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Which antibody is implicated in the Bickerstaff's brainstem encephalitis?

['In addition, BBE and Fisher syndrome, which are clinically similar and are both associated with the presence of the immunoglobulin G anti-GQ1b antibody, represent a specific autoimmune disease with a wide spectrum of symptoms that include ophthalmoplegia and ataxia.', 'The syndrome defined by Bickerstaff of progressive, external ophthalmoplegia and ataxia, with disturbance of consciousness or hyperreflexia, has subsequently been associated with anti-GQ1b antibodies.', 'An anti-GQ1b antibody syndrome has been proposed to underlie the common pathophysiology for the three disorders; however, other studies have found a positive anti-GM1 instead of anti-GQ1b antibody.', 'Serologic analysis of antibodies against ganglioside complexes (anti-GDIa, anti-GDIb, anti-GM1, anti-GM2, anti-GM3, anti-GQIb and anti-GTIb antibodies) showed negative results.', 'However, contrary to a proposed anti-GQ1b antibody syndrome, we would suggest that pathogenesis of this clinical spectrum is not limited to anti-ganglioside antibodies.', "Although there are usually no abnormalities in MFS by routine neuroimaging, in a few cases, contrast enhancement of nerve roots and signs of central nervous system involvement were described supporting the hypothesis of an anti-GQ1b-syndrome, a continuum involving GBS, MFS, and Bickerstaff's brainstem encephalitis. ", 'Anti-GM1 IgG, GD1a IgG, GQ1b IgG, and GT1a IgG antibodies were positive.', "The discovery of the association of the anti-GQ1b IgG antibody with the postinfectious clinical syndromes of ophthalmoplegia, ataxia, and areflexia helped house the phenotypes of the Miller Fisher syndrome (MFS), atypical MFS, Guillain-Barré syndrome with ophthalmoplegia, and Bickerstaff's brainstem encephalitis under one roof. ", "These findings suggest that host susceptibility may play a role in inducing the production of anti-ganglioside antibodies and the development of Bickerstaff's brainstem encephalitis.", "These antibodies should provide useful serological markers for identifying patients who have atypical GBS with preserved deep tendon reflexes, ataxic GBS, Bickerstaff's brainstem encephalitis or acute ophthalmoparesis, especially for those who have no antibodies to GM1, GD1a or GQ1b.", 'Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome.', "Among them, only one patient developed Bickerstaff's brainstem encephalitis, who carried anti-GQ1b IgG antibodies.", "Overlapping Guillain-Barré syndrome and Bickerstaff's brainstem encephalitis associated with anti-GQ1b IgG antibody after herpes simplex virus infection.", "Bickerstaff's brainstem encephalitis, Miller Fisher syndrome and Guillain-Barré syndrome overlap in an asthma patient with negative anti-ganglioside antibodies.", 'Bickerstaff brainstem encephalitis is a clinical syndrome of ophthalmoplegia, cerebellar ataxia, and central nervous system signs and is associated with the presence of anti-GQ1b antibodies.', 'This is only the second case in the literature of Bickerstaff brainstem encephalitis with raised titers of anti-GQ1b antibodies described in association with M pneumoniae infection.', "Of those patients with Fisher syndrome, Bickerstaff's brainstem encephalitis, ataxic GBS or acute ophthalmoparesis, 33% of 67 anti-GM1b-positive, and 52% of 25 anti-GalNAc-GD1a-positive patients had no anti-GQ1b antibodies.", 'Fisher syndrome or Bickerstaff brainstem encephalitis? Anti-GQ1b IgG antibody syndrome involving both the peripheral and central nervous systems.', 'Anti-GQ1b antibody has been found in Miller Fisher syndrome (MFS), Guillain-Barré syndrome (GBS) with ophthalmoplegia, Bickerstaff brainstem encephalitis (BBE), and acute ophthalmoplegia without ataxia (AO).', "This case presented clinical characteristics of three syndromes concurrently-Fisher syndrome, Bickerstaff brainstem encephalitis, and Guillain-Barré syndrome-that may be collectively called 'anti-GQ1b IgG antibody syndrome'.", 'This is the case of a 79-year-old man with chronic lymphocytic leukemia who presented with Guillain-Barré syndrome with features overlapping with the Miller Fisher syndrome and Bickerstaff brainstem encephalitis and positive antiganglioside GQ1b antibody about 6 months after treatment with bendamustine and rituximab.', 'Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome', "[A case report of Bickerstaff's brainstem encephalitis with positive anti GQ 1 b, GT 1 a, GM 1 ganglioside antibodies].", "[Probable Bickerstaff's brainstem encephalitis associated with anti-GQ1b antibody].", "Among them, only one patient developed Bickerstaff's brainstem encephalitis, who carried anti-GQ1b IgG antibodies. ", 'Nevertheless, 66% of patients with Bickerstaff syndrome have anti-GQ1b antibody during the acute phase period.', "Among them, only one patient developed Bickerstaff's brainstem encephalitis, who carried anti-GQ1b IgG antibodies.", "Overlapping Guillain-Barré syndrome and Bickerstaff's brainstem encephalitis associated with anti-GQ1b IgG antibody after herpes simplex virus infection."]

['The syndrome defined by Bickerstaff of progressive, external ophthalmoplegia and ataxia, with disturbance of consciousness or hyperreflexia, has subsequently been associated with antiganglioside antibody, anti-GQ1b']

['antiganglioside antibody']

Which bone protein is used in archaelogy for dating and species identification?

['Collagen was extracted from modern and archaeological cod bones using a weak HCl solution and analysed for its sulphur isotopic composition by isotope ratio mass spectrometry (IRMS)', 'With the high sensitivity of current generation mass spectrometers, ZooMS provides a non-destructive and highly cost-effective method to characterise collagen peptides.', 'Archaeological bones are usually dated by radiocarbon measurement of extracted collagen. ', 'we describe three complementary preparative HPLC procedures suitable for separating and isolating single amino acids from bone collagen or hair keratin with minimal isotopic contamination. ', 'Bulk bone collagen isotopic analysis of 11 skeletons of Iron Age and Roman date gave a typical C(3) terrestrial signal (', 'Comparison of liquid chromatography-isotope ratio mass spectrometry (LC/IRMS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) for the determination of collagen amino acid δ13C values for palaeodietary and palaeoecological reconstruction.', 'Although the primary focus was the compound-specific stable carbon isotope analysis of bone collagen AAs, because of its growing application for palaeodietary and palaeoecological reconstruction, the results are relevant to any field where AA δ(13)C values are required. ', 'In archaeological studies, the isotopic enrichment values of carbon and nitrogen in bone collagen give a degree of information on dietary composition. ', 'Liquid chromatography/isotope ratio mass spectrometry measurement of δ13C of amino acids in plant proteins.', 'A new procedure for extraction of collagen from modern and archaeological bones for 14C dating.', 'Bones are potentially the best age indicators in a stratigraphic study, because they are closely related to the layer in which they are found. Collagen is the most suitable fraction and is the material normally used in radiocarbon dating.', 'The developed strategy permitted unprecedented biochemical analyses of bone-matrix proteins, including collagen modifications, using nearly nanoscale amounts of exceptionally homogenous bone tissue. ', 'Amino acid delta13C analysis of hair proteins and bone collagen using liquid chromatography/isotope ratio mass spectrometry: paleodietary implications from intra-individual comparisons.', 'We report a novel method for the chromatographic separation and measurement of stable carbon isotope ratios (delta(13)C) of individual amino acids in hair proteins and bone collagen using the LC-IsoLink system, which interfaces liquid chromatography (LC) with isotope ratio mass spectrometry (IRMS).', 'Species identification by analysis of bone collagen using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry.', 'Analysis of the collagen from 32 different mammal species identified a total of 92 peptide markers that could be used for species identification, for example, in processed food and animal feed.', 'We used authentication tests developed for ancient DNA to evaluate claims by Asara et al. (Reports, 13 April 2007, p. 280) of collagen peptide sequences recovered from mastodon and Tyrannosaurus rex fossils', 'Analysis of amino acid 13C abundance from human and faunal bone collagen using liquid chromatography/isotope ratio mass spectrometry.', 'Stable nitrogen (delta(15)N) and carbon (delta(13)C) isotope ratios were measured in bone collagen and dentine from human skeletons excavated from this site in order to establish a weaning curve in mid-Holocene hunter-gatherers.', 'Mass spectrometric analysis of the stable carbon isotope composition (13C/12C or delta 13C) of bone collagen from human remains recovered at archaeological sites provides a direct chemical method for investigating dietary patterns of prehistoric human populations.', 'Coupled with more traditional archaeological methods, stable carbon isotope analysis of bone collagen can significantly enhance reconstruction of dietary patterns of prehistoric humans.']

['Collagen is the main protein extracted from bones and analyzed by mass spectrometry. It is traditionally used for radiocarbon dating but sophisticated new technologies are using collagen for species identification as well.']

['Collagen']

What is the indication of ARCALYST?

['Rilonacept (Arcalyst(TM); Regeneron) is the first us Food and Drug Administration-approved treatment for familial cold autoinflammatory syndrome and Muckle-Wells syndrome and the first in a new line of drugs designed for longer-acting IL-1 blockade.', ' In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older. ', "In February, 2008, 'Orphan Drug' approval from the Food and Drug Administration (FDA) for rilonacept (IL-1 Trap/Arcalyst(), Regeneron Pharmaceuticals, Inc) was given for the treatment of two CAPS disorders, FCAS and MWS in adults and children 12 years and older, making rilonacept the first therapy approved for the treatment of CAPS."]

['In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older.']

['cryopyrin-associated periodic syndromes (CAPS) disorders']

Is glycyl-tRNA synthetase gene involved in the development of Charcot-Marie-Tooth disease?

['Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D', 'Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy', 'Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene', 'mutations of human GlyRS (hGlyRS) were also found to be associated with Charcot-Marie-Tooth disease', 'Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration', 'A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement', 'Here we describe a 45-year-old woman with a long course of motor-dominant neuropathy. Distal weakness appeared in childhood and became worse with age. After a diagnosis of CMT type 2, the symptoms progressed, and in her fourth decade, facial and respiratory muscle weakness appeared, ultimately requiring non-invasive mechanical ventilation. There was no family history of CMT. Comprehensive analysis of known CMT-related genes revealed a novel heterozygous c.815T>A, p.L218Q mutation in glycyl-tRNA synthetase (GARS), a causative gene for both CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V)', 'Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS).', 'Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase.', 'Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.', '[A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement].', 'Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V).', 'These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system.', 'Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V.', 'Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D.', 'Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS).', 'Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS)', 'Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS', 'Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase', 'These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system', 'A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement.', 'Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). ', 'Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. ', 'An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.', 'We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. ', 'An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model.', 'Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS. ', 'Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration. ', ' Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood.', 'These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease,', ' Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D.', 'Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS).', 'Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS).', 'Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase.', 'Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.', 'These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system.', 'A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement.', 'An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model.', 'Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V).']

['Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration.', 'Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D']

['yes']

Which gene has been implicated in Majeed Syndrome?

['Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).', 'The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. ', 'We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. ', ' genetic alteration of LPIN2 in humans is known to cause Majeed syndrome', 'Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2', 'ittle is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome.', 'Recent studies have identified mutations that cause lipin-1 or lipin-2 deficiency in humans, leading to acute myoglobinuria in childhood or the inflammatory disorder Majeed syndrome, respectively.', 'An S734L mutation in LPIN2 causes Majeed syndrome', 'Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome.', 'A splice site mutation confirms the role of LPIN2 in Majeed syndrome.', 'These data confirm the role of LPIN2 mutations in the etiology of Majeed syndrome.']

['Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).', 'Genetic alteration of LPIN2 in humans is known to cause Majeed syndrome.']

['LPIN2']

Does burning mouth syndrome preferentially affect post-mepopausal women?

['It is observed principally in middle-aged patients and postmenopausal women and may be accompanied by xerostomia and altered taste.', 'It occurs more commonly in middle-aged and elderly women and often affects the tongue tip and lateral borders, lips, and hard and soft palate. ', 'BMS is a chronic disorder that frequently affects women and is characterised by burning symptoms of the oral mucosa without clinical signs.', 'It mostly affects elderly citizens, especially postmenopausal women with prevalence up to 12-18%. ']

['BMS is observed principally in middle-aged patients and postmenopausal women \nBMS mostly affects elderly citizens, especially postmenopausal women with prevalence up to 12-18%.']

['yes']

What is the treatment of acute pericarditis?

['Recurrences develop in up to 20-50% of patients with acute pericarditis. Although different causes of recurrent pericarditis have been identified, the etiology remains obscure in most cases which are therefore labelled as idiopathic.', 'A poor response to colchicine treatment and/or a steroid-dependence may be the clue to investigate TNFRSF1A mutations in patients with idiopathic recurrent pericarditis.', 'intravenous infusion of inotropic agents', 'medical treatment may be changed in these patients with a slower tapering of the dosage of steroidal and non-steroidal antiinflammatory drugs.', 'The incidence of purulent pericarditis has decreased considerably since the antibiotic era. It is typically an acute and potentially lethal disease, necessitating rapid diagnosis and adequate therapy to improve prognosis. Standard treatment combines appropriate antibiotic therapy with surgical drainage.', 'We report successful treatment of a non-resolving fibrino-purulent pericardial effusion by combined intrapericardial irrigation of fibrinolytics and systemic corticosteroids administration as an alternative to pericardectomy.', 'Prednisolone (20-30 mg/d) was used in addition to antituberculous chemotherapy in 11 of the 17 patients with effusive pericarditis', 'antibiotic therapy has been initiated. Use of appropriate parenterally administered antibiotics, in combination with early surgical pericardial drainage or partial pericardiectomy, should minimize morbidity and mortality and prevent acute constrictive sequelae.']

['A multidisciplinary approach is frequently necessary to treat acute pericarditis; the most frequent treatments are: antiinflammatory steroid and non-steroid drugs, antibiotic therapy, pericardial drainage and, less frequently ,intrapericardial irrigation of fibrinolytics; antituberculous chemotherapy in presence of Tuberculous Agent']

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List common features of Shapiro syndrome

['Shapiro syndrome is defined as the constellation of periodic hypothermia and hyperhidrosis along with agenesis of the corpus callosum by Shapiro et al. in 1969.', 'Shapiro syndrome is a rare entity, comprising a triad of recurrent hypothermia, hyperhidrosis and congenital agenesis of the corpus callosum. ', 'We present a case of an 80 year old woman presenting with recurrent bouts of shivering, sweating and profound malaise, who sought medical attention because the frequency and severity of attacks worsened in her later years. MRI Brain demonstrated agenesis of the corpus callosum; a rigorous work-up excluded other causes for her symptomatology.', 'These findings imply that aberrant thermoregulation in Shapiro syndrome involves a number of structures remote from the callosal region.', "A 6-year-old girl previously diagnosed with Shapiro's syndrome was admitted to our hospital on several occasions during a 1-year period with complaints of altered consciousness, syncope, hypothermia and episodes of sweating.", "Hypermelatoninemia should be considered in patients with spontaneous periodic hypothermia and hyperhidrosis, and also in patients with Shapiro's syndrome.", 'We present a patient diagnosed with Shapiro syndrome without corpus callosum agenesis. A 4-year-old-girl was admitted to the hospital with complaints of sweating, cooling, and drowsiness that continued during the last week of her admission.', 'Postmortem data regarding the hypothalamic and surrounding areas from future cases of Shapiro syndrome and spontaneous periodic hypothermia would be of great interest.']

['Shapiro syndrome is a rare entity, comprising a triad of recurrent hypothermia, hyperhidrosis and congenital agenesis of the corpus callosum. Hypermelatoninemia has also been described in a patient with Shapiro syndrome.']

['recurrent hypothermia', 'hyperhidrosis', 'congenital agenesis of the corpus callosum']

What is the role of extracellular signal-related kinases 1 and 2 (ERK1/2) proteins in craniosynostosis?

['Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis', 'we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf levels reduced to ∼30% of normal exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial development appears mildly delayed']

['Reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay.']

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what is the role of FGF-2 in cardiac regeneration after myocardial infarction?

['To investigate whether transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) can promote myocardial regeneration after acute myocardial infarction', 'The new method has shown to be capable of promoting CSCs proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following AMI and improving cardiac function. This may provide a new strategy for myocardial regeneration following AMI.', 'To investigate the effects of exogenous basic fibroblast growth factor (bFGF) on myocardial regeneration after acute myocardial infarction (AMI).', 'Exogenous bFGF was shown to have increased angiogenesis and myocardial perfusion, promoted myocardial regeneration by activating the SDF-1α/CXCR4 axis, and thereby improved the cardiac function, which may provide a new therapeutic strategy for AMI.', 'Support to the paracrine hypothesis is provided by data showing that several genes, coding for factors (VEGF, FGF-2, HGF, IGF-I, and TB4) that are potential mediators of the effects exerted by the Akt-MSC conditioned medium, are significantly up-regulated in the Akt-MSCs, particularly in response to hypoxia. Taken together, our data support Akt-MSC-mediated paracrine mechanisms of myocardial protection and functional improvement.', 'Prevascularization with basic fibroblast growth factor-incorporated microspheres enhances the benefits of cardiomyocyte transplantation. We expect that this system will contribute to regeneration medicine through its extensive application to other growth factors.']

['Exogenous FGF-2 was shown to increase angiogenesis and myocardial perfusion, promote myocardial regeneration by activating the SDF-1α/CXCR4 axis, and thereby improve the cardiac function after myocardial infarction. Furthermore, prevascularization with basic FGF-incorporated microspheres enhances the benefits of cardiomyocyte transplantation. In another study, transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) was shown to promote Cardiac Progenitor Cells proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following myocardial infarction and improving cardiac function.']

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How can microRNAs be used as potential biomarkers and therapeutic targets in the management of ovarian cancer?

[' in the carcinogenesis of ovarian cancer through deregulation of cell proliferation. They may be novel biomarkers for early detection or therapeutic targets of ovarian cancer", "MicroRNA let-7a: a potential marker for selection of paclitaxel in ovarian cancer management", " The study suggests that the beneficial impact of the addition of paclitaxel on EOC survival was significantly linked to let-7a levels, and that miRNAs such as let-7a may be a useful marker for selection of chemotherapeutic agents in EOC management", "miR-200c has potential as a predictor of survival, and is a biomarker of relapse, in stage I EOC", "MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer", " our results strongly suggest that let-7i might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response and survival in patients with ovarian cancer", "miRNAs-21, 92 and 93 are known oncogenes with therapeutic and biomarker potential", "Serum miR-132, miR-26a, let-7b, and miR-145 could be considered as potential candidates as novel biomarkers in serous ovarian cancer"]']

MicroRNAs can serve as potential biomarkers for early detection or therapeutic targets in the management of ovarian cancer. For example, miRNAs like let-7a, let-7i, miR-200c, miR-21, miR-92, miR-93, miR-132, miR-26a, let-7b, and miR-145 have been identified as biomarkers with therapeutic and predictive potential in ovarian cancer management. They can help in selecting chemotherapeutic agents, predicting survival, modulating chemotherapy response, and identifying relapse in patients with ovarian cancer.

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Which event results in the acetylation of S6K1?

['S6K1 is acetylated at lysine 516 in response to growth factor stimulation', 'In addition to phosphorylation, we have recently shown that S6K1 is also targeted by lysine acetylation', 'Here, using tandem mass spectrometry we have mapped acetylation of S6K1 to lysine 516, a site close to the C-terminus of the kinase that is highly conserved amongst vertebrate S6K1 orthologues', 'Using acetyl-specific K516 antibodies, we show that acetylation of endogenous S6K1 at this site is potently induced upon growth factor stimulation', 'We propose that K516 acetylation may serve to modulate important kinase-independent functions of S6K1 in response to growth factor signalling', 'Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo', 'Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300', 'Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 acetylation by nicotinamide suggests the additional involvement of sirtuin deacetylases in S6K deacetylation', 'Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300.', 'Furthermore, it appears that the acetylation sites targeted by p300 lie within the divergent C-terminal regulatory domains of both S6K1 and S6K2.', 'Furthermore, it appears that the acetylation sites targeted by p300 lie within the divergent C-terminal regulatory domains of both S6K1 and S6K2', 'We propose that K516 acetylation may serve to modulate important kinase-independent functions of S6K1 in response to growth factor signalling.']

['Using acetyl-specific K516 antibodies, we show that acetylation of endogenous S6K1 at this site is potently induced upon growth factor stimulation. We propose that K516 acetylation may serve to modulate important kinase-independent functions of S6K1 in response to growth factor signalling. Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300', 'Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 acetylation by nicotinamide suggests the additional involvement of sirtuin deacetylases in S6K deacetylationUsing acetyl-specific K516 antibodies, we show that acetylation of endogenous S6K1 at this site is potently induced upon growth factor stimulation', 'Using acetyl-specific K516 antibodies, we show that acetylation of endogenous S6K1 at this site is potently induced upon growth factor stimulation We propose that K516 acetylation may serve to modulate important kinase-independent functions of S6K1 in response to growth factor signalling', 'K516 acetylation may serve to modulate important kinase-independent functions of S6K1 in response to growth factor signalling, followed by interaction with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6K1 can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300.']

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Does surgery for ovarian endometriomas improve fertility?

['CONCLUSION: Endometriomas per se appear to be the main cause of the reduced long-term reproductive performance of the affected patients, with little or no contribution from surgery. Furthermore, endometrioma surgery seems to improve the success rates of fertility treatment.', 'Amongst the 38 women desiring pregnancy after endometrioma surgery, 19 (50%) achieved a spontaneous pregnancy during the follow-up period. ', 'Of 33 women who wished to conceive, 67% became pregnant, spontaneously in 59%', 'CONCLUSIONS: Recurrence and pregnancy rates are encouraging in that they seem comparable to the best reported results after endometrioma cystectomy. ', 'While laparoscopic excision is known to improve fertility, recurrence can cause significant ovarian damage and adverse affects on fertility.', 'Surgery is considered to play a role within the framework of the therapeutic options to cure infertile women with the disease even though its effectiveness is generally modest. ', 'Randomized controlled trials showed that the excision technique is associated with a higher pregnancy rate and a lower rate of recurrence although it may determine severe injury to the ovarian reserve. ', 'Surgical treatment is associated with a high recurrence rate and its employment for women undergoing assisted conception has recently been challenged.', 'Laparoscopic excision of ovarian endometrioma prior to IVF does not offer any additional benefit over expectant management. ', 'For those women subsequently attempting to conceive it was also associated with a subsequent increased spontaneous pregnancy rate in women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29).', 'here is insufficient evidence to favour excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intra-uterine insemination (OR 1.40 CI 0.47-4.15) . ', 'CONCLUSIONS: These findings suggest that in a context of more than one year infertility only related to endometriosis, it is reasonable to offer these patients a complete operative laparoscopic treatment of their lesions, which enables 65% of them to be pregnant within a 8.5 months post-surgical median time to pregnancy and spontaneously in 60%. ', " It was also associated with a subsequent increased rate of spontaneous pregnancy women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29). AUTHORS' CONCLUSIONS: There is some evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation, with regard to the recurrence of the endometrioma, recurrence of symptoms and subsequent spontaneous pregnancy in women who were previously subfertile. ", 'Surgery is an option for treatment, but there is no convincing evidence that it promotes a significant improvement in fertility.', 'In conclusion, ovarian surgery for the treatment of endometriosis reduces the ovarian outcome in IVF/ICSI cycles in women >35 years old, and might also decrease pregnancy rates. ', 'Improvement of pain symptoms occurred in 87% of the patients and fertility rate was 45%.', 'The long-term results, especially the fertility outcome, have been promising: 12 of 20 women (60%) achieved a term pregnancy following a laparoscopic endometrioma procedure alone. ', 'Among this group, 115 patients (54%) conceived following surgery; of these conceptions, 109 resulted in a living child.', 'WIDER IMPLICATIONS OF THE FINDINGS: Despite the available evidence that surgery for endometriomas does not improve the outcome of ART and may damage ovarian reserve, it seems that the majority of gynaecologists in the UK offer ovarian cystectomy to their patients.', 'Ovarian endometriomas does not exclude fertility.', 'Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study.', 'Conclusion(s): Laparoscopic cystectomy for endometriomas before commencing an IVF cycle does not improve fertility outcomes.', 'Despite the available evidence that surgery for endometriomas does not improve the outcome of ART and may damage ovarian reserve, it seems that the majority of gynaecologists in the UK offer ovarian cystectomy to their patients.', 'Furthermore, laparoscopic removal of endometriomas does not improve IVF results, but may cause a decrease of ovarian responsiveness to gonadotropins.', 'Furthermore, endometrioma surgery seems to improve the success rates of fertility treatment.', 'Laparoscopic cystectomy for endometriomas before commencing an IVF cycle does not improve fertility outcomes']

['Yes, endometrioma surgery seems to improve the success rates of fertility treatment.']

['yes']

What is REVIGO?

['REVIGO summarizes and visualizes long lists of gene ontology terms.', 'REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures. Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views. REVIGO is freely available at http://revigo.irb.hr/.', 'Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views.', 'The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret.REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures.', 'REVIGO summarizes and visualizes long lists of gene ontology terms', 'The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret.REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures', 'Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views', 'The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret.REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures.', 'REVIGO summarizes and visualizes long lists of gene ontology terms.', 'Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views.']

['REVIGO summarizes and visualizes long lists of gene ontology terms.', 'REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures. Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views. REVIGO is freely available at http://revigo.irb.hr/.', 'Outcomes of high-throughput biological experiments are typically interpreted by statistical testing for enriched gene functional categories defined by the Gene Ontology (GO). The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret.REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures. Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views. REVIGO is freely available at http://revigo.irb.hr/.']

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Is depression associated with poor prognosis of brain tumor patients?

['Before surgery 27 patients (35%) had BDI scores indicating the presence of depression. These scores were significantly higher in patients with a history of depression (p = 0.017) and in those with a lower functional outcome (p = 0.015).', 'A lower functional status (KPS score < or = 70) in patients was significantly associated with high depression scores at the 3-month (p = 0.000) and 1-year (p = 0.005) assessments.', 'At all follow-ups, depressed low-grade glioma patients had a significantly shorter survival time, 3.3-5.8 years, compared to non-depressed low-grade glioma patients, 10.0-11.7 years.', 'The results suggest that depression and decreased QOL among low-grade glioma patients is related to shorter survival at long-term follow-up.', 'The adverse impact of depression in relation to survival among cancer patients is currently a subject of great interest in research.', 'In the subgroup of patients with low-grade gliomas, depressive patients had a significantly shorter survival time compared with nondepressive subjects (P = 0.031, Kaplan-Meier survival analysis).', 'Preoperative depression seemed to be a significant prognostic factor for worse survival in low-grade glioma patients.', 'Major depressive disorder was marginally associated with outcomes, while surgical interventions and radiotherapy did not show strong associations with test performances.']

['Yes. In brain tumor patients depression is associated with shorter survival and worse functional outcomes.']

['yes']

How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?

['The use of cffDNA in fetal sex determination during the first trimester of pregnancy of female DMD carriers.', 'We determined fetal sex during the first trimester using a quantitative real-time polymerase chain reaction (PCR) assay of cffDNA in pregnant carriers of DMD.', 'Early fetal gender determination using real-time PCR analysis of cell-free fetal DNA during 6th-10th weeks of gestation.', 'Considerable 97.3% sensitivity and 97.3% specificity were obtained in fetal gender determination which is significant in the first trimester of pregnancy.', 'Therefore in this study, the probability of detecting sequences on the human Y-chromosome in pregnant women has been evaluated to identify the gender of fetuses. Peripheral blood samples were obtained from 80 pregnant women with gestational age between 6th to 10th weeks and the fetal DNA was extracted from the plasma.', 'We evaluated the feasibility and accuracy of non-invasive fetal gender determination using quantitative fluorescent-polymerase chain reaction (QF-PCR) analysis of circulating cffDNA in the first-trimester maternal plasma.', 'This study aims to validate a reliable method for non-invasive prenatal diagnosis of fetal gender using maternal plasma cell-free fetal DNA (cffDNA) for fetal sex assessment in the first trimester of pregnancy and test its clinical utility in the diagnosis of potentially affected pregnancies in carriers of X-linked disorders.', 'We performed a review of the published literature evaluating the use of cffDNA and ultrasound for prenatal determination of fetal sex during the first trimester of pregnancy.', 'The use of cffDNA in fetal sex determination during the first trimester of pregnancy of female DMD carriers', 'We performed a review of the published literature evaluating the use of cffDNA and ultrasound for prenatal determination of fetal sex during the first trimester of pregnancy', 'Fetal Sex Determination using Non-Invasive Method of Cell-free Fetal DNA in Maternal Plasma of Pregnant Women During 6(th)- 10(th) Weeks of Gestation', 'US allows reliable fetal sex determination only during the second trimester. ']

['Using cffDNA from maternal blood, the fetal gender can be determined as early as 6 to 10 weeks of gestation (during the first trimester of pregnancy).']

