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Which two drugs are included in the Harvoni pill?

['Will Sofosbuvir/Ledipasvir (Harvoni) Be Cost-Effective and Affordable for Chinese Patients Infected with Hepatitis C Virus?', 'The developed method was applied to the analysis of the two drugs after a single oral administration of Harvoni 400/90 mg film-coated tablets containing 400 mg sofosbuvir and 90 mg ledipasvir to four healthy volunteers.', 'After the introductions of sofosbuvir (Sovaldi) and ledipasvir plus sofosbuvir (Harvoni) for the treatment of hepatitis C, employers have become very sensitive to new, and especially unforeseen, factors that significantly raise healthcare costs.', 'The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor ledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir (ledipasvir/sofosbuvir; Harvoni(®)) was recently approved in the US and the EU. ', 'Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus infection.', 'Ledipasvir/sofosbuvir (Harvoni): improving options for hepatitis C virus infection.', 'Also reviewed were recent practice guidelines on the management of HCV infections, prescribing information on all HCV drugs approved by the US Food and Drug Administration, and health technology assessments of Sovaldi® and Harvoni(TM) (sofosbuvir/ledipasvir).', 'Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus infection.', "This review will summarize the data regarding these interferon-free regimens, including Gilead's Harvoni (sofosbuvir/ledipasvir), AbbVie's Viekira Pak (paritaprevir/ritonavir/ombitasvir with dasabuvir), and Janssen's Olysio (simeprevir) with sofosbuvir."]

['Harvoni contains 400 mg sofosbuvir and 90 mg ledipasvir. It used for treatment of hepatitis C virus infection.']

['sofosbuvir', 'ledipasvir']

What is the main symptom of Marfan syndrome patients?

['The diagnosis and surgical treatment of patients with Marfan syndrome remain controversial. It is of utmost importance to identify patients at risk for acute aortic events to establish the correct surgical timing and the appropriate surgical treatment', "The not-uncommon spinal abnormalities associated with Marfan's syndrome rarely undergird clinical problems, and neurological features accompanying such bone abnormalities are rare.", 'The major cardiovascular manifestations of this condition are aortic dilation, which may involve the proximal and distal aorta, aortic regurgitation, aortic dissection, mitral valve prolapse, and mitral regurgitation. ', 'For the first time Bernhard Marfan described the Marfan-Syndrome in 1896; it is a meso- and ectodermed variety with the conducting symptom of "arachnodactyly".', 'Initial physical examination revealed an aortic systolic murmur and musculoskeletal morphological abnormalities compatible with Marfan syndrome', 'Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, aortic valve regurgitation or - the most feared and life-threatening symptom - aortic root dissection are the most common manifestations.', 'Meningeal abnormalities such as dural ectasia are seen in Marfan syndrome, but spinal meningeal cysts are rarely seen.', 'Pathohistological alterations of the aorta in patients with Marfan syndrome consisted in pronounced restructuring of the wall with deep irreversible alternative changes. ', 'The characteristics of acute aortic dissection among young Chinese patients: a comparison between Marfan syndrome and non-Marfan syndrome patients.', 'The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome.', 'During a 16-year period, 300 patients with presumed Marfan syndrome underwent 398 operations on the aorta and branch arteries, including 125 aortic root operations, 59 aortic arch repairs, 31 descending thoracic aortic repairs, and 178 thoracoabdominal aortic repairs.', 'Aortic disease in patients with Marfan syndrome: aortic volume assessment for surveillance', 'To compare the clinical features of type A aortic dissection (AAD) in patients with Marfan syndrome (MFS) and bicuspid aortic valves (BAV)', 'Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome']

['The diagnosis and surgical treatment of patients with Marfan syndrome remain controversial. Pathohistological alterations of the aorta in patients with Marfan syndrome consisted in pronounced restructuring of the wall with deep irreversible alternative changes. The risk of aortic dissection, which is the most serious manifestation of the Marfan syndrome, increases as the aorta enlarges. Surgical replacement of the aortic root with a composite graft does not end the disease process.', 'Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, which may involve the proximal and distal aorta, mitral valve prolapse, and mitral regurgitation, aortic valve regurgitation or - the most feared and life-threatening symptom - aortic root dissection are the most common manifestations.', 'The diagnosis and surgical treatment of patients with Marfan syndrome remain controversial. It is of utmost importance to identify patients at risk for acute aortic events to establish the correct surgical timing and the appropriate surgical treatment']

['aortic root dissection']

Does thyroid hormone receptor beta1 affect insulin secretion?

['We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic beta cells rRINm5F and hCM via thyroid hormone receptor (TR) beta1.', 'The silencing of TRbeta1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt.', 'T3 is able to specifically activate Akt in the islet beta cells rRINm5F and hCM through the interaction between TRbeta1 and PI3K p85alpha, demonstrating the involvement of TRbeta1 in this novel T3 non-genomic action in islet beta cells.']

['No']

['no']

How is OCT3 associated with serotonin?

['The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. ', 'Interestingly, OCT3 mRNA is however also significantly up-regulated in the hippocampus of serotonin transporter knockout mice where it might serve as an alternative reuptake mechanism for serotonin.', 'Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior.', 'However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT).', 'Organic cation transporter 3 (OCT3) is a high-capacity, low-affinity transporter that mediates bidirectional, sodium-independent transport of dopamine, norepinephrine, epinephrine, serotonin, and histamine.', 'The effect of blockade of either 5-hydroxytryptamine (5-HT)/serotonin transporter (SERT) with citalopram or the organic cation transporter 3 (OCT3)/plasma membrane monoamine transporter (PMAT) with decynium-22 (D-22) on spontaneous and evoked release of 5-HT in the nucleus tractus solitarius (NTS) was investigated in rat brainstem slices treated with gabazine', 'Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior', 'However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT)', 'Interestingly, OCT3 mRNA is however also significantly up-regulated in the hippocampus of serotonin transporter knockout mice where it might serve as an alternative reuptake mechanism for serotonin', 'Organic cation transporter 3 (OCT3) is a high-capacity, low-affinity transporter that mediates bidirectional, sodium-independent transport of dopamine, norepinephrine, epinephrine, serotonin, and histamine', 'RESULTS: We found a drastic decrease in IL-4 production by stimulated basophils on exposure to serotonin (5-hydroxytryptamine [5-HT]) that is taken up by basophils through the specific high-affinity transporters serotonin transporter and the polyspecific, high-capacity organic cation transporter 3 (OCT3; or Slc22a3) but inhibits their function exclusively through the latter. ', 'Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. ', 'However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). ', 'Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice.', 'Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice.', 'Interestingly, OCT3 mRNA is however also significantly up-regulated in the hippocampus of serotonin transporter knockout mice where it might serve as an alternative reuptake mechanism for serotonin.', 'Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior.', 'However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT).', 'We found a drastic decrease in IL-4 production by stimulated basophils on exposure to serotonin (5-hydroxytryptamine [5-HT]) that is taken up by basophils through the specific high-affinity transporters serotonin transporter and the polyspecific, high-capacity organic cation transporter 3 (OCT3; or Slc22a3) but inhibits their function exclusively through the latter.']

['OCT3 plays a role in serotonin clearance']

['serotonin clearance']

Which disease is associated with mutated Sox2?

['Anophthalmia and microphthalmia (A/M) are developmental ocular malformations defined as the complete absence or reduction in size of the eye. A/M is a highly heterogeneous disorder with SOX2 and FOXE3 playing major roles in dominant and recessive pedigrees, respectively;', 'anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers.', 'Three causative SOX2 mutations were found in subjects with syndromic A.', 'SOX2 anophthalmia syndrome is an uncommon autosomal dominant syndrome caused by mutations in the SOX2 gene and clinically characterized by severe eye malformations (anophthalmia/microphthalmia) and extraocular anomalies mainly involving brain, esophagus, and genitalia.']

['SOX2 anophthalmia syndrome is an uncommon autosomal dominant syndrome caused by mutations in the SOX2 gene and clinically characterized by severe eye malformations (anophthalmia/microphthalmia) and extraocular anomalies mainly involving brain, esophagus, and genitalia.']

['SOX2 anophthalmia syndrome']

What are piggyBAC transposons?

['The Sleeping Beauty and PiggyBac DNA transposon systems have recently been developed as tools for insertional mutagenesis. ', 'The use of nonviral gene delivery approaches in conjunction with the latest generation transposon technology based on Sleeping Beauty (SB) or piggyBac transposons may potentially overcome some of these limitations. ', 'DNA transposons have emerged as flexible and efficient molecular vehicles to mediate stable cargo transfer. However, the ability to carry DNA fragments>10 kb is limited in most DNA transposons. Here, we show that the DNA transposon piggyBac can mobilize 100-kb DNA fragments in mouse embryonic stem (ES) cells, making it the only known transposon with such a large cargo capacity. The integrity of the cargo is maintained during transposition, the copy number can be controlled and the inserted giant transposons express the genomic cargo. Furthermore, these 100-kb transposons can also be excised from the genome without leaving a footprint. The development of piggyBac as a large cargo vector will facilitate a wider range of genetic and genomic applications.', 'In this report, we harnessed the highly efficient, nonviral, and plasmid-based piggyBac transposon system to enable concurrent genomic integration of multiple independent transposons harboring distinct protein-coding DNA sequences', 'Among the transposons active in mammalian cells, the moth-derived transposon piggyBac is most promising with its highly efficient transposition, large cargo capacity, and precise repair of the donor site', 'Transposons are promising systems for somatic gene integration because they can not only integrate exogenous genes efficiently, but also be delivered to a variety of organs using a range of transfection methods. piggyBac (PB) transposon has a high transposability in mammalian cells in vitro, and has been used for genetic and preclinical studies', 'Simple piggyBac transposon-based mammalian cell expression system for inducible protein production.', 'The piggyBac transposon displays local and distant reintegration preferences and can cause mutations at noncanonical integration sites.', 'The piggyBac transposon was developed as an alternative mutagenic vector for mutagenesis of non-P-element targeted genes in Drosophila because the piggyBac transposon can more randomly integrate into the genome. Previous studies suggested that the piggyBac transposon always excises precisely from the insertion site without initiating a deletion or leaving behind an additional footprint.', 'A single injection of piggyBac transposons could achieve long-term inducible gene expression in the livers of mice in vivo, confirming our multiple-transposon strategy used in cultured cells. The plasmid-based piggyBac transposon system enables constitutive or inducible gene expression in vivo for potential therapeutic and biological applications without using viral vectors.', 'In this report, we harnessed the highly efficient, nonviral, and plasmid-based piggyBac transposon system to enable concurrent genomic integration of multiple independent transposons harboring distinct protein-coding DNA sequences. Flow cytometry of cell clones derived from a single multiplexed transfection demonstrated approximately 60% (three transposons) or approximately 30% (four transposons) stable coexpression of all delivered transgenes with selection for a single marker transposon.']

['The piggyBAC transposons are a nonviral gene delivery approach, that have been developed as tools for insertional mutagenesis. It can mobilize 100-kb DNA fragments in mouse embryonic stem (ES) cells, making it the only known transposon with such a large cargo capacity. The integrity of the cargo is maintained during transposition, the copy number can be controlled and the inserted giant transposons express the genomic cargo. Furthermore, these 100-kb transposons can also be excised from the genome without leaving a footprint. The development of piggyBac as a large cargo vector will facilitate a wider range of genetic and genomic applications.']

