oxidative stress, improved defenses and lipid metabolism, which would result in an improvement in fitness.', 'CoQ(10) supplementation before strenuous exercise decreases the oxidative stress and modulates the inflammatory signaling, reducing the subsequent muscle damage.', "Heretofore, Cr's positive therapeutic benefits in various oxidative stress-associated diseases have been reported in the literature and, recently, Cr has also been shown to exert direct antioxidant effects.", 'These results indicate that Cr supplementation reduced oxidative DNA damage and lipid peroxidation induced by a single bout of RE.', 'Nevertheless, based upon the growing evidence that many athletic populations are vitamin D deficient or insufficient, it is recommended that athletes monitor their serum vitamin D concentration and consult with their health care professional and/or nutritionist to determine if they would derive health benefits from vitamin D supplementation.', 'This study examined the effects of 1,000 mg quercetin + 1,000 mg vitamin C (QC); 1,000 mg quercetin, 1,000 mg vitamin C, 400 mg isoquercetin, 30 mg epigallocatechin gallate, and 400 mg n-3 fatty acids (QFO)', 'The two strains, L. rhamnosus IMC 501(®) and L. paracasei IMC 502(®), exert strong antioxidant activity. Athletes and all those exposed to oxidative stress may benefit from the ability of these probiotics to increase antioxidant levels and neutralize the effects of reactive oxygen species.', 'These results indicate that supplementation with n-3 LCPUFAs significantly increased oxidative stress at rest and after a judo-training session.', 'Rhodiola Rosea, is an adaptogen plant which has been reported to promote fatty acids utilisation, to ameliorate antioxidant function, and to improve body resistance to physical strenuous efforts. ', 'Supplementation with antioxidant vitamin E to athletes at 267 mg (400 IUs) or greater has been reported to reduce levels of LP associated with exercise.', 'Results obtained at the end of the study indicate that zinc supplementation prevents production of free radicals by activating the antioxidant system.', 'The significant increase in the UI of erythrocyte membranes indicates the potential for harm, because a high intake of PUFA might increase susceptibility to lipid peroxidation not counterbalanced by a higher increase in TAA. Adherence to the Mediterranean diet seems to be the better choice.', 'A number of clinical trials have successfully been performed using whey and/or soy proteins in the treatment of many diseases. They both have antioxidant properties, which appears to be a factor in aerobic physical performance as well. ', 'The antioxidant effect of the two proteins is based on different mechanisms of action.']

['There are several antioxidant supplements belonging to different families, i.e. Vitamins, Polyphenols, alpha-lipoic acid, ubiquinones, n-3- polyunsaturated acids (PUFAs), minerals and others. Nonetheless the widespread use of these supplements, it is still debated their true usefulness, and it is not unanimously advised their use in athletes.']

['Resveratrol', 'Quercetin', 'Vitamin C', 'Biostimine', 'Astaxanthin', 'Melatonin', 'coenzyme Q(10)', 'Creatine', 'Isoquercetin', 'Epigallocatechin gallate', 'n-3 fatty acids', 'L. rhamnosus IMC 501', 'L. paracasei IMC 502', 'docosahexanoic acid (DHA)', 'eicosapentanoic acid (EPA)', 'Rhodiola Rosea', 'Vitamin E', 'Zinc', 'whey and/or soy proteins']

Does a linker histone exist in the yeast genome?

['Hho1p is a bona fide linker histone', 'In Saccharomyces cerevisiae, HHO1 encodes a putative linker histone with very significant homology to histone H1', 'HHO1p may play a similar role to linker histones, but at restricted locations in the chromatin', 'The putative linker histone in Saccharomyces cerevisiae, Hho1p, has two regions of sequence (GI and GII) that are homologous to the single globular domains of linker histones H1 and H5 in higher eukaryotes. ', 'The Saccharomyces cerevisiae homologue of the linker histone H1, Hho1p, has two domains that are similar in sequence to the globular domain of H1 (and variants such as H5)', 'Two homologous domains of similar structure but different stability in the yeast linker histone, Hho1p', 'Saccharomyces cerevisiae encodes a single linker histone, Hho1p, with two globular domains. ', 'The Saccharomyces cerevisiae linker histone Hho1p, with two globular domains, can simultaneously bind to two four-way junction DNA molecules', 'Here, we show in yeast, that the presence of yeast linker histone Hho1p represses expression of a pol II transcribed gene (MET15) embedded in the rDNA.', 'Yeast linker histone Hho1p is required for efficient RNA polymerase I processivity and transcriptional silencing at the ribosomal DNA', 'Saccharomyces cerevisiae linker histone Hho1p is not essential for cell viability, and very little is known about its function in vivo. ', 'Saccharomyces cerevisiae linker histone Hho1p functionally interacts with core histone H4 and negatively regulates the establishment of transcriptionally silent chromatin', ' Unlike canonical linker histones in higher eukaryotes that have a single conserved globular domain, Hho1p possesses two globular domains. We show that the carboxyl-terminal globular domain of Hho1p is dispensable for its function, suggesting that the mode of Hho1p action is similar to that of canonical linker histones', 'To identify new proteins involved in spore nuclear organization, we purified chromatin from mature spores and discovered a significant enrichment of the linker histone (Hho1)', 'Hho1 chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed increased genome-wide binding in mature spores and provides novel in vivo evidence of the linker histone binding to nucleosomal linker DNA', 'One of the peculiarities of S. cerevisiae cells is the unusual and less abundant linker histone, Hho1p.', 'Hho1p, the linker histone of Saccharomyces cerevisiae, is important for the proper chromatin organization in vivo', 'Characteristically, linker histone depleted chromatin generally exhibited longer chromatin loops than the wild-type. ', 'Saccharomyces cerevisiae linker histone-Hho1p maintains chromatin loop organization during ageing.', 'Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain.', 'Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain. ', 'Biochemical studies to date have not been able to identify the linker histone H1 protein in the budding yeast Saccharomyces cerevisiae. Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain.', 'Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain.']

['Here, we present our results showing a connection between the linker histones, the higher-order chromatin structures, and the process of chronological lifespan of yeast cells. Characteristically, linker histone depleted chromatin generally exhibited longer chromatin loops than the wild-type. These results suggest that HHO1p may play a similar role to linker histones, but at restricted locations in the chromatin. The binding was structure specific, since the use of double-stranded DNA, or a mutant Hho1p in which the second DNA binding site of globular domain 1 was abolished, resulted in a significant decrease in bridged binding.', 'Hho1p is a bona fide linker histone', 'In Saccharomyces cerevisiae, HHO1 encodes a putative linker histone with very significant homology to histone H1. The putative linker histone in Saccharomyces cerevisiae, Hho1p, has two regions of sequence (GI and GII) that are homologous to the single globular domains of linker histones H1 and H5 in higher eukaryotes.']

['yes']

What is the risk in G-CSF treatment for severe congenital neutropenia?

['We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN', 'This chapter focuses on cyclic and congenital neutropenia, two very interesting and rare hematological conditions causing severe chronic neutropenia. Both disorders respond well to treatment with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF)', 'Treatment with G-CSF is usually effective, but the dose of G-CSF required to normalize blood neutrophils varies greatly. Ten to thirty percent of severe congenital neutropenia patients evolve to develop acute myeloid leukemia, necessitating careful clinical monitoring.', 'In severe congenital neutropenia (SCN), long-term therapy with granulocyte colony-stimulating factor (G-CSF) has reduced mortality from sepsis, revealing an underlying predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML)', 'Granulocyte colony-stimulating factor (G-CSF) therapy has significantly reduced the frequency and severity of infections, but its possible influence on the risk of malignancy is not known', 'No septic deaths occurred during G-CSF therapy. Thirteen cases of MDS/AL were recorded. The cumulative incidence of MDS/AL was 2.7% (SD 1.3%) at 10 years and 8.1% (SD 2.7%) at 20 years', 'Owing to their particular susceptibility to infections, patients with severe congenital neutropenia had the strongest exposure to G-CSF; the risk of leukemia increased with the degree of G-CSF exposure in this subgroup', 'Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.', 'This specifically applies to children with severe congenital neutropenia who receive lifelong treatment with G-CSF and in which the high susceptibility to develop MDS and acute myeloid leukemia (AML) has now become a major clinical concern.', 'Owing to their particular susceptibility to infections, patients with severe congenital neutropenia had the strongest exposure to G-CSF; the risk of leukemia increased with the degree of G-CSF exposure in this subgroup.', 'As of January 1, 2000, myelodysplasia (MDS) or acute myelogenous leukemia (AML) has occurred in 35 of 387 patients with congenital neutropenia with a cumulative risk of 13% after 8 years of G-CSF treatment']

['Severe congenital neutropenia is a rare hematological condition causing severe chronic neutropenia. Treatment with the myeloid growth factor, granulocyte-colony stimulating factor (G-CSF) is usually effective, but the dose of G-CSF required to normalize blood neutrophils varies greatly. Ten to thirty percent of the patients evolve to develop acute myeloid leukemia or myelodysplastic syndromes, necessitating careful clinical monitoring.']