['6th to 10th week of gestation', 'first trimester of pregnancy']

What are the signatures of aggressive periodontitis?

['This pilot study examined gene expression signatures in pathological gingival tissues of subjects with chronic or aggressive periodontitis, and explored whether new subclasses of periodontitis can be identified based on gene expression profiles. A total of 14 patients, seven with chronic and seven with aggressive periodontitis, were examined with respect to clinical periodontal status, composition of subgingival bacterial plaque assessed by checkerboard hybridizations, and levels of serum IgG antibodies to periodontal bacteria assayed by checkerboard immunoblotting. In addition, at least two pathological pockets/patient were biopsied, processed for RNA extraction, amplification and labeling, and used to study gene expression using Affymetrix U-133 A arrays. Based on a total of 35 microarrays, no significantly different gene expression profiles appeared to emerge between chronic and aggressive periodontitis. However, a de novo grouping of the 14 subjects into two fairly robust clusters was possible based on similarities in gene expression. These two groups had similar clinical periodontal status and subgingival bacterial profiles, but differed significantly with respect to serum IgG levels against the important periodontal pathogens Porphyromonas gingivalis, Tannerella forsythensis and Campylobacter rectus. These early data point to the usefulness of gene expression profiling techniques in the identification of subclasses of periodontitis with common pathobiology', 'Gene ontology analysis identified 61 differentially expressed groups (adjusted P <0.05), including apoptosis, antimicrobial humoral response, antigen presentation, regulation of metabolic processes, signal transduction, and angiogenesis']

['Aggressive periodontitis does not differ from chronic periodontitis from a microbial profile point of view but there are distinctive immunological signatures, including a higher expression in IgG against most periodontal pathogens and a more intense regulatory mechanism of metabolic processes.']

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Which fimA genotypes are associated with disease?

[' FimA has been characterized as an important virulence factor for P. gingivalis, and many studies, both animal experiments and clinical investigations, have characterized fimA genotypes II, Ib, and IV to be associated with disease (periodontitis and cardiovascular disease) ', 'Long fimbriae (FimA) are important virulence factors of Porphyromonas gingivalis. Based on the diversity of the fimA gene, this species is classified into 6 genotypes. ', ' In cases of chronic apical periodontitis, P. gingivalis variant type IV was the most prevalent (24%), followed by types I (20%), II (16%), and III (8%). In acute abscess samples, variant type II was the most prevalent (12%), followed by types III and IV (8% of each) and type I (4%).', 'We show that P. gingivalis strains with genotype I and II of FimA are efficient in interaction with saliva or S. gordonii. ', 'A strong association between Porphyromonas gingivalis fimA genotypes II and Ib and chronic periodontitis exists in the Spanish population. The most prevalent genotype in periodontal patients is II.', 'Our results suggest that the presence of P. gingivalis is associated with periodontal diseases, and that the type II, IV and Ib/II combination are the most common among fimA genotypes.', 'Statistical analysis, however, revealed that a more significant correlation was found between periodontitis and the occurrence of type Ib fimA.', ' Type II of fimA was the most prevalent genotype of P. gingivalis in patients with AgP. ', 'The population of Tregs further decreased in patients with type II FimA compared with the other types. P.gingivlias FimA genotype II was the dominant type associated with decreased Treg population. ', 'A trend toward a greater frequency of FimA II genotype in patients with moderate and severe periodontitis was determined.', 'The fimA type Ib genotype of P. gingivalis was found to play a critical role in the destruction of peri-implant tissue, suggesting that it may be a distinct risk factor for peri-implantitis.']

['FimA has been characterized as an important virulence factor for P. gingivalis, and many studies, both animal experiments and clinical investigations, have characterized fimA genotypes II, Ib, and IV to be associated with disease (periodontitis and cardiovascular disease)']

['genotypes II', 'genotypes Ib', 'genotypes IV']

Which is the largest metabolic gene cluster in yeast?

['The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source.', 'The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source.', 'Birth of a metabolic gene cluster in yeast by adaptive gene relocation.', 'The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source', 'Birth of a metabolic gene cluster in yeast by adaptive gene relocation', 'The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. ', 'For example the DAL metabolic cluster in yeast was assembled in recent evolutionary times in the Hemiascomycetes lineage, through a set of rearrangements that brought together the genes involved in the allantoin degradation pathway. ', 'For example the DAL metabolic cluster in yeast was assembled in recent evolutionary times in the Hemiascomycetes lineage, through a set of rearrangements that brought together the genes involved in the allantoin degradation pathway.']

['The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source.', 'the dal cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable saccharomyces cerevisiae to use allantoin as a nitrogen source.', 'The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. The DAL cluster is located in a domain of modified chromatin involving both H2A.Z histone exchange and Hst1-Sum1-mediated histone deacetylation, and it may be a coadapted gene complex formed by epistatic selection.', 'The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. Six of the eight genes involved in allantoin degradation, which were previously scattered around the genome, became relocated to a single subtelomeric site in an ancestor of S. cerevisiae and Saccharomyces castellii.']

['The DAL cluster']

Global quantitative phosphoproteomic analyses are emerging. List the preferred technologies for the enrichment for phosphorylated peptides?

['TiSH--a robust and sensitive global phosphoproteomics strategy employing a combination of TiO2, SIMAC, and HILIC.', 'An initial TiO(2) phosphopeptide pre-enrichment step is followed by post-fractionation using sequential elution from IMAC (SIMAC) to separate multi- and mono-phosphorylated peptides, and hydrophilic interaction liquid chromatography (HILIC) of the mono-phosphorylated peptides (collectively abbreviated "TiSH").', 'After enrichment by anti-phosphotyrosine antibodies, we identified 29 potential novel c-Src substrate proteins.', 'Combining immunoprecipitation with an antiphosphotyrosine antibody, titanium dioxide phosphopeptide enrichment, isobaric tag for the relative and absolute quantitation methodology, and strong cation exchange separation, we were able to identify 2814 phosphopeptides.', 'Phosphopeptide fractionation by strong cation exchange chromatography combined with immobilized metal affinity chromatography (IMAC) enrichment enabled quantification of more than 8000 distinct phosphorylation sites in Ppt1 wild-type versus Ppt1-deficient yeast cells', 'By employing titanium dioxide in addition to antiphosphotyrosine antibodies as enrichment methods, we identified 4164 phosphopeptides on 1670 phosphoproteins.', 'Our method combines the use of strong cation exchange (SCX) and titanium dioxide (TiO(2)) for phosphopeptide enrichment, high-resolution MS for peptide and protein identification, and stable isotope labeling by amino acids in cell culture (SILAC) for quantification.', 'Phosphopeptides were isolated with high specificity through a simple derivatization procedure based on phosphoramidate chemistry.']

['There are many different approaches to enrich for phosphorylated peptides: titanium dioxide, IMAC, simple derivatization through phosphoramidate chemistry and antibodies.']

['enriched for phosphorylated peptides using titanium dioxide', 'sequential elution from IMAC', 'simple derivatization procedure based on phosphoramidate chemistry', 'antiphosphotyrosine antibodies']

How do septins as GTP-binding proteins impact various cellular functions like cytokinesis, apoptosis, infection, neurodegeneration, and neoplasia?

['["discover that septins, a component of the cytoskeleton, recognize membrane curvature at the micron scale, a common morphological hallmark of eukaryotic cellular processes.", "Septins are an evolutionarily conserved family of GTP-binding proteins. They are involved in diverse processes including cytokinesis, apoptosis, infection, neurodegeneration and neoplasia. ", "eptins are a family of cytoskeletal GTP-binding proteins that assemble into membrane-associated hetero-oligomers and organize scaffolds for recruitment of cytosolic proteins or stabilization of membrane proteins. Septins have been implicated in a diverse range of cancers, including gastric cancer, but the underlying mechanisms remain unclear. ", "nidulans septins contain the highly conserved GTP binding and coiled-coil domains seen in other septins.", "The septins: roles in cytokinesis and other processes.", "The septins are a novel family of proteins that were first recognized in yeast as proteins associated with the neck filaments.", "Septin9 is involved in septin filament formation and cellular stability.", "Here, we review these findings and discuss emerging mechanisms by which septins promote cell asymmetry in fungi and animals.<CopyrightInformation>\\u00a9 2011 John Wiley & Sons A/S.</C", "These observations together with conserved sequence motifs identify the septins as members of the GTPase superfamily.", "BACKGROUND: Septins belong to the GTPase superclass of proteins and have been functionally implicated in cytokinesis and the maintenance of cellular morphology.", "Septins are important components of the cytoskeleton that are highly conserved in eukaryotes and play major roles in cytokinesis, patterning, and many developmental processes.", "The septins also appear to be involved in various other aspects of the organization of the cell surface.", "Septins are a family of eukaryotic GTP binding proteins conserved from yeasts to humans.", "Septins are a highly conserved family of GTP-binding proteins involved in multiple cellular functions, including cell division and morphogenesis.", "Septin proteins are conserved structural proteins that often demarcate regions of cell division.", "Septins are GTP-binding proteins that form filaments and higher-order structures on the cell cortex of eukaryotic cells and associate with actin and microtubule cytoskeletal networks.", "Septins are guanosine-5\'-triphosphate-binding proteins involved in wide-ranging cellular processes including cytokinesis, vesicle trafficking, membrane remodelling and scaffolds, and with diverse binding partners", "Septins are a group of GTP-binding proteins that can organize into heteromeric complexes and then into large filaments. ", "Septins are a conserved family of GTPases that regulate important cellular processes such as cell wall integrity, and septation in fungi.", "Septins are a cytosolic GTP-binding protein family first characterized in yeast, but gaining increasing recognition as critical protagonists in higher eukaryotic cellular events. Mammalian septins have been associated with cytokinesis and exocytosis, along with contributing to the development of neurological disorder", "Septins are a family of proteins that assemble a ring structure at the mother-daughter neck during vegetative growth, where they control cytokinesis. ", "Septins are a class of GTP-binding proteins conserved throughout many eukaryotes. Individual septin subunits associate with one another and assemble into heteromeric complexes that form filaments and higher-order structures in vivo. ", "The septins are a conserved family of GTP-binding, filament-forming proteins. I", "The septins are filament-forming, GTP-binding proteins that are conserved from yeast to humans. Septins assemble into higher-order structures such as rings, bars, and gauzes with diverse functions including serving as membrane diffusion barriers and scaffolds for cell signaling. ", "Septins are a family of 14 cytoskeletal proteins that dynamically form hetero-oligomers and organize membrane microdomains for protein complexes", "Septins are highly conserved and essential eukaryotic cytoskeletal proteins that interact with the inner plasma membrane. They are involved in essential functions requiring cell membrane remodeling and compartmentalization, such as cell division and dendrite morphogenesis, and have been implicated in numerous diseases", "Septins are conserved GTP-binding proteins that assemble into heteromeric complexes that form filaments and higher-order structures in cells.", " Septins are members of a conserved family of GTPases found in organisms as diverse as budding yeast and mammal", "Septins are a family of conserved proteins that are essential for cytokinesis in a wide range of organisms including fungi, Drosophila and mammals.']

Septins, as GTP-binding proteins, impact various cellular functions like cytokinesis, apoptosis, infection, neurodegeneration, and neoplasia. They are involved in diverse processes including cytokinesis, apoptosis, infection, neurodegeneration, and neoplasia. Septins have been implicated in a diverse range of cancers, including gastric cancer, but the underlying mechanisms remain unclear.

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Which tool is used for the identification of recurrent variants in noncoding regions?

['LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations.', "In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).", 'LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations', 'LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations.']

['LARVA is an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers.']

['LARVA']

Which are the main histone modifications associated with enhancers?

['Using H3K4me2 as a mark for active enhancers', 'Hyperacetylation of histones H3 and H4, a mark of active chromatin, is established broadly across target loci by enhancers that function over long distances', 'The enhancer region itself was marked by mono-methylation at K4 and K9, distinguishing it from the methyl marks in the gene coding region', 'H3K4 methylation to monovalent and bivalent domains']

['Histone 3 lysine 4 mono- (H3K4me1) and di-methylation (H3K4me2) are the main post-transcriptional histone modifications related to enhancer activity.', 'Using H3K4me2 as a mark for active enhancers (PMID: 22270183) Hyperacetylation of histones H3 and H4, a mark of active chromatin, is established broadly across target loci by enhancers that function over long distances (PMID: 19021773) The enhancer region itself was marked by mono-methylation at K4 and K9, distinguishing it from the methyl marks in the gene coding region (PMID: 19021773) H3K4 methylation to monovalent and bivalent domains (PMID: 20621055)', 'H3K4 methylation to monovalent and bivalent domains. The enhancer region itself was marked by mono-methylation at K4 and K9, distinguishing it from the methyl marks in the gene coding region. Hyperacetylation of histones H3 and H4, a mark of active chromatin, is established broadly across target loci by enhancers that function over long distances. Using H3K4me2 as a mark for active enhancers. ']

['Histone 3 lysine 4 mono-methylation (H3K4me1)', 'Histone 3 lysine 4 di-methylation (H3K4me2)']

What is known about potential implication of thyroid hormone receptors in arterial hypertension?

['For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited.', 'The results of Western blot analyses showed that the levels of the three TR isoforms do not differ significantly between SHRs and control rats of the same age, either in the left or in the right ventricle.']

['thyroid hormone receptors are implicated in arterial hypertension', 'An associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension has been observed\nThe levels of the three thyroid hormone receptors isoforms do not differ significantly between spontaneous hypertensive rats and control rats of the same age, either in the left or in the right ventricle.\nThe published results are still unconclusive.']

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Which histone mutations have been associated with pediatric gliomas?

['Detecting the H3F3A mutant allele found in high-grade pediatric glioma by real-time PCR', ' It has been reported recently that about 80% of DIPG cases and 70% of midline glioblastomas contain a mutation at one allele of the H3F3A gene (encoding histone H3 variant H3.3), replacing the lysine 27 with methionine (K27M).', 'In order to facilitate diagnosis of DIPG patients, a quick and reliable method to identify the H3F3A K27M mutation is needed.', 'Using this optimized real-time PCR assay, we analyzed eleven samples, two of which containing H3F3A K27M mutation, and found that these two samples were differentially amplified from the nine others. ', 'we were able to discern the H3F3A K27M mutation in a newly obtained pediatric brainstem glioblastoma sample whose H3.3 status was not known previously, and in three other DIPG samples as well as paraffin embedded samples. These results demonstrate that we have developed a new reliable procedure for detecting the H3F3A K27M mutation in pediatric glioblastoma patient samples.', 'Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome and was shown to influence EZH2 function', 'A lesson learned from the H3.3K27M mutation found in pediatric glioma: a new approach to the study of the function of histone modifications in vivo?', 'Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1)', 'Genome-wide studies using ChIP-seq on H3.3K27M patient samples indicate a global reduction of H3K27me3 on chromatin.', 'Remarkably, we also found a dramatic enrichment of H3K27me3 and EZH2 (the catalytic subunit H3K27 methyltransferase) at hundreds of gene loci in H3.3K27M patient cells', 'Two new studies show that the known histone H3 alteration p.Lys27Met in pediatric glioma leads to globally diminished trimethylation at histone H3 lysine 27. ', 'The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.', 'Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases.', 'These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.', 'Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored.', 'Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas.', 'Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B).', 'Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3.', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.', 'Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation.', 'Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors.', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations', 'Recent sequencing studies have shown that ~30\xa0% of pediatric GBM and ~80\xa0% of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3', 'Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas', 'Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B)', 'Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3', 'Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors', 'Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas', 'Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. ', 'Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. ', 'We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. ', 'Recent sequencing studies have shown that ~30\xa0% of pediatric GBM and ~80\xa0% of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3.', 'Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis.', 'Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome and was shown to influence EZH2 function.The present study investigated the correlation of expression of EZH2 and other PRC2 genes (EZH1, SUZ12, EED) with overall survival of pediatric GBM patients and the cytotoxic impact of EZH2 inhibition by the novel agent Tazemetostat in pediatric GBM/DIPG cells harboring either a H3.3 mutation or a H3 wildtype.EZH2 gene expression does not c', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.', 'Important insights have also been uncovered in the field of pediatric glioma, including the identification of recurrent mutation, fusion, and/or duplication events of the BRAF, FGFR1, MYB, and MYBL1 genes in pediatric low-grade gliomas, mutations affecting histone components (H3F3A p.K27M or p.G34) in pediatric high-grade gliomas, and aggressive subsets developing in midline central nervous system structures.', 'K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival.', 'Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.', 'Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles.', 'K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival.', 'Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways.', 'Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation.', 'The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.', 'A lesson learned from the H3.3K27M mutation found in pediatric glioma: a new approach to the study of the function of histone modifications in vivo?']

['About 80% of Diffuse intrinsic pontine glioma (DIPG) cases and 70% of midline glioblastomas contain a mutation at one allele of the H3F3A gene (encoding histone H3 variant H3.3), replacing the lysine 27 with methionine (K27M). Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome. Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1)', 'Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome and was shown to influence EZH2 function Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1) Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases.', 'Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1). Two new studies show that the known histone H3 alteration p.Lys27Met in pediatric glioma leads to globally diminished trimethylation at histone H3 lysine 27. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.', ', approximately 30% of pediatric high grade gliomas (pedhgg) including gbm and dipg harbor a lysine 27 mutation (k27m) in histone 3.3 (h3.3) which is correlated with poor outcome and was shown to influence ezh2 function . the h3f3a mutant allele found in high-grade pediatric glioma by real-time pcr . studies on high-grade pediatric gbm have identified two recurrent mutations (k27m and g34r/v) in genes encoding histone h3 (h3f3a for h3.3 and hist1h3b for h3.1) . has been reported recently that about 80% of dipg cases and 70% of midline glioblastomas contain a mutation at one allele of the h3f3a gene (encoding histone h3 variant h3.3) , replacing the lysine 27 with methionine (k27m). . , discuss vaccine treatment for children diagnosed with malignant glioma , through targeting epha2 , il-13rα2 and/or histone h3 k27m , while in adults , treatments with rintega , prophage series g-100 and dendritic cells are explored. . studies have identified a lys 27-to-methionine (k27m) mutation at one allele of h3f3a , one of the two genes encoding histone h3 variant h3.3 , in 60% of high-grade pediatric glioma cases. . new studies show that the known histone h3 alteration p.lys27met in pediatric glioma leads to globally diminished trimethylation at histone h3 lysine 27 . were able to discern the h3f3a k27m mutation in a newly obtained pediatric brainstem glioblastoma sample whose h3.3 status was not known previously , and in three other dipg samples as well as paraffin embedded samples these results demonstrate that have developed a new reliable procedure for detecting the h3f3a k27m mutation in pediatric glioblastoma patient samples. . ']

['K27M in H3F3A', 'G34R/V in HIST1H3B']

Which glands are subject to attack by lymphocytes in Sjogren's syndrome?

["In Sjögren's syndrome the autoimmune response is directed against the exocrine glands, which, as histopathological hallmark of the disease, display persistent and progressive focal mononuclear cell infiltrates.", "Sjögren's syndrome (SS) is an autoimmune disease characterized by clonal B cell attack of the exocrine glands and dysregulated expression of B cell-activating factor (BAFF).", "Sjögren's syndrome (SjS) is a human autoimmune disease characterized by exocrine dysfunction resulting from chronic autoimmune attack primarily against the lacrimal and/or salivary glands.", "Sjögren's syndrome is an autoimmune disease in which immune cells chronically attack the lachrymal and salivary glands.", "Sjögren's syndrome (SjS) is a systemic autoimmune disease in which an immunological attack against the salivary and lacrimal glands results, respectively, in severe dry mouth and dry eye diseases.", "Sjögren's syndrome (SS) is a chronic autoimmune disease affecting epithelial tissues. Exocrine glands are the primary target and their functional impairment comes as a result of immune attack of epithelial cells of the affected organs (autoimmune epithelitis).", "Sjögren's syndrome (SjS) is a human autoimmune disease characterized by the loss of exocrine function as a result of a chronic immune attack directed primarily against the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes).", "The purpose of this qualitative research was to explore the lived experiences of women with Sjogren's Syndrome (SS), a chronic autoimmune syndrome in which invading lymphocytes attack moisture-producing glands of the body. This syndrome, affecting 4 million Americans, involves extreme dryness of the eyes and mouth and other systemic complications such as fatigue and muscle and joint pain.", "NOD mice manifest many features of autoimmune exocrinopathy (Sjögren's syndrome), a disease generally characterized by a chronic, progressive immunological attack against the exocrine tissues of the salivary and lacrimal glands."]

["Sjögren's syndrome (SjS) is a human autoimmune disease characterized by exocrine dysfunction resulting from chronic autoimmune attack primarily against the lacrimal and/or salivary glands."]

['The lacrimal and/or salivary glands']

Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?

[' In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.', 'In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors.', 'Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome.']

['SSCprofiler is a computational tool utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.']

['SSCprofiler']

What is the use of emulsion PCR in Next Generation Sequencing?

['Emulsion PCR-coupled target enrichment: an effective fishing method for high-throughput sequencing of poorly preserved ancient DNA', 'We present a unified strategy in which emulsion PCR is coupled with target enrichment followed by next-generation sequencing. The method made it possible to obtain efficiently non-duplicated reads mapped to target sequences of interest, and this can achieve deep and reliable sequencing of ancient DNA from typical materials, even though poorly preserved.', 'Three multiplex PCR reactions were carried out to amplify the coding exons of 328 genes including FBN1, TGFBR1 and TGFBR2. DNA fragments from different samples were ligated with barcoded sequencing adaptors. Template preparation and emulsion PCR, and Ion Sphere Particles enrichment were carried out using an Ion One Touch system. The ion sphere particles were sequenced on a 318 chip using the PGM platform.', 'In our NGS approach, the 16,569-bp mtDNA is enriched by long-range PCR and the 108 nuclear genes (which represent 1301 amplicons and 680 kb) are enriched by RainDance emulsion PCR. Sequencing is performed on Illumina HiSeq 2000 or MiSeq platforms, and bioinformatics analysis is performed using commercial and in-house developed bioinformatics pipelines.', 'However, pyrosequencing of emulsion PCR reactions, amplifying from only one molecule at a time, can generate megabases of clonally amplified loci at high coverage, thereby greatly simplifying allelic sequence determination.', "During genomic PCR, in this 4-primer system, the outer set of primers containing the MID and the 454 adaptor sequences are incorporated into an amplicon generated by the inner HLA target-specific primers each containing a common sequence tag at the 5' end of the forward and reverse primers. Pools of the resulting amplicons are used for emulsion PCR and clonal sequencing on the 454 Life Sciences GS FLX System, followed by genotyping with Conexio software.", 'The purpose of our study was to compare NGS enrichment methods for a clinical assay targeting the nine genes known to be associated with aortopathy. RainDance emulsion PCR and SureSelect RNA-bait hybridization capture enrichment methods were directly compared by enriching DNA from eight samples.', 'We show the efficacy by comparing the method to a commercial kit and further demonstrate that emulsion PCR can be used for bias free amplification and virtual immortalization of DNA template libraries.', 'Here, we describe a novel approach for normalization of multiplex next generation sequencing libraries after emulsion PCR.', 'Briefly, amplified libraries carrying unique barcodes are prepared by fluorescent tagging of complementary sequences and then resolved by high-speed flow cytometric sorting of labeled emulsion PCR beads.', 'The protocol is simple and provides an even sequence distribution of multiplex libraries when sequencing the flow-sorted beads. Moreover, since many empty and mixed emulsion PCR beads are removed, the approach gives rise to a substantial increase in sequence quality and mean read length, as compared to that obtained by standard enrichment protocols.', 'Based on the mechanism of emulsion PCR, a unique DNA template would only generate a unique sequence read after being amplified and sequenced on GS FLX.', 'Prior to SOLiD sequencing reaction, the libraries were amplified with emulsion PCR and enriched with the P2 enrichment beads. The library samples were loaded to sequencing Chip for Work Flow Analysis (WFA) or sequencing running with default parameters.']

['Prior to Next Generation Sequencing reactions, DNA libraries are constructed, amplified with emulsion PCR, and enriched with the use of enrichment beads. The library samples are then loaded to a sequencing chip and analyzed on an NGS platform.']

[]

Are shadow enhancers associated with development?

['Critical developmental control genes sometimes contain "shadow" enhancers that can be located in remote positions, including the introns of neighboring genes', 'These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes "bring about one definite end-result regardless of minor variations in conditions"', 'Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development.', " This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3' flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues", 'This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development.', "Recent reports have shown that developmental genes often possess multiple discrete enhancer modules that drive transcription in similar spatio-temporal patterns: primary enhancers located near the basal promoter and secondary, or 'shadow', enhancers located at more remote positions.", "Together, the similarities in their location, enhancer output, and dependence on retinoid signaling suggest that a conserved cis-regulatory cassette located in the 3' proximal regions adjacent to the HoxA and HoxB complexes evolved to modulate Hox gene expression during mammalian cardiac and endoderm development. ", 'This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development.']

['Yes. Critical developmental control genes sometimes contain shadow enhancers that can be located in remote positions, including the introns of neighboring genes']

['yes']

Abnormality in which vertebral region is important in the Bertolotti's syndrome?

["Bertolotti's syndrome (BS), a form of lumbago in lumbosacral transitional vertebrae, is an important cause of low back pain in young patients. ", ' Common causes of back pain were the ipsilateral L5-S1 facet joint, neoarticulation, the SI joint, and disc degeneration. ', "Patients with Bertolotti's syndrome have characteristic lumbosacral anomalies and often have severe sciatica. ", 'We suggest that the intractable sciatica in this syndrome could arise from impingement of the nerve root extraforaminally by compression caused by the enlarged transverse process.', "Radiofrequency sensory ablation as a treatment for symptomatic unilateral lumbosacral junction pseudarticulation (Bertolotti's syndrome): a case report.", "She was found to have an elongated right L5 transverse process that articulated with the sacral ala (Bertolotti's syndrome).", "Lumbosacral transitional vertebra is an anatomical variation of the fifth lumbar vertebra in which an enlarged transverse process can form a joint or fusion with the sacrum or ilium. The association of that variant with low back pain and the change in the biomechanical properties of the lumbar spine is called Bertolotti's syndrome. ", 'Radiographic investigation revealed an anomalous enlargement of the left transverse process of the fifth lumbar vertebra forming a pseudarthrosis with the infrajacent ala of the sacrum. ', "Transitional lumbosacral vertebrae and low back pain: diagnostic pitfalls and management of Bertolotti's syndrome.", " Bertolotti's syndrome is a spine disorder characterized by the occurrence of a congenital lumbar transverse mega-apophysis in a transitional vertebral body that usually articulates with the sacrum or the iliac bone. ", 'It is characterized by an enlarged transverse process at the most caudal lumbar vertebra with a pseudoarticulation of the transverse process and the sacral ala. ', "Bertolotti's syndrome is characterised by anomalous enlargement of the transverse process(es) of the most caudal lumbar vertebra which may articulate or fuse with the sacrum or ilium and cause isolated L4/5 disc disease. ", "Case report of surgically treated mechanical low back pain from the facet joint contralateral to a unilateral anomalous lumbosacral articulation (Bertolotti's syndrome). ", "Bertolotti's syndrome is mechanical low back pain associated with these transitional segments.", 'Repeated fluoroscopically guided injections implicated a symptomatic L6-S1 facet joint contralateral to an anomalous lumbosacral articulation. ', "We surgically treated 16 patients with Bertolotti's syndrome (chronic, persistent low back pain and radiographically diagnosed transitional lumbar vertebra).", 'Transitional vertebrae of the lumbar spine.', "Bertolotti's syndrome refers to the association of back pain with lumbosacral transitional vertebrae. "]

["Lumbosacral vertebral region is implicated in the Bertolotti's syndrome. Lumbosacral transitional vertebra is an anatomical variation of the fifth lumbar vertebra in which an enlarged transverse process can form a joint or fusion with the sacrum or ilium. Patients often complain of intractable sciatica that arises from impingement of the nerve root extraforaminally by compression caused by the enlarged transverse process."]