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Is nimodipine recommended for prevention of vasospasm in aneurysmal subarachnoid hemorrhage patients?

['This article discusses some of these unresolved issues, including the use of medications such as nimodipine, antifibrinolytics, statins, and magnesium; coiling or clipping for aneurysm securement; and the prevention and treatment of potential complications.', 'The results of this study were as follows: nimodipine demonstrated benefit following aneurysmal SAH; other calcium channel blockers, including nicardipine, do not provide unequivocal benefit; triple-H therapy, fasudil, transluminal balloon angioplasty, thrombolytics, endothelin receptor antagonists, magnesium, statins, and miscellaneous therapies such as free radical scavengers and antifibrinolytics require additional study.', 'The present results suggest that fasudil is equally or more effective than nimodipine for the prevention of cerebral vasospasm and subsequent ischemic injury in patients undergoing surgery for SAH.', 'Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage.', 'Nimodipine is the only preventative treatment that can be recommended.', 'Nimodipine (Nimotop), HMG Co-A reductase inhibitor (statins) and enoxaparin (Lovenox) were the only drugs with level-1 evidence available for the treatment of vasospasm from aneurysmal subarachnoid hemorrhage as defined by the US Preventative Services Task Force.', 'The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH).', 'There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively).', 'Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging.', 'The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH.', 'the risk of delayed cerebral ischemia is reduced with nimodipine and avoiding hypovolemia', 'A recommendations (standard) for the prophylaxis and treatment of cerebral vasospasm with oral Nimodipine in good grade patients.', 'Of the 75 patients initially considered for active treatment, 83% underwent surgery within 48 hours of rupture, all received nimodipine, 16% received tissue plasminogen activator to lyse subarachnoid or intraventricular clots, 40% underwent hypertensive treatment, and 7% underwent transluminal balloon angioplasty for vasospasm.', 'All patients with aneurysmal SAH should be treated with the calcium antagonist nimodipine, and in certain circumstances patients should receive anticonvulsants.', 'The following review gives an account of pathophysiological mechanisms; the importance of treatment with calcium antagonists, hypervolaemic haemodilution, and induced arterial hypertension is discussed in light of the current literature.', 'Seven placebo-controlled clinical studies have shown that nimodipine improves the outcome of patients with severe neurological damage due to cerebral vasospasm.', 'In a series of 100 individuals with a ruptured supratentorial aneurysm, who were subjected to aneurysm operation in the acute stage and who subsequently received intravenous treatment with the calcium channel blocker nimodipine, the occurrence of DID with FND was reduced to 5%.', 'There are many possible successful treatment options for preventing vasospasm, delayed ischemic neurologic deficits, and poor neurologic outcome following aneurysmal subarachnoid hemorrhage; however, further multicenter RCTs need to be performed to determine if there is a significant benefit from their use. Nimodipine is the only treatment that provided a significant benefit across multiple studies.', 'Absence of symptomatic vasospasm, occurrence of low density areas associated with vasospasm on CT, and occurrence of adverse events were similar between the two groups. The clinical outcomes were more favorable in the fasudil group than in the nimodipine group (p = 0.040). The proportion of patients with good clinical outcome was 74.5% (41/55) in the fasudil group and 61.7% (37/60) in the nimodipine group.', 'Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing.', 'Cerebral vasospasm is the classic cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage, leading to cerebral ischemia and infarction, and thus to poor outcome and occasionally death. Advances in diagnosis and treatment-principally the use of nimodipine, intensive care management, hemodynamic manipulations and endovascular neuroradiology procedures-have improved the prospects for these patients, but outcomes remain disappointing.', 'Cerebral vasospasm and delayed cerebral ischemia remain common complications of aneurysmal subarachnoid hemorrhage (SAH), and yet therapies for cerebral vasospasm are limited. Despite a large number of clinical trials, only calcium antagonists have strong evidence supporting their effectiveness.', 'The only proven therapy for vasospasm is nimodipine.', 'nimodipine is indicated after SAH and tirilazad is not effective.', 'Fasudil hydrochloride and nimodipine both showed inhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33 patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluated by the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34 patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine.']

['Yes, nimodipine is recommended and FDA approved for prevention of vasospasm after aneurysmal subarachnoid hemorrhage. Multiple studies have demonstrated that nimodipine (administered orally or intravenously) is safe and effective for prevention of vasospasm, and reduce frequency of ischemic complications, lowered mortality and improved overall outcomes. Other preventive medication can be also effective for vasomotor prevention in aneurysmal subarachnoid hemorrhage patients.']

['yes']

What is the genus for the common European honey bee?

['European honey bee (Apis mellifera)', ' European honey bees (Apis mellifera)', ' European honey bees (Apis mellifera', ' European honey bees, Apis mellifera']

['The genus and species of the European honey bee is Apis mellifera.']

['Apis']

Which protein is found to be mutated in Friedreich's ataxia?

["It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas", "Friedreich's ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron-sulfur (Fe-S) cluster biogenesis", "In eukaryotes, frataxin deficiency (FXN) causes severe phenotypes including loss of iron-sulfur (Fe-S) cluster protein activity, accumulation of mitochondrial iron and leads to the neurodegenerative disease Friedreich's ataxia", "Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich's ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner.", 'Friedreich ataxia (FRDA) is a neurodegenerative disease characterized by a decreased expression of the mitochondrial protein frataxin.', "Friedreich's ataxia results from a deficiency in the mitochondrial protein frataxin, which carries single point mutations in some patients.", "Friedreich's ataxia (FRDA), an autosomal recessive cardio- and neurodegenerative disease, is caused by low expression of frataxin, a small mitochondrial protein, encoded in the nucleus.", 'The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia.', 'Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia.', 'Friedreich ataxia is a human neurodegenerative and myocardial disease caused by decreased expression of the mitochondrial protein frataxin.', 'Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein.', 'Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused by a deficiency of frataxin, a conserved mitochondrial protein of unknown function.', 'This review will focus on the progress of potential treatment strategies for Friedreich ataxia that target the GAA expanded gene and seek to increase the level of frataxin message and protein.', 'Frataxin is a mitochondrial protein deficient in Friedreich ataxia (FRDA) and which is associated with abnormal intramitochondrial iron handling', 'The neurodegenerative disorder FRDA (Friedreich's ataxia) results from a deficiency in frataxin, a putative iron chaperone, and is due to the presence of a high number of GAA repeats in the coding regions of both alleles of the frataxin gene, which impair protein expression', "The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals.", "It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene.", "The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene.", "Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity.", "Although the Friedreich's ataxia phenotype results from decreased expression of a mitochondrially targeted protein, frataxin, mitochondrial myopathy has not been described as a feature of the disease."]

["It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas", "It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas."]

['Frataxin']

Which is the definition of pyknons in DNA?

['Among the millions of discovered patterns, we found a subset of 127,998 patterns, termed pyknons, which have additional nonoverlapping instances in the untranslated and protein-coding regions of 30,675 transcripts from 20,059 human genes.', "a nonrandom pattern of repeated elements, called pyknons, which are found more frequently in the 3' untranslated regions of genes than in other regions of the human genome", 'We discuss the general implications of molecular epigenetics with special emphasis on drug abuse, bar-codes, pyknons, and miRNAs for translational and clinical research', 'Here we report identification of ubiquitous template design sequences (templum intentio series, templints) of human genomes common for disease-associated SNPs, microRNAs and pyknons', "We demonstrate that genome-unique SNP-coding sequences associated with multiple common human disorders appear assembled from series of ubiquitous short octamer sequences shared by 5'-UTR pyknons and microRNAs", 'Allele-specific sequence variations link disease-associated SNPs to distinct sets of pyknons and microRNAs, suggesting that increased susceptibility to multiple common human disorders is associated with global alterations of genome-wide regulatory templates affecting the biogenesis and functions of non-coding RNAs', 'yknons are non-random sequence patterns significantly repeated throughout non-coding genomic DNA that also appear at least once among coding genes', 'Pyknons have only been discovered in the human genome, so it is unknown whether pyknons have wider biological relevance or are simply a phenomenon of the human genome', 'A. thaliana pyknons exhibit features similar to human pyknons, including being distinct sequence patterns, having multiple instances in genes and having remarkable similarity to small RNA sequences with roles in gene silencing', 'Chromosomal position mapping revealed that genomic pyknon density has concordance with siRNA and transposable element positioning density', 'Because the A. thaliana and human genomes have approximately the same number of genes but drastically different amounts of non-coding DNA, these data reveal that pyknons represent a biologically important link between coding and non-coding DNA', 'Because of the association of pyknons with siRNAs and localization to silenced regions of heterochromatin, we postulate that RNA-mediated gene silencing leads to the accumulation of gene sequences in non-coding DNA regions', ' The new GSCKs are produced by evolutionary consolidation of retro-transcripts into pyknons that collect and evolve at the end of the pericentromeric heterochromatin and are eventually incorporated into the MDP']

["Pyknons are non-random sequence patterns significantly repeated throughout non-coding genomic DNA, which have additional nonoverlapping instances in the untranslated and protein-coding regions. They are found more frequently in the 3' untranslated regions of genes than in other regions of the human genome."]

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Is there an association between bruxism and reflux?

['Sleep bruxism is prevalent in GERD patients, and GERD is highly associated with SB.', 'There was a statistical trend towards tooth wear progression being associated with gastric risk factors (p < 0.05). ', 'This article presents a case report of a 27-year-old male smoker with tooth wear and dentin sensitivity caused by GERD associated with bruxism. ', 'The aim of this cross-over, randomized, single-blinded trial was to examine whether intra-esophageal acidification induces sleep bruxism (SB). ', 'RMMA episodes including SB were induced by esophageal acidification. ', 'Chronic regurgitation of gastric acids in patients with gastroesophageal reflux disease may cause dental erosion, which can lead in combination with attrition or bruxism to extensive loss of coronal tooth tissue.', 'This clinical report describes treatment of severe tooth wear of a gastroesophageal reflux disease patient who is 54-year-old Turkish male patient. After his medical treatment, severe tooth wear, bruxism and decreased vertical dimensions were determined. ', 'Gastroesophageal reflux disease by itself or in combination with attrition, abrasion or bruxism may be responsible for the loss.', 'The association between bruxism, feeding and smoking habits and digestive disorders may lead to serious consequences to dental and related structures, involving dental alterations (wear, fractures and cracks), periodontal signs (gingival recession and tooth mobility) and muscle-joint sensitivity, demanding a multidisciplinary treatment plan. This paper presents a case report in which bruxism associated with acid feeding, smoking habit and episodes of gastric reflow caused severe tooth wear and great muscular discomfort with daily headache episodes. ', 'The frequencies of RMMA, single short-burst, and clenching episodes were significantly higher during decreased esophageal pH episodes than those during other times. ', 'These results suggest that most jaw muscle activities, ie, RMMA, single short-burst, and clenching episodes, occur in relation to gastroesophageal reflux mainly in the supine position.', 'Nocturnal bruxism may be secondary to nocturnal gastroesophageal reflux, occurring via sleep arousal and often together with swallowing.']