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By which methods can we evaluate the reliability of a phylogenetic tree?

['For robustness evaluation, we apply bootstrap and jackknife techniques to input data.', 'An alignment confidence score capturing robustness to guide tree uncertainty.', 'We build on the widely used bootstrap method for perturbing the phylogenetic tree.', 'SuperTRI: A new approach based on branch support analyses of multiple independent data sets for assessing reliability of phylogenetic inferences.', 'To overcome these limitations, we propose a new approach, called SuperTRI, which is based on the branch support analyses of the independent data sets, and where the reliability of the nodes is assessed using three measures: the supertree Bootstrap percentage and two other values calculated from the separate analyses: the mean branch support (mean Bootstrap percentage or mean posterior probability) and the reproducibility index.', 'In contrast to other similar software, the program FreeTree (available at http://www.natur.cuni.cz/~flegr/programs/freetree or http://ijs.sgmjournals.org/content/vol51/issue3/) can also assess the robustness of the tree topology by bootstrap, jackknife or operational taxonomic unit-jackknife analysis.', 'Unlike any previous tool for inferring phylogenies from rearrangement data, TIBA uses novel methods of robustness estimation to provide support values for the edges in the inferred tree.', 'Fast and accurate phylogenetic reconstruction from high-resolution whole-genome data and a novel robustness estimator.', 'Moreover, whereas phylogenetic analyses from sequence data are deemed incomplete unless bootstrapping scores (a measure of confidence) are given for each tree edge, no equivalent to bootstrapping exists for rearrangement-based phylogenetic analysis.', 'We also describe a novel approach to estimate the robustness of results-an equivalent to the bootstrapping analysis used in sequence-based phylogenetic reconstruction.', 'The standard deviation also suggests the reliability level of the branch order.', 'Assessment of the reliability of a given phylogenetic hypothesis is an important step in phylogenetic analysis.', 'The reliability of the phylogenetic trees was probed with the bootstrapping of 100 replicates of the original sequence alignments.']

['The methods for assessing the robustness/reliability of the topology of the inferred phylogenetic trees are: the widely used bootstrap method and the jackknife method.', 'In contrast to other similar software, the program FreeTree (available at http://www.natur.cuni.cz/~flegr/programs/freetree or http://ijs.sgmjournals.org/content/vol51/issue3/) can also assess the robustness of the tree topology by bootstrap, jackknife or operational taxonomic unit-jackknife analysis. (PMID: 11411692)']

['bootstrap', 'jackknife']

Is there any cross-talk between the Wnt and the Akt pathways?

['Our data demonstrate that engaging Wnt signaling at the receptor level by this method leads to necessary crosstalk between multiple signaling pathways including activation of Akt, mTOR, Wnt/β-catenin, PKA/CREB, and inhibition of RhoA/ROCK that substantially increase human β-cell proliferation while maintaining the β-cell phenotype.', 'The cross-talk role of Wnt/β-catenin and PI3K/Akt signaling pathway, with GSK-3β as the key enzyme bridging these pathways, may contribute to the inhibition of cholangiocarcinoma cells by hUC-MSCs.', 'We find that Wnt stimulation leads to phosphorylation of insulin signaling key mediators, including Akt, GSK3β, and ERK1/2, although with a lower fold stimulation and slower time course than observed for insulin.', 'Wnt induces phosphorylation of Akt, ERK1/2, and GSK3β, and this is dependent on insulin/IGF-1 receptors.', 'Pharmacologic inhibition of PI3K resulted in the downregulation of several members of the β-catenin pathway, including Fra-1, c-Myc, and cyclin D1.', 'Similar results were observed in vivo, as intratumoral injection of LY294002 downregulated the expression of the components of the β-catenin pathway and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts.', 'These results suggest that the PI3K/AKT signaling pathway regulates glioma cell proliferation, in part via repression of the Wnt/β-catenin pathway.', 'Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth', 'Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by activation [corrected] of GSK-3beta, [corrected] resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc.', 'These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease.', 'Western blot analyses revealed that the recombinant Wnt ligand Wnt-3A increased phosphorylation of AKT and the downstream kinase glycogen synthase kinase (GSK)-3beta as well as accumulation of activated, nuclear beta-catenin.', 'Chemical inhibition of PI3K abolished Wnt-dependent phosphorylation of AKT and GSK-3beta and trophoblast motility but did not affect appearance of activated beta-catenin or Wnt/TCF reporter activity.', 'The data suggest that Wnt-3A may activate canonical Wnt signaling and PI3K/AKT through distinct receptors.', 'Mutational activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in a wide variety of tumors, whereas activating Wnt pathway mutants are predominantly found in colon cancer. Because GSK3 is a key component of both pathways, it is widely assumed that active PI3K signaling feeds positively into the Wnt pathway by protein kinase B (PKB)-mediatefd inhibition of GSK3.', 'n addition, PKB has been proposed to modulate the canonical Wnt signaling through direct stabilization and nuclear localization of beta-catenin.', 'Here, we show that compartmentalization by Axin of GSK3 prohibits cross-talk between the PI3K and Wnt pathways and that Wnt-mediated transcriptional activity is not modulated by activation of the PI3K/PKB pathway.', 'Our recent study revealed a second mechanism for Cby-mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin, following phosphorylation of Cby by Akt kinase.', 'Therefore, our findings unravel a novel molecular mechanism regulating the dynamic nucleo-cytoplasmic trafficking of beta-catenin and provide new insights into the cross-talk between the Wnt and Akt signaling pathways.', 'Here, we review recent literature concerning Cby function and discuss our current understanding of the relationship between Wnt and Akt signaling.', 'As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT.', 'This explains why prostate tumors subjected to androgen ablation experience an increase in Akt phosphorylation, and suggest that the tumor compensates for the loss of one pathway with another. Different modes of interaction between the two pathways, including direct interaction, or regulation via downstream intermediates, such as the wnt/GSK-3beta/beta-catenin pathway, NF-kappaB, and the FOXO family of transcription factors, will be discussed.', 'FGF signals are transduced through FGF receptor to the FRS2-GRB2-GAB1-PI3K-AKT signaling cascade to downregulate GSK3beta activity depending on Ser 9 phosphorylation. Because GSK3beta-dependent phosphorylation of beta-catenin and SNAIL leads to FBXW1 (betaTRCP)-mediated ubiquitination and degradation, GSK3beta downregulation results in the stabilization and the nuclear accumulation of beta-catenin and SNAIL.', 'Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zeta', 'Concurrently, PTEN, an inhibitor of PI3K/Akt pathway, is also primarily inactivated in the ISCs, leading to activation of Akt. Thus, Akt may contribute to activation of beta-catenin in ISCs in coordination with Wnt signaling.', 'Thus, we propose that BMP signaling plays a role in inhibition of ISC self-renewal through suppression of Wnt/beta-catenin signaling in ISC, and this cross-talk is bridged, at least in part, through the PTEN/Akt pathway and further enforced by 14-3-3zeta.', 'In MC3T3-E1 osteoblast-like cultures, dexamethasone (DEX) activates glycogen synthase kinase-3beta (GSK3beta) and inhibits a differentiation-related cell cycle that occurs at a commitment stage immediately after confluence.', 'Here we show that DEX inhibition of the differentiation-related cell cycle is associated with a decrease in beta-catenin levels and inhibition of LEF/TCF-mediated transcription.', 'These inhibitory activities are no longer observed in the presence of lithium, a GSK3beta inhibitor.', 'DEX decreased the serum-responsive phosphorylation of protein kinase B/Akt-Ser(473) within minutes, and this inhibition was also observed after 12 h. When the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was inhibited by wortmannin, DEX no longer inhibited beta-catenin levels.', 'Furthermore, DEX-mediated inhibition of LEF/TCF transcriptional activity was attenuated in the presence of dominant negative forms of either PI3K or protein kinase B/Akt. These results suggest cross-talk between the PI3K/Akt and Wnt signaling pathways.', 'These results suggest that inhibition of a PI3K/Akt/GSK3beta/beta-catenin/LEF axis and stimulation of HDAC1 cooperate to mediate the inhibitory effect of DEX on Wnt signaling and the osteoblast differentiation-related cell cycle.', 'WISP-1 (Wnt-1-induced secreted protein) was identified as an oncogene regulated by the Wnt-1-beta-catenin pathway.', 'Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. ', 'Our results show that both TGFβ1 and Wnt3a lead to increased accumulation of β-catenin, phosphorylation of AKT and p44/42 MAPK.']