['lumbosacral']

Are piRNAs involved in gene silencing?

['In Drosophila ovaries, the nuclear Piwi protein is required for transcriptional silencing of transposons, though the precise mechanisms by which this occurs are unknown.', 'Here we show that the CG9754 protein is a component of Piwi complexes that functions downstream of Piwi and its binding partner, Asterix, in transcriptional silencing. Enforced tethering of CG9754 to nascent messenger RNA transcripts causes cotranscriptional silencing of the source locus and the deposition of repressive chromatin marks.', 'We have named CG9754 "Panoramix," and we propose that this protein could act as an adaptor, scaffolding interactions between the piRNA pathway and the general silencing machinery that it recruits to enforce transcriptional repression.', 'piRNA-guided slicing of transposon transcripts enforces their transcriptional silencing via specifying the nuclear piRNA repertoire', 'Caenorhabditis elegans piRNAs interact with both transposon and nontransposon mRNAs to initiate sustained silencing via the RNAi pathway.', 'To assess the dysregulation of gene silencing caused by lack of piRNAs, we restored RNA silencing in RNAi-defective animals in the presence or absence of piRNAs.', 'Thus, by reanimating RNAi, we uncovered a role for piRNAs in protecting essential genes from RNA silencing.', 'In different organisms, small RNAs were shown to be implicated in the posttranscriptional degradation of mRNA and/or transcriptional repression of the homologous locus. In Drosophila, the mechanism of piRNA-mediated silencing is still far from being understood', 'Analyses of piRNA-mediated transcriptional transposon silencing in Drosophila', 'Transcriptional silencing implies a piRNA-mediated formation of repressive chromatin which diminishes the transcriptional capacity of the target locus.', 'In mice, piRNA-guided transposon repression correlates with establishment of CpG DNA methylation on their sequences, yet the mechanism and the spectrum of genomic targets of piRNA silencing are unknown', 'Using a candidate gene KD-approach, we identified differences in the spatio-temporal requirements of the piRNA pathway components for piRNA-mediated silencing.', 'Spatio-temporal requirements for transposable element piRNA-mediated silencing during Drosophila oogenesis', 'In contrast, piRNA-mediated silencing is strong in germline stem cells in which TE mobilization is tightly repressed ensuring the continued production of viable germline cysts.', 'Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state.', 'In germ cells, early embryos, and stem cells of animals, PIWI-interacting RNAs (piRNAs) have an important role in silencing retrotransposons, which are vicious genomic parasites, through transcriptional and post-transcriptional mechanisms.', 'Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons.', ' Our observations confirm the pivotal role of piRNA-mediated silencing in defending the genome against selfish transposition, yet also suggest limits to the optimization of host genome defense.', 'Analysis of piRNA-mediated silencing of active TEs in Drosophila melanogaster suggests limits on the evolution of host genome defense', 'The Piwi-interacting RNA (piRNA) pathway defends animal genomes against the harmful consequences of transposable element (TE) infection by imposing small-RNA-mediated silencing.', 'A novel organelle, the piNG-body, in the nuage of Drosophila male germ cells is associated with piRNA-mediated gene silencing.', 'Proteins of the PIWI subfamily Aub and AGO3 associated with the germline-specific perinuclear granules (nuage) are involved in the silencing of retrotransposons and other selfish repetitive elements in the Drosophila genome. ', 'Telomeric retroelements HeT-A, TART and TAHRE, which are involved in telomere maintenance in Drosophila, are also the targets of piRNA-mediated silencing', 'Mechanism of the piRNA-mediated silencing of Drosophila telomeric retrotransposons.', 'Gene silencing mechanisms mediated by Aubergine piRNA complexes in Drosophila male gonad.', 'The epigenetic trans-silencing effect in Drosophila involves maternally-transmitted small RNAs whose production depends on the piRNA pathway and HP1.', 'Here, we show that mutations in squash and zucchini, which are involved in the piwi-interacting RNA (piRNA) silencing pathway, strongly affect TSE', 'MVH in piRNA processing and gene silencing of retrotransposons', 'piRNA-mediated silencing in Drosophila germlines.', 'These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility.', 'The most abundant piRNAs were those corresponding to antisense transcripts of Suppressor of Stellate [Su(Ste)] genes known to be involved in Stellate gene silencing', 'To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation', 'PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression', 'The piNG-body contains ribonucleoprotein complexes involved in piRNA-silencing of genome repeats including transposons in premeiotic spermatocytes with aid of short piRNAs', 'Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons', 'Recent studies have revealed not only the biogenesis of piRNAs and their roles in transposon silencing, but also the function of the Piwi-piRNA pathway in epigenetic and post-transcriptional regulation of gene expression', 'A growing number of studies on piRNAs have investigated piRNA-mediated gene silencing, including piRNA biogenesis', 'These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility', 'Telomeric retroelements HeT-A, TART and TAHRE, which are involved in telomere maintenance in Drosophila, are also the targets of piRNA-mediated silencing. ', 'MVH in piRNA processing and gene silencing of retrotransposons.', 'To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation. ', 'Therefore piRNA-mediated transcriptional mode of silencing is involved in the control of retrotransposon expression in the Drosophila germline.', 'Panoramix enforces piRNA-dependent cotranscriptional silencing.', 'The most abundant piRNAs were those corresponding to antisense transcripts of Suppressor of Stellate [Su(Ste)] genes known to be involved in Stellate gene silencing.', 'Our results indicate that piRNAs are involved in a posttranscriptional gene-silencing mechanism resulting in RNA nuclear accumulation.']

['Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. piRNA-guided slicing of transposon transcripts enforces their transcriptional silencing via specifying the nuclear piRNA repertoire. Transcriptional silencing implies a piRNA-mediated formation of repressive chromatin which diminishes the transcriptional capacity of the target locus.']

['yes']

What is the Orco protein in mosquitos?

['Insect odorant receptors function as heteromeric odorant-gated cation channels comprising a conventional odorant-sensitive tuning receptor, and a conserved co-receptor (Orco)', 'Insects sense odours via several chemosensory receptor families, including the odorant receptors (ORs), membrane proteins that form heteromeric odour-gated ion channels comprising a variable ligand-selective subunit and an obligate co-receptor called Orco', 'Surprisingly, mutation of the obligate olfactory coreceptor (Orco) does not abolish CO(2) aversion during walking yet eliminates CO(2) tracking in flight. ', ' Most odors are detected via a family of odorant receptors (ORs), which form heteromeric complexes consisting of a well-conserved OR co-receptor (Orco) ion channel and a non-conserved tuning OR that provides coding specificity to each complex. Orco functions as a non-selective cation channel and is expressed in the majority of olfactory receptor neurons (ORNs). ', 'a novel OR co-receptor (Orco)', 'In insects, odor cues are discriminated through a divergent family of odorant receptors (ORs). A functional OR complex consists of both a conventional odorant-binding OR and a nonconventional coreceptor (Orco) that is highly conserved across insect taxa. ', 'Insect odorant receptors (ORs) function as odorant-gated ion channels consisting of a conventional, odorant-binding OR and the Orco coreceptor. ']

['Odorant co-receptor.']

[]

List fish anti-freeze proteins.

['the anti-freeze glycoprotein of Antarctic and Arctic notothenoids, ', 'pe III anti-freeze protein (AFP)', 'AFP I or AFP III', 'type III anti-freeze proteins ', 'wild type III thermal hysteresis protein', 'Thermal hysteresis proteins (THPs) have been found in vertebrates, invertebrates, plants, bacteria and fungi and are able to depress the freezing point of water (in the presence of ice crystals) in a non-colligative manner by binding to the surface of nascent ice crystals', 'skin-type anti-freeze protein-3']

['AFP-I\nAFP-II\nAFP-III\nAnti-freeze glycoprotein\nThermal hysteresis protein']

['anti-freeze protein-3', 'AFP-III', 'anti-freeze glycoprotein', 'Thermal hysteresis protein', 'AFP-I', 'AFP-II']

What is the role of probiotics in gastrointestinal disease?

['The overall response rate was 80.5%, of which 69.5% of respondents said they recommended or prescribed probiotic food supplements to their patients, including 53.4% of surgeons and 80.8% of gastroenterologists (P = 0.00013). The most popular probiotic supplements among surgeons were probiotic-containing yoghurt and drinks (79.5% and 71.8%, respectively), whereas VSL#3 was more popular with gastroenterologists (83.3%). The most popular indications were irritable bowel syndrome (70.7% of prescribers) and pouchitis (67.5% of prescribers). Many respondents prescribed long-term probiotics.', 'Current evidence indicates that probiotic effects are strain-specific, they do not act through the same mechanisms, and nor are all probiotics indicated for the same health conditions. However, they do share several common features in that they exert anti-inflammatory effects, they employ different strategies to antagonize competing microorganisms, and they induce cytoprotective changes in the host either through enhancement of barrier function, or through the upregulation of cytoprotective host proteins.', 'Most surveyed physicians recommended probiotics for irritable bowel syndrome, antibiotic, and Clostridium difficile-associated diarrhea because they believed that the literature supports their usage for these conditions.', 'This study suggests most gastrointestinal disease specialists recognize a role for and have used probiotics as part of their therapeutic armamentarium', 'probiotics for these patients with small bowel bacterial overgrowth, inflammatory bowel disease, and radiation enteritis.', 'These results provide some evidence that viable Bifidobacterium lactis strain Bb 12, added to an acidified infant formula, has some protective effect against acute diarrhea in healthy children.', 'Probiotics are live, microbial food supplements that benefit the host animal by improving intestinal microbial balance. Their major role in preventing and treating gastrointestinal disease appears to be from their effect on the immune process, protection against abnormal invasive bacteria, and in the production of short-chain fatty acids from starch and non-starch polysaccharides.']

['Probiotics are live, microbial food supplements that benefit the host animal by improving intestinal microbial balance. Across all 11 probiotic species and eight different gastrointestinal diseases - Irritable Bowel Syndrome (IBS), Helicobacter pylori infection (HPP), Necrotizing Enterocolitis (NEC), Pouchitis (Pouch), Antibiotic Associated diarrhea (AAD), Clostridium difficile Disease (CDD), Infectious diarrhea (ID), and Travellers diarrhea (TD) - probiotics have been shown to have effect on prevention and treatment of gastrointestinal disease through enhancing the immune response, protection against abnormal invasive bacteria. Probiotics have a role in all age groups, incl. infants.']

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Does the TOP2B/TOP2A expression ratio affect the response to AML chemotherapy?

['High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia', 'Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.', 'Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy.', 'Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005)', 'High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia.', 'Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005).Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype', 'CONCLUSION: Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.', 'Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype..', 'High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia.', 'Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005).', 'Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy.']

['High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.', 'High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia. Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype. Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy. Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005). ', 'Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005). Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.', 'among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the top2b/top2a ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (hr, 0.24; p=0.002) and overall survival (hr, 0.29; p=0.005).', 'yes', 'Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy. Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.', 'High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia']

['yes']

Which enzymes synthesize catecholamines in adrenal glands?

['We analyzed the mRNA levels of catecholamine-synthesizing enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AAAD), dopamine-β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in adrenal glands of 18 pigs with chronic systolic non-ischaemic HF (tachycardia-induced cardiomyopathy due to right ventricle pacing) and 6 sham-operated controls.', 'This study aimed to investigate physical exercise-related changes in gene expression of catecholamine biosynthetic enzymes (tyrosine hydroxylase, dopamine-ß-hydroxylase and phenylethanolamine N-methyltransferase) and cyclic adenosine monophosphate response element-binding (CREB) in the adrenal medulla, concentrations of catecholamines and corticosterone (CORT) in the plasma and the weight of adrenal glands of chronically psychosocially stressed adult rats exposed daily to 20 min treadmill running for 12 weeks. ', 'In the adrenal medulla, despite the absence of morphological changes, immunohistochemistry for tyrosine hydroxylase, dopamine β-hydroxylase and phenyl-ethanolamine-N-methyltransferase demonstrated an increased immunopositivity for these cathecolamine-synthesizing enzymes after intense exercise. ', 'Using isolated adrenal medulla we observed no difference in basal catecholamine secretion percentile between obese and lean animals. However, the percentile of catecholamine secretion stimulated by high K+ concentration was lower in the obese group. There was a decrease in the tyrosine hydroxylase enzyme expression (57.3%, P<0.004) in adrenal glands of obese mice. Interestingly, the expression of dopamine beta-hydroxylase was also reduced (47.0%, P<0.005). Phenylethanolamine N-methyltransferase expression was not affected. ', 'Differential housing (single vs. group) and social defeat of rats is known to alter the activity of catecholamine-synthesizing enzymes in the medulla. The present studies examined the effect of 70 days of triad (3 rats per large cage) and individual housing of male rats on adrenal mRNA levels of tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) and on TH protein levels.', 'As a first step toward understanding the molecular mechanisms by which catecholamine synthesis is controlled in the tumor, we measured the levels of mRNA coding for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and catecholamines in 6 pheochromocytomas and 2 normal adrenal glands. ', 'We also examined the gene expression of the messengers of other catecholamine synthesizing enzymes, dopamine beta-hydroxylase (DBH) and aromatic 1-amino acid decarboxylase (AADC) in pheochromocytomas. ', 'These findings indicate that catecholamine overproduction in pheochromocytomas is mediated by the overexpression of genes coding for catecholamines synthesizing enzymes, TH, DBH, and AADC.', 'he present study investigated the cellular localization of 3 catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) ', 'tyrosine hydroxylase (TH) the rate limiting catecholamine biosynthetic enzyme and also of dopamine beta-hydroxylase (DBH)', 'tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) in sympathetic ganglia and adrenals', 'This study aimed to investigate physical exercise-related changes in gene expression of catecholamine biosynthetic enzymes (tyrosine hydroxylase, dopamine-ß-hydroxylase and phenylethanolamine N-methyltransferase) and cyclic adenosine monophosphate response element-binding (CREB) in the adrenal medulla, concentrations of catecholamines and corticosterone (CORT) in the plasma and the weight of adrenal glands of chronically psychosocially stressed adult rats exposed daily to 20 min treadmill running for 12 weeks', 'As a first step toward understanding the molecular mechanisms by which catecholamine synthesis is controlled in the tumor, we measured the levels of mRNA coding for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and catecholamines in 6 pheochromocytomas and 2 normal adrenal glands', 'We analyzed the mRNA levels of catecholamine-synthesizing enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AAAD), dopamine-β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in adrenal glands of 18 pigs with chronic systolic non-ischaemic HF (tachycardia-induced cardiomyopathy due to right ventricle pacing) and 6 sham-operated controls', 'This study aimed to investigate physical exercise-related changes in gene expression of catecholamine biosynthetic enzymes (tyrosine hydroxylase, dopamine-ß-hydroxylase and phenylethanolamine N-methyltransferase) and cyclic adenosine monophosphate response element-binding (CREB) in the adrenal medulla, concentrations of catecholamines and corticosterone (CORT) in the plasma and the weight of adrenal glands of chronically psychosocially stressed adult rats exposed daily to 20 min treadmill running for 12 weeks.', 'We used immunocytochemistry to study the ontogeny of leu-enkephalin and the catecholamine-synthesizing enzymes dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase in adjacent sections of 14 fetal rhesus and 31 fetal human adrenal glands.', 'As a first step toward understanding the molecular mechanisms by which catecholamine synthesis is controlled in the tumor, we measured the levels of mRNA coding for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and catecholamines in 6 pheochromocytomas and 2 normal adrenal glands.']

['The enzymes that synthesize catecholamines in adrenal glands are:\n1) Tyrosine Hydroxylase (TH)\n2) Aromatic L-amino acid decarboxylase (AAAD)\n3) Dopamine β-hydroxylase (DBH)\n4) Phenylethanolamine N-methyltransferase (PNMT)']

['Tyrosine Hydroxylase', 'TH', 'Aromatic L-amino acid decarboxylase', 'AAAD', 'AADC', 'DDC', 'Dopamine β-hydroxylase', 'DBH', 'Phenylethanolamine N-methyltransferase', 'PNMT']

What is the role of phycoerythrin as a major light-harvesting pigment in red algae and cyanobacteria?

['["An extensive range of pigments including phycobiliproteins are present in algae. C-phycocyanin (C-PC), a phycobiliprotein, is one of the key pigments of Spirulina", "Spirulina platensis produces nutraceutical product C-phycocyanin (C-PC)", "C-Phycocyanin (C-Pc) is one of the major biliprotein pigments of unicellular cyanbacterium of Spirulina platenesis", "Marine Synechococcus owe their specific vivid color (ranging from blue-green to orange) to their large extrinsic antenna complexes called phycobilisomes, comprising a central allophycocyanin core and rods of variable phycobiliprotein composition.", "Three major pigment types can be defined depending on the major phycobiliprotein found in the rods (phycocyanin, phycoerythrin I or phycoerythrin II)", "Phycocyanin--a major phycobiliprotein constitutively produced by many cyanobacteria--", "R-phycoerythrin was isolated and purified from a red alga, Polysiphonia urceolata Grev", "C-phycocyanin (C-PC), one of the major phycobiliproteins of Spirulina platensis (a blue-green alga)", "C-Phycocyanin (C-PC), the major light harvesting biliprotein from Spirulina platensis is of greater importance because of its various biological and pharmacological properties.", "B-Phycoerythrin (B-PE) is a major light-harvesting pigment of microalgae.", "Phycoerythrin is a major light-harvesting pigment of red algae and cyanobacteria that is widely used as a fluorescent probe and analytical reagent. In this paper, B-phycoerythrin and R-phycocyanin in native state, from the red alga Porphyridium cruentum were obtained by an inexpensive and simple process.", "Phycobiliproteins are derived from the photosynthetic apparatus of cyanobacteria and eukaryotic algae.", "the three major phycobiliprotein types, namely allophycocyanin, phycocyanin, and phycoerythrin", "Phycoerythrin is a major light-harvesting pigment of red algae and cyanobacteria widely used as a fluorescent probe.", "allophycocyanin (APC)", "R-phycoerythrin is the major light-harvesting pigment protein of most red algal phycobilisomes.", "The purified protein had three absorption peaks at 498, 535, and 565 nm and displayed a fluorescence maximum at 580 nm, which was consistent with the typical spectrum of R-phycoerythrin. The purified R-PE was also identified with electrophoresis.", "Phycobilisomes, the major light-harvesting complexes of cyanobacteria are multimolecular structures made up of chromophoric proteins called phycobiliproteins and non chromophoric linker polypeptides.", "We report here the isolation and nucleotide sequence of the genes, cpeA and cpeB, which in Calothrix PCC 7601 encode the alpha and beta subunits of phycoerythrin, one of the major phycobiliproteins.", "The major light-harvesting complex in eukaryotic red algae and prokaryotic cyanobacteria is the phycobilisome, a water-soluble complex located on the outer surface of the photosynthetic membranes and composed of both pigmented phycobiliproteins (85%) and non-pigmented linker (15%) polypeptides.", "Phycocyanin is a major protein produced by cyanobacteria, but very few phycocyanin-producing strains have been reported.", "In the present work, phycocyanin (PC) and phycoerythrin (PE) from a Nostoc species are proposed as protein markers for electrophoretic techniques.", "Rod structure of a phycoerythrin II-containing phycobilisome. I. Organization and sequence of the gene cluster encoding the major phycobiliprotein rod components in the genome of marine Synechococcus sp. WH8020.", "We now present data showing that the allophycocyanin genes and a second set of phycocyanin genes are transcribed into major mRNAs of 1400 and 1600 bases, respectively",']

Phycoerythrin is a major light-harvesting pigment of red algae and cyanobacteria that is widely used as a fluorescent probe and analytical reagent.

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Can mutations in Calmodulin cause ventricular fibrillation?

['We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without ECG or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another two were resuscitated from out-of-hospital cardiac arrest with documented VF at age 10 and 16, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.Phe90Leu) in the CALM1 gene encoding calmodulin. This mutation was also carried by one of the sibs who died suddenly, for whom DNA was available. The mutation was present in the mother and in an sibling, both asymptomatic but displaying a marginally prolonged QT-interval during exercise. CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that Phe90 mediates the direct interaction of CaM with target peptides', "Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. "]

['Yes, mutations in CALM underly IVF manifesting in childhood and adolescence.']

['yes']

Is low T3 syndrome related with high BNP in cardiac patients?

['BNP and fT3 are independently associated with exercise capacity in severely compromised HF patients.', 'fter adjustment for known confounders, NT-pro-BNP was significantly associated with fT3 and low-T3 syndrome. fT3 (HR 0.58, 95%CI 0.34-0.98) and low-T3 syndrome (HR 3.0, 95%CI 1.4-6.3) were predictive for mortality after adjustment for NT-pro-BNP levels and other cardiovascular prognostic variables.', 'fT3 and low-T3 syndrome are significantly related to NT-pro-BNP in patients with cardiovascular disease, but are predictors of mortality independently of NT-pro-BNP and other known cardiovascular risk parameters.', 'Higher NT-pro BNP concentrations were related to lower total T3 concentrations (r = -0.294, p = 0.011) and to higher reverse T3 concentrations (r = 0.353, p = 0.002)']

['BNP and fT3 are independently associated in severely compromised HF patients.\nNT-pro-BNP was significantly associated with low-T3 syndrome in cardiac patients.\nHigher NT-pro BNP concentrations are related to lower total T3 concentrations in cardiac patients']

['yes']

What is a benefit of being g6PD-deficient?

['A central position of the PPP for malaria parasites is supported by the fact that human G6PD deficiency protects to a certain degree from malaria infections.', ' The beneficial effect of thalassemia minor, sickle-cell trait, and glucose-6-phosphate dehydrogenase deficiency on survival of malaria infection may well be due to the shared feature of enhanced oxidative stress. This may inhibit parasite growth, enhance uptake of infected RBCs by spleen macrophages, and/or cause less cytoadherence of the infected cells to capillary endothelium.', ' In conclusion, genetic variants that confer resistance to malaria are associated with RBC traits in African-Americans.', ' G6PD deficiency has been positively selected by malaria, and recent knowledge seems to show that it also confers an advantage against the development of cancer, reduces the risk of coronary diseases and has a beneficial effect in terms of longevity.', 'G6PD enzyme activity was directly related to susceptibility to malaria in the Brazilian Amazon, where P. vivax predominates. Severe G6PDd was associated with considerable higher risk of malaria-related transfusions.', 'and G6PD (Xq28)-were associated (P ≤ 1 × 10(-6)) with RBC traits in the discovery cohort']

['Increased resistance to malaria, reduces the risk of coronary diseases, beneficial effect in terms of longevity']

['There is evidence of increased resistance to malaria.']

Which extra thyroid tissues have thyrotropin (TSH) receptors?

['GD orbital fibroblasts, which comprise a mixture of CD34(+) and CD34(-) cells, express much lower levels of Tg and TSHR', 'Previously, we found that CD34(+) progenitor cells, known as fibrocytes, express functional TSHR, infiltrate the orbit, and comprise a large subset of orbital fibroblasts in TAO. ', 'TSH induced lipolysis in adipose tissues.', 'TSH worked as a lipolytic factor in white adipose tissues,', 'These fibrocytes infiltrate orbital connective tissues in thyroid-associated ophthalmopathy and express functional TSH receptor (TSHR). ', 'TSHR levels are higher than those in orbital fibroblasts.']

['TSH receptors are expressed also in extrathyroid tissues. TSH receptors seem to be functional. Extrathyroid tissues include fibrobasts of the orbit and adipose tissue\nThe principal tissues with TSH receptors are:\nadippose tissue\n orbital fibrotic tissue']

['adipose tissue', 'fibrotic tissue']

Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?

["Nestin is a unique intermediate filament protein. While it is robustly expressed in developing brain, postnatal expression is limited to the brain's subventricular zone (SVZ)", 'nestin, a marker protein for precursor cells in the subventricular zone', 'adult subventricular zone (SVZ) stem and progenitor cells express nestin', 'the typical protein of neural progenitors, nestin', 'the nonspecific precursor cell marker Nestin', 'In the subventricular zone, this effect was exerted selectively on a precursor subpopulation expressing nestin but not neuronal or glial cell-specific proteins.', 'Nestin is an intermediate filament protein expressed in neuroepithelial stem cells during development and it is later replaced by cell specific neuronal or glial filaments.', 'The results indicate that administration of thyroid hormone and retinoic acid increases the expression of Ki67, a nuclear antigen associated with cell proliferation, and of nestin, a marker protein for precursor cells in the subventricular zone of adult male rats.', 'Only a minority of stem cells expressed nestin, a marker for neural precursor cells.', 'In addition, bone marrow transplantation promoted proliferation of ependymal and subependymal cells, identified by nestin (a neuroepithelial stem cell marker), within the ventricular zone and subventricular zone (VZ/SVZ).', 'The results indicate that administration of thyroid hormone and retinoic acid increases the expression of Ki67, a nuclear antigen associated with cell proliferation, and of nestin, a marker protein for precursor cells in the subventricular zone of adult male rats', 'In all animals, 20-40% of the newly generated cells in the dentate gyrus and subventricular zone expressed the neural progenitor cell markers Musashi1 or Nestin']

["Nestin can be used as a nonspecific marker protein for precursor cells in the subventricular zone (SVZ). Nestin is a unique intermediate filament protein. While it is robustly expressed in developing brain, postnatal expression is limited to the brain's SVZ."]

['Nestin']

Has protein citrullination been implicated in rheumatoid arthritis?

[': Citrullination has become a hot topic within recent years due to its involvement in diseases such as rheumatoid arthritis (RA), multiple sclerosis and fibrosis. ', 'Current literature suggests that increased levels of citrullinated proteins are found in several if not all inflammatory diseases. ', 'Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing RA. ', 'Citrullination of proteins is well described in rheumatoid arthritis (RA), and hypercitrullination of proteins may be related to inflammation in general. ', 'Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. ', 'Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide autoantibodies (ACPAs). ', 'Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment.', 'The implications of citrullination affecting integrin binding in disease open up a new area of study and might have implications for the pathogenesis of inflammatory diseases like rheumatoid arthritis and periodontitis.', 'In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation.', 'Citrullinated collagen II (CII) is a well-known autoantigen in rheumatoid arthritis (RA). ', 'Among the RA-associated autoantibodies, especially anti-citrullinated protein antibodies (ACPAs) have been studied intensively in the last decade.', 'Protein citrullination is a posttranslational modification that has attracted increased attention, especially for its involvement in rheumatoid arthritis (RA).', 'Identification of citrullinated cellular fibronectin in synovial fluid from patients with rheumatoid arthritis.', 'Cellular fibronectin (cFn) has been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously demonstrated the presence of citrullinated cFn in rheumatoid synovial tissues. ', '. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ']

['Yes, protein citrullination been implicated in rheumatoid arthritis.']

['yes']

Do patients with Pendred syndrome present congenital deafness?