['Yes, bruxism is associated with reflux. Sleep bruxism is prevalent in GERD patients.']

['yes']

What is the link between Ctf4 and Chl1 in cohesion establishment?

['Ctf4 Links DNA Replication with Sister Chromatid Cohesion Establishment by Recruiting the Chl1 Helicase to the Replisome.', 'The Eco1 acetyltransferase, helped by factors including Ctf4 and Chl1, concomitantly acetylates the chromosomal cohesin complex to stabilize its cohesive links. Here we show that Ctf4 recruits the Chl1 helicase to the replisome via a conserved interaction motif that Chl1 shares with GINS and polymerase α.', "The Chl1 helicase facilitates replication fork progression under conditions of nucleotide depletion, partly independently of Ctf4 interaction. Conversely, Ctf4 interaction, but not helicase activity, is required for Chl1's role in sister chromatid cohesion. A physical interaction between Chl1 and the cohesin complex during S phase suggests that Chl1 contacts cohesin to facilitate its acetylation. Our results reveal how Ctf4 forms a replisomal interaction hub that coordinates replication fork progression and sister chromatid cohesion establishment.", 'Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3.', 'Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that might hold important clues as to the mechanism of sister chromatid cohesion establishment.', 'We show here that CTF8, CTF4 and a helicase encoded by CHL1 are required for efficient sister chromatid cohesion in unperturbed mitotic cells, and provide evidence that Chl1 functions during S-phase.', 'Our results suggest that Chl1 and Ctf4 are directly involved in homologous recombination repair rather than acting indirectly via the establishment of sister chromatid cohesion.', 'Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that might hold important clues as to the mechanism of sister chromatid cohesion establishment.', 'Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that might hold important clues as to the mechanism of sister chromatid cohesion establishment', 'We show here that CTF8, CTF4 and a helicase encoded by CHL1 are required for efficient sister chromatid cohesion in unperturbed mitotic cells, and provide evidence that Chl1 functions during S-phase', 'Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3', 'Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II.', 'Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3. ', 'Ctf4 Links DNA Replication with Sister Chromatid Cohesion Establishment by Recruiting the Chl1 Helicase to the Replisome.', 'Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that might hold important clues as to the mechanism of sister chromatid cohesion establishment..', 'Our results suggest that Chl1 and Ctf4 are directly involved in homologous recombination repair rather than acting indirectly via the establishment of sister chromatid cohesion..']

['Ctf4 links DNA replication with sister chromatid cohesion establishment by recruiting the Chl1 helicase to the replisome. The Eco1 acetyltransferase, helped by factors including Ctf4 and Chl1, concomitantly acetylates the chromosomal cohesin complex to stabilize its cohesive links.', 'Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3. Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that might hold important clues as to the mechanism of sister chromatid cohesion establishment.']

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How effective is the dentritic cells treatment on cancer?

['BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. ', ' silencing of suppressor of cytokine signalling 1 (Socs1) or stably expressing transgenic protein Ags in antigen-presenting dentritic cells (DCs) strongly enhances antigen-specific anti-tumour immunity. However, whether the strong and long-lasting T cell responses induced by the modified DCs could modulate the immunosuppressive tumour microenvironment has not been clarified. In this study, we explored the anti-tumour immunity of DCs modified by Socs1-shRNA lentiviral transduction combined with sustained expression of TRP2 in different tumour models. We showed that transfer Socs1-silenced or tumour antigen TRP2 persistent expressed DCs, or DCs modified by combination of Socs1-silencing and sustaining TRP2 expression prior to inoculation of tumour cells delayed B16 tumour cell growth, prolonged mouse survival and increased the ratio of CD8+ T/Treg as well as the CTL activity in tumours. ', 'To morphometrically quantify CD1a+ dentritic cells and DC-SIGN+ dendritic cells in HIV-positive patients with anal squamous intraepithelial neoplasia and to evaluate the effects of HIV infection, antiretroviral therapy and HPV infection on epithelial and subepithelial dendritic cells.', 'Our data support an enhancement of the synergistic action caused by HIV-HPV co-infection on the anal epithelium, weakening the DC for its major role in immune surveillance. Notoriously in patients with severe anal intraepithelial neoplasia, the density of CD1a+ epithelial dendritic cells was influenced by the viral load of HIV-1. Our study describes for the first time the density of subepithelial DC-SIGN+ dendritic cells in patients with anal severe anal intraepithelial neoplasia and points to the possibility that a specific therapy for HIV ', 'transfer of CD40 ligand (CD40L) holds promise as a novel therapy for lymphoid malignancies and a number of solid carcinomas because of its multiple anti-tumor activities. However, membrane-bound CD40L can be cleaved into a soluble form, sCD40L, which contributes to systemic inflammatory and cardiovascular diseases, and induces survival signals in the absence of protein synthesis block, suggesting a deleterious side effect of CD40L gene therapy. We generated a plasmid encoding non-cleavable human CD40L mutant (pcDNA3.1+-CD40L-M) to determine the direct anti-proliferative and pro-apoptotic effects in CD40-positive lung adenocarcinoma cell line A549, to verify activation of immature dentritic cells (DCs) by co-cultivation with the transfected A549 cells and to evaluate the lower expression of sCD40L relative to that of wild-type CD40L (CD40L-WT) transfectant in cell-free supernatants. These studies suggest that gene transfer of the membrane-stable CD40L mutant into CD40-positive cells may provide an efficient and safe method to treat non-small cell lung cancer', ' (AITL) is a rare and aggressive neoplasm clinically characterized by sudden onset of constitutional symptoms, lymphadenopathy, hepatosplenomegaly, frequent autoimmune phenomena, particularly hemolytic anemia and thrombocytopenia, and polyclonal hypergammaglobulinemia. The lymph node histological picture is also distinctive, constituted by a polymorphic infiltrate, a marked proliferation of high endothelial venules, and a dense meshwork of dentritic cells. The neoplastic CD4+ T-cells represent a minority of the lymph node cell population; its detection is facilitated by the aberrant expression of CD10. Almost all cases arbor an EBV infected B-cell population. Patients with AITL have a poor prognosis with conventional treatment, with a median overall survival of less than 3 years. Patients achieving a good clinical response seem beneficiate from a consolidation with high-dose therapy and autologous stem cell transplantation. Constitutional symptoms and autoimmune phenomena, and some times also the neoplastic masses may respond to immunosuppressive or immunomodulatory agents such as thalidomide', 'Survivin expression is a poor prognostic marker in a number of cancers. Clinical trials are currently underway evaluating anti-sense oligonucleotides against Survivin, immunotherapy using Survivin primed dentritic cells and peptide mimics that block interaction of Survivin with Hsp90 resulting in loss of Survivin protein stability. Additional approaches using ribozymes against Survivin mRNA, or dominant-negative cDNA to block Survivin function are in pre-clinical stages. Like many genes, Survivin is alternately spliced and a number of new splice variants have recently been identified. Expression of some of these splice variants correlates with loss of steroid receptors as well as the tumor suppressor p53, in some cancers, suggesting that like wild-type Survivin, at least some of these splice variants may also have prognostic relevance. This review will focus on the current understanding of the function of Survivin splice variants and their expression and sub-cellular localization in normal and neoplastic tissues as well as critically evaluating the potential toxicity of the Survivin directed therapies and their predicted effect on the alternatively spliced Survivin isoforms', ' Immunotherapy applying ex vivo-generated and tumor antigen-loaded dentritic cells has been successfully introduced in clinical vaccination protocols and has proven to be feasible and effective in some patients. A better understanding of how dentritic cells succeed to induce and modulate immunity is necessary to optimally exploit dentritic cells in anticancer vaccines. The authors will review novel insights in antigen loading, activation and migration of dentritic cells and their impact on the application of ex vivo-generated dentritic cell vaccines. In addition, novel means to exploit dentritic cells in cancer vaccines by loading and activation of dentritic cells directly in situ and possible obstacles that should be overcome to induce long-lasting immunity in therapeutic settings will be discussed']

["Another approach to cancer therapy takes advantage of the normal role of the dendritic cell as an immune educator. Dendritic cells grab antigens from viruses, bacteria, or other organisms and wave them at T cells to recruit their help in an initial T cell immune response. This works well against foreign cells that enter the body, but cancer cells often evade the self/non-self detection system. By modifying dendritic cells, researchers are able to trigger a special kind of autoimmune response that includes a T cell attack of the cancer cells. Because a cancer antigen alone is not enough to rally the immune troops, scientists first fuse a cytokine to a tumor antigen with the hope that this will send a strong antigenic signal. Next, they grow a patient's dendritic cells in the incubator and let them take up this fused cytokine-tumor antigen. This enables the dendritic cells to mature and eventually display the same tumor antigens as appear on the patient's cancer cells. When these special mature dendritic cells are given back to the patient, they wave their newly acquired tumor antigens at the patient's immune system, and those T cells that can respond mount an attack on the patient's cancer cells."]

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In which diseases have electronic patient diaries been applied ?

["WiiPD is an approach for the objective home based assessment of Parkinson's disease which utilizes the intuitive and sensor rich Nintendo Wii Remote. Combined with an electronic patient diary, a suite of mini-games, a metric analyzer, and a visualization engine, we propose that this system can complement existing clinical practice by providing objective metrics gathered frequently over extended periods of time.", 'This research paper examines the challenges in the development and adoption of an electronic patient diary within the Pathways Home for Respiratory Illness Project', 'This project supported community-based patients suffering from chronic obstructive pulmonary disease (COPD) to achieve increased levels of self-management and self-efficacy using electronic-monitoring techniques and mentoring by community health nurses.', 'Instead of measuring physiological parameters, a Smartphone based Personal Allergy Assistant (PAA) allows patients to keep an electronic patient diary by scanning the barcode of the consumed food products.', 'Telemedicine assisted diet and diagnosis management in food hypersensitivity', 'The Flushing ASsessment Tool (FAST) was developed to assess flushing symptoms and their impact on patients receiving niacin therapy.', ' This was a prospective, randomized, double-blind, placebo-controlled, parallel-group 8-week study conducted to evaluate the psychometric characteristics of the FAST. The instrument is administered daily using an electronic patient diary.', 'Haemoassist--a hand-held electronic patient diary for haemophilia home care.', 'A comparison of self-documentation in diabetics: electronic versus paper diaries.', 'Subjects with self-perceived heartburn without known gastrointestinal disease or interfering treatments were selected with questionnaires. The study was performed unsupervised, whenever heartburn required medication. An electronic patient diary gave instructions when to take study medication', 'Self-medication of a single headache episode with ketoprofen, ibuprofen or placebo, home-monitored with an electronic patient diary.']

["Parkinson's disease\nCOPD\nFood hypersensitivity\nNiacin induced flushing\nHemophilia\nHeartburn\nHeadache"]

["Parkinson's disease", 'COPD', 'Chronic obstructive pulmonary disease', 'Chronic Obstructive Airways Disease', 'Chronic Obstructive Lung Disease', 'Food hypersensitivity', 'Allergy', 'Niacin induced flushing', 'Hemophilia', 'Heartburn', 'Reflux', 'GERD', 'Esophageal reflux', 'Headache', 'Migraine', 'migraine headache', 'Migraine Disorder', 'Migraine Headaches']

Which signaling pathway does sonidegib inhibit?