['The Wnt/β-catenin and PI3K/Akt signaling pathways cross-talk mainly through the activity of GSK-3β, a common component of both pathways, but also through the activity of other signaling transducers, such as Cby or WISP-1.']

['yes']

Are EDNRB mutations involved in the development of Hirschsprung disease?

['QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations', 'As reported previously, when the same null mutation of the Ednrb gene, Ednrb(sl), was introgressed into the F344 strain, almost 60% of F344-Ednrb(sl/sl) pups did not show any symptoms of aganglionosis, appearing healthy and normally fertile.', 'Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl) mutations', 'In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb(sl) mutations.', 'New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease.', 'The aim of this study was to evaluate the implication of the EDN3 and EDNRB genes in a series of patients with Hirschsprung disease from Spain and determinate their mutational spectrum.', 'A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease', 'Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR.', 'Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. ', 'Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease', 'Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR', 'Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease', 'Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.', 'EDNRB/EDN3 and Hirschsprung disease type II.', 'Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease', 'wo susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene.', 'We conclude that Ednrb loss only in neural crest cells is sufficient to produce the Hirschsprungs disease phenotype observed with genomic Ednrb mutations', 'EDNRB mutations were detected in 2 of the 13 short-segment HD', "The mutations of EDNRB gene and EDN-3 gene are found in the short-segment HD of sporadic Hirschsprung's disease in Chinese population, which suggests that the EDNRB gene and EDN-3 gene play important roles in the pathogenesis of HD", "Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease", "Hirschsprung's disease (HSCR) is one the most common congenital intestinal disease. It leads to aganglionic megacolon in the early childhood. Several susceptibility genes have been identified : RET protooncogene and its ligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) and its receptor B (EDNRB). EDNRB mutations are found in 5% of familial or sporadic HSCR", 'Enteric aganglionosis in Hirschsprung disease has been linked to genes coding for endothelin-3 (EDN3) and the endothelin B receptor (EDNRB)', "To date, three genes have been identified as susceptibility genes for Hirschsprung's disease (HSCR), the RET proto-oncogene, the endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3)", 'Our data indicate that RET and EDNRB mutations have a role in the aetiology of some sporadically occurring HSCR', "Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung's disease", "The endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3) have recently been recognized as susceptibility genes for Hirschsprung's disease (HD)", 'These observations confirm that impaired function of the endothelin-B receptor or endothelin-3 is involved in the aetiology of some human HD cases. EDNRB mutations appear to be associated with short-segment HD, in contrast to RET mutations, which are found mainly in long-segment aganglionosis', 'In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease.', 'Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease.', 'QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations.', 'Homozygous mutations in the endothelin-B receptor gene (EDNRB) on 13q22 have been identified in humans and mice with Hirschsprung disease type 2 (HSCR2).', 'A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease.', 'Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association.', 'These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features.', 'Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease.', 'Mutations in genes encoding the RET receptor tyrosine kinase and endothelin receptor type B (EDNRB) are involved in HSCR pathogenesis; however, also important in ENS development are molecules that mediate events that are more restricted than those of RET and EDNRB, act later in development and which might not be HSCR-associated.', 'Several missense mutations of the endothelin-B receptor (EDNRB) associated with Hirschsprung disease have recently been identified.', 'These findings indicate that these missense mutations result in loss of function of EDNRB, and may provide the molecular pathological basis of Hirschsprung disease in some individuals.', 'Manifestation of the disease has been linked to mutations in genes that encode the crucial signals for the development of the enteric nervous system-the RET and EDNRB signalling pathways.', 'In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease', 'In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM)', 'However, the similarity between the distal colonic aganglionosis in Hirschsprung disease and that due to EDN3 or EDNRB mutations led to the hypothesis that levels of expression of these genes might be affected in the absence of mutation, thus causing the Hirschsprung disease phenotype', 'Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.']

['Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR.', "Hirschsprung's disease (HSCR) is one the most common congenital intestinal disease, which leads to aganglionic megacolon in the early childhood. Several susceptibility genes have been identified, including RET protooncogene and its ligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) and its receptor B (EDNRB). More specifically, EDNRB mutations are found in 5% of familial or sporadic HSCR."]

['yes']

For the constructions of which organs has 3D printing been tested?

['To determine the potential of an integrated, image-based computer-aided design (CAD) and 3-dimensional (3D) printing approach to engineer scaffolds for head and neck cartilaginous reconstruction for auricular and nasal reconstruction.', 'Subcutaneous in vivo implantation of auricular and nasal scaffolds was performed in a porcine model.', 'Auricular and nasal constructs with several types of microporous architecture were rapidly manufactured with high fidelity to human patient anatomy. Subcutaneous in vivo implantation of auricular and nasal scaffolds resulted in an excellent appearance and complete soft tissue ingrowth. Histological analysis of in vitro scaffolds demonstrated native-appearing cartilaginous growth that respected the boundaries of the scaffold.CONCLUSION: Integrated, image-based CAD and 3D printing processes generated patient-specific nasal and auricular scaffolds that supported cartilage regeneration.', 'A prototype meniscus cartilage was prepared to illustrate the potential application in bioengineering.', 'As a proof of concept, we generated a bionic ear via 3D printing of a cell-seeded hydrogel matrix in the anatomic geometry of a human ear, along with an intertwined conducting polymer consisting of infused silver nanoparticles. This allowed for in vitro culturing of cartilage tissue around an inductive coil antenna in the ear, which subsequently enables readout of inductively-coupled signals from cochlea-shaped electrodes. The printed ear exhibits enhanced auditory sensing for radio frequency reception, and complementary left and right ears can listen to stereo audio music. ', 'In this study, we describe the construction of a hybrid inkjet printing/electrospinning system that can be used to fabricate viable tissues for cartilage tissue engineering applications.', 'Before 3D Printing can be used routinely for the regeneration of complex tissues (e.g. bone, cartilage, muscles, vessels, nerves in the craniomaxillofacial complex), and complex organs with intricate 3D microarchitecture (e.g. liver, lymphoid organs), several technological limitations must be addressed', '3D Printing promises to produce complex biomedical devices according to computer design using patient-specific anatomical data', '3D printing of HEK 293FT cell-laden hydrogel into macroporous constructs with high cell viability and normal biological functions.', '3D-printing of lightweight cellular composites.', '3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. ', 'In this paper, we reported a novel study of 3D printing of cell lines derived from human embryonic kidney tissue into a macroporous tissue-like construct. ', 'Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. ', 'Organ printing, which we define as computer-aided, jet-based 3D tissue-engineering of living human organs, offers a possible solution. Organ printing involves three sequential steps: pre-processing or development of "blueprints" for organs; processing or actual organ printing; and postprocessing or organ conditioning and accelerated organ maturation.', 'Organ printing involves three sequential steps: pre-processing or development of "blueprints" for organs; processing or actual organ printing; and postprocessing or organ conditioning and accelerated organ maturation.', 'Bioprinting has no or little side effect to the printed mammalian cells and it can conveniently combine with gene transfection or drug delivery to the ejected living systems during the precise placement for tissue construction.', 'Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues.', 'Innovations in 3D printing: a 3D overview from optics to organs.', 'Organ printing: computer-aided jet-based 3D tissue engineering.']

['Nose, ear and meniscus prototypes/constructs have been produced with 3D (3-dimesional) printing.']

['nose', 'ear', 'meniscus']

Is single guide RNA part of the CRISPR/Cas9 tool or an inhibitor of its function?

['Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding.', 'Although the lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. ', 'This new type of genetic library is constructed through the lentiviral delivery of single-guide RNA collections that direct Cas9 or inactive dead Cas9 fused with effectors to interrogate gene function or regulate gene transcription in targeted cells. ', 'The CRISPR/Cas9 system has recently emerged as a\xa0powerful tool for functional genomic studies in Drosophila melanogaster. However, single-guide RNA (sgRNA) parameters affecting the specificity and efficiency of the system in flies are still not clear. Here, we found that off-target effects did not occur in regions of genomic DNA with three or more nucleotide mismatches to sgRNAs.', 'Our work demonstrates a comprehensive optimization of sgRNA and promises to vastly simplify CRISPR/Cas9 experiments in Drosophila.', 'Targeted genome engineering is expected to contribute significantly to future varietal improvement, and genome editing technologies using zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9/single guide RNA (sgRNA) have already been successfully used to genetically modify plants.', 'A unique capability of the CRISPR/Cas9 system is multiplex genome engineering by delivering a single Cas9 enzyme and two or more single guide RNAs (sgRNAs) targeted to distinct genomic sites.', 'To determine if the Cas9 and single guide RNA (sgRNA) genes were functional in C. reinhardtii, we tested the ability of a codon-optimized Cas9 gene along with one of four different sgRNAs to cause targeted gene disruption during a 24-h period immediately following transformation.', 'Recently, compared to the wildtype nuclease, paired Cas9 nickase (Cas9n) combined with single guide RNA (sgRNA) molecules has been found to enhance the specificity of genome editing while reducing off-target effects.', 'Here we utilized a CRISPR/CAS9-based system with single guide RNAs to disrupt genes in T.\xa0gondii.', 'To address the need for uniform and sustained delivery of multiplex CRISPR/Cas9-based genome engineering tools, we developed a single lentiviral system to express a Cas9 variant, a reporter gene and up to four sgRNAs from independent RNA polymerase III promoters that are incorporated into the vector by a convenient Golden Gate cloning method.', 'A unique capability of the CRISPR/Cas9 system is multiplex genome engineering by delivering a single Cas9 enzyme and two or more single guide RNAs (sgRNAs) targeted to distinct genomic sites. ', 'Using synthetic single RNA guides, Cas9 can be reprogrammed to create specific double-stranded DNA breaks in the genomes of a variety of organisms, ranging from human cells to bacteria, and thus constitutes a powerful tool for genetic engineering. ']

['Single guide RNA is part of the CRISPR/Cas9 system.']

['Single guide RNA is part of the CRISPR/Cas9 system.']

Do carmustine wafers improve survival of glioblastoma patients?

['At recurrence, treatment options include repeat surgery (with or without Gliadel wafer placement), reirradiation or systemic therapy. ', 'DISCUSSION: Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival.', 'Gliadel wafer is a new approach to the treatment of glioblastoma, which involves controlled release delivery of carmustine from biodegradable polymer wafers. It has shown promising results and provides a silver lining for glioblastoma patients.', 'For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89).', 'According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma', 'CONCLUSION: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival.', 'Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. ', 'CONCLUSIONS: The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone.', 'OBJECT: Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). ', 'BACKGROUND: Gliadel (polifeprosan 20 with carmustine [BCNU] implant) is commonly used for local delivery of BCNU to high-grade gliomas after resection and is associated with increased survival.', 'Temozolomide administered according to this protocol produced a median survival benefit of 2 months in glioblastomas, and carmustine a similar benefit in high-grade gliomas.', 'Analysis of a large trial by Westphal and colleagues (n = 240) showed a 29% risk reduction (P = 0.03) in the BCNU wafer-treated group over the course of the 30-month trial.', 'Median survival of patients treated with BCNU wafers was 13.8 months vs 11.6 months in placebo-treated patients (P = 0.017) with a hazard ratio of 0.73 (P = 0.018), representing a 27% significant risk reduction. This survival advantage was maintained at 1, 2, and 3 years and was statistically significant (P = 0.01) at 3 years.', 'CONCLUSION: Malignant glioma patients treated with BCNU wafers at the time of initial surgery in combination with radiation therapy demonstrated a survival advantage at 2 and 3 years follow-up compared with placebo.', 'OBJECTIVE: Recently a randomized placebo-controlled phase III trial of biodegradable polymers containing carmustine has demonstrated a significant survival benefit for patients treated with local chemotherapy. ', 'CONCLUSION: In this subgroup analysis of a phase III trial population both the clinical progression and radiological progression were significantly delayed in patients treated with local chemotherapy, resulting in an increased survival time.', 'A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers.', 'Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). ', 'Controlled release delivery of carmustine from biodegradable polymer wafers was approved as an adjunct to surgical resection in the treatment of recurrent glioblastoma multiforme after it was shown in clinical trials to be well tolerated and effective. ', 'Clinical trials have demonstrated significant improvements in survival and quality of life for patients after complete tumour resection and BCNU wafer implantation.', 'BCNU wafers are an effective means of increasing survival and quality of life in patients diagnosed with malignant glioma, and are a valuable addition to the overall multimodal treatment strategy for these tumours.', 'CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone.', 'Median overall survival in 14 studies of newly-diagnosed patients suggested a modest improvement versus resection followed by Stupp protocol or resection with BCNU wafers, with an acceptable and manageable safety profile.', 'The efficacy of carmustine wafers for older patients with glioblastoma multiforme: prolonging survival.', 'DISCUSSION: Older patients with GBM may benefit from carmustine wafers. The survival for older patients who received carmustine wafers is significantly longer than matched patients who did not receive carmustine wafers.', 'For glioblastoma patients who received ≥90% resection in the BCNU wafer study, median survival increased for BCNU wafer versus placebo (14.5 versus 12.4\xa0months, respectively; P\u2009=\u20090.02), but no survival increase was found for <90% resection (11.7 versus 10.6\xa0months, respectively; P\u2009=\u20090.98).', 'A wafer impregnated with carmustine, for use as an implant after surgical removal of recurrent GBM showed a prolongation in the median survival time of only 2 mo, from 20 to 28 wk in a study with a total of 222 patients. ', 'No clear survival benefit associated with wafer implantation was identified.', 'In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers. ', 'TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . ', 'The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events. ', 'For patients undergoing repeat resection for malignant glioma, a randomized, blinded, placebo-controlled trial demonstrated a median survival for 110 patients who received carmustine polymers of 31 weeks compared with 23 weeks for 122 patients who only received placebo polymers.', 'Median survival was improved from 11.6 to 13.9 months (P = 0.03), with a 29% reduction in the risk of death. When patients with glioblastoma multiforme alone were analyzed, the median survival improved from 11.4 to 13.5 months, but this improvement was not statistically significant. ', 'OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide.', 'Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival.', 'The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events.', 'However, patients with carmustine wafers demonstrated prolonged survival as compared to patients without wafers.', 'The median survival for patients with carmustine wafers was 8.7 months, while median survival for patients without wafers was 5.5 months (P=0.007).', 'Likewise, in subgroup analysis, patients older than 70 years (P=0.0003) and 75 years (P=0.04) who had carmustine wafers had significantly longer survival than matched patients without wafers.', 'Implantation of carmustine wafers did not significantly improve progression-free survival', 'In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers', 'A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme', 'A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers', 'Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival', 'Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival', 'The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events', 'TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials ']

['Yes, it has been documented that implantation of carmustine wafers improves survival of newly diagnosed and recurrent glioblastoma patients.']

['yes']

What is the treatment of acute myocarditis?

['ibuprofen 400 mg twice a day as therapy', 'Acute fulminant myocarditis commonly manifests itself as severe, rapidly progressive hemodynamic deterioration and circulatory collapse that may be resistant to high doses of inotropic agents and steroids and to mechanical support by intra-aortic balloon pump', 'the TandemHeart percutaneous ventricular assist device, can enable patients to recover in a few days.', 'he authors report a typical case of fulminating myocarditis with electromechanical dissociation, which recovered completely after a period of circulatory assistance.', 'To clarify the effects of Astragalus Membranaceus (AM) combined with taurine and/or coenzyme Q10(CoQ10) on coxsackievirus B3 (CVB3) murine myocarditis', 'AM, taurine and CoQ10 have some curative effects on CVB3 murine myocarditis, AM combined with taurine and CoQ10 is the best.']

['Treatment of acute myocarditis includes antiinflammatory drugs like ibuoprofen and steroids, inotropic agents and mechanical support (intra-aortic ballon pump). TandemHeart percutaneous ventricular assist device may be used in some, more compromised, patients for few days.']

['antiinflammatory steroid and non steroid drugs', 'inotropic agents', 'mechanical support']

Which genes are regulated by MEF-2 in the heart?