['Pendred Syndrome can be characterized by the triad composed of familial goitre, abnormal perchlorate discharge and congenital deafness.', 'Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and goiter. ', 'Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. ', 'The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients.', 'Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and goiter.', 'Pendred syndrome is the autosomal recessively transmitted association of familial goiter and congenital deafness.', 'Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect.', 'Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre.', 'Pendred syndrome, a common autosomal-recessive disorder characterized by congenital deafness and goiter, is caused by mutations of SLC26A4, which codes for pendrin.', 'These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.', 'Mutations in the Pendred syndrome gene have been observed in patients with deafness and vestibular aqueduct dilatation, in the absence of other Pendred syndrome features.', "The occurrence of congenital deafness, mutism and goitre unassociated with cretinism or mental retardation in euthyroid patients is known as Pendred's Syndrome.", "The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification.", "Pendred's syndrome is an autosomal recessive disease characterized by goiter, impaired iodide organification, and congenital sensorineural deafness.", 'Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goiter, and impaired iodide organification.', "Pendred's syndrome is manifested by congenital sensorineural deafness in association with familial goiter due to defective organic binding of iodine in the thyroid gland.", 'Although the textbook view of the Pendred syndrome is that of an autosomal recessive condition characterised by deafness and goitre, it is increasingly clear that not all patients present this classical clinical description.', "Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness.", 'Pendred syndrome comprises the association of severe congenital sensorineural deafness with thyroid pathology.', 'The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present.', 'Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter.', 'Pendred syndrome and non-syndromic recessive deafness associated with enlarged vestibular aqueduct (NSRD with EVA) are caused by mutations in the SLC26A4 (PDS) gene.', 'Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. ', "The occurrence of congenital deafness, mutism and goitre unassociated with cretinism or mental retardation in euthyroid patients is known as Pendred's Syndrome. ", 'The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. ', 'The discovery of mutations in the SLC26A4 gene in patients with Pendred syndrome (congenital deafness, goiter, and defective iodide organification) suggested a possible role for the encoded protein, pendrin, as an apical iodide transporter. ', 'Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. ', 'Pendred&apos;s syndrome is manifested by congenital sensorineural deafness in association with familial goiter due to defective organic binding of iodine in the thyroid gland. The majority of patients with Pendred&apos;s syndrome are euthyroid. We report on an unusual case of a patient with Pendred&apos;s syndrome presenting with amenorrhea and late-onset hypothyroidism.', ' Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome.', 'The occurrence of congenital deafness, mutism and goitre unassociated with cretinism or mental retardation in euthyroid patients is known as Pendred&apos;s Syndrome. It has been estimated that 4-10 % of children with congenital deafness suffer from this condition.', 'Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome. Since this is the most common radiological malformation of the cochlea in deaf patients, we investigated what proportion of such cases were due to mutation of the PDS gene.', 'Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome.']

['Congenital deafness is one of the characteristics of Pendred syndrome patients.']

['yes']

Are there transposon-free regions in mammalian genomes?

['Transposon-free regions in mammalian genomes.', 'Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length. The majority of human TFRs correlate with orthologous TFRs in the mouse, despite the fact that most transposons are lineage specific. Many human TFRs also overlap with orthologous TFRs in the marsupial opossum, indicating that these regions have remained refractory to transposon insertion for long evolutionary periods. Over 90% of the bases covered by TFRs are noncoding, much of which is not highly conserved. Most TFRs are not associated with unusual nucleotide composition, but are significantly associated with genes encoding developmental regulators, suggesting that they represent extended regions of regulatory information that are largely unable to tolerate insertions, a conclusion difficult to reconcile with current conceptions of gene regulation.', 'All three elements insert only rarely within many Polycomb-regulated regions, a property that may contribute to the origin of "transposon-free regions" (TFRs) in metazoan genomes.', 'Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length.', 'RESULTS: Here we report that transposon-free regions (TFRs) are prominent genomic features of amphibian and fish lineages, and that many have been maintained throughout vertebrate evolution, although most transposon-derived sequences have entered these lineages after their divergence. ', 'Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length. ', 'All three elements insert only rarely within many Polycomb-regulated regions, a property that may contribute to the origin of "transposon-free regions" (TFRs) in metazoan genomes. ', 'Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length.', 'Here we report that transposon-free regions (TFRs) are prominent genomic features of amphibian and fish lineages, and that many have been maintained throughout vertebrate evolution, although most transposon-derived sequences have entered these lineages after their divergence.']

['Yes. Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length. The majority of human TFRs correlate with orthologous TFRs in the mouse, despite the fact that most transposons are lineage specific. Many human TFRs also overlap with orthologous TFRs in the marsupial opossum, indicating that these regions have remained refractory to transposon insertion for long evolutionary periods. Over 90% of the bases covered by TFRs are noncoding, much of which is not highly conserved. Most TFRs are not associated with unusual nucleotide composition, but are significantly associated with genes encoding developmental regulators, suggesting that they represent extended regions of regulatory information that are largely unable to tolerate insertions, a conclusion difficult to reconcile with current conceptions of gene regulation.']

['yes']

How do autoantibodies affect ion channels in LES and SCLC?

['["The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to inhibit ICa and INa in bovine adrenal chromaffin cells, also significantly inhibited INa in SCLC cells.", "These results indicate that (i) action potentials in human SCLC cells result from the regenerative increase in voltage-gated Na+ channel conductance; (ii) fundamental characteristics of SCLC Na+ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na+ channels are an additional target of the pathological IgG present in the patients\' sera.", "Clinical features were those of LES and occurred insidiously in this 68-year old man: proximal weakness predominant in the lower limbs, generalized areflexia, dryness of the mouth and partial right eye palsy. Investigations disclosed a small cell lung cancer.", "Voltage-gated Ca2+ channels may be important to the secretion of ectopic hormones and the etiology and pathogenesis of Lambert-Eaton syndrome, an autoimmune disorder of the motor nerve terminal in which autoantibodies directed against voltage-gated Ca2+ channels are produced.", "Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin which is often associated with anaplastic small-cell lung cancer.", "Small-cell lung cancer (SCLC) is the most common cause of LES.", "We report an unusual case of LES associated with large-cell neuroendocrine carcinoma (LCNEC) of the lung.", "The Lambert-Eaton syndrome is caused by antibodies against voltage-gated calcium channels and often occurs in patients with small cell lung cancer.", "A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma.", "LEMS is generally associated with small cell lung cancer occurring in three percent of cases.", "However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition.", "LEMS has a high degree of coincidence (approximately 60%) with small cell lung cancer; the remaining 40% of patients with LEMS have no detectable tumor.", "BACKGROUND: To enhance the acknowledgement of Lambert-Eaton syndrome in patients with small cell lung cancer.", "There were 10 cases of Lambert-Eaton syndrome in 332 pathologically diagnosed small cell lung cancer", "Treatment of small cell lung cancer may improve the symptoms of Lambert-Eaton syndrome", "Improving the recognition of Lambert-Eaton syndrome may be helpful to identify early small cell lung cancer and improve the prognosis,as the symptom of muscular weakness usually appears early before the diagnosis of small cell lung cancer.", "The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer.", "Paraneoplastic Lambert-Eaton myasthenia syndrome is presented in two cases with small cell lung cancer.", "Human small-cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired.", "Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder caused by an IgG-mediated reduction in number of presynaptic voltage-gated calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, the stimulus for antibody production may be VGCC on small cell lung cancer (SCLC)", "Also, there was no obvious band pattern distinguishing patients with LES from those with LES and concurrent SCLC.", "The cancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and epidermoid lung carcinoma in 3 cases.", "Etiology of this disease is uncertain but in view of its frequent association with small cell lung cancer, this specific type of neoplasm may be implicated in the initiation of autoimmune response.", "Recent studies indeed support the possibility that the antigenic stimulus in the neoplastic form of LES may arise from voltage-dependent Ca2+ channels found in the lung cancer cells.", "In the majority of LEMS patients, those having detectable tumor, the disease is thought to occur as a result of immune response', '["The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to inhibit ICa and INa in bovine adrenal chromaffin cells, also significantly inhibited INa in SCLC cells.", "These results indicate that (i) action potentials in human SCLC cells result from the regenerative increase in voltage-gated Na+ channel conductance; (ii) fundamental characteristics of SCLC Na+ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na+ channels are an additional target of the pathological IgG present in the patients\' sera.", "Clinical features were those of LES and occurred insidiously in this 68-year old man: proximal weakness predominant in the lower limbs, generalized areflexia, dryness of the mouth and partial right eye palsy. Investigations disclosed a small cell lung cancer.", "Voltage-gated Ca2+ channels may be important to the secretion of ectopic hormones and the etiology and pathogenesis of Lambert-Eaton syndrome, an autoimmune disorder of the motor nerve terminal in which autoantibodies directed against voltage-gated Ca2+ channels are produced.", "Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin which is often associated with anaplastic small-cell lung cancer.", "Small-cell lung cancer (SCLC) is the most common cause of LES.", "We report an unusual case of LES associated with large-cell neuroendocrine carcinoma (LCNEC) of the lung.", "The Lambert-Eaton syndrome is caused by antibodies against voltage-gated calcium channels and often occurs in patients with small cell lung cancer.", "A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma.", "LEMS is generally associated with small cell lung cancer occurring in three percent of cases.", "However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition.", "LEMS has a high degree of coincidence (approximately 60%) with small cell lung cancer; the remaining 40% of patients with LEMS have no detectable tumor.", "BACKGROUND: To enhance the acknowledgement of Lambert-Eaton syndrome in patients with small cell lung cancer.", "There were 10 cases of Lambert-Eaton syndrome in 332 pathologically diagnosed small cell lung cancer", "Treatment of small cell lung cancer may improve the symptoms of Lambert-Eaton syndrome", "Improving the recognition of Lambert-Eaton syndrome may be helpful to identify early small cell lung cancer and improve the prognosis,as the symptom of muscular weakness usually appears early before the diagnosis of small cell lung cancer.", "The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer.", "Paraneoplastic Lambert-Eaton myasthenia syndrome is presented in two cases with small cell lung cancer.", "Human small-cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired.", "Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder caused by an IgG-mediated reduction in number of presynaptic voltage-gated calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, the stimulus for antibody production may be VGCC on small cell lung cancer (SCLC)", "Also, there was no obvious band pattern distinguishing patients with LES from those with LES and concurrent SCLC.", "The cancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and epidermoid lung carcinoma in 3 cases.", "Etiology of this disease is uncertain but in view of its frequent association with small cell lung cancer, this specific type of neoplasm may be implicated in the initiation of autoimmune response.", "Recent studies indeed support the possibility that the antigenic stimulus in the neoplastic form of LES may arise from voltage-dependent Ca2+ channels found in the lung cancer cells.", "In the majority of LEMS patients, those having detectable tumor, the disease is thought to occur as a result of immune response']

The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES) inhibit ICa and INa in bovine adrenal chromaffin cells and significantly inhibit INa in SCLC cells.

[]

Is Titin the largest single protein molecule found in Nature?

['Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly.', 'Titin is the largest protein in mammals; it forms an elastic filament along the myofibril of cardiac and skeletal muscles.', 'Titin is recently known as the largest protein which exists in the striated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions. ', 'Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains.', 'The giant sarcomere protein titin/connectin is the largest protein known to date.', 'Titin is the largest protein known to date and acts as a mechanosensor that regulates muscle protein expression in a sarcomere strain-dependent fashion.', 'Titin is the largest protein known, and is essential for organising muscle sarcomeres.', 'It has many domains with a variety of functions, and stretches from the Z-line to the M-line in the muscle sarcomere. ', 'Titin, is definitely the largest protein in the body, with a molecular weight of 3 million Dalton and composed of 27,000 amino acids.', 'Titin, the largest protein identified to date (over 1 micron long, almost 3 million daltons in mass) is the third most abundant component of the sarcomere.', 'Titin is the largest polypeptide yet described (relative molecular mass approximately 3 x 10(6); refs 1, 2) and an abundant protein of striated muscle.', 'Titin is at present the largest known protein (M(r) 3000 kDa) and its expression is restricted to vertebrate striated muscle.', 'Titin is the largest protein known, and is essential for organising muscle sarcomeres', 'Titin is at present the largest known protein (M(r) 3000 kDa) and its expression is restricted to vertebrate striated muscle', 'Titin is the largest polypeptide yet described (relative molecular mass approximately 3 x 10(6); refs 1, 2) and an abundant protein of striated muscle', 'Titin is recently known as the largest protein which exists in the striated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions', 'Titin, the biggest single (poly) peptide found in humans, and throughout nature so far, was long considered as a good candidate for inherited muscle diseases']

['Titin, is definitely the largest protein in the body, with a molecular weight of 3 million Dalton and composed of 27,000 amino acids. Titin is the largest protein known to date and acts as a mechanosensor that regulates muscle protein expression in a sarcomere strain-dependent fashion.', 'Yes. Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. Titin is recently known as the largest protein which exists in the striated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions.', 'Titin is the largest protein known to date and acts as a mechanosensor that regulates muscle protein expression in a sarcomere strain-dependent fashion.Titin, the largest protein identified to date (over 1 micron long, almost 3 million daltons in mass) is the third most abundant component of the sarcomere.', 'Titin is the largest protein known, and is essential for organising muscle sarcomeres.The giant sarcomere protein titin/connectin is the largest protein known to date.']

['yes']

Does thyroid hormone affect cardiac remodeling ?

['Thyroid hormones exert important effects on heart remodeling through mir-208.', 'RV and RA function and mechanics are significantly affected by SHT. l-T4 therapy and 1-year maintenance of euthyroid status improved but did not completely recover RV and RA function and deformation in the SHT patients, which implies that right heart remodeling caused by SHT is not reversible in a 1-year period.', 'These results suggest that long-term T4 treatment after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.']

['Cardiac function and mechanics are significantly affected by low thyroid function. l-T4 therapy improves but does not completely recover cardiac function in patients with mild hypothyroidism.\nLong-term T4 treatment after myocardial infarction has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.']

['yes']

Which tumor suppressor is referred to as "the guardian of the genome"?

['The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence.', "p53-Based cyclotherapy: exploiting the 'guardian of the genome' to protect normal cells from cytotoxic therapy", 'The tumor suppressor protein p53 has been described "as the guardian of the genome" for its crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, senescence, or apoptosis in response to various stress signals. ', 'the critical tumor suppressor p53, known as the guardian of the genome', 'p53 is well known as the "guardian of the genome" for differentiated and neoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability.', "The classical functions of p53 protein are those related to its role on DNA damage, cell growth arrest, senescence and apoptosis. For this reason it is called 'the guardian of the genome' and is considered one of the most important players in the development of cancer.", 'Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle.', 'The p53 gene is a tumor suppressor gene that acts as "guardian of the genome.', 'Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the "guardian of the genome," is the most frequent event found in 50% of human cancers.', 'The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death.', 'This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the "guardian of the genome.', 'Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome.', 'The tumor suppressor p53 is often referred to as "the guardian of the genome" because of its central role in the cellular response to oncogenic stress and prevention of tumor development.', 'The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death.', 'p53, the guardian of the genome, is the most important tumor suppressor.', 'The tumor suppressor protein p53 is often referred to as the guardian of the genome.', 'The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the "guardian of the genome".', 'The p53 tumor suppressor protein is often referred to as the "guardian of the genome" since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses.', 'Tumor suppressor p53, known as the guardian of the genome, has the ability to prevent the emergence of transformed cells by the induction of cell cycle arrest and apoptosis.', 'Tumor suppressor p53 functions as a "guardian of the genome" to prevent cells from transformation. p53 is constitutively ubiquitinated and degradated in unstressed conditions, thereby suppressing the expression.', 'Commonly referred as a "guardian of the genome", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged.', 'The p53 gene is involved in genome stability and thus is referred to as "the guardian of the genome.', 'p53 has been referred to as the guardian of the genome because of its role in protecting the cell from DNA damage. p53 performs its duties by regulating cell-cycle progression and DNA repair and, in cases of irreparable DNA damage, by executing programmed cell death.', 'The p53 gene has been referred to as the guardian of the genome because it controls apoptosis and cell cycle arrest.', 'The tumor suppressor protein, p53, is often referred to as the guardian of the genome.', 'The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the "guardian of the genome".', 'Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome.', 'Commonly referred as a "guardian of the genome", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged.', 'The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death.', 'p53, sometimes referred to as the "guardian of the genome," helps regulate cell-cycle arrest, DNA-damage repair, apoptosis, and senescence.', 'The tumor suppressor protein p53 is often referred to as the guardian of the genome', 'The p53 tumor suppressor protein is often referred to as the "guardian of the genome" since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses', 'The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the "guardian of the genome"', 'Remarkably, the guardians--p53, p73, and p63--of the genome are in control of most of the known tumor suppressor miRNAs, tumor suppressor genes, and metastasis suppressors by suppressing c-myc through miR-145/let-7/miR-34/TRIM32/PTEN/FBXW7', 'The p53 gene is involved in genome stability and thus is referred to as "the guardian of the genome." To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice', 'The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network.', 'Therefore, while p53 can be rightly defined as the guardian of the genome, we could think of p73 as the "assistant" guardian of the genome!', 'The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death', 'The tumor suppressor protein, p53, is often referred to as the guardian of the genome', 'This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the "guardian of the genome."']

['The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. It plays a crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, DNA repair, angiogenesis, cell senescence, or apoptosis in response to various stress signals, and is considered one of the most important players in the development of cancer. p53 contributes to the maintenance of genomic stability. Thus, p53 has been described as "the guardian of the genome".']

['p53']

Which diseases have been associated with the PTPN22 620W allele?

['The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P\u2009=\u20090.005, χ(2\u2009)=\u20097.858, odds ratio (OR)\u2009=\u20091.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P\u2009=\u20090.00012, χ(2\u2009)=���14.73, OR\u2009=\u20092.31)', 'The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset', "The PTPN22 620W allele is a risk factor for Wegener's granulomatosis", 'Analyses of families with multiple autoimmune disorders have revealed a functional polymorphism, 620W, in the intracellular tyrosine phosphatase gene PTPN22 as a predisposing factor for type 1 diabetes, seropositive rheumatoid arthritis, systemic lupus erythematosus, and Hashimoto thyroiditis, and the presence of the PTPN22 protein appears to herald the development of autoantibodies in these disorders', 'The PTPN22 620W allele frequency was significantly increased in antineutrophil cytoplasmic antibody (ANCA)-positive WG patients compared with healthy controls', 'The PTPN22 620W allele appears to be involved in the pathogenesis of WG, and ANCA positivity seems to be the hallmark', 'Rheumatoid arthritis seropositive for the rheumatoid factor is linked to the protein tyrosine phosphatase nonreceptor 22-620W allele', 'The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes for lymphoid tyrosine phosphatase LYP, involved in the negative regulation of early T-cell activation. An association has recently been reported between the PTPN22-620W functional allele and rheumatoid factor-positive (RF+) rheumatoid arthritis (RA), among other autoimmune diseases', 'A functional variant (R620W) of the intracellular protein tyrosine phosphatase N22 (PTPN22) has now been conclusively shown to confer approximately two-fold risk for seropositive RA as well as several other autoimmune disorders', 'the PTPN22 620W allele associates with multiple autoimmune phenotypes', 'We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis', 'The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT).', 'The risk of developing RA later in life in patients with type 1 DM may be attributed, in part, to the presence of the 620W PTPN22 allele, suggesting that this risk factor may represent a common pathway for the pathogenesis of these 2 diseases.', 'The minor allele of the R620W missense single-nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo.', 'An association has recently been reported between the PTPN22-620W functional allele and rheumatoid factor-positive (RF+) rheumatoid arthritis (RA), among other autoimmune diseases', 'The minor allele of the R620W missense single-nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo', 'The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT)', 'The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT)', 'PTPN22 620W risk allele was associated with ACPA production [odds ratio (OR)\u2009=\u20092.21, 95% CI 1.4, 3.4, P\u2009<\u20090.0001]', 'An association has recently been reported between the PTPN22-620W functional allele and rheumatoid factor-positive (RF+) rheumatoid arthritis (RA), among other autoimmune diseases']

["The functional polymorphism 620W in the intracellular tyrosine phosphatase PTPN22 gene has been shown to confer susceptibility to the development of type 1 diabetes, seropositive rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis, and Wegener's granulomatosis (granulomatosis with polyangiitis)."]

['type 1 diabetes', 'seropositive rheumatoid arthritis', 'systemic lupus erythematosus', 'Hashimoto thyroiditis', "Wegener's granulomatosis (granulomatosis with polyangiitis)"]

What is the use of MammaPrint and Oncotype DX?

['Molecular tests such as the 21 gene expression test (Oncotype DX(TM)) and 70 gene microarray test (MammaPrint(®)) have revolutionized the predictive and prognostic tools in the clinic. By stratifying the risk of recurrence for patients, the tests are able to provide clinicians with more information on the treatment outcomes of using chemotherapy, HER2 targeted therapy or endocrine therapy or the combination of the therapies for patients with particular genetic expressions.', 'Gene expression profiling tests are used in an attempt to determine the right treatment for the right person with early-stage breast cancer that may have spread to nearby lymph nodes but not to distant parts of the body. These new diagnostic approaches are designed to spare people who do not need additional treatment (adjuvant therapy) the side effects of unnecessary treatment, and allow people who may benefit from adjuvant therapy to receive it. In the present review we discuss in detail the major diagnostic tests available such as MammaPrint dx, Oncotype dx, PAM50, Mammostrat, IHC4, MapQuant DX, Theros-Breast Cancer Gene Expression Ratio Assay, and their potential clinical applications.', 'Oncotype DX, PAM50, and MammaPrint are multigene tests that are being used clinically for early-stage breast cancer to predict recurrence risk and guide adjuvant chemotherapy decisions.', 'We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit. METHODS: Independent evaluation of six genomic tests [Oncotype Dx™, MammaPrint(®), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria. PANEL', "Gene expression profiling (GEP) is being used increasingly for risk stratification to identify women with lymph node-negative, estrogen receptor-positive, early stage breast cancer who are most likely to benefit from adjuvant chemotherapy. The authors of this report evaluated the cost effectiveness of recurrence score-guided treatment using 2 commercially available GEP tests, Oncotype DX (Genomic Health, Redwood City, Calif) and MammaPrint (Agendia Inc., Irvine, Calif), from a third-party payer's perspective.", "genomic tumor signatures that predict a patient's risk of breast cancer recurrence and response to chemotherapy. The paper builds on empirical evidence from the two trials to explore the emergence of diverse regulatory-scientific hybrids; that is, the paper discusses configurations of genomic practice and bioclinical work that depend on linkages between technical, commercial, patient, clinical, and legal interests and institutions. The development of the genomic signatures for each trial--Oncotype DX and MammaPrint--has followed quite different routes.", 'Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes.', 'We will review the primary tools in clinical use: Adjuvant!, Oncotype DX, and MammaPrint as well as intrinsic subtypes and the plans for their further assessment in the clinical trial setting. The expected benefit from these models are that treatment recommendations for women with early-stage breast cancer will become more individualized and thereby appropriate by combining standard clinicopathologic and molecular features.', 'newer prognostic markers with a focus on the 21-gene recurrence score (Oncotype DX(™)), 70-gene prognosis profile (Mammaprint(®)), and Adjuvant! Online. Conclusion: These techniques differ in their execution and application and have been demonstrated to provide further data on risk stratification as compared with conventional breast-cancer-risk factors.', 'diagnostic tools such as MammaPrint and oncotype-DX are beginning to have impact on clinical practice of breast cancer. They are based on gene expression profiling, i.e., gene expression analysis of a large number of genes. Their unique characteristic is the use of a score calculated from expression values of a number of genes, for which the Food and Drug Administration (FDA) created a new diagnostic category entitled "in vitro diagnostic multivariate index assay (IVDMIA)."', 'the gene expression signatures that define specific prognostic subtypes in other breast cancer datasets, such as luminal A and B, basal, normal-like, and ERBB2+, and prognostic signatures including MammaPrint and Oncotype DX, predicted genomic instability in our samples.']

['The MammaPrint and Oncotype DX assays are used to predict breast cancer recurrence risk and guide adjuvant chemotherapy decisions.']

[]

How are CpG island shores defined?

["Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. ", ' Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts', 'Recent genome-wide descriptions of CpG methylation patterns in mammalian cells identified many differentially methylated regions (DMRs) located at CpG island "shores."', 'Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands.', 'This analysis revealed leukemia-associated differentially methylated regions that included gene promoters, gene bodies, CpG islands and CpG island shores.', 'We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control.', 'Aberrant DNA methylation of CpG islands, CpG island shores and first exons is known to play a key role in the altered gene expression patterns in all human cancers. ', 'In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors.']

['CpG island "shores" are defined as genomic regions up to 2kb distant to known CpG islands. Differential DNA methylation correlates with gene expression more strongly at CpG island shores than CpG islands.']

[]

Which phenomenon is known as the "calcium paradox" in the isolated perfused heart?