['The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.', 'Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. ', 'We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.', 'Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened-a key Hh pathway regulator.', 'This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.', 'The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects.', 'Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification.', 'We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.', 'We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. ', 'PURPOSE: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. ', 'PURPOSE: The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects. ', 'Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. ', 'PURPOSE: The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects. METHODS: Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74 kBq, 2.0 µCi) under fasting conditions. ', ' The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects. Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74 kBq, 2.0 µCi) under fasting conditions.', 'Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification. .', 'The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.', ' This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors. Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period.', 'Preliminary clinical data also suggest that inhibition of the Hh pathway, alone or in combination with JAK2 inhibition, may enable disease modification in patients with MF. Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification.', 'The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects. Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74 kBq, 2.', 'including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib,', 'This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors. Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period.', 'Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.']

['Sonidegib is a Hedghog signalling pathway inhibitor.']

['Hedghog signalling pathway']

Which library is used for fixed-length approximate string matching?

['libFLASM: a software library for fixed-length approximate string matching.', 'We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds.', 'Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable', 'libFLASM: a software library for fixed-length approximate string matching.', 'We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching.', 'We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models.', 'Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction.']

['libFLASM is a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models.']

['libFLASM']

Which are the cardiac manifestations of Marfan syndrome?

['Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP).', 'Marfan syndrome (MFS) is a genetic disorder of the connective tissue. Aortic root dilation is a main criterion of the Ghent Nosology. Dural ectasia and the presence of mitral valve prolapse (MVP) contribute to its systemic score.', 'The typical cardiac manifestations of Marfan syndrome are aortic regurgitation with progressive dilatation of the aortic root, which may cause dissection and rupture of the ascending aorta, mitral valve prolapse and mitral valve regurgitation.', 'To describe the clinical cardiac manifestations and temporal evolution of Marfan syndrome in children; to estimate the incidence of annuloaortic ectasia and mitral valve prolapse', 'the presence of mitral valve prolapse, aortic root diameter, mitral and aortic valves regurgitation, and aortic enlargement during beta-blocker therapy', 'Cardiovascular manifestations in Marfan syndrome.', 'The major cardiac diagnoses were aortic dilatation (1/3) and mitral valve prolapse with severe mitral regurgitation (2/3).', 'Marfan syndrome is a hereditable disorder of connective tissue that causes several distinct cardiovascular abnormalities, including aortic regurgitation, dissection, and aneurysm.']

['Cardiac manifestations of Marfan syndrome include aortic root dilation,aortic regurgitation, mitral valve prolapse and mitral valve regurgitation.']

['aortic root dilation', 'mitral valve prolapse', 'aortic regurgitation', 'mitral valve regurgitation']

What are Septins?

['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>© 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. ', 'The human genome codes for 13 members of a family of filament-forming GTP-binding proteins known as septins.', 'Septins are evolutionary conserved cytoskeletal GTPases forming heteropolymer complexes involved in cytokinesis and other cellular processes', 'Septins comprise a conserved family of GTPases important in cytokinesis.', 'Septins are a highly conserved family of GTP-binding cytoskeletal proteins implicated in multiple cellular functions, including membrane transport, apoptosis, cell polarity, cell cycle regulation, cytokinesis, and oncogenesis']

['Septins are an evolutionarily conserved family of GTP-binding proteins. They are involved in diverse processes including cytokinesis, apoptosis, infection, neurodegeneration and neoplasia. In yeast, septins assemble into a highly ordered array of filaments at the mother bud neck in Saccharomyces cerevisiae cells. Septins have been implicated in a diverse range of cancers, including gastric cancer, but the underlying mechanisms remain unclear.', 'Septins are an evolutionarily conserved family of GTP-binding proteins. discover that septins, a component of the cytoskeleton, recognize membrane curvature at the micron scale, a common morphological hallmark of eukaryotic cellular processes. 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. ']

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What is the catalytic mechanism of DNA (cytosine-5) methyltransferases?

['All DNA (cytosine-5)-methyltransferases contain a single conserved cysteine. It has been proposed that this cysteine initiates catalysis by attacking the C6 of cytosine and thereby activating the normally inert C5 position.', 'Kinetic and catalytic mechanism of HhaI methyltransferase.', 'Kinetic and catalytic properties of the DNA (cytosine-5)-methyltransferase HhaI are described. With poly(dG-dC) as substrate, the reaction proceeds by an equilibrium (or processive) ordered Bi-Bi mechanism in which DNA binds to the enzyme first, followed by S-adenosylmethionine (AdoMet). After methyl transfer, S-adenosylhomocysteine (AdoHcy) dissociates followed by methylated DNA.', 'Our studies reveal that the catalytic mechanism of DNA (cytosine-5)-methyltransferases involves attack of the C6 of substrate cytosines by an enzyme nucleophile and formation of a transient covalent adduct.', 'Catalytic mechanism of DNA-(cytosine-C5)-methyltransferases revisited: covalent intermediate formation is not essential for methyl group transfer by the murine Dnmt3a enzyme.', 'We propose that correct positioning of the flipped base and the cofactor and binding to the transition state of methyl group transfer are the most important roles of the Dnmt3a enzyme in the catalytic cycle of methyl group transfer.', 'Co-transfections of reporter plasmids and plasmids encoding the catalytic domain of the murine Dnmt3a DNA methyltransferase lead to inhibition of reporter gene expression. As Dnmt3a mutants with C-->A and E-->A exchanges in the conserved PCQ and ENV motifs in the catalytic center of the enzyme also cause repression, we checked for their catalytic activity in vitro.', 'In contrast, enzyme variants carrying E-->A, E-->D or E-->Q exchanges of the ENV glutamate are catalytically almost inactive, demonstrating that this residue has a central function in catalysis.', 'Therefore, covalent complex formation is not essential in the reaction mechanism of Dnmt3a. We propose that correct positioning of the flipped base and the cofactor and binding to the transition state of methyl group transfer are the most important roles of the Dnmt3a enzyme in the catalytic cycle of methyl group transfer.', 'Our results point to a possible connection between the catalytic mechanism of C5 Mtases and of enzymes that transfer methyl groups to N(4) of cytosine.', 'Previous X-ray crystallographic studies have revealed that the catalytic domain of a DNA methyltransferase (Mtase) generating C5-methylcytosine bears a striking structural similarity to that of a Mtase generating N6-methyladenine.', 'Spontaneous and reversible proton transfer between a conserved Glu in the active site and cytosine N3 at the transition state was observed in our simulations, revealing the chemical participation of this Glu residue in the catalytic mechanism.', 'The mechanism of DNA cytosine-5-methylation catalyzed by the bacterial M.HhaI enzyme has been considered as a stepwise nucleophilic addition of Cys-81-S- to cytosine C6 followed by C5 nucleophilic replacement of the methyl of S-adenosyl-L-methionine to produce 5-methyl-6-Cys-81-S-5,6-dihydrocytosine.', 'Hydroxide at 10(-7) mole fraction (pH = 7) is shown to be sufficient for the required catalysis.', 'On the basis of amino acid sequence alignments and structural data of related enzymes, we have performed a mutational analysis of 14 amino acid residues in the catalytic domain of the murine Dnmt3a DNA-(cytosine C5)-methyltransferase.', 'We demonstrate that Phe50 (motif I) and Glu74 (motif II) are important for AdoMet binding and catalysis. D96A (motif III) showed reduced AdoMet binding but increased activity under conditions of saturation with S-adenosyl-L-methionine (AdoMet), indicating that the contact of Asp96 to AdoMet is not required for catalysis.', 'R130A displayed a strong reduction in catalytic activity and a complete change in flanking sequence preferences, indicating that Arg130 has an important role in the DNA interaction of Dnmt3a.', 'While Asn167 might contribute to the positioning of residues from motif VI, according to structural data Arg202 has a role in catalysis of cytosine-C5 methyltransferases. The R295A variant was catalytically inactive most likely because of destabilization of the hinge sub-domain of the protein.', 'These two methyltransferases recognize CpG and GCGC sequences, respectively, and transfer a methyl group to the C5 atom of cytosine (C).', 'Most prokaryotic (cytosine-5)-DNA methyltransferases increase the frequency of deamination at the cytosine targeted for methylation in vitro in the absence of the cofactor S-adenosylmethionine (AdoMet) or the reaction product S-adenosylhomocysteine (AdoHcy).', 'The target (methylatable) cytosine, if flipped out of the double helical DNA as seen for DNA methyltransferases that generate 5-methylcytosine, would fit into the concave active site next to the AdoMet.', 'These methylation patterns are established and maintained by DNA cytosine-5 methyltransferase (MTase), a approximately 1500 amino acid enzyme containing a regulatory N-terminal domain and a catalytic C-terminal domain.', 'These results lend strong support to a catalytic mechanism in which an enzyme sulfhydryl group undergoes Michael addition to the C5-C6 double bond, thus activating position C-5 of the substrate DNA cytosine residue for electrophilic attack by the methyl donor SAM.', "2'-Deoxyoligonucleotides with 5-fluorocytosine residues incorporated at specific positions of the nucleotide sequence are tools of great potential in the study of the catalytic mechanism by which DNA cytosine methyltransferases methylate the 5-position of DNA cytosine residues in specific sequence contexts.", 'The enzyme has Mr 130 000, and introduces methyl groups from S-adenosylmethionine into the 5 position of cytosines in DNA.']

['The catalytic mechanism of the DNA (Cytosine-5-)-methyltransferase involves nucleophilic attack of the C6 of the substrate cytosine by the single conserved cysteine of the enzyme, followed by C5 nucleophilic replacement of the methyl group of the cofactor S-adenosyl-L-methionine (AdoMet) to produce 5-methyl-6-Cys-81-S-5,6-dihydrocytosine. It has been also demonstrated that Phe and Glu, which are found in the catalytic motifs I and II of the enzyme are important for AdoMet binding and catalysis.']

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Which human disease is associated with mutated UBQLN2

['Finally, we found that mutations in UBQLN2, which lead to neurodegeneration in humans, are defective in chaperone binding, impair aggregate clearance, and cause cognitive deficits in mice.', 'UBQLN2 mutations are detected in ALS cases.', 'C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand', 'Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). ', 'Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10\xa0% of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others.', 'A mutation in the ubiquilin 2 gene (UBQLN2) was recently identified as a cause of X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) ', 'Interest in the proteins has been heightened by the discovery that gene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS).']

['Ggene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS).']

['ALS', 'amyotrophic lateral sclerosis']

What is the role of 3,4-diaminobenzoic acid derivatives in the immune system?

['3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties.', 'Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.', '3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties', 'Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses.', '3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties.']

['3,4-diaminobenzoic acid derivatives are inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties. Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells.']

['Inhibition of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties.']

What are the SINEUPs?