['Inhibition of MEF2A using siRNA attenuated HB-EGF-induced COX-2, ANF expression and cell size.', 'This genetic reprogramming coincides with a pronounced increase in expression of the estrogen receptor (ER)alpha gene, which we show to be a direct MEF2 target gene', 'cardiac calsequestrin gene (casq2)', 'Functional studies demonstrated that site-directed mutagenesis of the proximal MEF-2 and CArG box sites significantly decreased the transcription of the gene in cardiac and skeletal muscle cells, indicating that they are important to drive cardiac and skeletal muscle-specific transcription of the casq2 gene.', 'DTEF-1 also interacts with MEF- 2 by coimmunoprecipitation and independently or cooperatively (with MEF-2) trans-activates the cTnT promoter', 'An 85-bp region within the enhancer is highly conserved between human and mouse and contains a central AT-rich site, which is essential for enhancer activity. This site binds myocyte enhancer factor (MEF)2 factors, principally MEF2D and MEF2A in cardiocyte nuclear extracts. These results are discussed in the context of MEF2 activity and of the regulation of the alpha-cardiac actin locus.', 'The cis-acting elements, MEF-2, E boxes and A/T rich elements present in the enhancer region of the mouse MCK gene are known to regulate the expression of the gene', 'The sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) belong to a family of active calcium transport enzymes encoded by the SERCA1, 2, and 3 genes. In this study, we describe the complete structure of the human SERCA2 gene and its 5 -regulatory region.', 'Among the DNA cis-elements present in these two regulatory regions there are potential binding sites for: GATA-4, -5, -6, Nkx-2.5/Csx, OTF-1, USF, MEF-2, SRF, PPAR/RXR, AP-2, and TREs. Upstream from position -1.5 kb, there is no significant homology among the SERCA2 genes cloned.', "The cardiac calsequestrin gene consists of 11 exons and its 5' flanking region is characterized by the presence of a TATA-like box, muscle specific promoter elements such as 7 E-boxes, 1 MEF-2, 1 MCBF and 1 Repeat (musS) motifs, as well as several muscle non-specific transcriptional elements (AP-2A, NRE1, NRE2, p53, Spel and TFI-IIA).", 'our laboratory identified a 28 bp HF-la/MEF-2 element in the MLC-2v promoter region, which confers cardiac ventricular chamber-specific gene expression during murine cardiogenesis,', 'In this study, we investigated T3R alpha 1-vs. T3R beta 1-specific interactions with the myocyte enhancer-specific factor-2 (MEF-2) on the expression of the SERCA 2 gene in transient transfection assays in embryonal heart-derived H9c2 cells.', 'point to T3R isoform-specific interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression.', 'In multiple independent transgenic mouse lines, we found that both a 250 base pair myosin light chain-2 ventricular promoter fragment, as well as a dimerized 28 bp sub-element (HF-1) containing binding sites for HF1a and HF1b/MEF2 factors, directed ventricular-specific reporter expression from as early as the endogenous gene, at day 7.5-8.0 post coitum.', 'Myocyte-specific enhancer-binding factor (MEF-2) regulates alpha-cardiac myosin heavy chain gene expression in vitro and in vivo', 'In the MLC-2 gene, an AT-rich element (HF-1b) which contains a consensus MEF-2 site is required for cardiac tissue-specific expression.', 'Role of myocyte-specific enhancer-binding factor (MEF-2) in transcriptional regulation of the alpha-cardiac myosin heavy chain gene.', 'In order to analyze the transcriptional regulation of the muscle-specific subunit of the human phosphoglycerate mutase (PGAM-M) gene, chimeric genes composed of the upstream region of the PGAM-M gene', 'These observations define the PGAM-M enhancer as the only cardiac- and skeletal-muscle-specific enhancer characterized thus far that is mainly activated through MEF-2.', 'Transcription of each gene is independently controlled but coordinately regulated. During each embryogenesis, the beta-MHC gene is expressed as part of the cardiac myogenic program under the control of NKX-2.5, MEF-2C, and GATA-4/5/6.', 'We have characterized the specific DNA regulatory elements responsible for the function of the human cardiac troponin C gene (cTnC) muscle-specific enhancer in myogenic cells. We used functional transient transfection assays with deletional and site-specific mutagenesis to evaluate the role of the conserved sequence elements. Gel electrophoresis mobility shift assays (EMSA) demonstrated the ability of the functional sites to interact with nuclear proteins. We demonstrate that three distinct transcription activator binding sites commonly found in muscle-specific enhancers (a MEF-2 site, a MEF-3 site, and at least four redundant E-box sites) all contribute to full enhancer activity but a CArG box does not.']

['COX-2, ANF, estrogen receptor (ER)alpha gene, calsequestrin gene, casq2, cTnT, MCK, alpha-cardiac actin, sarco(endo)plasmic reticulum Ca2+-ATPase, SERCA, MLC-2, alpha-cardiac myosin heavy chain gene, phosphoglycerate mutase and PGAM-M are regulated by MEF-2 in the heart']

['COX-2', 'ANF', 'estrogen receptor (ER)alpha gene', 'calsequestrin gene', 'casq2', 'cTnT', 'MCK', 'alpha-cardiac actin', 'sarco(endo)plasmic reticulum Ca2+-ATPase', 'SERCA', 'MLC-2', 'alpha-cardiac myosin heavy chain gene', 'phosphoglycerate mutase', 'PGAM-M', 'cardiac troponin C', 'cTnC']

Which gene is responsible for the development of Sotos syndrome?

['Sotos syndrome is a well-known overgrowth syndrome characterized by excessive growth during childhood, macrocephaly, distinctive facial appearance and learning disability. This disorder is caused by mutations or deletions in NSD1 gene', 'Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS', 'Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome.', 'The NSD1 gene was recently found to be responsible for Sotos syndrome, and more than 150 patients with NSD1 alterations have been identified.', 'Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients.', 'Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes.', 'Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome.', 'Two cases of Sotos syndrome with novel mutations of the NSD1 gene.', 'Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome', 'Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations is the major cause of Sotos syndrome characterized by generalized overgrowth, large hands and feet with advanced bone age, craniofacial dysmorphic features, learning disability, and possible susceptibility to tumors', 'Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome', 'Haploinsufficiency of the NSD1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients', 'Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations is the major cause of Sotos syndrome characterized by generalized overgrowth, large hands and feet with advanced bone age, craniofacial dysmorphic features, learning disability, and possible susceptibility to tumors. ', 'Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations.', 'Craniofacial and oral features of Sotos syndrome: differences in patients with submicroscopic deletion and mutation of NSD1 gene.', 'Prenatal diagnosis and molecular cytogenetic characterization of a 1.07-Mb microdeletion at 5q35.2-q35.3 associated with NSD1 haploinsufficiency and Sotos syndrome.', 'Autosomal dominant mutations and deletions of the nuclear receptor set domain gene (NSD1), which is located at chromosome 5q35, are responsible for most of the cases. ', 'There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). ', 'Sotos syndrome is a rare genetic disorder characterized by overgrowth associated with macrocephaly and delayed psychomotor development. Patients with Sotos syndrome show 5q35 deletions involving NSD1 or its point mutations.', 'Mutations in NSD1 are responsible for Sotos syndrome,', 'Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome.', 'The NSD1 gene was recently found to be responsible for Sotos syndrome, and more than 150 patients with NSD1 alterations have been identified.', 'Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes.']

['Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS.', 'Sotos syndrome is a well-known overgrowth syndrome characterized by excessive growth during childhood, macrocephaly, distinctive facial appearance and learning disability. This disorder is caused by mutations or deletions in NSD1 gene']

['NSD1 gene']

What are the pregnancy outcomes in rheumatoid arthritis?