['"Calcium paradox" as a term describes the deleterious effects conferred to a heart perfused with a calcium-free solution followed by repletion, including loss of mechanical activity and sarcomere disruption.', 'Calcium paradox was found to markedly activate members of the MAPKs (p43-ERK, JNKs, p38-MAPK). ', 'To our knowledge, this is the first time that the calcium paradox has been shown to induce apoptosis in amphibians, with p38-MAPK and calpain playing significant roles.', 'The Ca(2+) paradox represents a good model to study Ca(2+) overload injury in ischemic heart diseases. We and others have demonstrated that contracture and calpain are involved in the Ca(2+) paradox-induced injury.', 'The Ca(2+) paradox was elicited by perfusing isolated rat hearts with Ca(2+)-free KH media for 3 min or 5 min followed by 30 min of Ca(2+) repletion.', 'These results provide evidence suggesting that contracture is the main cause for contractile dysfunction, while activation of calpain mediates cell death in the Ca(2+) paradox.', 'The Ca2+ -paradox is an important phenomenon to study cell injury induced by Ca2+ -overload in myocardium. Although intracellular Ca2+ -overload acts as a trigger and modulator of cell death due to apoptosis under various pathophysiological conditions, the presence of apoptosis in hearts subjected to Ca2+ -paradox has not been demonstrated.', 'Ca2+ -paradox was induced by perfusing the isolated rat heart with Ca2+ -free medium for 5 min followed by reperfusion with Ca2+ -containing medium for 30 min.', 'This study suggests that cardiac dysfunction due to Ca2+ -paradox may be associated with apoptosis.', 'Normothermic 3 min lasting perfusion of the isolated rat heart by Krebs--Henseleit solution in which Ca2+ was replaced by EDTA and subsequent perfusion with a Ca2+ containing medium induced structural and metabolic changes demonstrated electron microscopically and histochemically. In contrast to the ischemic reperfusion damage, in calcium paradox, the histochemically studied enzymes alpha-glucan-phosphorylase, lactate dehydrogenase, succinic dehydrogenase, beta-hydroxybutyric dehydrogenase, and ATPases were better preserved in the subendocardial region of the left ventricle.', 'On the other hand, myocytes in the subepicardial region and in the midmyocardium were markedly damaged and all characteristic signs of calcium paradox were present, including hypercontraction bands with myofilament fusion, extrusion and accumulation of edematous mitochondria with occurrence of electron dense material in mitochondrial cristae, ruptures of the sarcolemma in all its layers, separation of intercalated discs, etc.', 'Intracellular Ca2+-overload in the myocardium can be induced not only after readmission of Ca2+-containing fluid to rat hearts previously perfused with a Ca2+-free buffer, a phenomenon called "the calcium paradox", but also during administration of a Ca2+-ionophore to cardiac tissue. In rat hearts, the myocardial damage induced by the Ca2+ paradox was more pronounced than that after administration of the Ca2+-ionophore A23187, as indicated by the amount of lactate dehydrogenase released.', 'When hearts were reperfused with Ca++ after a short period of Ca++-free perfusion, irreversible loss of electrical and mechanical activity was observed. This phenomenon, first described by Zimmerman and Hulsmann, was termed the "calcium paradox". Chizzonite and Zak recently reported that rat hearts exhibited an age-dependent response in a calcium paradox model. ', "Injury is sustained by isolated hearts on repletion with calcium after a short period of perfusion with calcium-free medium at 37 degrees. A possible mechanism for the 'calcium paradox' is that exposure to a calcium-fre medium removes extracellular calcium rendering the sarcolemma more permeable to calcium. On calcium repletion, cell injury is triggered by calcium influx.", 'Isolated perfusion of the heart with a Ca2+-free perfusate followed by a Ca2+-containing perfusate causes dramatic alterations in the physiology and biochemistry of the tissue, a phenomenon known as the calcium paradox. A similar paradoxical effect of Ca2+ has also been reported to occur in the kidney', 'It is concluded that there is no calcium paradox in canine kidney under these conditions and it is suggested that the Ca2+ paradox may be characteristics only of muscle tissue that can undergo Ca2+-dependent contraction.', 'When isolated rat hearts are perfused with Ca2+-containing medium, after a brief Ca2+-free period, irreversible cell damage occurs (calcium paradox). This phenomenon is concomitant with a rapid consumption of myocardial high-energy phosphate stores, prior to the appearance of these compounds in the effluent perfusion medium. ', 'Isolated perfusion of the heart with a Ca2+-free perfusate followed by a Ca2+-containing perfusate causes dramatic alterations in the physiology and biochemistry of the tissue, a phenomenon known as the calcium paradox.', 'Isolated perfusion of the heart with a Ca2+-free perfusate followed by a Ca2+-containing perfusate causes dramatic alterations in the physiology and biochemistry of the tissue, a phenomenon known as the calcium paradox']

['"Calcium paradox" as a term describes the deleterious effects conferred to a heart perfused with a calcium-free solution followed by repletion, including loss of mechanical activity and sarcomere disruption.Isolated perfusion of the heart with a Ca2+-free perfusate followed by a Ca2+-containing perfusate causes dramatic alterations in the physiology and biochemistry of the tissue, a phenomenon known as the calcium paradox. A similar paradoxical effect of Ca2+ has also been reported to occur in the kidney', 'When hearts are reperfused with Ca++ after a short period of Ca++-free perfusion, irreversible loss of electrical and mechanical activity is observed. This phenomenon, first described by Zimmerman and Hulsmann, was termed the "calcium paradox". This phenomenon is concomitant with a rapid consumption of myocardial high-energy phosphate stores. The Ca(2+) paradox represents a good model to study Ca(2+) overload injury in ischemic heart diseases. The Ca(2+) paradox can be elicited by perfusing isolated hearts with Ca(2+)-free media for 3 min or 5 min followed by 30 min of Ca(2+) repletion. A possible mechanism for the \'calcium paradox\' is that exposure to a calcium-free medium removes extracellular calcium rendering the sarcolemma more permeable to calcium. On calcium repletion, cell injury is triggered by calcium influx. Cardiac dysfunction due to Ca2+ -paradox may be associated with apoptosis.', 'Isolated perfusion of the heart with a Ca2+-free perfusate followed by a Ca2+-containing perfusate causes dramatic alterations in the physiology and biochemistry of the tissue, a phenomenon known as the calcium paradox. A similar paradoxical effect of Ca2+ has also been reported to occur in the kidney When isolated rat hearts are perfused with Ca2+-containing medium, after a brief Ca2+-free period, irreversible cell damage occurs (calcium paradox). This phenomenon is concomitant with a rapid consumption of myocardial high-energy phosphate stores, prior to the appearance of these compounds in the effluent perfusion medium. ', 'Isolated perfusion of the heart with a Ca2+-free perfusate followed by a Ca2+-containing perfusate causes dramatic alterations in the physiology and biochemistry of the tissue, a phenomenon known as the calcium paradox. A similar paradoxical effect of Ca2+ has also been reported to occur in the kidney When isolated rat hearts are perfused with Ca2+-containing medium, after a brief Ca2+-free period, irreversible cell damage occurs (calcium paradox). This phenomenon is concomitant with a rapid consumption of myocardial high-energy phosphate stores, prior to the appearance of these compounds in the effluent perfusion medium. When hearts were reperfused with Ca++ after a short period of Ca++-free perfusion, irreversible loss of electrical and mechanical activity was observed. This phenomenon, first described by Zimmerman and Hulsmann, was termed the calcium paradox . Chizzonite and Zak recently reported that rat hearts exhibited an age-dependent response in a calcium paradox model. ']

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List medication interfering with purine metabolism that are used for treatment of T-cell prolymphocytic leukemia?

['Treatment with purine analogues and alemtuzumab has resulted in significantly higher response rates and improved survival. ', ' Treatment with purine analogs and the monoclonal antibody alemtuzumab has resulted in significantly higher response rates and increased survival.', 'Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.', 'T-cell prolymphocytic leukemia has an aggressive course with short median survival and poor response to chemotherapy. With the use of the purine analogue pentostatin more than half of patients will have a major response and a minority will have a complete remission, usually lasting months.', ' T-cell prolymphocytic leukaemia (T-PLL) is a rare post-thymic T-cell malignancy with an aggressive clinical course. It has generally been resistant to alkylating chemotherapy, but some effect has been observed with the purine analog 2-deoxycoformicin with documented partial or complete response rates in up to 45% of patients.', 'Fifteen patients with T-PLL, most of whom had received the purine analog deoxycoformycin (DCF), were treated with CAMPATH-1H.', "Pentostatin (2'-deoxycoformycin; DCF) is a purine analogue that has shown activity in treatment of chronic lymphoid malignancies.", 'Trials using DCF or other purine analogues alone or in combination with standard chemotherapeutic agents in front-line or salvage therapy are warranted to improve the prognosis of patients with prolymphocytic leukemia.']

['Deoxycoformycin and pentostatin are purine analogs that interfere with purine metabolism and are used for treatment of T-cell prolymphocytic leukemia patients.']

['deoxycoformycin', 'pentostatin', 'nelarabine']

What is the function of the Mis18 protein?

['Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres', 'Here we report identification of five fission yeast centromere proteins, Mis14-18. Mis14 is recruited to kinetochores independently of CENP-A, and, conversely, CENP-A does not require Mis14 to associate with centromeres.', 'In contrast, Mis15, Mis16 (strong similarity with human RbAp48 and RbAp46), Mis17, and Mis18 are all part of the CENP-A recruitment pathway.', 'Mis16 and Mis18 form a complex and maintain the deacetylated state of histones specifically in the central core of centromeres. Mis16 and Mis18 are the most upstream factors in kinetochore assembly as they can associate with kinetochores in all kinetochore mutants except for mis18 and mis16, respectively. ', 'The Mis18 complex, and, in particular, its member M18BP1 was shown to be essential for both incorporation and maintenance of CENP-A.', ' CENP-A nucleosome assembly requires the Mis18 complex and the CENP-A chaperone HJURP.', 'Roles of Mis18α in epigenetic regulation of centromeric chromatin and CENP-A loading', 'The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome.', 'Here, we generated Mis18α conditional knockout mice and found that Mis18α deficiency resulted in lethality at early embryonic stage with severe defects in chromosome segregation caused by mislocalization of CENP-A.', "Further, we demonstrate Mis18α's crucial role for epigenetic regulation of centromeric chromatin by reinforcing centromeric localization of DNMT3A/3B", 'Mis18α interacts with DNMT3A/3B, and this interaction is critical for maintaining DNA methylation and hence regulating epigenetic states of centromeric chromatin', 'Mis18α deficiency led to reduced DNA methylation, altered histone modifications, and uncontrolled noncoding transcripts in centromere region by decreased DNMT3A/3B enrichment', 'Together, our findings uncover the functional mechanism of Mis18α and its pivotal role in mammalian cell cycle.', 'Centromere licensing: Mis18 is required to Polo-ver', 'The Mis18 complex is a critical player in determining when and where centromeres are built', 'Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A.', 'Mis16 and Mis18 are subunits of a protein complex required for incorporation of the histone H3 variant CenH3 (Cnp1/CENP-A) into centromeric chromatin in Schizosaccharomyces pombe and mammals.', 'The Mis18 proteins (Mis18α, Mis18β, and M18BP1) are pivotal to the deposition of CENP-A at the centromere during cell cycle progression and are indispensable for embryonic development.', 'Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres.', 'Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A.', 'Ectopically targeted CENP-A chromatin at the LacO array was sufficient to direct the assembly of a functional centromere as indicated by the recruitment of the constitutive centromere-associated network proteins, the microtubule-binding protein NDC80, and the formation of stable kinetochore-microtubule attachments.', 'Replication-independent incorporation of CENP-A at centromeres depends on its chaperone HJURP(Scm3), and Mis18 in vertebrates and fission yeast.', 'Our findings suggest that Eic1 serves a function analogous to that of Mis18BP1(KNL2), thus representing the functional counterpart of Mis18BP1(KNL2) in fission yeast that connects with a module within the CCAN/Mis6/Ctf19 complex to allow the temporally regulated recruitment of the Mis18/Scm3(HJURP) Cnp1(CENP-A) loading factors.', 'Here, we show that Mis18â, a component of Mis18 complex governing CENP-A localization, is a new substrate of âTrCP-containing SCF complex.', 'Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex.', 'The fission yeast Schizosaccharomyces pombe and mammalian Mis16 and Mis18 form a complex essential for CENP-A recruitment to centromeres.', 'Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded β-meanders packing at a roughly right angle and coordinating a zinc ion at their apex', 'Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex', 'In contrast, Mis15, Mis16 (strong similarity with human RbAp48 and RbAp46), Mis17, and Mis18 are all part of the CENP-A recruitment pathway', 'Eic1 links Mis18 with the CCAN/Mis6/Ctf19 complex to promote CENP-A assembly.', 'Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres.', 'No Mis18BP1(KNL2) orthologue has been identified in fission yeast, consequently it remains unknown how the key Cnp1(CENP-A) loading factor Mis18 is recruited. ', 'In contrast, Mis15, Mis16 (strong similarity with human RbAp48 and RbAp46), Mis17, and Mis18 are all part of the CENP-A recruitment pathway. ', 'In fission yeast, Scm3sp and the Mis18 complex, composed of Mis16, Eic1, and Mis18, function as a CENP-A(Cnp1)-specific chaperone and a recruiting factor, respectively, and together ensure accurate delivery of CENP-A(Cnp1) to centromeres.', 'Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded β-meanders packing at a roughly right angle and coordinating a zinc ion at their apex.', 'No Mis18BP1(KNL2) orthologue has been identified in fission yeast, consequently it remains unknown how the key Cnp1(CENP-A) loading factor Mis18 is recruited.', 'CENP-A nucleosome assembly requires the Mis18 complex and the CENP-A chaperone HJURP.', 'We find that Mis18α directly interacts with the N terminus of Mis18BP1, whereas Mis18β directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes.']

["Kinetochores assemble on a specialized chromosomal locus termed the centromere, which is characterized by the replacement of histone H3 in centromeric nucleosomes with the essential histone H3 variant CENP-A (centromere protein A). The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome. Further, we demonstrate Mis18α's crucial role for epigenetic regulation of centromeric chromatin by reinforcing centromeric localization of DNMT3A/3B. Mis18α interacts with DNMT3A/3B, and this interaction is critical for maintaining DNA methylation and hence regulating epigenetic states of centromeric chromatin. Together, our findings uncover the functional mechanism of Mis18α and its pivotal role in mammalian cell cycle. The Mis18 complex is a critical player in determining when and where centromeres are built.", 'Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres Here we report identification of five fission yeast centromere proteins, Mis14-18. Mis14 is recruited to kinetochores independently of CENP-A, and, conversely, CENP-A does not require Mis14 to associate with centromeres. In contrast, Mis15, Mis16 (strong similarity with human RbAp48 and RbAp46), Mis17, and Mis18 are all part of the CENP-A recruitment pathway. Mis16 and Mis18 form a complex and maintain the deacetylated state of histones specifically in the central core of centromeres. Mis16 and Mis18 are the most upstream factors in kinetochore assembly as they can associate with kinetochores in all kinetochore mutants except for mis18 and mis16, respectively.', 'The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome.', 'Mis16 and Mis18 form a complex and maintain the deacetylated state of histones specifically in the central core of centromeres. A fundamental process in centromere establishment is the incorporation of the histone variant CENP-A into centromeric chromatin, which provides a binding platform for the other centromeric proteins. CENP-A nucleosome assembly requires the Mis18 complex and the CENP-A chaperone HJURP. Thus, CENP-C provides a link between existing CENP-A chromatin and the proteins required for new CENP-A nucleosome assembly. The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome. This is a critical step that is essential for proper centromere function and maintaining the integrity of the genome.', 'The Mis18 complex is a critical player in determining when and where centromeres are built. The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome. Eukaryotic chromosomes segregate by attaching to microtubules of the mitotic spindle through a chromosomal microtubule binding site called the kinetochore. Centromeres are important structural constituents of chromosomes that ensure proper chromosome segregation during mitosis by providing defined sites for kinetochore attachment. Centromeres contain specialized chromatin that includes the centromere-specific histone H3 variant, spCENP-A/Cnp1.', 'Together, our findings uncover the functional mechanism of Mis18α and its pivotal role in mammalian cell cycle. The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome.', 'the mis18 complex has been identified as a critical factor for the centromeric localization of a histone h3 variant, centromeric protein a (cenp-a), which is responsible for the specification of centromere identity in the chromosome.']

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Which is the enzymatic activity of OTULIN?

['deubiquitinase OTULIN', 'OTULIN (FAM105B), encoding a deubiquitinase ', ' Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.', 'Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, ', ' are disassembled by the linear ubiquitin-specific deubiquitinase OTULIN', 'deubiquitinases CYLD and OTULIN', 'We recently discovered OTULIN as a deubiquitinase that specifically cleaves Met1-linked polyUb', 'deubiquitinase OTULIN specifically disassembles Met1-Ub.', ' Our data suggest that OTULIN regulates Met1-polyUb signaling.', 'OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.']

['OTULIN is a deubiquitinase, that specifically cleaves Met1-linked polyUb.']

['deubiquitination']

What are some of the effects of Zika Virus in infected individuals?

['Maternal-fetal transmission of Zika virus has been documented; evidence suggests that congenital Zika virus infection is associated with microcephaly and other adverse pregnancy and infant outcomes', 'Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy.', 'While the symptoms associated with Zika virus infection are generally mild, consisting of fever, maculopapular rash, arthralgia and conjunctivitis, there have been reports of more severe reactions that are associated with neurological complications. In pregnant women, fetal neurological complications include brain damage and microcephaly, while in adults there have been several cases of virus-associated Guillain-Barre syndrome.', 'ika virus is a flavivirus transmitted primarily by Aedes species mosquitoes, and symptoms of infection can include rash, fever, arthralgia, and conjunctivitis (1).* Zika virus infection during pregnancy is a cause of microcephaly and other severe brain defects (2). Infection has also been associated with Guillain-Barré syndrome', 'To better understand the etiologic role and mechanism(s) of Zika virus in causing birth defects such as microcephaly,', 'Most persons infected with Zika virus have a mild illness or are asymptomatic. However, increasing evidence supports a link between Zika virus infection during pregnancy and adverse pregnancy and birth outcomes (1), and a possible association between recent Zika virus infection and Guillain-Barré syndrome has been reported (2).', 'There is now strong biologic evidence of causality between Zika virus and microcephaly and other neurologic abnormalities identified.', 'Several pieces of evidence suggest that maternal Zika virus infection is associated with adverse neonatal outcomes, most notably microcephaly.', ' Zika virus has gained international attention due to concerns for infection in pregnant women potentially causing fetal microcephaly.', 'Zika virus is a flavivirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes, and infection can be asymptomatic or result in an acute febrile illness with rash (1). Zika virus infection during pregnancy is a cause of microcephaly and other severe birth defects (2). Infection has also been associated with Guillain-Barré syndrome (GBS) (3) and severe thrombocytopenia (4,5)', 'Most Zika virus infections are asymptomatic (1,6). Clinical illness, when it occurs, is generally mild and characterized by acute onset of fever, maculopapular rash, arthralgia, or nonpurulent conjunctivitis. However, Zika virus infection during pregnancy can cause adverse outcomes such as fetal loss, and microcephaly and other serious brain anomalies ', 'In 2015, Zika virus infection was diagnosed in Brazil where it was associated with microcephaly in the infants of some women who were pregnant when they contracted the disease. Cases of the Guillain-Barré syndrome were also found to be associated with Zika virus', 'These findings strengthen the putative association between Zika virus and cases of microcephaly in neonates in Brazil', ' In response to the current cluster of congenital malformations (microcephaly) and other neurological complications (Guillain-Barré Syndrome) that could be linked to Zika virus infection, WHO declares that Zika virus is of global public health importance. ', 'Zika virus infection during pregnancy can cause spontaneous abortion and birth defects, including microcephaly', 'n the case of Zika virus, an accumulating body of recent evidence implicates the virus in the etiology of serious pathologies of the human nervous system, that is, the occurrence of microcephaly in neonates and Guillain-Barré syndrome in adults.', 'We describe the first case of Guillain-Barré syndrome (GBS) occurring immediately after a Zika virus infection, during the current Zika and type 1 and 3 dengue fever co-epidemics in French Polynesia.', 'We report a case of Zika virus infection in an Australian traveler who returned from Indonesia with fever and rash', 'woman who recently traveled to Thailand came to a local emergency department with a fever and papular rash. She was tested for measles, malaria, and dengue. Positive finding for IgM antibody against dengue and a failure to seroconvert for IgG against dengue for multiple blood samples suggested an alternate flavivirus etiology. Amplification of a conserved region of the non-structural protein 5 gene of the genus Flavivirus yielded a polymerase chain reaction product with a matching sequence of 99% identity with Zika virus. A urine sample and a nasopharygeal swab specimen obtained for the measles investigation were also positive for this virus by reverse transcription polymerase chain reactio', ' It is estimated that approximately 18% of individuals infected with ZIKV will go on to develop symptoms. When symptoms develop, it is usually within 3-12 days, although this may vary. Most often, symptoms are mild and self-limited. The most common symptoms are fever, arthralgia, maculopapular rash, and conjunctivitis lasting up to seven days. Less frequent symptoms include headache, vertigo, myalgia, vomiting, and diarrhea. At present, there is no vaccine available to prevent ZIKV and no specific antiviral treatment. Supportive care consisting of rest, hydration, analgesics, antihistamines, and antipyretics is recommended as needed. ', 'marked increase in infants born with microcephaly in Brazil after a 2015 outbreak of Zika virus (Zika virus) disease suggests an association between maternal Zika virus infection and congenital microcephaly.', 'Zika virus causes a self-limiting, systemic illness; however, the current outbreak of Zika virus in the Americas has been associated with increased rates of fetal malformations and Guillain-Barré syndrome']

['While most of the symptoms of zika virus are relatively mild, zika virus in pregnant mothers can cause microcephaly and other congenital defects in the fetus.']

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Aleglitazar is agonist of which receptor?

['Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes.', 'Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. ', 'Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics.', 'Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles.', 'Aleglitazar acts through balanced activation of peroxisome proliferator-activated receptors α and γ; warfarin is a commonly prescribed anticoagulant. ', 'Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study.', 'This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist', 'Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist in clinical development, designed to offer a balanced activation of PPAR-α and PPAR-γ', 'The PPARalpha- and PPARgamma-related effects occurred over similar dose ranges, indicating that aleglitazar is a balanced agonist of the two receptor subtypes', 'Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist with a balanced activity (similar half-maximal effective concentrations) toward PPAR-α and -γ that is in clinical development for the treatment of patients who have experienced an acute coronary syndrome and have type 2 diabetes mellitus', 'Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects', 'Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome', 'Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study', 'Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study', 'Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies', 'This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ (PPARα/γ) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys', 'This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist', 'Evaluation of the dual peroxisome proliferator-activated receptor �/� agonist aleglitazar to reduce cardiovascular events in patients with acute coronary syndrome and type 2 diabetes mellitus: rationale and design of the AleCardio trial.', 'Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study.', 'Aleglitazar is a potent dual PPAR agonist with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles and biomarkers of cardiovascular risk. The AleCardio trial examines whether the addition of aleglitazar to standard medical therapy reduces the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and recent acute coronary syndrome.STUDY DESIGN: AleCardio is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. ', 'To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes.', 'Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of fibrates and the insulin-sensitizing benefits of thiazolidinediones. To investigate the pharmacokinetic effects of co-administration of atorvastatin or rosuvastatin with aleglitazar.']

['Aleglitazar is a balanced peroxisome proliferator-activated receptor-α/γ agonist.']

['peroxisome proliferator-activated receptor-α/γ']

Which genes have been found to be associated with restless leg syndrome

['We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). ', 'The genotypes of five specific single-nucleotide polymorphisms (SNPs) in three genes that have been previously associated with iron status and/or restless leg syndrome (RLS)', 'Homozygosity for the T-allele of BTBD9 rs9296249 was associated with lower serum ferritin. ', 'A frequent polymorphism in BTBD9 was significantly associated with serum ferritin. This polymorphism has previously been associated with RLS, but not low iron stores in blood donors.', ' In the German sample, variants in MEIS1 and BTBD9 were associated with RLS in ESRD (P(nom)≤0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9', ' This is the first demonstration of a genetic influence on RLS in ESRD patients with BTBD9 being significantly associated.', 'Four family members developed dopa-responsive dystonia, with onset in their late teens, and subsequently developed restless leg syndrome and migraine. CONCLUSIONS: This is the first report of an intragenic guanosine triphosphate cyclohydrolase-1 duplication in a dopa-responsive dystonia family.', 'To date, no gene mutation has been found, but five gene loci have been mapped in primary RLS to chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1 through 5)', 'We demonstrate linkage to a locus on chromosome 9p that is probably distinct from RLS3. Our family with a rather homogeneous phenotype and very early disease onset represents a unique opportunity to further elucidate the genetic causes of the frequent restless leg syndrome.', 'A case of restless leg syndrome in a family with LRRK2 gene mutation.', 'The association between RLS and LRRK2 gene mutation may be casual, but it can hypothesized that RLS is a possible phenotypic presentation in PARK8.']

['Human L-Ferritin\nThe genotypes of five specific single-nucleotide polymorphisms (SNPs) in three genes\nHomozygosity for the T-allele of BTBD9 rs9296249\nMEIS1\nIntragenic guanosine triphosphate cyclohydrolase-1 duplication\nLRRK2 gene mutation']

['LRRK2 gene mutation', 'Human L-Ferritin', 'The genotypes of five specific single-nucleotide polymorphisms (SNPs) in three genes', 'Homozygosity for the T-allele of BTBD9 rs9296249', 'MEIS1', 'Intragenic guanosine triphosphate cyclohydrolase-1 duplication']

Which is the genetic basis of Spinal Muscular Atrophy (SMA)?

['Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown.', 'We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a redu', 'Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3.', 'Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA', 'Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region.', 'A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.', 'A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy', 'A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA).', 'Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer.', 'Autosomal recessive childhood proximal SMA is the commonest form and is due to mutations in a gene encoding a novel protein, SMN, that appears to play a critical role in RNA metabolism but has also been shown to interact with actin-binding proteins and mediators of programmed cell death.', 'Mutations of the SMN1 gene are responsible for SMA.', 'All patients were found to be homozygous for the loss of either exon 7 or exons 7 and 8 of the SMN1 gene', 'Six additional patients had anterior horn cell disease but were negative for the SMN1 gene deletion. All six had exclusion features listed in the international guidelines.', 'The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1)', 'The structures of the SMN1 gene and SMN2 pseudogene, mutations distorting the SMN1 function, the structure and functions of the Smn neurotrophic protein, its role in biogenesis of small nuclear ribonucleoproteins (snRNPs), and the principles and prdblems of molecular diagnosis in SMA are described.', 'SMA are caused by mutations of the survival of motor neuron gene (SMN1) leading to a reduction of the SMN protein amount.', 'From a better knowledge of the genetic basis of SMA and the defects resulting from the mutations of SMN1 in cellular or animal models, several therapeutics strategies have been selected aiming at targeting SMN2, a partially functional copy of SMN1 gene which remains present in patients, or to prevent neurons from death.', 'We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH', 'SMN1 and SMN2 quantification was undertaken to investigate the genotype-phenotype relationship.RESULTS: Two novel point mutations were identified in exon 3 of SMN1 (p.Tyr130Cys and p.Tyr130His) in the highly conserved Tudor domain of the Smn protein.CONCLUSIONS: The genetic basis of SMA in the rare cases of compound heterozygous carriers of SMN1 deletions is complex. ']

['The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1). Mutations of the SMN1 gene are responsible for SMA. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.\nThe molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1).']

['The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1)']

what is the role of MEF-2 in cardiomyocyte differentiation?

['The growth and differentiation factor bone morphogenetic protein-2 (BMP-2) regulates cardiac development during vertebrate embryogenesis. In cardiac precursor cells, BMP-2 has recently been shown to induce expression of cardiac transcription factors, including myocyte enhancer factor 2A (MEF-2A).', 'BMP-2 increased PI 3-kinase activity in these cells in a time-dependent manner, resulting in increased expression of sarcomeric myosin heavy chain (MHC) and MEF-2A.', 'Furthermore expression of MEF-2A increased MHC expression in a PI 3-kinase-dependent manner.', 'Gene expression profiling revealed decreased levels of transcription factors transforming growth factor-β/bone morphogenetic protein, serum response factor, GATA4, and myocyte enhancer factor 2, linked to increased Ca(2+)-dependent calcineurin activity and Notch1 signaling that impaired ESC differentiation.', 'Dominant interference of calcineurin/mAKAP binding blunts the increase in MEF2 transcriptional activity seen during myoblast differentiation, as well as the expression of endogenous MEF2-target genes. Furthermore, disruption of calcineurin binding to mAKAP in cardiac myocytes inhibits adrenergic-induced cellular hypertrophy.', 'Hypertrophic agonist stimulation of neonatal ventricular cardiomyocytes increased Mef2 expression by enhancing its translation, without changing its transcription or blocking degradation of the protein. MEF2 abundance was increased by Calcineurin overexpression in vivo and was reduced by Calcineurin inhibition in vitro, without affecting Mef2 mRNA levels.', "In addition, chromatin immunoprecipitation (ChIP) revealed association of Gli2 to the Mef2c gene, and of MEF2C to the Gli2 gene in differentiating P19 cells. Finally, co-immunoprecipitation studies showed that Gli2 and MEF2C proteins formed a complex, capable of synergizing on cardiomyogenesis-related promoters containing both Gli- and MEF2-binding elements. We propose a model whereby Gli2 and MEF2C bind each other's regulatory elements, activate each other's expression and form a protein complex that synergistically activates transcription, enhancing cardiac muscle development. ", 'MC1568 arrests myogenesis by (i) decreasing myocyte enhancer factor 2D (MEF2D) expression, (ii) by stabilizing the HDAC4-HDAC3-MEF2D complex, and (iii) paradoxically, by inhibiting differentiation-induced MEF2D acetylation.', 'The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. ', 'Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. ', 'The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors that are essential for differentiation of all muscle lineages but their mechanisms of action remain largely undefined. ', 'Inactivation of the MEF2C gene causes cardiac developmental arrest and severe downregulation of a number of cardiac markers including atrial natriuretic factor (ANF).', 'We provide evidence that MEF2 proteins are recruited to target promoters by the cell-specific GATA transcription factors, and that MEF2 potentiates the transcriptional activity of this family of tissue-restricted zinc finger proteins.', 'During differentiation into cardiac muscle, Nkx2-5 expression resulted in the activation of myocyte enhancer factor 2C (MEF2C), but not MEF2A, -B, or -D', 'Similar to Nkx2-5, MEF2C expression initiated cardiomyogenesis, resulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, Nkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression.', 'These findings indicate the presence of a positive regulatory network between Nkx2-5 and MEF2C and show that both factors can direct early stages of cell differentiation into a cardiomyogenic pathway.']

['The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors that are essential for differentiation of all muscle lineages but their mechanisms of action remain largely undefined. MEF2C expression initiates cardiomyogenesis, resulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, Nkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression. Inactivation of the MEF2C gene causes cardiac developmental arrest and severe downregulation of a number of cardiac markers including atrial natriuretic factor (ANF). BMP-2, a regulator of cardiac development during embryogenesis, was shown to increase PI 3-kinase activity in cardiac precursor cells, resulting in increased expression of sarcomeric myosin heavy chain (MHC) and MEF-2A. Furthermore, expression of MEF-2A increased MHC expression in a PI 3-kinase-dependent manner. Other studies showed that Gli2 and MEF2C proteins form a complex, capable of synergizing on cardiomyogenesis-related promoters. Dominant interference of calcineurin/mAKAP binding blunts the increase in MEF2 transcriptional activity seen during myoblast differentiation, as well as the expression of endogenous MEF2-target genes. These findings show that MEF-2 can direct early stages of cell differentiation into a cardiomyogenic pathway.']