['SINEUPs: A new class of natural and synthetic antisense long non-coding RNAs that activate translation', 'In this review, we will detail the discovery of a new functional class of natural and synthetic antisense lncRNAs that stimulate translation of sense mRNAs. These molecules have been named SINEUPs since their function requires the activity of an embedded inverted SINEB2 sequence to UP-regulate translation. Natural SINEUPs suggest that embedded Transposable Elements may represent functional domains in long non-coding RNAs. Synthetic SINEUPs may be designed by targeting the antisense sequence to the mRNA of choice representing the first scalable tool to increase protein synthesis of potentially any gene of interest', 'SINEUPs are modular antisense long non-coding RNAs that increase synthesis of target proteins in cells', 'In summary, SINEUPs represent the first scalable tool to increase synthesis of proteins of interest. We propose SINEUPs as reagents for molecular biology experiments, in protein manufacturing as well as in therapy of haploinsufficiencies', 'In summary, SINEUPs represent the first scalable tool to increase synthesis of proteins of interest', 'We propose SINEUPs as reagents for molecular biology experiments, in protein manufacturing as well as in therapy of haploinsufficiencies', 'These molecules have been named SINEUPs since their function requires the activity of an embedded inverted SINEB2 sequence to UP-regulate translation', 'Natural SINEUPs suggest that embedded Transposable Elements may represent functional domains in long non-coding RNAs', 'Synthetic SINEUPs may be designed by targeting the antisense sequence to the mRNA of choice representing the first scalable tool to increase protein synthesis of potentially any gene of interest', 'We have previously identified SINEUPs as a new functional class of natural and synthetic long non-coding RNAs that through the activity of an inverted SINEB2 element are able to promote translation of partially overlapping sense coding mRNAs', 'Here we show that by taking advantage of their modular structure, synthetic SINEUPs can be designed to increase production of secreted proteins', 'These results lead us to propose synthetic SINEUPs as new versatile tools to optimize production of secreted proteins in manufacturing pipelines and natural SINEUPs as new regulatory RNAs in the secretory pathways. <CopyrightInformation>Copyright © 2015 Elsevier B.V. All rights reserved.</', 'It is the representative member of SINEUPs (SINEB2 sequence to UP-regulate translation), a new functional class of natural antisense lncRNAs that activate translation of their sense genes', 'Recently, an antisense lncRNA to mouse Ubiquitin carboxyl-terminal hydrolase L1 (Uchl1) was reported to increase UCHL1 protein synthesis, representing a new functional class of lncRNAs, designated as SINEUPs, for SINE element-containing translation UP-regulators.', 'We have previously identified SINEUPs as a new functional class of natural and synthetic long non-coding RNAs that through the activity of an inverted SINEB2 element are able to promote translation of partially overlapping sense coding mRNAs.', 'We named this class of RNAs SINEUPs for their requirement of the inverted SINEB2 sequence to UP-regulate translation in a gene-specific manner.', 'It is the representative member of SINEUPs (SINEB2 sequence to UP-regulate translation), a new functional class of natural antisense lncRNAs that activate translation of their sense genes.', 'SINEUPs are long antisense non-coding RNAs that up-regulate translation in mammalian cells in a gene-specific manner, although, so far evidence of SINEUP efficacy has only been demonstrated in in vitro systems.']

['SINEUPs represent a new class of natural and synthetic antisense long non-coding RNAs that activate translation. These molecules have been named SINEUPs since their function requires the activity of an embedded inverted SINEB2 sequence to UP-regulate translation. Natural SINEUPs suggest that embedded Transposable Elements may represent functional domains in long non-coding RNAs. Synthetic SINEUPs may be designed by targeting the antisense sequence to the mRNA of choice representing the first scalable tool to increase protein synthesis of potentially any gene of interest.']

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Name monoclonal antibody against SLAMF7.

['BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma.', 'Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells.', 'This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM.', 'One of the most promising MoAb is elotuzumab, the only humanized IgG1 MoAb specifically targeting CS1 (SLAMF7), a cell surface glycoprotein that is highly expressed in plasma cells. ', 'This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM.', 'Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells.', ' New agents are awaited for the treatment of multiple myeloma and research is ongoing for the development of monoclonal antibodies (MoAbs) targeting the tumor cells. One of the most promising MoAb is elotuzumab, the only humanized IgG1 MoAb specifically targeting CS1 (SLAMF7), a cell surface glycoprotein that is highly expressed in plasma cells.', 'This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM.', 'Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma.']

['Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer cell-mediated antibody-dependent cellular cytotoxicity of SLAMF7-expressing myeloma cells.']

['signaling lymphocytic activation molecule-F7']

Which are the clinical characteristics of Diamond-Blackfan anemia?

['The results indicated that out of 45 children diagnosed as DBA, 14 cases (31.1%) had short stature and physical malformation. All patients had anemia with reticulocytopenia. Thirty-four patients (75.6%) had mean corpuscular volume. Eleven patients (24.4%) had macrocytic anemia. Bone marrow examination showed a marked erythroid hypoplasia in all patients', 'Diamond-Blackfan anemia (DBA) is a rare congenital erythroid hypoplastic anemia that usually presents early in infancy and is inherited in up to 45% of cases. It is characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer', 'Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations.', 'Diamond Blackfan Anemia (DBA) is a rare hypoplastic anemia that presents in infancy with macrocytic anemia and reticulocytopenia.', 'Diamond Blackfan anemia is characterized by a severe hypoplastic anemia and a heterogeneous collection of other clinical features.', 'Diamond-Blackfan anaemia (congenital hypoplastic anaemia) is a rare hereditary disease with isolated congenital hypoplasia of red blood cells precursors in bone marrow, and its important characteristic is successful treatment', 'Diamond-Blackfan anemia is a rare, inherited disease that characteristically presents as a chronic, normochromic macrocytosis due to red cell lineage bone marrow failure', 'Diamond Blackfan anemia is characterized by a severe hypoplastic anemia and a heterogeneous collection of other clinical features']

['Diamond-Blackfan anemia (DBA) is a rare congenital erythroid hypoplastic anemia that usually presents early in infancy and is characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer.']

['Red cell aplasia', 'Congenital anomalies', 'Predisposition to cancer']

Which are the mammalian orthologs of Drosophila Yki?

['Yorkie ortholog YAP', 'Yorkie ortholog, Yap1', 'human ortholog of Yorkie, YAP', 'YAP1, the ortholog of Drosophila Yorkie', 'Yorkie ortholog YAP', ' Yorkie homolog YAP', 'Yki (YAP/TAZ in vertebrates']

['There are two mammalian orthologs of Yki: YAP and TAZ']

['YAP', 'TAZ']

Treprostinil is an analogue for which prostaglandin?

['We investigated the effects of 3 conventional (iloprost, beraprost, and treprostinil) and 1 new (ONO-1301) PGI2 analogs, on the expression of MIP-1α expression in human monocytes.', 'PGI(2) analogues (iloprost, treprostinil and beraprost) significantly increased IL-17A and IL-22 in vitro while decreasing IFNγ production both in SSc and HD PBMC.', 'The effects of PGI(2) analogs iloprost and treprostinil on cytokine production, maturation and T-cell stimulatory function of human mDCs were investigated.', 'Treprostinil, a stable prostacyclin analogue used in the treatment of pulmonary arterial hypertension, is in development as a sustained release oral tablet, treprostinil diolamine (United Therapeutics Corp, Research Triangle Park, NC)', 'Treprostinil diolamine is an oral prostacyclin analogue; sustained release tablets of oral treprostinil are currently being evaluated for efficacy and safety as a potential therapy in patients with PAH', 'Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue under evaluation for the treatment for pulmonary arterial hypertension (PAH)', 'Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue currently being evaluated for the treatment of pulmonary arterial hypertension as a sustained-release (SR) oral tablet', 'Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet', 'Epoprostenol, a synthetic analogue of prostacyclin, and the chemically stable analogues iloprost, beraprost and treprostinil were tested in randomised controlled trials', 'Treprostinil is a synthetic prostacyclin analogue with antiplatelet and vasodilatory properties', 'Treprostinil is a stable analogue of prostacyclin, which can be administered subcutaneously, intravenously or by inhalation', 'We recently showed that the stable prostacyclin analogue treprostinil, a clinically approved drug for pulmonary arterial hypertension (PAH), significantly reduced the recruitment of fibrocytes to sites of vascular remodeling in experimental hypoxic pulmonary hypertension. Here we report on the molecular mechanism underlying the inhibitory action of treprostinil on the adhesion and differentiation of human fibrocytes. Human fibrocytes expressed the prostanoid receptors, prostaglandin I (IP) receptors and prostaglandin E subtype receptors (EP2 and EP4). ', 'Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease.', 'Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.', 'The prostacyclin analogue treprostinil blocks NFkappaB nuclear translocation in human alveolar macrophages.', 'The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. ', 'Iloprost (ILO) and treprostinil (TRP), two prostaglandin I2 analogues, were conjugated to fluorescein-labeled BSA (FLUO-BSA) and compared for IP1 receptor binding/uptake in different lung cell lines.']

['Treprostinil is a prostaglandin I(2) (PGI(2)) analog.']

['Prostaglandin I(2)']

Is there any tool that facilitates the functional analysis of cis-regulatory regions in zebrafish?

['Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish.', 'he cis-regulatory sequences control when, where, and how much genes are transcribed and can activate (enhancers) or repress (silencers) gene expression. Here, we describe a novel Tol2 transposon-based vector for assessing enhancer activity in the zebrafish (Danio rerio). This Zebrafish Enhancer Detector (ZED) vector harbors several key improvements, among them a sensitive and specific minimal promoter chosen for optimal enhancer activity detection, insulator sequences to shield the minimal promoter from position effects, and a positive control for transgenesis. Additionally, we demonstrate that highly conserved noncoding sequences homologous between humans and zebrafish largely with enhancer activity largely retain their tissue-specific enhancer activity during vertebrate evolution. More strikingly, insulator sequences from mouse and chicken, but not conserved in zebrafish, maintain their insulator capacity when tested in this model.', 'Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish', 'Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish.']

['Yes. The zebrafish enhancer detection (ZED) vector is a tool that facilitates transgenesis and the functional analysis of cis-regulatory regions in zebrafish.']

['yes']

What is the role of the histidine rich calcium binding protein (HRC) in cardiomyopathy?

['The histidine-rich Ca-binding protein (HRC) is a Ca-storage protein in cardiac sarcoplasmic reticulum. Recent transgenic studies revealed that this protein inhibits the maximal rates of sarcoplasmic reticulum Ca-transport, leading to cardiac dysfunction. In view of the role of sarcoplasmic reticulum Ca-cycling in myocardial ischemia/reperfusion injury, we designed this study to gain further insight into the role of HRC during ischemia/reperfusion.', 'Our findings suggest that increased cardiac HRC expression protects against ischemia/reperfusion injury in the heart, resulting in improved recovery of function and reduced infarction.', 'The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients', 'The HRC(S96A) mutant exacerbated the inhibitory effects of HRC(WT) on the amplitude of Ca(2+) transients, prolongation of Ca(2+) decay time, and caffeine-induced sarcoplasmic reticulum Ca(2+) release. Consistent with these findings, HRC(S96A) reduced maximal sarcoplasmic reticulum calcium uptake rate to a higher extent than HRC(WT). Furthermore, the frequency of spontaneous Ca(2+) sparks, which was reduced by HRC(WT), was increased by mutant HRC(S96A) under resting conditions although there were no spontaneous Ca(2+) waves under stress conditions. However, expression of the HRC(S96A) genetic variant in cardiomyocytes from a rat model of postmyocardial infarction heart failure induced dramatic disturbances of rhythmic Ca(2+) transients. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers.']