['Patients with rheumatic disease can have successful pregnancy outcomes, particularly when a collaborative approach between the rheumatologist and obstetrician is applied. ', 'Of 78 JIA pregnancies, 53 (68%) were delivered by either Caesarean section (n = 40, 51%) or instrumental delivery (n = 13, 17%); compared with other women, those with JIA had significantly higher rates of pre-eclampsia, postpartum haemorrhage and severe maternal morbidity. Compared with other infants, those with mothers with JIA were more likely to be born prematurely, but were not at increased risk of being small for gestational age, requiring neonatal intensive care, having a low Apgar score at 5 min or severe neonatal morbidity. CONCLUSIONS: Infants of women with JIA did not have an increased risk of adverse neonatal outcomes. Intensive obstetric care might be required during pregnancy for women with JIA given the increased risk of maternal morbidity.', 'High rate of preterm birth in pregnancies complicated by rheumatoid arthritis.', 'Women with RA may be at higher risk for preterm delivery.', 'A significant increase in frequency and number of cesarean deliveries, besides a higher number of pregnancies with preeclampsia, were found after RA onset. Additionally, four newborns with congenital anomalies were reported after the disease onset compared to none before RA onset. CONCLUSIONS: compared to pre-RA obstetric events, a higher frequency and number of adverse outcomes was found in pregnancies that occurred after RA onset.', 'There is increased obstetrical and neonatal morbidity in Canadian women with RA or SLE.', 'Most pregnancies in women with rheumatologic disease will result in the delivery of a healthy baby. Pregnancy can be particularly risky in women with active disease or on teratogenic medications,', 'Rheumatoid arthritis typically improves and does not have a major impact on pregnancy outcomes.', 'Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy.', 'Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications. These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases,', 'We conclude that pregnancy outcome in patients with SLE in India is worse in comparison to patients with RA. ', 'Women with RA had an increased risk of LBW, SGA babies, preeclampsia and CS compared with unaffected women.', 'Infants of women with rheumatoid arthritis had increased risk of cesarean delivery (adjusted approximate relative risk, aRR=1.66, 95% CI (1.22, 2.26)), prematurity (aRR=1.78, 95% CI (1.21, 2.60)), and longer birth hospitalization (aRR=1.86, 95% CI (1.32, 2.60)) compared to those born to women without rheumatoid arthritis.', 'Women with SLE, RA, and pregestational DM had significantly increased rates of hypertensive disorders compared with the general obstetric population (23.2%, 11.1%, 27.4%, and 7.8%, respectively), longer hospital stays, and significantly higher risk of cesarean delivery. Although women with SLE, RA, and pregestational DM were significantly older than women in the general obstetric population, disparities in the risk of adverse outcomes of pregnancy remained statistically significant after adjustment for maternal age.', 'women with SLE and RA appear to have a higher age-adjusted risk of adverse outcomes of pregnancy and longer hospital stays than do pregnant women in the general population, and careful antenatal monitoring should be performed.', 'In this uncontrolled study we failed to demonstrate tertogenicity of MTX. However, the possibility of abortion due to MTX use remains.', 'In general, active inflammation from rheumatic diseases poses a stronger threat to the well-being of both mother and foetus than many immunosuppressant medications. Therefore, continued immunosuppression with the least risky medications will allow for the most optimal pregnancy outcomes.']

['There is increased obstetrical and neonatal morbidity. Women with RA had an increased risk of LBW, SGA babies, preeclampsia and CS compared with unaffected women.\nWomen with RA appear to have a higher age-adjusted risk of adverse outcomes of pregnancy and longer hospital stays than do pregnant women in the general population, and careful antenatal monitoring should be performed.Patients with rheumatic disease can have successful pregnancy outcomes, particularly when a collaborative approach between the rheumatologist and obstetrician is applied.\nIn general, active inflammation from rheumatic diseases poses a stronger threat to the well-being of both mother and foetus than many immunosuppressant medications. Therefore, continued immunosuppression with the least risky medications will allow for the most optimal pregnancy outcomes.']

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What is plantar fasciitis

['Plantar fascia (PF) disorders commonly cause heel pain and disability', 'Plantar fasciitis (PF) is a common foot complaint, affects both active sportsmen and physically inactive middle age group. It is believed that PF results from degenerative changes rather than inflammation', 'Plantar fasciitis (PF) is present in 10% of the population and is the most common cause of plantar heel pain', 'Plantar fasciitis, a chronic degenerative process that causes medial plantar heel pain, is responsible for approximately 1 million physician visits each year', 'Plantar fasciitis (PF)is the most common cause of plantar heel pain', 'Plantar fasciitis is the most common cause of heel pain and is estimated to affect 2 million people in the United States alone.For adults suffering from plantar fasciitis, are foot orthoses a viable treatment option to reduce pain', 'Plantar fasciitis: a degenerative process (fasciosis) without inflammation.', 'BACKGROUND: Plantar fasciitis is a common foot disorder that impacts many functional activities.', 'The second purpose was to determine whether chronic plantar fasciitis is accompanied by atrophy of plantar intrinsic foot muscles and tibialis posterior.METHODS: Magnetic resonance images were taken bilaterally in eight subjects with unilateral plantar fasciitis.', 'Plantar fasciitis, a common injury in runners, has been speculated to be associated with weakness of the intrinsic foot muscles', 'Although plantar fasciitis is the most common cause of heel pain,', 'Plantar fasciitis, a self-limiting condition, is a common cause of heel pain in adults. It affects more than 1 million persons per year, and two-thirds of patients with plantar fasciitis will seek care from their family physician', 'Plantar fasciitis is a common cause of heel pain and is the result of a degenerative process of the plantar fascia at its calcaneal attachment.']

['Plantar fascia (PF) disorders like plantar fasciitis commonly cause heel pain and disability and are thought to be degenerative rather than inflammatory in nature']

['heel pain']

Which are the most abundant human lincRNA?

['One abundant such RNA, ci-ankrd52, largely accumulates to its sites of transcription, associates with elongation Pol II machinery, and acts as a positive regulator of Pol II transcription', 'long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant transcript 2), is a highly conserved nuclear noncoding RNA (ncRNA) and a predictive marker for metastasis development in lung cancer.', 'Because viruses borrow molecular mechanisms from their hosts, we searched highly abundant human long-noncoding RNAs and identified putative ENE-like structures in metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and multiple endocrine neoplasia-β (MENβ) RNAs. ', 'MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) locus is misregulated in many human cancers and produces an abundant long nuclear-retained noncoding RNA.', 'Many long noncoding RNAs (lncRNAs) appear to have epigenetic regulatory function in humans, including HOTAIR and XIST.', 'metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis.', 'It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution.', 'Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.', "bundant expression of the long noncoding (lnc) PAN (polyadenylated nuclear) RNA by the human oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) depends on a cis-element called the expression and nuclear retention element (ENE)", 'alat1 is an abundant long, noncoding RNA that localizes to nuclear bodies known as nuclear speckles, which contain a distinct set of pre-mRNA processing factors.', "Malat1 (metastasis associated lung adenocarcinoma transcript 1) is among the most abundant and highly conserved lncRNAs, and it exhibits an uncommon 3'-end processing mechanism", 'H19 large intergenic non-coding RNA (lincRNA) is one of the most highly abundant and conserved transcripts in mammalian development, being expressed in both embryonic and extra-embryonic cell lineages, yet its physiological function is unknown. ', 'Our genome-wide screens in two mammalian species reveal no more than three abundant large non-coding polyadenylated RNAs in the nucleus; the canonical large noncoding RNA XIST and NEAT1 and NEAT2', '19, which is one of the most abundantly expressed imprinted genes during mammalian embryonic and foetal development, has been cloned from a ruminant', 'H19 mRNA is highly abundant in most ovine embryonic and foetal tissues of mesodermal and endodermal origins but was not detected in tissues of ectodermal origin such as the trophectoderm and the foetal brain', 'Abundant expression of H19 was evident in fetal bladder but was absent in normal adult bladder', 'urthermore, we discuss results showing an abundant expression of H19 gene in some adenocarcinomas of bad prognosis, in the context of the otherwise established tumor-suppressor role of this gene, or the strictly controlled gene dosage, which could be overridden in these particular cases.', 'One of the first lncRNA genes discovered was MALAT1, the metastasis-associated lung adenocarcinoma transcript 1,21 later also referred to as NEAT2 for nuclear-enriched abundant transcript 2. MALAT1 is highly abundant and is expressed in many healthy organs, most strongly in pancreas and lung']

['MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) locus is misregulated in many human cancers and produces an abundant long nuclear-retained noncoding RNA. MALAT/NEAT2 highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. H19 large intergenic non-coding RNA (lincRNA) is one of the most highly abundant and conserved transcripts in mammalian development, being expressed in both embryonic and extra-embryonic cell lineages, yet its physiological function is unknown. Our genome-wide screens in two mammalian species reveal no more than three abundant large non-coding polyadenylated RNAs in the nucleus; the canonical large noncoding RNA XIST and NEAT1 and NEAT2.']

['MALAT1', 'MALAT-1', 'NEAT2', 'NEAT1', 'H19', 'XIST']

Which value of nuchal translucency thickness is set as the threshold for high-risk for Down Syndrome?