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Are there web based self management strategies for chronic pain ?

['Fibromyalgia Symptom Reduction by Online Behavioral Self-monitoring, ', 'This study aimed to evaluate effects of a web-based, self-monitoring and symptom management system (SMARTLog) that analyzes personal self-monitoring data and delivers data-based feedback over time.', 'Moderate use (3 times weekly x 3 months) increased likelihood of clinically significant improvements in pain, memory, gastrointestinal problems, depression, fatigue, and concentration; heavy use (4.5 times weekly x five months) produced the above plus improvement in stiffness and sleep difficulties.', 'Results suggest that the tailored online chronic pain management program showed promising effects on pain at 1 and 6 months posttreatment and quality of life at 6 months posttreatment in this naturalistic study.', 'Results suggest the potential value of self-management for chronic pain patients and the potential acceptability of web-based delivery of intervention content.', 'Patient involvement can be fostered by web-based applications combining health information with decision support or behaviour change support. These so-called Interactive Health Communication Applications (IHCAs) can reach great numbers of patients at low financial cost and provide information and support at the time, place and learning speed patients prefer.', 'Web-based interventions may also be effective in enhancing self-management for individuals with chronic pain, but little is known about long-term effects. Research on Web-based interventions to support self-management following participation in pain management programs is limited. OBJECTIVE: The aim is to examine the long-term effects of a 4-week smartphone-intervention ']

['Results suggest the potential value of self-management for chronic pain patients and the potential acceptability of web-based delivery of intervention content. ', 'Yes, there are successful web based self management strategies for chronic pain.']

['yes']

Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica

['OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica.', 'We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.', 'We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates.', 'OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica', 'We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates', 'We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. ']

['OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/) is a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information and will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.']

['OikoBase']

Is ospemifene effective for treatment of dyspareunia?

['Ospemifene, a novel selective estrogen receptor modulator, has been developed for the treatment of vulvovaginal atrophy and dyspareunia in postmenopausal women. ', 'For the comparison of short-term ospemifene with placebo, parabasal cells (the standardized mean difference [SMD]\u2009=\u2009-37.5, 95% confidence interval [CI]\u2009=\u2009-41.83 to -33.17, P < 0.00001), superficial cells (SMD = 9.24, 95% CI = 7.70 to 10.79, P < 0.00001), vaginal PH (SMD =\u2009-0.89, 95% CI =\u2009-0.98 to -0.80, P = 0.00001), and dyspareunia (SMD =\u2009-0.37, 95% CI =\u2009-0.43 to -0.30, P = 0.00001) indicated that ospemifene was more effective than the placebo. ', 'This meta-analysis indicates that ospemifene to be an effective and safe treatment for dyspareunia associated with postmenopausal vulvar and vaginal atrophy.', 'Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women.', 'In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. ', 'To characterize the pharmacokinetics of the oral, non-estrogen agent ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also called a selective estrogen receptor modulator) that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women.', 'Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically.', ' Long-term studies on the endometrial safety of local estrogen and ospemifene are lacking. ', 'Ospemifene is a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor modulator) recently approved by the US Food and Drug Administration for treatment of dyspareunia, a symptom of VVA, due to menopause.', 'SERMs with positive vaginal effects (such as improvement in the vaginal maturation index, reduced vaginal pH, and improvement in the signs and symptoms of VVA) on postmenopausal symptomatic women include lasofoxifene (clinical development on hold) and ospemifene, which was recently approved for the treatment of VVA-related dyspareunia, with a class effect warning of potential venous thrombosis risk. ', 'Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy. ', 'This article summarizes the milestones in the development of ospemifene leading to this first approval for moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy.', 'The aim of this work was to study the role of ospemifene, a novel selective estrogen receptor modulator, in the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia and physiological vaginal changes. ', 'In this study, once-daily oral ospemifene 60 mg was effective for the treatment of vulvar and vaginal atrophy in postmenopausal women with dyspareunia.', 'Clinical trials have confirmed that daily doses are well-tolerated and that it is effective in normalizing vaginal maturation index and pH as well as improving the symptoms associated with VVA including dyspareunia.', 'Ospemifene was shown to be effective and well tolerated for the treatment of the symptoms of vaginal dryness and dyspareunia associated with vulvovaginal atrophy over and above the use of provided lubricants.']

['Yes, ospamifene is effective for treatment of dyspareunia. Ospemifene is a selective estrogen receptor modulator, or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy.']

['yes']

Which server is used for simulation of macromolecular diffusional association?

['webSDA: a web server to simulate macromolecular diffusional association.', 'Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results.', "webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules.", 'Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: SDA docking to generate structures of the diffusional encounter complexes of two macromolecules, SDA association to calculate bimolecular diffusional association rate constants, and SDA multiple molecules to simulate the diffusive motion of hundreds of macromolecules.', 'webSDA: a web server to simulate macromolecular diffusional association', 'webSDA: a web server to simulate macromolecular diffusional association.', 'webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures.', "webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules."]

['Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results.', 'Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures.', "webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules."]

['webSDA']

What are the outcomes of Renal sympathetic denervation?

['Significant decreases and progressively higher reductions of systolic and diastolic blood pressure were observed after RSD. The complication rate was minimal. ', 'In conclusion, the RSD presents itself as an effective and safe approach to resistant hypertension.', 'Renal sympathetic denervation delivers not only a decrease in blood pressure levels but also renal as well as systemic sympathetic nerve activity. The reduction in blood pressure appears to be sustained over 3 years after the procedure, which implies no counterregulatory mechanism or re-innervation of afferent renal sympathetic nerve so far.', 'Renal sympathetic denervation not only reduces blood pressure but also renal as well as systemic sympathetic nerve activity in such patients. The reduction in blood pressure appears to be sustained over 3 years after the procedure, which suggests absence of re-innervation of renal sympathetic nerves. Safety appears to be adequate.', 'Clinical trials of renal sympathetic denervation have shown significant reductions in blood pressure in these patients. Renal sympathetic denervation also reduces heart rate, which is a surrogate marker of cardiovascular risk. ', 'Small studies suggest that RSD can produce dramatic blood pressure reductions: In the randomized Symplicity HTN-2 trial of 106 patients, the mean fall in blood pressure at 6 months in patients who received the treatment was 32/12 mm Hg. However, there are limitations to the evidence for RSD in the treatment of resistant hypertension. These include the small number of patients studied; the lack of any placebo-controlled evidence; the fact that blood pressure outcomes were based on office assessments, as opposed to 24-hour ambulatory monitoring; the lack of longer-term efficacy data; and the lack of long-term safety data.', 'Clinical evaluation of selective renal sympathetic denervation demonstrated a decrease of renal norepinephrine spillover and renin activity, an increase of renal plasma flow, and has confirmed clinically significant, sustained reductions in blood pressure in patients with resistant hypertension.', 'In addition to drug treatment, baroreceptor stimulation therapy and renal sympathetic denervation are promising new approaches in this group of patients.', 'Early clinical evaluation with catheter-based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses.', 'Novel procedure- and device-based strategies to control hypertension include renal sympathetic denervation and baroreflex sensitization.']

['Significant decreases and progressively higher reductions of systolic and diastolic blood pressure were observed after RSD. The complication rate was minimal.\nRenal sympathetic denervation also reduces heart rate, which is a surrogate marker of cardiovascular risk.']

[]

Describe what is the usage of the Theatre software tool for genomic analysis.

['Theatre is a web-based computing system designed for the comparative analysis of genomic sequences, especially with respect to motifs likely to be involved in the regulation of gene expression. Theatre is an interface to commonly used sequence analysis tools and biological sequence databases to determine or predict the positions of coding regions, repetitive sequences and transcription factor binding sites in families of DNA sequences. The information is displayed in a manner that can be easily understood and can reveal patterns that might not otherwise have been noticed. In addition to web-based output, Theatre can produce publication quality colour hardcopies showing predicted features in aligned genomic sequences.', 'Theatre: A software tool for detailed comparative analysis and visualization of genomic sequence.', 'Theatre is a web-based computing system designed for the comparative analysis of genomic sequences, especially with respect to motifs likely to be involved in the regulation of gene expression. Theatre is an interface to commonly used sequence analysis tools and biological sequence databases to determine or predict the positions of coding regions, repetitive sequences and transcription factor binding sites in families of DNA sequences. ']

['Theatre is a web-based computing system designed for the comparative analysis of genomic sequences, especially with respect to motifs likely to be involved in the regulation of gene expression. Theatre is an interface to commonly used sequence analysis tools and biological sequence databases to determine or predict the positions of coding regions, repetitive sequences and transcription factor binding sites in families of DNA sequences. The information is displayed in a manner that can be easily understood and can reveal patterns that might not otherwise have been noticed. In addition to web-based output, Theatre can produce publication quality colour hardcopies showing predicted features in aligned genomic sequences.', 'Theatre is a web-based computing system designed for the comparative analysis of genomic sequences, especially with respect to motifs likely to be involved in the regulation of gene expression. The information is displayed in a manner that can be easily understood and can reveal patterns that might not otherwise have been noticed. Theatre can be accessed at http://www.hgmp.mrc.ac.uk/Registered/Webapp/theatre/.']

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What are the symptoms of Rotor syndrome?

['The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. ', '[A case with Rotor syndrome in hyperbilirubinemic family].', 'Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome)', 'Rotor syndrome is a rare, benign familial disorder characterized by chronic fluctuating, nonhemolytic and predominantly conjugated hyperbilirubinemia with normal hepatic histology', "Jaundice is often the first and sometimes the only symptom of liver disease. Besides in parenchymal liver disease jaundice is also observed in chronic non-haemolytic hyperbilirubinemias (Crigler-Najjar type I and II, Gilbert's syndrome) and in hereditary conjugated hyperbilirubinaemias (Dubin-Johnson- and Rotor-syndrome).", ' Rotor syndrome is a rare, benign familial disorder characterized by chronic fluctuating, nonhemolytic and predominantly conjugated hyperbilirubinemia with normal hepatic histology. In contrast to Dubin-Johnson syndrome, there is no liver pigmentation in Rotor syndrome.', 'The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome).', 'Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome).', '[A case with Rotor syndrome in hyperbilirubinemic family].']

['Rotor syndrome is characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics.']

['conjugated hyperbilirubinemia', 'coproporphyrinuria', 'near-absent hepatic uptake of anionic diagnostics']

Have germline variants been associated to colorectal cancer?

['Overall, we identified aberrant transcripts in 8% of the patients (familial cases 30%; early-onset manifestation 21%). In eight of them, two different out-of-frame pseudoexons were found consisting of a 167-bp insertion from intron 4 in five families with a shared founder haplotype and a 83-bp insertion from intron 10 in three patients. The pseudoexon formation was caused by three different heterozygous germline mutations, which are supposed to activate cryptic splice sites', 'We apply OS-Seq to resequence the exons of either 10 or 344 cancer genes from human DNA samples. In our assessment of capture performance, >87% of the captured sequence originated from the intended target region with sequencing coverage falling within a tenfold range for a majority of all targets. Single nucleotide variants (SNVs) called from OS-Seq data agreed with >95% of variants obtained from whole-genome sequencing of the same individual.', 'The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001).', 'In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.', 'We identified 22 nonsynonymous somatic mutations of which the majority was of missense type. In germline, three novel nonsynonymous variants were identified in the following genes: CSMD3, EPHB6 and C10orf137, and none of the variants were present in 890 population-matched healthy controls. It is possible that the identified germline variants modulate predisposition to CRC.', 'One patient proved to carry an APC whole-gene deletion; 4 of 25 (16%) patients showed biallelic and 3 of 25 (12%) monoallelic MUTYH mutations. In the three heterozygous subjects no pathogenetic variants were found in OGG1, MTH1, APE1, MSH2, and MSH6 genes. Frequency assessment of MUTYH mutations in healthy subjects showed that only Y165C and G382D reach a subpolymorphic frequency.', 'Scrutinizing the molecular genetic results and family data of 242 index patients with pathogenic APC mutations led to the identification of 10 mosaic cases (4%). C>T transitions were observed in CGA sites in four of the 10 cases with somatic mosaicism, which is significantly more than 26 of the 232 non-mosaic cases (p = 0.02). Phenotypes of patients with somatic mosaicism ranged from an attenuated form of polyposis coli to florid polyposis with major extracolonic manifestations.', 'Altogether 12 previously reported changes and four novel genetic alterations, mostly in intronic sequences, were identified. The results revealed the presence of biallelic germline MYH mutations in two patients. These patients were compound heterozygotes for two of the most common germline mutations c.494 A>G (p.Y165C); c.1,145 G>A (p.G382D). These variants are established to be associated with adenomatous polyposis and colorectal cancer.']

['Yes. Whole-genome sequencing (WGS) applied to medical research has revealed how germline variants and mutations may be associated with colorectal cancer. It is likely that this level of knowledge can be translated into predictions of predisposition.']

['yes']

Have Quantitative Trait Loci affecting splicing (splicing QTLs) been linked to disease?

[]

['Yes, mutations in the DNA that affect the splicing pattern of genes have been linked in transcriptome population studies to a number of diseases.']

['yes']

List the human acrocentric chromosomes that are involved in Robertsonian translocation.

['Sperm segregation analysis of a (13;22) Robertsonian translocation carrier by FISH: a comparison of locus-specific probe and whole chromosome painting.', 'The t(13;22) Robertsonian translocation constitutes a rare form of rearrangement between acrocentric human chromosomes. Most of the meiotic segregation studies of human Robertsonian translocations have been performed on common t(13;14) and t(14;21) translocations. ', 'Robertsonian translocations (ROBs) are the most common chromosomal rearrangements in humans. ROBs are whole-arm rearrangements between the acrocentric chromosomes 13-15, 21, and 22. ROBs can be classified into two groups depending on their frequency of occurrence, common (rob(13q14q) and rob(14q21q)), and rare (all remaining possible nonhomologous combinations). ', 'Robertsonian translocations (ROBs) are the most common rearrangements in humans, contributing significantly to genetic imbalance, fetal wastage, mental retardation and birth defects. Rob(14q21q) and rob(13q14q), which are formed predominantly during female meiosis, comprise the majority (approximately 85%) of all ROBs. Previous studies have shown that the breakpoints are consistently located within specific regions of the proximal short arms of chromosomes 13, 14, and 21. ', 'To localize the chAB4 sequences more precisely on the acrocentrics, chAB4-specific probes together with rDNA and a number of satellite sequences were hybridized to metaphase chromosomes of normal probands and of carriers of Robertsonian translocations of the frequent types rob(13q14q) and rob(14q21q). ', 'Chromosome 22, most probably, is the only chromosome where chAB4 is found in the direct neighbourhood of the centromere. Fluorescence in situ hybridization analyses of metaphase chromosomes of carriers of rob(21q22q) revealed breakpoint diversity for this rare type of Robertsonian translocation chromosome. ', 'This process is suggested for the evolution of an alpha satellite subfamily recently found on chromosomes 13, 14 and 21. The presence of this alpha subfamily may allow pairing between these chromosomes leading to the observed non-random participation of these chromosomes in t(13q14q) and t(14q21q) Robertsonian translocations.', 'The pattern of association of acrocentric chromosomes was examined in ten and five carriers of a 15/21 and a 13/14 Robertsonian translocation, respectively, and was compared with that of the same numbers of relatives with normal karyotypes.', 'Homologous alpha satellite sequences on human acrocentric chromosomes with selectivity for chromosomes 13, 14 and 21: implications for recombination between nonhomologues and Robertsonian translocations.', 'Out of 21 structural chromosomal anomalies and polymorphic variants, six deletions and microdeletions, four situations with abnormal long "p" arm of acrocentric chromosomes, two duplications, two reciprocal translocations, two inversions, two additions, one Robertsonian translocation associating trisomy 13, one 9q heteromorphism and one complex chromosome rearrangement were noticed', 'The purpose of this study was to search for cytologic evidence of robertsonian translocation formation that involves chromosomes 14q and 21q in human oogenesis with the use of dual color fluorescent in situ hybridization with whole chromosome paints.The oocytes from a chromosomally normal fetus at 23.5 weeks of gestation underwent cohybridization with chromosome specific DNA libraries from chromosomes 14 and 21', 'The t(13;22) Robertsonian translocation constitutes a rare form of rearrangement between acrocentric human chromosomes', 'Homologous alpha satellite sequences on human acrocentric chromosomes with selectivity for chromosomes 13, 14 and 21: implications for recombination between nonhomologues and Robertsonian translocations.', 'The t(13;22) Robertsonian translocation constitutes a rare form of rearrangement between acrocentric human chromosomes.']

['Robertsonian translocations (ROBs) are the most common chromosomal rearrangements in humans. ROBs are whole-arm rearrangements between the acrocentric chromosomes 13, 14, 15, 21, and 22.']

['13', '14', '15', '21', '22']

Which is the substrate of the haspin kinase during mitosis?

['aspin phosphorylates histone H3 at Thr3 (H3T3ph) during mitosis', 'protein kinase Haspin-mediated spreading of H3T3ph ', 'Haspin localizes predominantly to chromosomes and phosphorylates histone H3 at threonine-3 during mitosis', 'haspin/Gsg2 plays an important role in mitosis, where it specifically phosphorylates Thr-3 in histone H3 (H3T3', 'aspin/Gsg2 is a kinase that phosphorylates histone H3 at Thr-3 (H3T3ph) during mitosis.', 'H3T3 phosphorylation is catalyzed by Haspin', 'aspin is an atypical protein kinase that in several organisms phosphorylates histone H3Thr3', 'histone H3 that is phosphorylated at T3 (H3T3ph) by Aurora B-stimulated Haspin.', 'phosphorylating Thr3 of histone H3, Haspin promotes centromeric recruitment of the chromosome passenger complex (CPC) during mitosis.', 'aspin phosphorylates histone H3 at threonine-3 (H3T3ph),', 'Haspin-dependent histone H3 phosphorylatio', 'aspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis', 'Haspin is a protein kinase the only known target of which is phosphorylation of histone H3 at Thr3 residue (H3T3ph)', 'Haspin in vitro phosphorylates histone H3 at threonine 3', 'Haspin is a histone H3 Thr3 kinase that has important roles in chromosome cohesion during mitosis', 'phosphorylation of histone H3 threonine 3 (H3-pT3) mediated by Haspin', 'histone H3 specifically when it is phosphorylated at threonine 3, a mark that is placed by the mitotic kinase, haspin', 'H3T3 kinase haspin', 'phosphorylation of histone H3-threonine 3 (H3-pT3) mediated by Haspin', 'kinase activity of Haspin, which phosphorylates H3T3,', 'istone H3 Thr-3 phosphorylation by Haspin', 'phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin', 'Haspin/Gsg2 is a histone H3 threonine-3 kinase', 'During mitosis haspin is phosphorylated, associates with the chromosomes, centrosomes and spindle, and is responsible for phosphorylation of histone H3 at threonine-3', 'haspin, a member of a distinctive group of protein kinases present in diverse eukaryotes, phosphorylates H3 at Thr 3', 'Haspin phosphorylated histone H3 at both Thr3 and Thr11 in vitro.', 'Haspin kinase is a histone H3 threonine kinase', 'Haspin phosphorylated histone H3 at both Thr3 and Thr11 in vitro']

['Haspin phosphorylates histone H3 at Thr3 (H3T3ph) during mitosis']

['Histone 3 at Thr3']

What is the mechanism of action of Nalmefene?

['Opioids that stimulate the μ-opioid receptor (MOR1) are the most frequently prescribed and effective analgesics. Here we present a structural model of MOR1. Molecular dynamics simulations show a ligand-dependent increase in the conformational flexibility of the third intracellular loop that couples with the G protein complex. These simulations likewise identified residues that form frequent contacts with ligands. We validated the binding residues using site-directed mutagenesis coupled with radioligand binding and functional assays. The model was used to blindly screen a library of ∼1.2 million compounds. From the 34 compounds predicted to be strong binders, the top three candidates were examined using biochemical assays. One compound showed high efficacy and potency. Post hoc testing revealed this compound to be nalmefene, a potent clinically used antagonist, thus further validating the model. ', 'The neurobiological mechanism by which opioid modulators affect drinking behavior is based on the strong connection between the endogenous opioid system, the dopamine system and the influence of the CNS stress response.', 'Naltrexone- and to a lesser extent nalmefene- is an agent that modulates opioidergic transmission in the CNS and it shows a limited but well-studied efficacy in treating alcohol dependence. ', 'Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. ']

['Nalmefene shows opioid receptor antagonism, binds the μ-opioid receptor (MOR1) and modulates opioidergic transmission in the CNS.']

[]

Is desmin an intermediate filament protein involved in Dilated Cardiomyopathy (DCM)?

['Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known.', 'The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.', 'According to the predominant view, desmin mutations cause dilated cardiomyopathy (DCM). We evaluated a family with restrictive cardiomyopathy (RCM) associated with a novel desmin mutation and reviewed recent reports regarding the frequency of RCM in patients with desmin myopathy.', 'Dilated cardiomyopathy (DCM) is characterized by enlargement and dilation of all heart compartments associated with serious decrease of its contractile function. DCM hallmark is the combination of dystrophic and hypertrophic alterations of cardiomyocytes. Since the power output of cardiac cells is directly related to remodeling of their contractile machinery we investigated expression of selected contractile and cytoskeletal proteins in the left ventricle of DCM patients using immunoblotting. The content of the recognized protein markers of cardiomyocyte hypertrophy such as tubulin, desmin and slow skeletal myosin heavy chain isoform, MHCbeta, was significantly elevated in DCM compared to normal myocardium.', 'In contrast, overexpression of desmin filaments by itself is not detrimental to the heart. Although loss-of-function studies have been more limited, ablation of the desmin gene causes mitochondrial dysfunction and apoptosis, resulting in cardiomyopathy in mice. From function studies, abnormal desmin aggregation and disruption of the desmin networks resulting from expression of either mutant desmin or mutant CryAB have been shown to remodel the heart and compromise cardiac function, suggesting their synergistic roles in disease pathogenesis.', 'A missense mutation in the desmin gene (DES) causes DCM in a human family.', 'Mice deficient in desmin, the muscle-specific member of the intermediate filament gene family, display defects in all muscle types and particularly in the myocardium. Desmin null hearts develop cardiomyocyte hypertrophy and dilated cardiomyopathy (DCM) characterized by extensive myocyte cell death, calcific fibrosis and multiple ultrastructural defects. Several lines of evidence suggest impaired vascular function in desmin null animals.', 'Familial DCM is commonly inherited as autosomal dominant trait; less frequently it is autosomal recessive, X-linked or matrilinear. The disease is clinically and genetically heterogeneous. Genes causally linked to this phenotype include dystrophin, dystrophin-associated glycoproteins, actin, desmin, beta-miosin heavy chain, cardiac troponin T, and mitochondrial DNA genes, mostly transfer RNAs.', 'Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene.', 'Mutations of the desmin, delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities.', 'Autosomal dominant DCM is the most frequent form (56% of our cases), and several candidate disease loci have been identified by linkage analysis. Three disease genes are presently known: the cardiac actin gene, the desmin gene, and the lamin A/C gene.', 'Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), whereas three other genes (actin, lamin A/C, and desmin) cause autosomal dominant DCM;', 'Desmin defects were also recently identified in 1 familial dilated cardiomyopathy.', 'By candidate gene screening, the molecular diagnosis can be provided for dystrophin, DAG, mitochondrial DNA, actin and desmin gene defects.', 'Desmin (z-bands) are partly destroyed in DCM. Anti-desmin antibody titers as indicators of a possible secondary immune response are found high in patients with acute myocarditis declining during reconvalescence and are also elevated in DCM. ', 'Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice', 'Desmin, the muscle-specific intermediate filament, is involved in myofibrillar myopathies, dilated cardiomyopathy and muscle wasting']

['According to the predominant view, desmin mutations cause dilated cardiomyopathy (DCM). Mice deficient in desmin, the muscle-specific member of the intermediate filament gene family, display defects in all muscle types and particularly in the myocardium. Desmin null hearts develop cardiomyocyte hypertrophy and dilated cardiomyopathy (DCM) characterized by extensive myocyte cell death, calcific fibrosis and multiple ultrastructural defects. Desmin defects were also recently identified in 1 familial dilated cardiomyopathy.']

['yes']

Is there any role of TBR1 in autism?

['TBR1 regulates autism risk genes in the developing neocortex', 'Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.', 'T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders.', 'T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs.', 'Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism.', 'The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders. ', 'Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). ', 'Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism.', 'T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1 (-∕-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs.', 'TBR1 regulates autism risk genes in the developing neocortex.', 'De novo TBR1 mutations in sporadic autism disrupt protein functions.', 'In humans, PAX6, EOMES, and TBR1 have been linked to intellectual disability and autism.', 'It is therefore possible that TBR1 controls the expression of other autism risk factors.', 'Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.', 'T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor.', 'Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs).', 'Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism.', 'Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis.', 'Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs).', 'T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor', 'Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis', 'Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs)', 'Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis.', 'It is therefore possible that TBR1 controls the expression of other autism risk factors.', 'TBR1 regulates autism risk genes in the developing neocortex.', 'De novo TBR1 mutations in sporadic autism disrupt protein functions.', 'Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.']

['Yes. Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including T-Brain-1 (TBR1), a master regulator of cortical development. T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1 (-∕-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1.']

['yes']

Which are the causes of the Koebner phenomenon?

['Lichen sclerosus has been reported at sites of injury as a Koebner phenomenon. ', 'Therefore, lower expression of keratinocyte-derived factors, including SCF, in vitiliginous keratinocytes, which could result from keratinocyte apoptosis, might be responsible for passive melanocyte death and may explain the Koebner phenomenon.', 'Deprivation of survival factors causes the apoptosis of melanocytes. Vitiligo often develops following physical trauma, even if this is minor. The exact mechanism of the Koebner phenomenon in vitiligo is unclear.', 'First described in 1877 as the appearance of psoriatic lesions in the uninvolved skin of psoriatic patients as a consequence of trauma, the Koebner phenomenon has since been described in numerous diseases. ', 'The Koebner phenomenon is known to occur (lichen sclerosus occurs in skin already scarred or damaged), so trauma, injury, and sexual abuse have been suggested as possible triggers of symptoms in genetically predisposed people. ', 'The triggering role of physical stress is seen in the "deep Koebner" phenomenon, which causes inflammation in the synovial membrane and in enthesis, resulting in peripheral arthritis. ', 'The triggering role of physical stress is seen in the "deep Koebner" phenomenon, which causes inflammation in the synovial membrane and in enthesis, resulting in peripheral arthritis.', 'Two patients with unusual skin stimuli causing koebner phenomenon in psoriasis are reported.', 'To document the role of striae distensae and striae gravidarum in causing Koebner phenomenon in cases of vitiligo, psoriasis and lichen planus.', 'In addition, psoriasis can be caused by a\xa0local cutaneus trauma, known as Koebner phenomenon.', "Striae are documented to cause Koebner phenomenon in patients with preexisting vitiligo, psoriasis and lichen planus, the three conditions where 'true kobenerisation' has been suggested according to Boyd and Nelder classification.", '[Unusual Koebner phenomenon in psoriasis caused by varicella and UVB].', 'A 48 year-old woman developed an exacerbation of a latent psoriasis as a Koebner phenomenon in a migrating erythema caused by Borrelia afzelii infection.', '[Psoriasis as Koebner phenomenon in erythma migrans].', '[Characteristics of the Koebner phenomenon in patients with psoriasis vulgaris].', 'Vitiligo appearing in striae distensae as a Koebner phenomenon.', 'The appearance of vitiligo in striae distensae as a form of Koebner phenomenon has been reported rarely.', 'The Koebner phenomenon originally described the appearance of psoriatic lesions in the uninvolved skin of patients with psoriasis as a consequence of trauma.', 'The triggering role of physical stress is seen in the "deep Koebner" phenomenon, which causes inflammation in the synovial membrane and in enthesis, resulting in peripheral arthritis', 'To document the role of striae distensae and striae gravidarum in causing Koebner phenomenon in cases of vitiligo, psoriasis and lichen planus.Striae are documented to cause Koebner phenomenon in patients with preexisting vitiligo, psoriasis and lichen planus, the three conditions where true kobenerisation has been suggested according to Boyd and Nelder classification.Striae distensae and striae gravidarum are examples of blunt trauma', '[Unusual Koebner phenomenon in psoriasis caused by varicella and UVB]', 'A 48 year-old woman developed an exacerbation of a latent psoriasis as a Koebner phenomenon in a migrating erythema caused by Borrelia afzelii infection', 'Intradermal antigen tests and the Koebner phenomenon in psoriasis', 'In addition, intensity of delayed hypersensitivity reaction and resolution times demonstrate no significant difference between psoriatic and nonpsoriatic subjects statistically (P > 0.05).These findings may indicate that intradermal antigens used in this study were more effective in inducing the Koebner phenomenon than injury alone', "RESULTS: Striae are documented to cause Koebner phenomenon in patients with preexisting vitiligo, psoriasis and lichen planus, the three conditions where 'true kobenerisation' has been suggested according to Boyd and Nelder classification. ", 'According to the presence of Koebner phenomenon they were divided in two groups, one with positive and the other with negative Koebner phenomenon which presented the control group at the same time.RESULTS AND DISCUSSION: The Koebner reaction is often thought to be more frequent in actively spreading, severe psoriasis.', 'We describe a case of concurrent lichen planus and sarcoidosis in the auditory canal, which represents an unusual manifestation of the Koebner phenomenon.', 'According to the presence of Koebner phenomenon they were divided into two groups, 20 patients with positive and 40 patients with negative Koebner reaction, who were the control group at the same time.RESULTS AND DISCUSSION: 95% of patients treated with PUVA, were cleared of psoriatic changes in the Koebner positive, as well as in the Koebner negative group.', "Striae are documented to cause Koebner phenomenon in patients with preexisting vitiligo, psoriasis and lichen planus, the three conditions where 'true kobenerisation' has been suggested according to Boyd and Nelder classification."]