['The histidine-rich Ca-binding protein (HRC), a 165 kDa sarcoplasmic reticulum (SR) protein, regulates SR Ca cycling during excitation–contraction coupling. HRC mutations or polymorphisms lead to cardiac dysfunction. The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias and sudden death in idiopathic dilated cardiomyopathy (DCM).']

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Is Cryptococcus neoformans a frequent cause of isolated skin infections in immunocompromised individuals

[' Cryptococcus is an opportunistic yeast with a worldwide distribution that primarily causes significant infections in immunocompromised individuals, generally by affecting the respiratory tract. But primary cutaneous cryptococcosis (PCC) without systemic infection is rare. ', 'Cryptococcus is a ubiquitous fungus and is known for causing meningitis and cutaneous infections in immunocompromised individuals.', 'Cryptococcus neoformans is an encapsulated yeast that can cause primary pulmonary infections or disseminate and cause infections of the central nervous system, meninges, skin, and bone in the immunocompromised host.', 'The authors report a male patient, a seller with no detected immunosuppression, with an extensive ulcerated skin lesion localized on the left forearm, caused by Cryptococcus neoformans var.']

['Primary cutaneous cryptococcosis (PCC) without systemic infection is rare.']

['no']

What are assassin bugs?

['The complete mitochondrial genome of an assassin bug Peirates arcuatus (Hemiptera: Reduviidae).', 'First complete mitochondrial genome sequence from the tribelocephaline assassin bugs (Hemiptera: Reduviidae).', 'The complete mitochondrial genome (mitogenome) of Opistoplatys sp. was determined, which was the first representation from the assassin bug subfamily Tribelocephalinae. ', 'The family Reduviidae (Hemiptera: Heteroptera), or assassin bugs, is among the most diverse families of the true bugs, with more than 6,000 species.', 'Comparative mitogenomics of the assassin bug genus Peirates (Hemiptera: Reduviidae: Peiratinae) ']

['The family Reduviidae (Hemiptera: Heteroptera), or assassin bugs, is among the most diverse families of the true bugs, with more than 6,000 species.']

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What is the role of thyroid hormone in Stem cell differentiation?

['During T3-dependent amphibian metamorphosis, the digestive tract is extensively remodeled from the larval to the adult form for the adaptation of the amphibian from its aquatic herbivorous lifestyle to that of a terrestrial carnivorous frog. This involves de novo formation of ASCs that requires T3 signaling in both the larval epithelium and nonepithelial tissues.', 'Our results revealed that T3 induces distinct tissue-specific gene regulation programs associated with the remodeling of the intestine, particularly the formation of the ASCs, and further suggested the existence of potentially many novel stem cell-associated genes, at least in the intestine during development.', 'BMP signaling is an important modulator of the late differentiation stages in MSC chondrogenesis and the thyroid hormone induces this pathway. ', 'In addition, thyroid hormone treatment of hiPS-CMs attenuated the fetal gene expression in favor of a more adult-like pattern. ', 'Exposure of embryos at this developmental stage for 24 h to either a TH antagonist, NH-3, or to tetrabromobisphenol A, a flame retardant and known TH disruptor, differentially modulated the expression of a number of TH target genes implicated in neural stem cell function or neural differentiation. ', 'In the intestinal epithelium and the retina, TRα1 and TRβ2 are expressed at the level of the precursors where they induce cell proliferation and differentiation, respectively. ', 'Thyroid hormone signaling acts as a neurogenic switch by repressing Sox2 in the adult neural stem cell niche.', 'We will discuss observations suggesting that liganded T3 receptor (TR) regulates cell autonomous formation of adult intestinal progenitor cells and that T3 action in the connective tissue is important for the establishment of the stem cell niche.', 'In general, in vitro stem cell differentiation techniques stimulate a wide range of developmental programs, including thyroid hormone receptor (TR) pathways.', 'Although no difference of in vitro proliferation of NSCs was observed in the presence of epidermal growth factor, maturation of oligodendrocytes (defined by process number and length) was enhanced in hyperthyroidism, suggesting a more mature state than in control animals. ', "Terminal erythroid maturation was significantly improved by adding human serum and thyroid hormone (3,5,3'-triiodothyronine [T3]) to the differentiation medium.", 'This resulted in highly synchronous differentiation of the cells toward enucleated erythrocytes within 6 days', 'T(3) alone stimulated neural differentiation in a similar fashion as that seen with RA in both wtES and mES cells. ', 'Thus, c-erbA/TR appears to act as a binary switch affecting erythroid cell fate: unliganded c-erbA/TR supports growth while ligand-activated c-erbA/TR induces differentiation. ', 'The thyroid hormone receptor functions as a ligand-operated developmental switch between proliferation and differentiation of erythroid progenitors.', 'Thyroid hormones induce hemopoietic pluripotent stem cell differentiation toward erythropoiesis ']

['Thyroid hormone treatment of Human-induced pluripotent stem cell-derived cardiomyocytes attenuates the fetal gene expression and induces differentiation. Liganded T3 receptor (TR) regulates cell autonomous formation of adult intestinal progenitor cells and that T3 action in the connective tissue is important for the establishment of the stem cell niche. In the intestinal epithelium, TRα1 and TRβ2 are expressed at the level of stem/progenitor cell populations where they induce cell proliferation and differentiation, respectively. Thyroid hormone is implicated in neural stem cell function and differentiation and acts as a neurogenic switch in the adult neural stem cell niche. Furthermore, thyroid hormone enhances maturation of oligodendrocyte precursor cells. Thyroid hormones also induce hemopoietic pluripotent stem cell differentiation toward erythropoiesis and c-erbA/TR appears to act as a binary switch affecting erythroid cell fate: unliganded c-erbA/TR supports growth while ligand-activated c-erbA/TR induces differentiation. Finally, thyroid hormone modulates late differentiation stages of mesenchymal stem cells chondrogenesis via BMP signaling.']

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Are alterations in ultraconserved elements implicated in breast cancer?

['SNPs in ultraconserved elements and familial breast cancer risk', ' In the present study, we investigated the influence of six SNPs within UCEs on familial breast cancer risk. Two out of six SNPs showed an association with familial breast cancer risk', 'This is the first study indicating that SNPs in UCEs might be associated with cancer risk', 'SNPs in ultraconserved elements and familial breast cancer risk.', 'Recent studies have indicated that UCEs are not mutation cold regions and likely to be concerned with cancers, including breast cancer (BC). ', 'SNPs in ultraconserved elements and familial breast cancer risk.', 'Genetic variants in ultraconserved elements and risk of breast cancer in Chinese population.']

['Yes. SNPs in ultraconserved elements (UCEs) might be associated with cancer risk.']

['yes']

Is Thalidomide currently a marketed drug?

['In this retrospective study, pharmacy claims were analyzed for those patients with a diagnosis of MM who received thalidomide,', 'The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome,', 'Thalidomide could relieve clinical symptoms and intestinal mucosal lesions effectively in children with refractory inflammatory bowel disease (IBD) from the pre-clinical study.', 'Thalidomide is now available as an investigational drug in the USA.', 'The STEPStrade mark (System for Thalidomide Education and Prescribing Safety) Program has been developed by Celgene, the commercial manufacturer of thalidomide, to ensure compliance with prescription and usage protocols.', 'New uses of thalidomide.', 'Thalidomide is an anti-angiogenesis agent that currently is being evaluated in the treatment of various types of cancer.', 'The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL)', 'Thalidomide is considered the drug of choice for the treatment of ENL, but for other conditions, it is recommended only when resistance to the currently available form of therapy is encountered', 'Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy', "Thalidomide, once banned, has returned to the center of controversy with the Food and Drug Administration's (FDA's) announcement that thalidomide will be placed on the market for the treatment of erythema nodosum leprosum, a severe dermatological complication of Hansen's disease. ", 'In 1998, FDA approved the marketing of thalidomide (Thalomid, Celgene). ', 'In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects.', 'BACKGROUND: The use of thalidomide during the 1950s resulted in teratogenic effects in thousands of infants. Although thalidomide is currently approved for the treatment of a complication of leprosy, it is commercially available to treat other diseases through a controlled distribution system.', 'The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL).']

['Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide is considered the drug of choice for the treatment of ENL, but for other conditions, it is recommended only when resistance to the currently available form of therapy is encountered. THE USE OF A DRUG WITH A TEMPORARY MARKETING AUTHORISATION: Thalidomide is currently available in France for nominative or cohort use with a temporary marketing authorisation (TMA). Examples of the basis for such regulation are drawn from historical situations (thalidomide, benoxaprofen) as well as currently marketed drugs (arylpropionic acids, disopyramide, indacrinone). In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. The US Food and Drug Administration (FDA) has approved Thalomid (thalidomide) capsules for the acute treatment of the cutaneous manifestations of moderate to severe ENL. The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties.', 'Thalidomide is currently used to treat multiple Myeloma, possibly POEMS (Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes ) syndrome and IBS']

['yes']

Does nifedipine inhibit L-type calcium channels?

['Nifedipine, an L-type calcium channel blocker, reduced the expression of synaptogamin and syntaxin and blocked the suppressive effect of vecuronium, suggesting that both agents inhibit presynaptic L-type calcium channels.', 'Treatment with nifedipine to inhibit calcium influx via the L-type channel Cav1.2 (alpha(1C)) inhibited the TGFbeta stimulated increase in ANK expression at all phases of chondrogenesis.', 'Finally, we found that PKCepsilon-induced stellation was significantly reduced by the specific L-type channel blocker nifedipine, indicating that calcium influx through VGCC mediates the change in astrocyte morphology induced by PKCepsilon.', 'However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol.', 'Both the metallic ions Cd2+ and Ni2+, known to inhibit voltage-gated calcium channels and T-type channels, respectively, and verapamil and nifedipine, typical blocker of L-type calcium channels completely prevented the hypoxic neuronal NO generation.', 'Further, the L-type calcium channel blocker, nifedipine, was able to inhibit the initial increase in [Ca2+]i, suggesting that at least this phase of the TMT effect was mediated by calcium channels, although nifedipine had no significant effect on the time to reach the maximal [Ca2+]i level', 'Treatment with omega-conotoxin GVIA (3 microM) or nifedipine (10 microM) to inhibit Ca(2+) influx through N- or L-type voltage-dependent calcium channels (VDCCs), respectively, also decreased the rate of AP repolarization and increased AP duration', 'Concentrations of nifedipine (10 microM) and nimodipine (3 microM) that maximally inhibit L-type calcium channels reduced the sI(AHP) by 30 and 50%, respectively', 'Consequently, it was demonstrated in the present study that nimodipine and nitrendipine inhibit both L- and N-type calcium channels and thus seem to be unique among the dihydropyridines examined in their effects on calcium channels in dibutyryl cAMP-differentiated neuroblastoma x glioma hybrid NG 108-15 cells, whereas nifedipine and niguldipine appear to block mainly L-type calcium channels', 'However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol', 'Calcium-channel antagonists, omega-conotoxin GVIA (omega-CgTx GVIA; N-type), nifedipine (L-type), and omega-conotoxin MVIIC (omega-CmTx MVIIC; P/Q type), were used to characterize the voltage-operated Ca(2+) channels (VOCCs) involved in this release', 'The T- and L-type calcium channel blocker (CCB) mibefradil attenuates leg edema induced by the L-type CCB nifedipine in the spontaneously hypertensive rat: a novel differentiating assay.', 'L-type calcium channel antagonist nifedipine reduces neurofilament restitution following traumatic optic nerve injury.', 'Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine.', 'Comparison of L-type calcium channel blockade by nifedipine and/or cadmium in guinea pig ventricular myocytes.', 'Nifedipine inhibits picrotoxin-induced seizure activity: further evidence on the involvement of L-type calcium channel blockers in epilepsy.']