['Combined prenatal screening was always positive for Down syndrome when NT thickness exceeded 4.0 mm', 'In women aged 35 to 37 years, combined prenatal screening was always positive when NT exceeded 2.8 mm, 3.0 mm, and 3.4 mm at 11, 12, and 13 weeks of gestation, respectively', 'NT is physiological for a measurement < 3 mm but the incidence of chromosomal abnormalities (essentially trisomies 21, 18 and 13) increases when NT > or = 3 mm']

['NT is physiological for a measurement < 3 mm but the incidence of chromosomal abnormalities (essentially trisomies 21, 18 and 13) increases when NT > or = 3 mm. As women aged, this upper NT threshold value changed according to gestational age. In women aged 35 to 37 years, combined prenatal screening was always positive when NT exceeded 2.8 mm, 3.0 mm, and 3.4 mm at 11, 12, and 13 weeks of gestation, respectively.']

['3mm']

What is Path2PPI?

['Path2PPI: an R package to predict protein-protein interaction networks for a set of proteins', 'We introduce Path2PPI, a new R package to identify protein-protein interaction (PPI) networks for fully sequenced organisms for which nearly none PPI are known. Path2PPI predicts PPI networks based on sets of proteins from well-established model organisms, providing an intuitive visualization and usability. It can be used to combine and transfer information of a certain pathway or biological process from several reference organisms to one target organism.', ': We introduce Path2PPI, a new R package to identify protein-protein interaction (PPI) networks for fully sequenced organisms for which nearly none PPI are known.', 'Path2PPI predicts PPI networks based on sets of proteins from well-established model organisms, providing an intuitive visualization and usability.']

['Path2PPI is an R package to identify protein-protein interaction (PPI) networks for fully sequenced organisms for which nearly none PPI are known. Path2PPI predicts PPI networks based on sets of proteins from well-established model organisms, providing an intuitive visualization and usability. It can be used to combine and transfer information of a certain pathway or biological process from several reference organisms to one target organism.']

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Is there a role of regorafenib for sarcoma treatment?

['Regorafenib has been approved for third-line therapy.', 'Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial.', 'DISCUSSION: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial.', 'This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371).', 'Thus, the Phase III studies with pazopanib, regorafenib, muramyl tripeptide (MTP) and ridaforolimus are extensively discussed as well as the biological rationale for the use of these compounds.', 'Currently, regorafenib is examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and soft tissue sarcoma (STS).', 'Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P<0.05).', 'Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05).', 'We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05).', 'We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05).', 'We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib.', 'After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05).']

['Yes, there is evidence to suggest that regorafenib can be effective for sarcoma treatment. Clinical trials are under-way.']

['yes']

What is the principle of the PAR-CLIP methodology?

['We developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs.', 'To gain insight into the complexity of snoRNA processing and the functional relevance of snoRNA-derived small RNAs, we sequence long and short RNAs, small RNAs that co-precipitate with the Argonaute 2 protein and RNA fragments obtained in photoreactive nucleotide-enhanced crosslinking and immunoprecipitation (PAR-CLIP) of core snoRNA-associated proteins.', 'A large amount of miRNA-target interactions (MTIs) have been identified by the crosslinking and immunoprecipitation (CLIP) and the photoactivatable-ribonucleoside-enhanced CLIP (PAR-CLIP) along with the next-generation sequencing (NGS)', 'PAR-CLIP shows high efficiency of RNA co-immunoprecipitation, but it also lead to T to C conversion in miRNA-RNA-protein crosslinking regions', 'A recent method, PAR-CLIP, uses photoreactive nucleosides to crosslink RBPs to target RNAs in cells prior to immunoprecipitation.', 'In this article, we review crosslinking and immunoprecipitation (CLIP) methods adapted for large-scale identification of target RNA-binding sites and the respective RNA recognition elements.', 'CLIP methods have the potential to detect hundreds of thousands of binding sites in single experiments although the separation of signal from noise can be challenging.', 'We focus on photoactivatable ribonucleoside-enhanced CLIP, which relies on the intracellular incorporation of photoactivatable ribonucleoside analogs into nascent transcripts, and yields characteristic sequence changes upon crosslinking that facilitate the separation of signal from noise.', 'Photo-Activatable Ribonucleoside-enhanced CrossLinking and ImmunoPrecipitation (PAR-CLIP) method was recently developed for global identification of RNAs interacting with proteins.', 'The strength of this versatile method results from induction of specific T to C transitions at sites of interaction.', 'PAR-CLIP reveals a collection of RNAs bound to a protein whereas SILAC-based RNA pull-downs identify a group of proteins bound to an RNA. ', 'Here we present a step-by-step protocol and guidelines for the computational analysis for the large-scale identification of miRNA target sites in cultured cells by photoactivatable ribonucleoside enhanced crosslinking and immunoprecipitation (PAR-CLIP) of AGO proteins.', 'In particular, PAR-CLIP utilizes a photoactivatable nucleoside for more efficient crosslinking.', 'rosslinking and immunoprecipitation (CLIP) protocols have made it possible to identify transcriptome-wide RNA-protein interaction sites', "In this issue of Molecular Cell, Mukherjee et al. (2011) and Lebedeva et al. (2011) identify transcriptome-wide HuR-RNA interactions using PAR-CLIP, unveiling HuR's nuclear role in pre-mRNA processing.", 'ross-linking and immunoprecipitation (CLIP) is increasingly used to map transcriptome-wide binding sites of RNA-binding proteins.', 'We developed a method for CLIP data analysis, and applied it to compare CLIP with photoactivatable ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in cross-linking and ribonuclease digestion affect the identified sites.', 'In order to increase the specificity and positional resolution, a strategy referred to as CLIP (UV cross-linking and immunoprecipitation) was introduced.', 'Recently, PAR-CLIP was introduced that uses photoreactive ribonucleoside analogs for cross-linking', 'AR-CliP--a method to identify transcriptome-wide the binding sites of RNA binding proteins', 'We developed a powerful cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs that we term PAR-CliP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation)', 'The method relies on the incorporation of photoreactive ribonucleoside analogs, such as 4-thiouridine (4-SU) and 6-thioguanosine (6-SG) into nascent RNA transcripts by living cells. ', 'One characteristic feature of cDNA libraries prepared by PAR-CliP is that the precise position of crosslinking can be identified by mutations residing in the sequenced cDNA. ']

['In particular, PAR-CLIP utilizes a photoactivatable nucleoside for more efficient crosslinking. A recent method, PAR-CLIP, uses photoreactive nucleosides to crosslink RBPs to target RNAs in cells prior to immunoprecipitation. One characteristic feature of cDNA libraries prepared by PAR-CliP is that the precise position of crosslinking can be identified by mutations residing in the sequenced cDNA. ', 'A powerful cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs was termed PAR-CliP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation). PAR-CLIP shows high efficiency of RNA co-immunoprecipitation, but it also lead to T to C conversion in miRNA-RNA-protein crosslinking regions. It relies on the intracellular incorporation of photoactivatable ribonucleoside analogs into nascent transcripts, and yields characteristic sequence changes upon crosslinking that facilitate the separation of signal from noise.', 'AR-CliP--a method to identify transcriptome-wide the binding sites of RNA binding proteinsOne characteristic feature of cDNA libraries prepared by PAR-CliP is that the precise position of crosslinking can be identified by mutations residing in the sequenced cDNA. ', 'In particular, PAR-CLIP utilizes a photoactivatable nucleoside for more efficient crosslinking. A recent method, PAR-CLIP, uses photoreactive nucleosides to crosslink RBPs to target RNAs in cells prior to immunoprecipitation. ', 'In particular, PAR-CLIP utilizes a photoactivatable nucleoside for more efficient crosslinking. A recent method, PAR-CLIP, uses photoreactive nucleosides to crosslink RBPs to target RNAs in cells prior to immunoprecipitation. One characteristic feature of cDNA libraries prepared by PAR-CliP is that the precise position of crosslinking can be identified by mutations residing in the sequenced cDNA. Photo-Activatable Ribonucleoside-enhanced CrossLinking and ImmunoPrecipitation (PAR-CLIP) method was recently developed for global identification of RNAs interacting with proteins. PAR-CLIP shows high efficiency of RNA co-immunoprecipitation, but it also lead to T to C conversion in miRNA-RNA-protein crosslinking regions ']

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How are lincRNA affecting the regulation of gene expression?