['The causes of the Koebner phenomenon are:\n1) Lichen sclerosus\n2) Vitiligo\n3) Psoriasis and \n4) Physical stress.']

['Lichen sclerosus', 'Vitiligo', 'Psoriasis', 'Physical stress', 'Lichen planus']

Which DNA repair system is involved in HNPCC?

["The HNPCC syndrome (hereditary non polyposis colon cancer) or Lynch syndrome stands for an autosomic dominant condition leading to the most prevalent hereditary colo-rectal cancers (CCR). MMR (mismatch repair)'s genes are involved in carcinogenesis as they play a role in ADNA mismatch repair.", 'Mutations in the genes of the mismatch DNA repair system and of the TGF-beta-II-receptor, the main defects of the HNPCC (hereditary nonpolyposis colorectal cancer), are exclusively identified in sequences of microsatellites. ', 'In HNPCC families, germline mutations in any of four genes encoding proteins of a specialized DNA repair system, the mismatch repair, predispose to cancer development. ']

['In HNPCC families, germline mutations in any of four genes encoding proteins of a specialized DNA repair system, the mismatch repair, predispose to cancer development.']

['In HNPCC, the mismatch DNA repair system is involved.']

Which gene(s) should be genotyped in order to prescribe the drug Cetuximab (anti-EGFR)?

['Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).', '. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532-536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness. ', 'KRAS mutations are strong predictors for clinical outcomes of EGFR-targeted treatments such as cetuximab and panitumumab in metastatic colorectal cancer (mCRC).', 'KRAS mutation is widely accepted as a strong, negative predictive marker for anti-epidermal growth factor receptor antibodies, including cetuximab and panitumumab. ', 'KRAS status is now a mandatory prerequisite in order to treat metastatic colorectal patients with anti-Epidermal Growth Factor Receptor (EGFR) antibodies, such as cetuximab or panitumumab. KRAS mutations are unambiguously linked to a lack of response to these targeted therapies.', 'The EGFR-R497K polymorphism is a potential predictor for overall survival in HNSCC patients treated with cetuximab based therapy in the palliative setting.', "Laboratories are increasingly required to perform molecular tests for the detection of mutations in the KRAS gene in metastatic colorectal cancers to allow better clinical management and more effective treatment for these patients. KRAS mutation status predicts a patient's likely response to the monoclonal antibody cetuximab.", 'KRAS mutation has been unambiguously identified as a marker of resistance to cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients. ', ' This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer.', 'Intratumoral gene expression levels of EGFR, VEGFR2 and NRP as well as polymorphisms in FCGR3A, CyclinD1 and EGFR could predict clinical outcome in mCRC patients enrolled in BOND2, independent of KRAS mutation status.', 'Numerous clinical studies have shown that anti-EGFR therapies are effective only in a subset of patients with colorectal cancer. Even though mutations in the KRAS gene have been confirmed as negative predictors of the response to EGFR-targeted therapies, not all KRAS wild-type (wt-KRAS) patients will respond to treatment. Recent studies have demonstrated that additionally wild-type BRAF (wt-BRAF) genotype is required for response to panitumumab or cetuximab, suggesting that BRAF genotype criteria should be used together with KRAS genotype for selecting the patients who are about to benefit from the anti-EGFR therapy.', 'KRAS mutation is a dramatic example of single nucleotide polymorphism, which is able to identify a priori patients that could receive or not an anti-EGFR monoclonal antibody such as cetuximab or panitumumab. ', 'While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate.', 'Cetuximab and panitumumab, mAbs targeting EGFR, are registered for metastatic colorectal carcinoma (mCRC) patients whose tumors express EGFR as determined by immunohistochemistry. However, this method is not predictive of treatment efficacy.', '. This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.', 'A KRAS mutation confers resistance to cetuximab, which reduces treatment options, especially in first-line. ', 'KRAS genotyping was recently introduced as predictive biomarker, since only tumors carrying a wildtype were found to respond to treatment with panitumumab.']

['KRAS mutation has been unambiguously identified as a marker of resistance to cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients.\nOther genes are such as EGFR, BRAF and T53 have also been suggested to be genotyped in order to evaluate the drug responsivness.']

['KRAS', 'EGFR', 'BRAF', 'T53']

Which hormone abnormalities are common in Williams syndrome

['A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies.', 'TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2].', 'We report a boy with confirmed Williams-Beuren syndrome, who was found to have classical growth hormone deficiency and responded well to growth hormone therapy.', 'A 31-year-old man who had been under regular hemodialysis for 6 months was diagnosed as Williams syndrome (WS) by fluorescence in situ hybridization (FISH) chromosomal analysis. The association of WS and chronic renal failure (CRF) is only rarely encountered. Endocrinological examinations revealed hypergonadotropic hypogonadism. Prolonged and exaggerated responses of adrenocorticotropin (ACTH) to insulin-induced hypoglycemia and corticotropin releasing hormone (CRH) were also noted.', 'Involvement of the calcitonin/CGRP gene in Williams syndrome is postulated on the basis that Williams syndrome children often have infantile hypercalcemia and deficient expression of calcitonin, a hormone that lowers serum calcium levels. To test the hypothesis that mutations in the calcitonin/CGRP gene might be responsible for the reduced calcitonin levels', 'It has been suggested that a defect in calcitonin function may play a role in Williams syndrome', 'Imparied calcitonin secretion in patients with Williams syndrome.', 'in patients with Williams syndrome, we studied five such children, with intravenous calcium and parathyroid hormone infusions as provocative stimuli. These patients were found to have significantly higher mean baseline calcium concentrations, delayed clearance of calcium after intravenous calcium loading, and blunted calcitonin responses after calcium infusion', 'Our studies demonstrate that patients with Williams syndrome have a defect in the synthesis or release of immunoreactive calcitonin. A deficiency of calcitonin may explain the abnormalities of calcium metabolism seen in these patients and can serve as an important endocrine marker for Williams syndrome.', 'A 16-year-old male adolescent diagnosed to have the Williams-Beuren syndrome was referred to our obesity outpatient clinic, due to his morbid obesity (body mass index 39.2 kilograms per square metre) and gluttony. After several unsuccessful dietary treatments, we started therapy with sibutramine. As growth hormone (GH) deficiency was diagnosed by an additional GH-stimulation test, we commenced with a GH-treatment. ', ' Subclinical hypothyroidism is a frequent but stable finding in young children with WS.', 'Thyroid involvement in Williams syndrome (WS) was recently reported in two small groups of patients, both showing an increased prevalence of elevation of TSH serum concentration; ', 'in a population of 95 WS patients, half of them followed for more than 5 years. Our study confirms the increased incidence of both elevated TSH serum values (37.9% in our sample)', 'This study confirms the presence of alterations of thyroid function in WS ', 'We report a female infant with confirmed WBS who, through provocative testing, was found to have GHD', 'the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS', ' a female presenting with congenital heart defects, liver hemangiomas, and facial dysmorphisms admitted to hospital at 3 months of age because of feeding difficulties and poor growth. She had hypotonia and large tongue, "coarse" face, and umbilical hernia in presence of complex congenital cardiovascular malformations. In spite of normal neonatal screening we performed serum levels of thyroid hormones. Thyrotropin level was very high ', 'WS and TD participants had similar profiles in a familiar setting, while participants with WS had elevated cortisol late in the day in the novel setting when social demands were higher. ', 'Results suggest that adults with WS have a typical diurnal cortisol profile ', 'Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP', 'high prevalence of impaired glucose regulation, adults with WS ', 'Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration', 'WBS and abnormalities of thyroid function are common in patients with this feature. T']

['Elevated Thyrotropin - TSH\nLow FT4\nGrowth Hormone deficiency\nCalcitonin deficiency\nElevated Prolactin\nElevated Cortisol\nElevated Oxytocin\nElevated Vasopressin']

['Elevated Thyrotropin -', 'Elevated TSH', 'Low FT4', 'Low Thyroxine', 'Growth Hormone deficiency', 'GHD', 'Calcitonin deficiency', 'Elevated Prolactin', 'Elevated Cortisol', 'Elevated Oxytocin', 'Elevated OT', 'Elevated Vasopressin', 'Elevated AVP']

Which are the most frequent syndromes associated with inherited bone marrow failure?

['Ocular and orbital manifestations of the inherited bone marrow failure syndromes: Fanconi anemia and dyskeratosis congenita', 'The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS)', 'The major inherited bone marrow failure syndromes associated with development of pancytopenia include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and amegakaryocytic thrombocytopenia.', 'The major inherited bone marrow failure syndromes associated with development of pancytopenia include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and amegakaryocytic thrombocytopenia']

['The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) ', 'The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS).']

['Fanconi anemia', 'Dyskeratosis congenita', 'Diamond-Blackfan anemia', 'Shwachman-Diamond syndrome']

Is nucleosome eviction ATP-dependent?

["ATP-dependent chromatin remodeling and nucleosome-depleted 'barriers' co-operate to determine the kinetics of nucleosome organization", 'ATP-dependent nucleosome-remodeling factors endow chromatin with structural flexibility by promoting assembly or disruption of nucleosomes and the exchange of histone variants.', 'remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes.', 'which promotes histone deposition onto DNA, and a novel activity, which prevents nucleosome eviction but not remodeling mediated by the ATP-dependent RSC complex', 'ATP-dependent chromatin remodeling complex SWI/SNF regulates transcription and has been implicated in promoter nucleosome eviction', 'ATP-dependent nucleosome-remodeling enzyme involved in transcription, replication, and the DNA damage response', 'Iec1-Ino80 complex promotes transcription through nucleosome eviction', 'Ino80 complex from fission yeast mediates ATP-dependent nucleosome remodeling in vitro', 'reconstitution of nucleosome disassembly using the ATP-dependent chromatin remodeler Rsc and Vps75 revealed that these proteins can cooperate to remove H2A/H2B dimers from nucleosomes.', 'TP-dependent chromatin-remodeling complexes, such as RSC, can reposition, evict or restructure nucleosome', 'TP-dependent chromatin remodeling complexes play a critical role in chromatin dynamics', ' activity of SWI/SNF to histone eviction in trans from gene promoters.']

['Yes, nucleosome eviction and chromatin remodelling depends on ATP']

['yes']

Mutation of which gene and which chromosome cause Neurofibromatosis type I?

['The von Recklinghausen neurofibromatosis (NF1) gene has been localized to the pericentromeric region of chromosome 17.', 'Nine markers from the pericentromeric region of chromosome 17 were typed in 16 British and five South African families with neurofibromatosis type 1 (NF1).', 'Inspection of recombinant events in families informative for several markers suggests that the NF1 gene is located between the markers EW301 (cen-p11.2) and EW206 (cen-q12) and possibly distal to pHHH202 (q11.2-q12).', 'The gene for von Recklinghausen neurofibromatosis type 1 (NF1) has recently been mapped to the pericentromeric region of human chromosome 17.', 'In addition to reporting, in accompanying papers, their individual analyses of mapping the neurofibromatosis type 1 (NF1) gene on chromosome 17, members of the International Consortium for NF1 Linkage contributed their data for our joint analysis to determine the exact sequence of flanking markers and to obtain precise estimates and confidence limits of the recombination fractions for the closest markers, in anticipation of clinical use.', 'To better map the location of the von Recklinghausen neurofibromatosis (NF1) gene, we have characterized a somatic cell hybrid designated 7AE-11. This microcell-mediated, chromosome-transfer construct harbors a centromeric segment and a neo-marked segment from the distal long arm of human chromosome 17.', "The cosmids in the NF1 region will be an important resource for testing DNA blots of large-fragment restriction-enzyme digests from NF1 patient cell lines, to detect rearrangements in patients' DNA and to identify the 17;22 NF1 translocation breakpoint.", 'The frequent LOH surrounding the NF1 locus and lack of neurofibromin expression in these tumors suggest that NF1 gene mutations may contribute to the development of adrenal gland neoplasms in patients with NF1.', 'In the latter, the breakpoint in 17q occurred below the centromere and is at or in the region of the Neurofibromatosis Type 1 (NF1) gene.', 'Neurofibromatosis type I (NF1) is an autosomal dominant condition associated with mutations in the long arm of chromosome 17, and characterised by neurofibromas, café-au-lait spots and axillary freckling.', "In addition, the mother's and maternal grandmother's genetic analysis showed identical mutations in the neurofibromatosis I gene on the long arm of chromosome 17, confirming the diagnosis of NF1.", 'Duplicon-mediated microdeletions around the NF1 gene are frequently associated with a severe form of neurofibromatosis type I in a subgroup of patients who show an earlier onset of cutaneous neurofibromas, dysmorphic facial features, and lower IQ values.', 'Neurofibromatosis had been diagnosed in infancy, and genetic testing showed that the patient had a mutation in chromosome 17, consistent with neurofibromatosis type I.', 'Neurofibromatosis Type 1 (NF1) is one of the most common inherited diseases in humans. It is caused by a mutation in the NF1 gene on chromosome 17, and is associated with numerous central and peripheral nervous system manifestations.', 'In 95% of NF1 individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several flanking genes.', 'Herein, we describe a unique case of anaplastic de novo astroblastoma-sarcoma, in essence a variant of gliosarcoma, occurring in a 50-year-old female with documented NF1. Genetic study (fluorescence in situ hybridization) demonstrated no chromosomal losses or gains. Testing for abnormalities of chromosomes 7, 9, 10, 12, 17, 19 and 20, including the EGFR, p16, PTEN, MDM2 and NF1 gene regions, we found the tumor to exhibit a deletion of PTEN, monosomy 17 and gains of chromosomes 19 and 20q.', 'Neurofibromatosis type I (NF1) is an autosomal dominant disorder affecting 1 in 3000 people. The NF1 gene is located on chromosome 17q11.2, spans 350 kb of genomic DNA, and contains 60 exons.', 'A patient with recurrent-remittent multiple sclerosis associated with neurofibromatosis type I is described. The case is interesting for two reasons: 1) the difficulty of evaluating MRI findings, since both entities involve similar anomalies and 2) the relation between the two entities, according to evidence from recent genetic studies showing that the myelin protein gene associated to oligodendrocytes is part of an intron of the neurofibromatosis-1 gene of chromosome 17.', 'Neurofibromatosis type I (NFI) is a common autosomal dominant disorder with an increased risk for developing benign and malignant tumors. The NFI gene has been cloned and maps to 17q11.2, and the gene product acts as a tumor suppressor gene.', 'Direct sequencing of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with loss of the wild-type allele in 84% (21/25) of cases.', 'A novel mutation c.4821delA was identified in NF1 gene, which predicted truncation of neurofibromin (p.Leu1607fs).', 'She had a genotype of heterozygous c.6709C>T mutation of NF1 gene.', 'RESULTS: The mutational analysis of the NF1 gene revealed a novel frameshift insertion mutation in exon 4c (c.654 ins A) in all affected family members.', 'Using lymphoblastoid, fibroblast, and buccal cell samples collected from both twins and from other family members in three generations, we discovered a pathogenic nonsense mutation in exon 40 of the NF1 gene.', 'We also found a novel non-synonymous change in exon 16 of the NF1 gene that was transmitted from the unaffected mother to both twins and co-segregated with the pathogenic mutation in the ensuing generation.', 'The disease gene of the Chinese NF1 family was linked to NF1 locus, and a nonsense mutation, G1336X in the NF1 gene was identified.', 'The present study demonstrated that G1336X mutation in the NF1 gene cause Neurofibromatosis type I in the family.']

['Neurofibromatosis Type I is an autosomal dominant condition associated with NF-1 gene mutation that is located in the long arm of chromosome 17 (17q11.2). In the majority (95%) of Neurofibromatosis Type I individuals, the mutation is found in the NF1 gene, while the remaining 5% of the patients have different types of genetic abnormalities.\n']

['NF1 gene', 'chromosome 17']

What role do Kupffer cells play in innate immunity and inflammation?

['["Kupffer cells (KCs) play a role in the development of drug induced liver injury (DILI).", "Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. ", "Kupffer cells (KCs) are the main source of MMP.", "liver, both Kupffer cells and recruited hepatic macrophages can contribute to decreased hepatic insulin sensitivity.", "Macrophages such as Kupffer cells in the liver are multifunctional cells.", "Kupffer cells--the resident macrophages of the liver--are able to release a tremendous array of mediators upon inflammatory conditions, such as infection, and their role in innate immunity is well described in the literature.", "Kupffer cells are the tissue macrophages in the liver and play an important role in the defense mechanisms of the body"]']

Kupffer cells are able to release a tremendous array of mediators upon inflammatory conditions, such as infection, and their role in innate immunity is well described in the literature.

[]

Is there an association between Muenke Syndrome and FGFR3 gene mutation?

['RESULTS: Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years).', 'Muenke is a fibroblast growth factor receptor 3 (FGFR-3)-associated syndrome, which was first described in late 1990 s. ', 'The syndrome is defined molecularly by a unique point mutation c.749C>G in exon 7 of the FGFR3 gene which results to an amino acid substitution p.Pro250Arg of the protein product. ', 'Muenke syndrome caused by point mutation (C749G) in the FGFR3 gene affects 1 in 30,000 newborns and accounts for 25% to 30% of genetic causes of craniosynostosis.', 'Phenotypic variability in two families of Muenke syndrome with FGFR3 mutation.', 'PURPOSE: There are a number of craniosynostosis syndromes with hearing loss-including Muenke, Apert, Pfeiffer, Crouzon, Beare-Stevenson, Crouzon with acanthosis nigricans, and Jackson-Weiss syndromes-that result from mutations in the fibroblast growth factor receptor (FGFR) genes. ', 'Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the Fibroblast Growth Factor Receptor3 (FGFR3) gene.', 'Talocalcaneal coalition in Muenke syndrome: report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism.', 'To better understand the pathophysiology of the Muenke syndrome, we present collective findings from several recent studies that have characterized a genetically equivalent mouse model for Muenke syndrome (FgfR3 (P244R)) and compare them with human phenotypes.', 'We show in this study that knock-in mice harboring the mutation responsible for the Muenke syndrome (FgfR3(P244R)) display postnatal shortening of the cranial base along with synchondrosis growth plate dysfunction characterized by loss of resting, proliferating and hypertrophic chondrocyte zones and decreased Ihh expression.', 'Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene.', 'The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes.', 'Epilepsy in Muenke syndrome: FGFR3-related craniosynostosis.', 'Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature.', 'The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes.', 'PURPOSE: The Muenke syndrome mutation (FGFR3 (P250R)), which was discovered 15 years ago, represents the single most common craniosynostosis mutation.', 'The heterozygous Pro250Arg substitution mutation in fibroblast growth factor receptor 3 (FGFR3), which increases ligand-dependent signalling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome.', 'P250R mutation in the FGFR3 gene also known as Muenke syndrome is associated with coronal craniosynostosis, sensorineural deafness, craniofacial, and digital abnormalities.', 'Muenke syndrome caused by the FGFR3 Pro250Arg mutation is associated with craniosynostosis, hearing loss, and various bony anomalies.', 'Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene.', 'Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans.', 'In addition, sensorineural hearing loss is detected in all FgfR3 (P244R) mutant mice as in the majority of Muenke syndrome patients.', 'Genetic testing identifies a pathogenic mutation or chromosomal abnormality in ∼ 21% of cases, but it is likely that further causative mutations remain to be discovered.To identify a shared signature of genetically determined craniosynostosis by comparing the expression patterns in three monogenic syndromes with a control group of patients with non-syndromic sagittal synostosis.Fibroblasts from 10 individuals each with Apert syndrome (FGFR2 substitution S252W), Muenke syndrome (FGFR3 substitution P250R), Saethre-Chotzen syndrome (various mutations in TWIST1) and non-syndromic sagittal synostosis (no mutation detected) were cultured', 'The craniosynostosis syndromes: Apert syndrome, Beare-Stevenson syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Muenke syndrome, Pfeiffer syndrome and Saethre-Chotzen syndrome can be caused by mutation in either FGFR1, FGFR2, or FGFR3', 'Identical proline-->arginine gain-of-function mutations in fibroblast growth factor receptor (FGFR) 1 (Pro252Arg), FGFR2 (Pro253Arg) and FGFR3 (Pro250Arg), result in type I Pfeiffer, Apert and Muenke craniosynostosis syndromes, respectively', 'The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes', 'Mutation analysis of FGFR-3 revealed a missense mutation in exon 6, c.749 C>G, with a resultant amino acid change from proline to arginine at codon 250 (P250R), in keeping with Muenke syndrome (Am J Hum Genet 1997;60:555-564)', 'In an attempt to delineate functional features separating SCS from Muenkes syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3', 'Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis', 'Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730).Here we report a clinical and molecular study in a large cohort of 125 Portuguese patients with these skeletal disorders. ', 'The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. ', 'P250R mutation in the FGFR3 gene also known as Muenke syndrome is associated with coronal craniosynostosis, sensorineural deafness, craniofacial, and digital abnormalities. ', 'METHODS: Fibroblasts from 10 individuals each with Apert syndrome (FGFR2 substitution S252W), Muenke syndrome (FGFR3 substitution P250R), Saethre-Chotzen syndrome (various mutations in TWIST1) and non-syndromic sagittal synostosis (no mutation detected) were cultured. ', 'Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. ', 'Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). ', 'In spite of a variable phenotype, Muenke syndrome has been related to a unique mutation on the FGFR3 gene, Pro 250 to Arg, which is characteristic of this disease. ', 'Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis syndrome.', 'Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene.', 'Epilepsy in Muenke syndrome: FGFR3-related craniosynostosis.', 'Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3).', 'The Muenke syndrome mutation (FGFR3 (P250R)), which was discovered 15 years ago, represents the single most common craniosynostosis mutation.']

['Yes, Muenke syndrome is caused by point mutation (C749G) in the Fibroblast Growth Factor Receptor3 (FGFR3) gene. It affects 1 in 30,000 newborns and accounts for 25% to 30% of genetic causes of craniosynostosis.']

['yes']

Is factor XI deficient in Hemophilia C?

['Factor XI deficiency is a rare hematologic disorder. Hemophilia C (factor XI deficiency) affects both genders and it is usually asymptomatic,', 'Congenital factor XI deficiency (also known as the Rosenthal syndrome or hemophilia C)', 'rare case of an acute cerebral aneurysm rupture in a patient with a known factor XI deficiency. Aneurysmal subarachnoid hemorrhage (SAH) accounts for a high mortality and morbidity rate. When SAH is associated with an inherited coagulation disorder such as hemophilia C', 'Factor XI deficiency (Hemophilia C)', 'Factor XI deficiency, also called hemophilia C,']

['Factor XI deficiency is associated with a bleeding tendency called Hemophilia C.']

['yes']

Which mutations of SCN5A gene are implicated in Brugada syndrome?

['This was the first study to systematically investigate sodium channel variants in Chinese patients with ARVD; a new SCN5A mutation, I137M, was found. ', 'We describe a family showing the association between Brugada syndrome and epilepsy in which a known mutation in the SCN5A gene (p.W1095X, c.3284G>A) was identified. ', 'Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) of the SCN5A gene for identification of mutations and larger rearrangements were performed, respectively. Eight patients (10.5%) had point mutations (R27H, E901K, G1743R (detected in three families), V728I, N1443S and E1152X).', 'Brugada syndrome (BrS) is a life-threatening arrhythmia disorder associated with autosomal-dominant mutations in the SCN5A gene. We aimed to characterize the diagnostic challenges and clinical manifestations of a novel SCN5A mutation associated with BrS. RESULTS: From a novel SCN5A mutation (c.664C>T; p.Arg222X) identified in a proband with the characteristic electrocardiographic pattern and the history of sudden collapse, 122 family members were studied including 40 carriers of the mutation. ', 'We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A).', 'The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x).', 'One missense mutation (G400A) in SCN5A was detected in a conserved region among the cohort of 19 patients. A H558R polymorphism was detected on the same allele. ', 'Thus, we studied the functional restoration of nonsense-mutated SCN5A. RESULTS: HEK293 cells were transfected with SCN5A cDNA or its mutant carrying W822X, a nonsense mutation associated with Brugada syndrome and sudden cardiac death. ', 'Among the cohort of 19 patients, one missense mutation (G400A) in SCN5A was detected in a conserved region. An H558R polymorphism was detected on the same allele.', 'Novel SCN5A mutation (Q55X) associated with age-dependent expression of Brugada syndrome presenting as neurally mediated syncope.', 'A novel nonsense SCN5A mutation (Q55X) was identified in the proband, his mother, and his asymptomatic brother.', 'Novel SCN5A gene mutations associated with Brugada syndrome: V95I, A1649V and delF1617', 'An intronic mutation (c.4810+3_4810+6dupGGGT) in the SCN5A gene, located outside the consensus splice site, was detected in this study in a family with a highly variable clinical phenotype of Brugada syndrome and/or conduction disease and in a patient with Brugada syndrome.', 'We genetically screened 30 asymptomatic probands (29 men and 1 woman; mean age 47.1 years) exhibiting a spontaneous Brugada-type ECG. Family members of patients with Brugada syndrome were excluded from the study. ', 'Genetic screening failed to identify SCN5A mutations in most cases but demonstrated a novel double missense mutation (K1527R and A1569P) located on the same allele in another asymptomatic subject (case 2).', 'We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome.', 'One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III.', 'The substitution (D1790G) causes LQTS and the insertion (D1795) induces both LQTS and Brugada syndromes in carrier patients.']

['The following mutations of SCN5A gene have been linked to Brugada syndrome:I137M, p.W1095X; c.3284G>A, R27H, E901K, G1743R, V728I, N1443S, E1152X, c.664C>T; p.Arg222X, Ala2>Thr, Ala735, Ala735>Thr, Val1340>Ile, IVS18-1G>A, E1784K (14x), F861WfsX90 (11x), D356N (8x), G1408R (7x), G400A, H558R, W822X, Q55X, V95I, A1649V, delF1617, c.4810+3_4810+6dupGGGT, K1527R, A1569P, R367H, A735V, R1192Q, D1795.']