['Yes, nifedipine is a typical blocker of L-type calcium channels.']

['yes']

Have thyronamines effects on fat tissue?

['Intraperitoneal or central injection of 3-T(1)AM or T(0)AM into mice, rats, or Djungarian hamsters caused various prompt effects, such as metabolic depression, hypothermia, negative chronotropy, negative inotropy, hyperglycemia, reduction of the respiratory quotient, ketonuria, and reduction of fat mass. ']

['thyronamines cause reduction of fat mass']

['yes']

What are the exonic splice enhancers?

['In humans, much of the information specifying splice sites is not at the splice site. Exonic splice enhancers are one of the principle non-splice site motifs. Four high-throughput studies have provided a compendium of motifs that function as exonic splice enhancers, but only one, RESCUE-ESE, has been generally employed to examine the properties of enhancers.', 'Exonic splice enhancers are one of the principle non-splice site motifs.', 'Exonic splice enhancers are one of the principle non-splice site motifs.']

["In mammals there is a bias in amino acid usage near splice sites that is explained, in large part, by the high density of exonic splicing enhancers (ESEs) in these regions. Exonic splicing enhancers (ESEs) activate pre-mRNA splicing by promoting the use of the flanking splice sites. Some of these variants may have an effect on pre-mRNA splicing, either by altering degenerate positions of splice site sequences or by affecting intronic or exonic splicing regulatory sequences such as exonic splicing enhancers (ESEs). For inherited disease, the main mechanism responsible for the splicing defect is splice site loss, whereas for cancer the predominant mechanism of splicing disruption is predicted to be exon skipping via loss of exonic splicing enhancers or gain of exonic splicing silencer elements. FELINES was shown to be useful for characterizing branchsites, polypyrimidine tracts and 5' and 3' splice sites in the intron databases and exonic splicing enhancers (ESEs) in S.pombe exons. Unexpectedly, a fully experimental dataset identifies motifs that commonly behave opposite to the consensus, for example, being enriched in exon cores where splice-associated mutations are rare.Prior analyses that used the RESCUE-ESE set of hexamers captured the properties of consensus exonic splice enhancers.", 'Exonic splice enhancers are one of the principle non-splice site motifs. Four high-throughput studies have provided a compendium of motifs that function as exonic splice enhancers, but only one, RESCUE-ESE, has been generally employed to examine the properties of enhancers. In humans, much of the information specifying splice sites is not at the splice site.', 'In humans, much of the information specifying splice sites is not at the splice site. Exonic splice enhancers are one of the principle non-splice site motifs. Four high-throughput studies have provided a compendium of motifs that function as exonic splice enhancers, but only one, RESCUE-ESE, has been generally employed to examine the properties of enhancers.']

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In what proportion of children with heart failure has Enalapril been shown to be safe and effective?

['The responses to IV KCl were attenuated by concomitant furosemide (p\xa0=\xa00.01), amphotericin B (p\xa0<\xa00.01), and KCl in parenteral nutrition (p\xa0<\xa00.01). The responses were augmented by concomitant enalapril', 'To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer.', 'Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year', 'Patients with intraatrial baffle procedure for transposition of the great arteries (TGA) have diastolic dysfunction, decreased exercise capacity, stroke volume response and elevated systemic vascular resistance (SVR) during exercise.', 'We conclude that short-term (<1 year) use of enalapril does not improve exercise performance in patients with TGA in whom the intraatrial baffle procedure has been performed.', 'A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer.', 'In doxorubicin-treated long-term survivors of childhood cancer, enalapril-induced improvement in LV structure and function is transient. The primary defect, which is LV wall thinning, continues to deteriorate, and thus the short-term improvement was mostly related to lowered diastolic blood pressure.', 'Patients who have undergone the Fontan procedure have decreased cardiac output, increased systemic vascular resistance, abnormal diastolic function, and decreased exercise capacity compared with normal people.', 'We conclude that enalapril administration for 10 weeks does not alter abnormal systemic vascular resistance, resting cardiac index, diastolic function, or exercise capacity in patients who have undergone a Fontan procedure.', 'Angiotensin convertase inhibitor (Enalapril) was used in 51 children aged 4 days up to 18 years (mean 4.3 +/- 5.5, years). As many as 27 subjects were newborns (4) and infants (23). The patients suffered from circulatory insufficiency due to congestive cardiomyopathy (13 cases). 6 treated subjects suffered from circulatory insufficiency due to congenital heart malformations before cardiac surgery and 22 after it (including complex malformations operated according to Fontan method). 10 children were treated because of arterial hypertension. 4 subjects suffered form life-threatening arrhythmias coexisting with circulatory insufficiency.', '4 patients (8%) died during treatment but their deaths can not be related to angiotensin convertase inhibitor therapy. In the other children (82%) the beneficial influence of angiotensin convertase inhibitor use was found (improvement in comparison with the state before convertase inhibitor introduction). In 10% of subjects enalapril did not show any significant therapeutic effect', 'We conclude that the combination of ACE inhibitor and beta-blocker deserves further exploration for inclusion in any management regimen for the treatment of muscular dystrophy-associated cardiomyopathy.', 'Addition of these medications, never before attempted in the management of cardiomyopathy associated with generalized myopathic disease, complemented each other in relieving symptoms and reversing signs of congestive heart failure and DCM.', 'Enalapril was clinically safe and effective for children with cardiac failure secondary to ventricular impairment, valvar regurgitation, or after cardiac surgery. Renal failure was a problem in young infants with left-to-right shunts.', 'In a tertiary referral centre 63 patients underwent 67 treatment periods with enalapril. The median age was 5.4 months. All children had signs of heart failure: congestive cardiac failure with breathlessness at rest was present in 88%. Haemodynamic groups were left-to-right shunt (n = 15), impaired ventricular function (n = 14), after cardiac surgery (n = 23), valvar regurgitation (n = 12), and hypertension (n = 3). Serial clinical, radiological, and laboratory data were used to judge outcome. The mean (SD) maximal dose was 0.30 (0.21) mg/kg/day. Thirty nine (58%) patients improved, 20 (30%) showed no improvement, and eight (12%) had side effects requiring discontinuation of enalapril.', 'We studied the inhibition of angiotensin converting enzyme (ACE) in eight infants with congestive heart failure (CHF) poorly controlled with digoxin and diuretics, treated orally with 0.25 mg kg-1 enalapril maleate once a day', 'In infants with CHF, mean baseline ACE activity was significantly higher than in control infants', 'Converting enzyme inhibitors may benefit "heart failure" associated with large ventricular septal defects and normal or mildly elevated pulmonary resistance.']

['In children with heart failure evidence of the effect of enalapril is empirical. Enalapril was clinically safe and effective in 50% to 80% of for children with cardiac failure secondary to congenital heart malformations before and after cardiac surgery, impaired ventricular function , valvar regurgitation, congestive cardiomyopathy, , arterial hypertension, life-threatening arrhythmias coexisting with circulatory insufficiency. \nACE inhibitors have shown a transient beneficial effect on heart failure due to anticancer drugs and possibly a beneficial effect in muscular dystrophy-associated cardiomyopathy, which deserves further studies.']

['50% to 80%']

Is shotgun lipidomics the direct infusion of a lipid sample into a mass spectrometer?

['In direct infusion/injection (or shotgun) lipidomics', 'An efficient shotgun lipidomics strategy was established and optimized for fast phospholipid profiling of viscera from three fish species: Lateolabrax japonicas, Ctenopharyngodon idellus, and Carassius auratus. This strategy relies on direct infusion of total lipid extracts into a tandem mass spectrometer without additional separation of the individual molecular species. ', 'Top-down shotgun lipidomics relies on direct infusion of total lipid extracts into a high-resolution tandem mass spectrometer', 'shotgun lipidomic approaches that use direct infusion', 'direct infusion (shotgun lipidomics) ', 'direct infusion-based shotgun lipidomics approaches', 'shotgun lipidomics (MDMS-SL) data, which are acquired directly from lipid extracts after direct infusion ', 'Through direct infusion of the resultant enriched solution, we identified and quantitated a variety of very-low-abundance sphingolipid classes (e.g., sphingosine, psychosine, and lysosphingomyelin) and molecular species (e.g., sphingomyelin) using electrospray ionization mass spectrometry (i.e., shotgun sphingolipidomics).']

['Yes, shotgun lipidomics relies on direct infusion of total lipid extracts into a high-resolution tandem mass spectrometer.']

['yes']

How does dabigatran therapy affect aPTT in patients with atrial fibrillation?

['He had been started on dabigatran 150\u2009mg twice a day about 4 months ago as an outpatient by his cardiologist. His prothrombin time (PT) was 63 seconds with international normalized ratio (INR) of 8.8 and his activated partial thromboplastin time (aPTT) was 105.7 seconds. ', 'The aPTT assay is relatively insensitive to dabigatran, and normal aPTT results may be observed even with therapeutic dabigatran concentrations.', 'The APTT values became prolonged under dabigatran usage and exhibited a remarkable diversity. Although major bleeding did not occur unless APTT was prolonged excessively, minor bleeding arose irrespective of the APTT values even within the range of the APTT values not exceeding 80s.', 'Dabigatran led to a dose-dependent prolongation of the clotting times in coagulometric tests and influenced the majority of the parameters measured. Statistically significant interference could be observed with the prothrombin time (PT), activated partial thromboplastin time (aPTT) and PT/aPTT-based assays (extrinsic/intrinsic factors, APC-resistance test) as well as lupus anticoagulant testing.', 'Although aPTT does not provide a linear response to dabigatran therapy, the presence of a completely normal PTT may exclude therapeutic dabigatran anticoagulation.', 'Commonly available global coagulation time assessments (e.g. prothrombin time and activated partial thromboplastin time) are highly influenced by rivaroxaban and dabigatran but these assays are relatively insensitive. ', 'The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. ', 'We found a wide distribution of APTT in NVAF patients under dabigatran treatment. High APTT might help screen for bleeding risks among patients under dabigatran, but requires future investigation.']

['Dabigatran increases aPTT in patients with atrial fibrillation, although aPTT does not respond linearily to dabigatran therapy.']

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Do mutations of AKT1 occur in meningiomas?