['We detected a considerable number of cis expression quantitative trait loci (cis-eQTLs) and demonstrated that the genetic regulation of lincRNA expression is independent of the regulation of neighboring protein-coding genes.', 'We observe biases in lincRNA genomic locations and expression profiles that are consistent with some of these lincRNAs being involved in the regulation of neighboring protein-coding genes with developmental functions.', 'In\xa0this issue of Developmental Cell, Wang et\xa0al. (2013) find that linc-RoR maintains human embryonic stem cell self-renewal by functioning as a sponge to trap miR-145, thus regulating core pluripotency factors Oct4, Nanog, and Sox2', 'Enrichment of expressed lincRNA promoters in enhancer marks provides an additional argument for the involvement of lincRNAs in the regulation of transcription in cis. ', 'Together, these findings suggest that lincRNA-p21 is an important player in the regulation of the Warburg effect and also implicate lincRNA-p21 as a valuable therapeutic target for cancer.', 'Our findings implicate a novel RNA gene, lincRNA AC068718.1, as risk factor for PTSD in women and add to emerging evidence that non-coding RNA genes may play a crucial role in shaping the landscape of gene regulation with putative pathological effects that lead to phenotypic differences.', 'Taken together, our results imply that mdig is involved in the regulation of H3K9me3 to influence the heterochromatin structure of the genome and the expression of genes important for cell growth or transformation.', 'ndogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal.', 'Here, we demonstrate that a lincRNA, linc-RoR, may function as a key competing endogenous RNA to link the network of miRNAs and core TFs, e.g., Oct4, Sox2, and Nanog.', 'We suggest that linc-RoR forms a feedback loop with core TFs and miRNAs to regulate ESC maintenance and differentiation.', 'ammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription.', 'Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.']

['lincRNA may function either as modulators of epigenetic mark deposition or as endogenous antagonists for microRNA binding. A lincRNA, linc-RoR, may function as a key competing endogenous RNA to link the network of miRNAs and core TFs, e.g., Oct4, Sox2, and Nanog. Mdig is involved in the regulation of H3K9me3 to influence the heterochromatin structure of the genome and the expression of genes important for cell growth or transformation. Observed biases in lincRNA genomic locations and expression profiles are consistent with some of these lincRNAs being involved in the regulation of neighboring protein-coding genes with developmental functions.']

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What is the function of the mammalian gene Irg1?

['IRG1 is highly upregulated in murine ANA-1 macrophages by several proinflammatory cytokines and Toll-like receptor (TLR) agonists, as well as in spleen and lung of Listeria monocytogenes or Toxoplasma gondii infected mice, respectively', 'The proinflammatory cytokine-induced IRG1 protein associates with mitochondria', 'multiple genes induced by Borrelia burgdorferi in macrophages to regulate Lyme disease inflammation', 'One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis.', 'Murine immune-responsive gene 1 (IRG1) plays significant roles in embryonic implantation and neurodegeneration', 'the IRG1 gene is differentially expressed in human fetal PBMCs and LPS-stimulated adult PBMCs.', 'we identified the immune-responsive gene 1 (IRG1), which was expressed substantially higher in lipopolysaccharide (LPS)-stimulated than in MAP-infected murine macrophage cell lines.', 'The inhibitor also blocked induction by LIF of several LIF-regulated genes in the LE including Irg1, which has been shown previously to be essential for implantation.', 'Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse.', 'our studies identified Irg1 as a novel target of PR in the pregnant uterus and also revealed that it is a critical regulator of the early events leading to implantation', ' This resulted in the identification of one novel P4-regulated gene that had been previously found in lipopolysaccharide-stimulated macrophages and called immune response gene-1 (Irg1) and which is the mammalian ortholog of the bacterial gene encoding methylcitrate dehydratase', 'the mammalian ortholog of methylcitrate dehydratase (immune response gene 1)', 'Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). T', 'Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). This gene exhibits significant homology to interferon (IFN)-alpha/beta-inducible human genes p27 and 6-16, indicating that these genes may belong to the same family', 'The level of IRG1 mRNA again rose transiently on day 4 immediately preceding implantation.', 'Although the functional roles of IRG1 and p27 remain unclear, we describe for the first time, identification of a gene family regulated by IFNalpha in both rodent and human uteri', 'Hence, the induction of IRG1 by LPS is mediated by tyrosine kinase and protein kinase C pathway.']

['Human IRG1 and mouse Irg1 mediates antiviral and antimicrobial immune responses, without its exact role having been elucidated. Irg1 has been suggested to have a role in apoptosis and to play a significant role in embryonic implantation. Irg1 is reported as the mammalian ortholog of methylcitrate dehydratase.']

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Can clonidine be used to reduce agitation in children.

['Children receiving clonidine immediately after anesthesia induction had statistically significant improvement in postoperative agitation at the 15-minute mark (P = .096) and last score obtained (P = .095) using the Watcha scale.', 'Clonidine has proven to be effective in reducing the incidence of post-operative agitation at a higher dose (3 and 2 μg kg⁻¹).', 'Post-anaesthetic agitation was observed in two patients (6.6%) in group 1, eight patients (26.6%) in group 2 as compared to 12 patients (40%) in group 3 after 15 min of post-operative observation.', 'The mean scores in group 1 at 15 and 30 min were significantly lower than those in group 3 (P value <0.05)', 'Caudal clonidine at a lower dose (1 μg kg⁻¹) could be effective in reducing the incidence of sevoflurane-induced emergence agitation in children undergoing urogenital and lower limb surgery without any significant adverse effects.', 'Only the 4 microg kg-1 dose of clonidine was associated with a significant reduction in emergence agitation.', 'Fewer children in the clonidine 4 microg kg-1 group displayed agitation (25%) than in the midazolam group (60%) (P=0.025).', 'In comparison with midazolam, clonidine 4 microg kg-1 reduced sevoflurane-induced emergence agitation without increasing postoperative side-effects.', 'Prophylactic use of clonidine against sevoflurane-induced agitation may represent a new and promising application.', 'One hundred and twenty children were included in this study: 59 of whom received clonidine, and 61 placebo; 41% of those in the placebo group exhibited moderate-severe EA compared with only 22% of those in the clonidine group (P < 0.03).', 'Findings demonstrate that i.v. clonidine administered after induction of anesthesia significantly reduces the incidence of EA in young children, but is associated with sleepiness postoperatively.', 'Clonidine could not prevent agitation (incidence 54%, 13/24)', 'Clonidine 1.5 microg/kg did not differ from placebo with respect to postoperative agitation.', 'Clonidine is effective in treating sevoflurane-induced postanesthesia agitation in children.', 'Pain and discomfort scores were significantly decreased in the clonidine group; the incidence of agitation was reduced by 57% (P = 0.029) and the incidence of severe agitation by 67% (P = 0.064). Relative risks for developing agitation and severe agitation were 0.43 (95% confidence interval, 0.24-0.78) and 0.32 (0.09-1.17), respectively.', 'Clonidine produces a substantial reduction in the risk of postsevoflurane agitation in children.', 'Agitation was observed in 12 midazolam-treated and five clonidine-treated patients (P=0.05).', 'Compared with midazolam, clonidine premedication reduced agitation during sevoflurane induction.', 'Clonidine 3 micrograms kg-1 prevented agitation after sevoflurane anaesthesia, independently of the route of administration. The effect of clonidine appears to be dose-dependent, as an epidural dose of 1 microgram kg-1 failed to reduce it.', 'Clonidine prevents sevoflurane-induced agitation in children.', 'In 16 placebo and 2 clonidine-treated patients agitation was observed (P < 0.001)', 'In 6 patients of the Placebo group, agitation was graded as severe, whereas none of the patients in the Clonidine group developed severe agitation (P = 0.02).', 'We conclude that clonidine effectively prevents agitation after sevoflurane anesthesia.', 'Clonidine 2 microg/kg IV after anesthetic induction effectively reduces the incidence of agitation without resulting in clinically relevant bradycardia and hypotension.', 'Children receiving clonidine prior to undergoing strabismus surgery have a small but noticeable reduction in postoperative agitation, stay slightly longer in the post-anesthesia care unit, and have higher rates of parent satisfaction.', 'We report three cases of preoperative use of intranasal clonidine in pediatric patients, all for different indications. One patient was treated for preoperative agitation and hallucinations associated with oral midazolam. One patient was given clonidine as a premedicant. The third patient was treated for preoperative agitation and hypertension. All three patients had subjective resolution of indicated symptoms and none experienced adverse outcomes.', 'Oral or intravenous clonidine has been successfully used for the prevention of sevoflurane-induced agitation during emergence from anaesthesia.']

['Yes, clonidine is effective in prevention of post-anesthesia agitation in children.']

['yes']