['I137M', 'p.W1095X, c.3284G>A', 'R27H', 'E901K', 'G1743R', 'V728I', 'N1443S', 'E1152X', 'c.664C>T; p.Arg222X', 'Ala2>Thr, Ala735', 'Ala735>Thr', 'Val1340>Ile', 'IVS18-1G>A', 'E1784K (14x)', 'F861WfsX90 (11x)', 'D356N (8x)', 'G1408R (7x)', 'G400A', 'H558R', 'W822X', 'Q55X', 'V95I', 'A1649V', 'delF1617', 'c.4810+3_4810+6dupGGGT', 'K1527R', 'A1569P', 'R367H', 'A735V', 'R1192Q', 'D1795', 'p.I848fs', 'p.R965C', 'p.1876insM', 'R1232W/T1620M']

Abnormalities in which chromosomes were linked to the Moyamoya disease?

['Complex chromosome rearrangement of 6p25.3->p23 and 12q24.32->qter in a child with moyamoya.', 'Routine karyotype demonstrated extra chromosomal material on 6p. Single nucleotide polymorphism microarray revealed a previously unreported complex de novo genetic rearrangement involving subtelomeric segments on chromosomes 6p and 12q.', 'In terms of the genetics, recent literature suggests a low penetrance autosomal dominant or polygenic mode of transmission involving chromosomes 3, 6, 8, 12, and 17 for familial MMD. ', 'Furthermore, the current literature on familial MMD has pointed to a low penetrance autosomal dominant or polygenic mode of transmittance at loci on chromosomes 3, 6, 8, 12, and 17.', 'Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. ', 'We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. ', 'A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. ', 'Investigations included neuroimaging, cardiologic and ophthalmologic evaluation, hormonal testing, hemoglobin electrophoresis, chromosomal karyotyping, muscle biopsy for morphology, immunohistochemistry and enzyme assays, mtDNA mutation screening, and haplotype analysis of 2 loci previously linked to moyamoya, on chromosomes 10 (ACTA2) and 17.', 'These data strongly suggest that this family is affected by a hereditary moyamoya multisystem disorder with X-linked recessive pattern of inheritance.', 'Her features were consistent with TS and chromosome analysis revealed mosaicism in which 17% of the cells showed a pseudoisodicentric Y chromosome: 45,X (25)/46,X psu idic (Y)(11.2) (5). ', 'The small number of cases does not allow detailed analysis other than noting patient age (two older than 40 years), karyotype (two others associated with isochrome Xq), and associated cardiac risk factors (one with BAV).', ' Studies have shown a possible genetic association of MMD linked to chromosome 17 in Japanese cases as well as in cases found in other demographics. ', 'The gene responsible for NF1 is located on the chromosome region 17q11.2 and for familial moyamoya disease on chromosome 17q25. ', 'Autosomal dominant moyamoya disease maps to chromosome 17q25.3.', 'Under both classifications, significant evidence of linkage was only observed on chromosome 17q25.3, with maximum multipoint logarithm of odds (lod) scores of 6.57 (under the narrow classification) and 8.07 (under the broad classification) at D17S704. Haplotype analysis revealed segregation of a disease haplotype in all families but one, and informative crossovers enabled mapping of the MMD locus to a 3.5-Mb region between D17S1806 and the telomere of 17q, encompassing 94 annotated genes. CONCLUSIONS: Our data suggest that there is a major gene locus for autosomal dominant moyamoya disease on chromosome 17q25.3.', 'However, the mitochondrial DNA and Y chromosomal genotype showed that affected members had the same sequence of the Mitochondrial 3 portion of D-loop with Japanese patients. ', 'Smith-Magenis syndrome and Moyamoya disease in a patient with del(17)(p11.2p13.1).', 'We have employed a combination of aCGH, FISH, and MLPA to characterize an approximately 6.3 Mb deletion spanning chromosome region 17p11.2-p13.1 in this patient, with the proximal breakpoint within the RAI1 gene. ', 'Moyamoya syndrome in a child with trisomy 12p syndrome.', 'This report presents the first case of moyamoya syndrome with trisomy 12p with a familial pericentric inversion of chromosome 12.', ' She had been prenatally diagnosed with trisomy 12p with a familial pericentric inversion of chromosome 12 originating from her mother. She manifested developmental delay and some dysmorphic features of the face and limbs compatible with the clinical features of trisomy 12p.', 'The genes encoding tissue inhibitor of metalloproteinase (TIMP) 4 and TIMP2 span chromosomes 3p24.2-p26 and 17q25, respectively, which are the locations of familial moyamoya disease (FMMD) genes. ', "We postulate that a protein encoded on chromosome 21 may be related to the pathogenesis of Down's syndrome with moyamoya syndrome.", '[Molecular screening for moyamoya disease by use of expressed sequence tag on chromosome 3p].', ' To identify the expressed sequence tags (ESTs) with monoallelic expressions on chromosome 3, we used mouse A9 hybrid cells having human chromosome 3. Two ESTs showed only maternal expression in mouse A9 hybrid cells, and four showed non-expression in the lymphocytes derived from moyamoya patients. ', 'A novel susceptibility locus for moyamoya disease on chromosome 8q23.', 'Previous linkage studies have indicated that susceptibility loci for the disease are located on chromosomes 3p, 6q, and 17q. In the present study, we searched for loci linked to the disease in 12 Japanese families using 428 microsatellite markers and found significant evidence for linkage to 8q23 [maximum LOD score (MLS) of 3.6] and suggestive evidence for linkage to 12p12 (MLS=2.3). ', 'Considering the function, we selected nine genes as candidates from a total of 65 genes identified in the 9-cM region of D17S785-D17S836 in chromosome 17q25, and performed sequence analysis on the DNA samples obtained from a pedigree of familial moyamoya disease, which showed a complete linkage to the region by a haplotype analysis. ', 'Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25.', 'The characteristic lesions of moyamoya disease are occasionally seen in neurofibromatosis type 1, of which the causative gene (NF1) has been assigned to chromosome 17q11.2.', 'CONCLUSIONS: A gene for familial moyamoya disease is located on chromosome 17q25.', 'Recent genetic studies suggest some responsible genetic foci in chromosomes 3, 6 and 17.', 'To further specify the genetic component of moyamoya disease, a linkage study of moyamoya disease using markers on chromosome 6, where the HLA gene is located, was performed. ', 'Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26.', 'A linkage was found between the disease and markers located at 3p24.2-26.', 'We postulate that a protein encoded on chromosome 21 may be related to the pathogenesis of moyamoya disease. ', 'The diagnosis of PWS was confirmed genetically by the method of fluorescence in situ hybridization which showed the deletion of chromosome 15. ']

['chromosomes 3, 6, 8, 12, 15, 17, 21, X and Y were implicated in the Moyamoya disease.']

['3', '6', '8', '12', '15', '17', '21', 'X', 'Y']

Which mushroom is poisonous, Amanita phalloides or Agaricus Bisporus

["Seventeen edible mushrooms commercially available in Korea were analysed for their umami taste compounds (5'-nucleotides: AMP, GMP, IMP, UMP, XMP; free amino acids: aspartic, glutamic acid) and subjected to human sensory evaluation and electronic tongue measurements. Amanita virgineoides featured the highest total 5'-nucleotide content (36.9 ± 1.50 mg/g), while monosodium glutamate-like components (42.4 ± 6.90 mg/g) were highest in Agaricus", "liver transplantation improves patients' short-term post liver transplantation survival in Amanita phalloides poisoning"]

['The well-known cultivated species Agaricus bisporus is safe to eat while Amanita Phalloides is poisonous.']

['Amanita phalloides']

List mouse models for autism spectrum disorder (ASD).

['maternal immune activation (MIA) mouse model that is known to display features of ASD.', 'BTBR T+tf/J (BTBR), a model of ASD with cognitive deficits,', 'C58/J mouse strain, a model of ASD core symptoms. ', 'the C58/J mouse model of autism', 'Both C58/J and Grin1 knockdown mice, another model of ASD-like behavior, ', 'Mice injected subcutaneously with 600\u2009mg/kg valproic acid (VPA600) at gestational day 12.5 show reduced social interaction in adulthood (at 8 weeks of age), and they have been proposed as a mouse model of autism.', 'BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes ', 'The Autism ProSAP1/Shank2 mouse model ', 'Shank3-deficient mice', 'a panel of Shank mutant mouse models', 'maternal immune activation (MIA) mouse model of gestational poly(IC) exposure ', 'poly(IC) mouse model of autism spectrum disorders', 'BTBR T+ tf/J strain, a mouse model of autism.', 'The inbred BTBR T+ tf/J (BTBR) strain, a putative mouse model of autism,', 'C57BL/6J strain', 'SYNGAP1 mouse model of ID/ASD', 'Tsc2f/-;Cre mice demonstrated increased repetitive behavior as assessed with marble burying activity', 'BTBR T+ tf/J mouse model for autism spectrum disorders', 'Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD.', 'NR1(neo-/-) mice', 'mice heterozygous for the Gabrb3 gene', 'Gestational immune activation and Tsc2 haploinsufficiency', 'novel transgenic mouse, MALTT,', 'sing a mouse model, CD38, a transmembrane protein expressed in immune cells but also in brain, was found to be critical for social behavior via regulation of oxytocin secretion. ', 'fmr1 knockout mouse model', 'TS2-neo mouse', 'Congenic Tbx1 heterozygous (HT) mice ', 'the valproic acid (VPA) mouse model of autism', ' indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.', '(Dp(11)17/+) ', 'BTBR T+tf/J (BTBR) inbred mice are frequently used as a model of autism spectrum disorders (ASD)', 'Intact and impaired executive abilities in the BTBR mouse model of autism.']

['Numerous mouse models exists for autism spectrum disorder, such as: BTBR T+tf/J (BTBR), maternal immune, activation (MIA) mouse model of gestational poly(IC) exposure, C58/J and ProSAP1/Shank2.']

['maternal immune activation (MIA) mouse model of gestational poly(IC) exposure', 'C58/J', 'Grin1', 'Shank3-deficient mice', 'C57BL/6J', 'SYNGAP1', 'Tsc2f/-', 'MALTT', '(Dp(11)17/+)', 'NR1(neo-/-)', 'TS2-neo mouse', 'Tbx1 heterozygous (HT) mice', 'BTBR T+tf/J (BTBR)', 'VPA600', 'ProSAP1/Shank2']

Is TREM2 associated with Alzheimer's disease in humans?

["Genetic deficits and loss of function for the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in Alzheimer's disease.", "Recent works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer's disease (AD),", 'possible involvement of TREM2 in AD pathogenesis.', "TREM2 is associated with the risk of Alzheimer's disease in Spanish population.", "Two recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD).", 'we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD.', "(TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD).", 'In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls.', "We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set", "The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001).", "Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease", "Recent works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer's disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele.", "The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD).", 'BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.', "CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.", "RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10))."]

["TREM2 variants have been found to be associated with early as well as with late onset Alzheimer's disease."]

['yes']

What is the mechanism of microRNA deregulation in carcinogenesis?

["MicroRNAs are a class of small non-coding RNAs that negatively regulate gene expression by interacting with the 3'UTR of protein-coding mRNA. MicroRNAs are implicated in nearly all major biological and cellular events, and recent findings further link microRNA deregulation to human carcinogenesis.", 'MiR-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through NF-κB pathways.', 'MicroRNAs (miRNAs), which are small non-coding RNAs, are involved in diverse biological functions and carcinogenesis.', "Moreover, we demonstrated that miR-106b downregulates APC expression by directly targeting the 3'-untranslated region of APC messenger RNA.", 'Furthermore, miRNAs present a mechanism by which genes with diverse functions on multiple pathways can be simultaneously regulated at the post-transcriptional level. However, little is known about the cancer-related pathways through which cancer-associated miRNAs (CA-miRNAs) regulate these processes representing either positive or negative functions in carcinogenesis.', 'MicroRNAs, known as small noncoding MiRNAs, 19 to 24 nt in length, are important gene regulators and recognized as key players in carcinogenesis. The mechanism lies in that the MiRNAs can conjugate with their targeted mRNA and then lead to the targeted mRNA degradation or repress their translation. Bioinformatic analysis indicates that each MiRNA can regulate hundreds of gene targets and could serve functionally as "oncogenes" or "tumor suppressor genes", and therefore regulate multiple cellular processes relevant to carcinogenesis and cancer progression.', 'microRNAs (miRs) are endogenous small non-coding RNAs that are aberrantly expressed in various carcinomas.', 'While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown.', 'In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown.', 'These are microRNAs (miRNAs), a class of noncoding RNAs, 20-23 nucleotides in length, that can up or downregulate gene expression of downstream gene targets (including transcription factors, oncogenes, and tumour suppressor genes) at the post-transcriptional level. Some members of this new class of genes seem to have the potential to act simultaneously either as oncogenes or as tumour suppressor genes depending on the molecular microenvironment of the cell.', 'MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis.', 'Regulation of hepatocarcinogenesis by microRNAs.', 'MicroRNAs are implicated in nearly all major biological and cellular events, and recent findings further link microRNA deregulation to human carcinogenesis.', 'miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma.', 'However, little is known about the cancer-related pathways through which cancer-associated miRNAs (CA-miRNAs) regulate these processes representing either positive or negative functions in carcinogenesis.', 'Combined with previous cancer studies, the analysis of the relevance between functions of CA-miRNAs and cancer-related pathways exploring different internal carcinogenesis stimuli also revealed the potential of the top five pathways to regulate core carcinogenesis processes.', 'MicroRNAs, known as small noncoding MiRNAs, 19 to 24 nt in length, are important gene regulators and recognized as key players in carcinogenesis.', 'Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis.', 'Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated.', 'MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo.', 'MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis and have great potential for the diagnosis and treatment of cancer. However, the roles of miRNAs in hepatocellular carcinogenesis are still not fully elucidated.', 'Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis.', 'UNLABELLED: Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated.', 'Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown.']

['MicroRNAs (miRNAs) are endogenous non-protein coding single-stranded RNAs (19–25 nucleotides in length) generated from cleavage of larger non-coding RNAs by the ribonuclease III enzyme Dicer. They become part of the RNA-induced silencing complex and negatively regulate gene expression by binding to homologous 3\'-UTR region of target protein-coding mRNAs as an imperfect match, causing translational repression or degradation. Approximately one-third of the protein-coding genes are susceptible to miRNA regulation. Accumulating evidence indicates that deregulated miRNA expression is associated with the onset and progression of a number of human cancers. Therefore, cancer-associated miRNAs (CA-miRNAs) could regulate target genes by acting either as "oncogenes" or "tumor suppressor miRNA (TS-miRNAs)". In line with this, numerous cancers (e.g. breast, lung, oesophageal, prostate, pancreatic, gastric and colon cancer) have been classified based on their unique miRNA expression profile.']

[]

Does administration of triiodothyronine improve outcome following coronary artery bypass grafting?

['Serum T3 concentrations were significantly higher with fewer patients having T3 concentrations below the normal range in the T3 group than the placebo group throughout the postoperative period. Hemodynamic variables, postoperative inotrope requirement, and outcome variables showed no differences between the groups', 'We conclude that although widespread interest has been shown on the use of thyroid hormones in the perioperative period, and the effect of cardiopulmonary bypass on thyroid hormone metabolism widely studied, there is no substantial evidence to justify routine use of thyroid hormones in patients undergoing coronary artery bypass grafting.', 'Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery.', 'Perioperative administration of triiodothyronine increased cardiac output slightly and decreased systemic vascular resistance, but it had no effect on operative outcome.', 'Parenteral triiodothyronine given after crossclamp removal during elective coronary artery bypass grafting significantly improved postoperative ventricular function, reduced the need for treatment with inotropic agents and mechanical devices, and decreased the incidence of myocardial ischemia. The incidence of atrial fibrillation was slightly decreased, and the need for postoperative pacemaker support was reduced.', 'Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.', ' Intravenous T(3) does not have dramatic effects on hemodynamic variables in this setting as has been previously suggested. ', 'Raising serum triiodothyronine concentrations in patients undergoing coronary-artery bypass surgery increases cardiac output and lowers systemic vascular resistance, but does not change outcome or alter the need for standard postoperative therapy.', 'No significant differences were noted in the pre and post CPB hemodynamics between the two groups for the most part of the study except that heart rate was increased in T3 group.', 'The haemodynamic parameters were no different between the two groups at any postoperative time point. Likewise, density and affinity of lymphocyte beta-adrenoceptors were not significantly different from pre-operative values in either group.']

['Perioperative administration of synthetic thyroid hormone therapy have positive hemodynamic effects (consisting of increases cardiac output, lowered systemic vascular resistance) determining improved postoperative ventricular function, reduced the need for treatment with inotropic agents and mechanical devices, in the absence of relevant effects on outcome ad exception of lower incidence of atrial fibrillation.']

['no']

What is the HSP70-HSP110 disaggregase machinery?

['Clearance of misfolded and aggregated proteins is central to cell survival.', 'UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act. ']

['Clearance of misfolded and aggregated proteins is central to cell survival. UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act.']

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What is the inheritance pattern of Hunter disease or mucopolysaccharidosis II?

['ysosomal diseases (LD) are inherited as autosomal recessive traits, but two important conditions have X-linked inheritance: Fabry disease and Mucopolysaccharidosis II (MPS II).', 'unter disease, Mucopolysaccharidosis type II, is an X-linked recessive lysosomal storage disorder', 'unter syndrome is an X-linked recessive disorder', 'X chromosome heterozygosity and confirmed the paternal origin of one of the X chromosomes', " Hunter's disease in a female with an X-chromosome deletion", 'Chromosome studies on the patient revealed a partial deletion of the long arm of one X-chromosome,', 'unter disease, an X-linked recessive lethal', 'X-linked disease', 'Hunter syndrome in females']

['X- linked recessive']

['X- linked recessive']

List variants of the MC1R gene.

['All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant.', 'The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane receptor primarily expressed on melanocytes and melanoma cells.', 'for V60L to 2.74 (1.53-4.89) for D84E. ', ' We aim to examine the influence of the MC1R variants (RHC: D84E, R151C, R160W; NRHC: V60L, R163Q and the synonymous polymorphism T314T) on the MM risk in a population from the Canary Islands. ']

['V60L\nD84E\nV92M\nR151C\nR160W\nR163Q\nD294H']

['V60L', 'D84E', 'V92M', 'R151C', 'R160W', 'R163Q', 'D294H']

Which is the major function of sororin?

['Sororin pre-mRNA splicing is required for proper sister chromatid cohesion in human cells.', 'ororin accumulation during S phase, and are, therefore, essential to the maintenance of genome stability.', 'Defective sister chromatid cohesion is a general consequence of dysfunctional pre-mRNA splicing, resulting from the selective downregulation of the cohesion protection factor Sororin', 'the cohesion protein sororin', 'sororin, a factor required for the stable association of cohesin with chromatin, ', ' sororin, a critical regulator that stabilizes cohesin rings in sister chromatids,', 'Sister chromatid cohesion depends on Sororin, a protein that stabilizes acetylated cohesin complexes on DNA by antagonizing the cohesin release factor Wings-apart like protein (Wapl). ', 'Three additional factors Pds5, Wapl, and Sororin bind to cohesin and modulate its dynamic association with chromatin.', 'Sister chromatid cohesion, mediated by cohesin and regulated by Sororin, is essential for chromosome segregation. ', 'Sororin is a master regulator of sister chromatid cohesion and separation.', 'The maintenance of sister chromatid cohesion from S phase to the onset of anaphase relies on a small but evolutionarily conserved protein called Sororin.', 'Sororin mediates sister chromatid cohesion by antagonizing Wapl.', 'Sororin is a positive regulator of sister chromatid cohesion that interacts with the cohesin complex.']

['Sororin is a positive regulator of sister chromatid cohesion that interacts with the cohesin complex.']

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Where is the proteasome located?

['Cellular regulation by UPS- mediated protein degradation is a highly specific and selective process that depends on time (e.g. cell cycle) and location (nucleus, mitochondria or endoplasmic reticulum). ', 'In eukaryotic cells, regulated protein degradation of intracellular proteins is mediated largely by the ubiquitin proteasome system (UPS). ', 'We followed two key parameters of this process: the distribution of proteasomes in nuclear and cytosolic compartments, and the formation of cytoplasmic aggregate-like structures called proteasome storage granules (PSGs). ', 'Subsequently, cellular distribution of the PAI-2·proteasome complexes was established by immunogold staining and electron microscopy analyses. As judged by confocal microscopy, both proteins appeared in a diffuse cytosolic pattern, but they also could be found in a dense perinuclear and nuclear location. ', ' Frequently ubiquitinated proteins are targeted to the proteasome for degradation in the cytosol. ', ' More recently, proteasome-mediated degradation of cell cycle regulatory proteins, production and loading of antigenic peptides onto HLA molecules, and transient homing of diverse virion proteins required for entry and/or egress have been shown to be coordinated at the centrosome. ', 'We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP.', 'Two new forms of proteasomes, designated as the endoplasmic reticulum (ER) membrane-associated proteasome (ERa proteasome) and ER membrane-bound proteasome (ERb proteasome), were purified to homogeneity from 0.0125 and 2.5% sodium cholate extracts, respectively, of a rat liver microsomal fraction.', 'The proteasome is a large multicatalytic, proteinase complex located in the cytosol and the nucleus of eukaryotic cells.', 'Subcellular distribution of proteasomes implicates a major location of protein degradation in the nuclear envelope-ER network in yeast.', 'JAB1, which is thought to bind p27KIP1 and transport it from the nucleus to the cytoplasm for proteasome/ubiquitin-mediated degradation, was found to be localized both in the cytoplasm and the nucleus in undifferentiated and differentiating tumors whereas located predominantly in the nucleus of differentiated tumor cells.', '20S proteasomes are present in all areas where ATPase subunits are detected, consistent with the presence of intact 26S proteasomes.', 'Inhibition of proteasomes located in axons resulted in an accumulation of ubiquitinated proteins in these axons.', 'All these observations indicate that the mouse sperm proteasome participates in the binding to the zona pellucida and the acrosome reaction and that there is a pool of proteasomes located on the sperm head..', 'Thus, newly synthesized apoB is localized throughout the entire ER and degraded homogeneously, most likely by neighboring proteasomes located on the cytosolic side of the ER membrane.', 'While misfolded and short-lived proteins are degraded in proteasomes located in the nucleus and cytoplasm, the degradation of organelles and long-lived proteins in the lysosome occurs by the process of autophagy.', 'The GFP-tagged proteasomes were located within both the cytoplasm and the nucleus.', 'Proteasomes are large multicatalytic proteinase complexes located in the cytosol and the nucleus of eukaryotic cells.', 'Immunohistochemically, proteasomes (26S) were located in the cytoplasm in normal human muscle, but the staining intensity was weak.', 'In DMRV, proteasomes often were located within or on the rim of rimmed vacuoles, and in the cytoplasm of atrophic fibers.']

['The proteasome can be found in perinuclear and nuclear location, as well as in cytosolic compartments, such as mitochondria and endoplasmic reticulum. Proteasome-mediated degradation of cell cycle regulatory proteins, production and loading of antigenic peptides onto HLA molecules, and transient homing of diverse virion proteins required for entry and/or egress have been also shown to be coordinated at the centrosome.']

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What is the mechanism of action of raxibacumab?

[' Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. ', 'RESULTS: Interesting results were obtained using monoclonal antibodies: raxibacumab, cAb29 or cocktails of antibodies.', 'We showed previously in a 96-h sedated canine model that raxibacumab, a monoclonal antibody against protective antigen, augmented hemodynamic support (HS) and improved survival with lethal toxin challenge.', 'On December 14, 2012, the FDA approved Raxibacumab, the first monoclonal antibody product developed under Project BioShield to achieve this milestone, and the first biologic product to be approved through the FDA animal efficacy rule (or "Animal Rule").', 'With the only anthrax toxin inhibiting therapy (protective antigen-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, the situation, in our view, is still insecure.', 'Raxibacumab is a recombinant human monoclonal antibody developed against inhalational anthrax.', 'Raxibacumab is the first monoclonal antitoxin antibody made available that can be used with the antibiotics recommended for treatment of the disease.', 'Antibiotics can control B. anthracis bacteremia, whereas raxibacumab binds PA and blocks lethal toxin effects. ', 'Blocking the activity of the toxins with raxibacumab, a fully-human mAb directed against the protective antigen of Bacillus anthracis, may serve as an adjunct treatment. ', 'Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin.', 'Raxibacumab (ABthrax) is a human IgG1 monoclonal antibody against Bacillus anthracis protective antigen. ', 'Raxibacumab for the treatment of inhalational anthrax.', 'Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax.', "To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. ", 'Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin. ', 'Bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/ raxibacumab-treated New Zealand white rabbits.', 'Raxibacumab is approved for the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibiotic drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or not appropriate.', 'The availability of bioterrorism countermeasures has become more important since the September 2001 anthrax attacks, and development of raxibacumab is a significant advance in this area.', 'With the only anthrax toxin inhibiting therapy (protective antigen-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, the situation, in our view, is still insecure.', 'anthracis bacteremia, whereas raxibacumab binds PA and blocks lethal toxin effects.', 'Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit.CONCLUSIONS: A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax.', 'Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin.METHODS: We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys.', 'Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax.', 'Raxibacumab provides additional protection against inhalational anthrax via a mechanism different from that of either antibiotics or active immunization.', 'Raxibacumab for the treatment of inhalational anthrax.', 'Raxibacumab for inhalational anthrax: an effective specific therapeutic approach?', 'Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax.', 'Approval of Raxibacumab for the Treatment of Inhalation Anthrax Under the US Food and Drug Administration "Animal Rule".']

['Raxibacumab is a recombinant human IgG1 monoclonal antibody that binds the protective antigen of Bacillus anthracis, thus blocking toxin effects.\nIt is approved to treat inhalational anthrax.']

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Which histone modification is primarily linked to elongating transcription?

['Similarly, H3K36 trimethylation, a mark associated with transcription elongation, was specifically increased at the HD locus in the striatum and not in the cerebellum.', 'y expressing Myc protein fused with the estrogen receptor (Myc-ER) in fibroblasts, we observed that Myc, binding to the regulatory elements of Suz12, Ezh2, and Eed, induces the acetylation of histones H3 and H4 and the recruitment of elongating RNA polymerase II at their promoters', 'A basal level of JIL-1 binding can be defined that correlates best with the methylation of histone H3 at lysine 36, a mark that is placed co-transcriptionally', 'RNA polymerase II signals for deacetylation through the methylation of histone H3 lysine 36 (H3K36), which provides the recruitment signal for the Rpd3S histone deacetylase complex (HDAC)', 'Recent studies reviewed here demonstrate that histone deacetylation on the body of a transcribed gene is regulated via Set2-mediated methylation of histone H3-K36', 'H3K56 acetylation: a chromatin mark associated with the elongating RNA polymerase II', 'Furthermore, Rtt109 and H3K56 acetylation appear to correlate with actively transcribed genes and associate with the elongating form of polymerase II in yeast', 'In addition to coordinating the processing of the nascent transcript, elongating RNA polymerase II recruits histone methyltransferases to methylate lysines 4 and 36 of histone H3 in nucleosomes in the body of actively transcribed genes', "Set1, the yeast histone H3-lysine 4 (H3-K4) methylase, is recruited by the Pol II elongation machinery to a highly localized domain at the 5' portion of active mRNA coding regions."]

['Similarly, H3K36 trimethylation, a mark associated with transcription elongation, was specifically increased at the HD locus in the striatum and not in the cerebellum. Recent studies reviewed here demonstrate that histone deacetylation on the body of a transcribed gene is regulated via Set2-mediated methylation of histone H3-K36.']

['H3K36me3', 'H3K36 trimethylation']

Are there drugs for Tick-borne Encephalitis?

[' tick-borne encephalitis (TBE) have been detected in Bulgaria. Considering the remarkable increase in TBE morbidity in Europe over the past two decades, we conducted a study of TBE among patients with acute viral meningitis who were hospitalised in Bulgaria during 2009 to 2012. ', 'Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist.']

['No drug therapy available today']

['No drug therapy available today']