['The recent identification of somatic mutations in components of the SHH-GLI1 and AKT1-MTOR signaling pathways indicates the potential for cross talk of these pathways in the development of meningiomas.', 'A mutation in PIK3CA or AKT1 was found in around 9 % of the cases.', 'AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry.', 'AKT1E17K mutations were exclusively seen in meningiomas and occurred in 65 of 958 of these tumors. A strong preponderance was seen in the variant of meningothelial meningioma WHO grade I of basal and spinal localization. In contrast, AKT1E17K mutations were rare in WHO grade II and absent in WHO grade III meningiomas. ', 'We observed strong up-regulation of SFRP1 expression in all meningiomas with AKT1E17K mutation and in HEK293 cells after transfection with mutant AKT1E17K, but not in meningiomas and HEK293 cells lacking this mutation.', 'SMO and AKT1 mutations occur in non-NF2 meningiomas.', 'Recurrent mutations in SMO and AKT1 are mutually exclusive with NF2 loss in meningioma.', 'Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.', ' A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways.', 'Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.', 'A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways.', 'SMO and AKT1 mutations occur in non-NF2 meningiomas', 'The recent identification of somatic mutations in components of the SHH-GLI1 and AKT1-MTOR signaling pathways indicates the potential for cross talk of these pathways in the development of meningiomas', 'A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways', 'Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO', 'Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations', 'Recurrent mutations in SMO and AKT1 are mutually exclusive with NF2 loss in meningioma', 'A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. ', 'A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. ']

['Yes, AKT1 mutation occurs in meningiomas.']

['yes']

How is primary intestinal lymphangiectasia (PIL) caused?

['Primary intestinal lymphangiectasia (PIL) is a rare disorder of unknown etiology characterized by diffuse or localized dilation and eventual rupture of the enteric lymphatic vessels in mucosa, submucosa, and/or subserosa. Lymph, rich in all kinds of proteins and lymphocytes, leaks into the gastrointestinal tract via the affected lymphatic vessels causing hypoproteinemia and lymphopenia. ', 'PIL, effusions, and lymphedema can be the features of multisegmental generalized lymphatic dysplasia.', 'A number of disorders have been described to cause protein losing enteropathy (PLE) in children. Primary intestinal lymphangiectasia (PIL) is one mechanism leading to PLE.', 'Primary intestinal lymphangiectasia is a rare cause of protein-losing enteropathy and usually presents with intermittent diarrhea or malnutrition. Diagnosis depends largely on its pathologic condition demonstrating greatly dilated lymphatics mainly in the lamina propria of the mucosa. ', 'The histopathologic condition of the resected small intestine showed lymphatic dilation limited mainly to the subserosa and mesentery but was not prominent in the mucosa.', 'Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lymphatics and the development of protein-losing enteropathy.', "Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is an exudative enteropathy resulting from morphologic abnormalities in the intestinal lymphatics.", "Primary intestinal lymphangiectasia (PIL), so-called Waldmann's disease, is an uncommon condition, characterized by dilated intestinal submucosal and subserosal lymphatics of the gastrointestinal tract.", 'Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia.', "Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia.", 'Primary intestinal lymphangiectasia (PIL) is a protein-losing, exsudative gastroenteropathy causing lymphatic obstruction.', 'Primary intestinal lymphangiectasia (PIL) is a protein-losing enteropathy characterized by tortuous and dilated lymph channels of the small bowel.', 'Primary intestinal lymphangiectasia (PIL) is a rare disease of intestinal lymphatics presenting with hypoproteinemia, bilateral lower limb edema, ascites, and protein losing enteropathy.', 'Exudative enteropathy secondary to primary intestinal lymphangiectasia (PIL) is characterized by lymphopenia, hypogammaglobulinemia and hypoalbuminemia resulting from leakage of lymph fluid into the intestinal tract', 'Primary intestinal lymphangiectasia (PIL) is a rare protein-losing enteropathy with lymphatic leakage into the small intestine', 'Primary intestinal lymphangiectasia (PIL) is a protein-losing enteropathy characterized by tortuous and dilated lymph channels of the small bowel', 'Primary intestinal lymphangiectasia (PIL) is a rare disease of intestinal lymphatics presenting with hypoproteinemia, bilateral lower limb edema, ascites, and protein losing enteropathy', 'Primary intestinal lymphangiectasia (PIL), so-called Waldmanns disease, is an uncommon condition, characterized by dilated intestinal submucosal and subserosal lymphatics of the gastrointestinal tract', 'Primary intestinal lymphangiectasia (Waldmanns disease) is a rare disease characterized by dilated lymphatics in the small bowel leading to an exudative enteropathy with lymphopenia, hypoalbuminemia and hypogammaglobulinemia.We report the case of a 23 year-old male who presented with chronic anemia and in whom primary intestinal lymphangiectasia was diagnosed', 'We report a series of 4 children from Chennai, India presenting with anasarca, recurrent diarrhea, hypoproteinemia and confirmatory features of PIL on endoscopy and histopathology.', 'Primary intestinal lymphangiectasia (PIL) is a protein-losing, exsudative gastroenteropathy causing lymphatic obstruction. ', 'Primary intestinal lymphangiectasia (PIL) is a rare protein-losing enteropathy characterized by a congenital malformation of the lymphatic vessels of the small intestine causing insufficient drainage and leakage of lymph fluid.', 'Primary intestinal lymphangiectasia (PIL) is a rare protein-losing enteropathy with lymphatic leakage into the small intestine.', "Primary intestinal lymphangiectasia (PIL) or Waldmann's disease is a rare protein-losing gastroenteropathy of unknown etiology."]

['Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by diffuse or localized dilation and eventual rupture of the enteric lymphatic vessels in mucosa, submucosa, and/or subserosa. Lymph, rich in all kinds of proteins and lymphocytes, leaks into the gastrointestinal tract via the affected lymphatic vessels causing hypoproteinemia and lymphopenia.']

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Is osteocrin expressed exclusively in the bone?

['Evolution of Osteocrin as an activity-regulated factor in the primate brain.', 'Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons.', 'Osteocrin (Ostn) is a recently discovered secreted protein produced by cells of the osteoblast lineage that shows a well conserved homology with members of the natriuretic peptide (NP) family. ', 'Osteocrin (Ostn), a bone-active molecule, has been shown in animals to be highly expressed in cells of the osteoblast lineage. ', 'Osteocrin, a novel bone-specific secreted protein that modulates the osteoblast phenotype.']

['No, Osteocrin (Ostn) has been detected in the bones and the brain.']

['no']

List programs suitable for protein docking

['We present CSBB-ConeExclusion, a methodology and computer program which provides a measure of the applicability of solution dockings to solid support', 'The structure of the α1I-peptide complex was investigated using data from NMR, small angle x-ray scattering, and size exclusion chromatography that were used to generate and validate a model of the complex using the data-driven docking program, HADDOCK (High Ambiguity Driven Biomolecular Docking). ', 'We report the performance of our approaches for protein-protein docking and interface analysis in CAPRI rounds 20-26. At the core of our pipeline was the ZDOCK program for rigid-body protein-protein docking', 'GalaxyDock protein-ligand docking program is introduced. GalaxyDock performs conformational space annealing (CSA) global optimization to find the optimal binding pose of a ligand both in the rigid-receptor mode and the flexible-receptor mode', 'Utilizing NMR titration data, we generated the structural models of S100B-FGF2 complex from the computational docking program, HADDOCK which were further proved stable during 15ns unrestrained molecular dynamics (MD) simulations', 'Thereafter, all molecules were docked into the newly generated active site environment of the selected protein using glide docking program, and the 3D-QSAR analysis was performed in PHASE program utilizing the docking based alignment of the molecules', 'DockRank uses interface residues predicted by partner-specific sequence homology-based protein-protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). ', 'In this study, we developed a novel scoring program, HotLig, which applies the Connolly surface of a protein to calculate hydrophobic interaction and paired pharmacophore interactions with ligands. In addition to molecular surface distance, ligand-contacting areas and hydrogen-bond angles were also introduced to the scoring functions in HotLig', 'a method called residue contact frequency (RCF), which uses the complex structures generated by the protein-protein docking algorithm ZDOCK to predict interface residues', 'devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy', 'improves the binding energy scoring by the local energy optimization of the ligand docked pose and a simple linear regression on the base of available experimental data', 'The template-based methods showed similar performance to a docking method (ZDOCK) when the latter was allowed one prediction for each complex, but when the same number of predictions was allowed for each method, the docking approach outperformed template-based approaches', 'VinaMPI is a massively parallel Message Passing Interface (MPI) program based on the multithreaded virtual docking program AutodockVina, and is used to distribute tasks while multithreading is used to speed-up individual docking tasks', 'Prime and the binding energy function in YASARA suggested it could be possible to evaluate the quality of the orthosteric binding site based on the prediction of relative binding energies', ' is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments', 'This article presents DockTrina, a novel protein docking method for modeling the 3D structures of nonsymmetrical triangular trimers', 'To account for the important docking interactions between the UBSAs ligand and hCA II enzyme, a molecular docking program AutoDock Vina is used. The molecular docking results obtained by AutoDock Vina revealed that the docked conformer has root mean square deviation value less than 1.50 Å compared to X-ray crystal structures.', 'Four possible binding pockets (Pocket A, B, C, and D) at the stalk region of hemagglutinin were detected and defined using the CAVITY program', 'Within this context, low-resolution shape data obtained from either ion-mobility mass spectrometry (IM-MS) or SAXS experiments have been integrated into the conventional scoring function of the information-driven docking program HADDOCK', 'a novel de novo design program, called LiGen, we developed a docking program, LiGenDock, based on pharmacophore models of binding sites, including a non-enumerative docking algorithm.', 'we present the functionalities of LiGenDock and its accompanying module LiGenPocket, aimed at the binding site analysis and structure-based pharmacophore definition', 'Here we describe the application of the program AutoDock to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K(d) = ~100 fM). ', ' the method yields improved success over the standard DOCK energy function for pose identification across a large test set of experimental co-crystal structures, for crossdocking, and for database enrichment', 'The pose prediction success rate of each docking program alone was found in this trial to be 55% for Autodock, 58% for DOCK, and 64% for Vina.']

['Macromolecular docking is the computational modelling of the quaternary structure of complexes formed by two or more interacting biological macromolecules. Protein–protein complexes are the most commonly attempted targets of such modelling, followed by protein–nucleic acid complexes.\nThe ultimate goal of docking is the prediction of the three-dimensional structure of the macromolecular complex of interest as it would occur in a living organism. Docking itself only produces plausible candidate structures. These candidates must be ranked using methods such as scoring functions to identify structures that are most likely to occur in nature.\nNowadays there a lot of programs suitable for proteins docking such as CSBB-ConeExclusion, HADDOCK, ZDOCK, GalaxyDock, PHASE, DockRank, HotLig, SOL, AutodockVina, DockoMatic, DockoMatic, DockTrina, CAVITY, LiGenDock and DOCK.']

['CSBB-ConeExclusion', 'HADDOCK', 'ZDOCK', 'GalaxyDock', 'PHASE', 'DockRank', 'HotLig', 'SOL', 'AutodockVina', 'DockoMatic', 'DockTrina', 'CAVITY', 'LiGenDock', 'DOCK', 'DISCORE']

What are the treatments of choice for GIST (gastrointestinal stromal tumor)?

['Traditionally, the treatment of choice for primary disease is surgical resection', 'no single surgeon or institution gets extensive exposure to these patients so appropriate decision-making is difficult, particularly since the introduction of the tyrosine kinase inhibitor imatinib, which has become an important additional management tool', 'Surgery aiming at an R0 resection remains the mainstay of treatment.', 'The treatment of choice for GIST is surgical resection', 'Extra luminal colonic gastrointestinal stromal tumors are very rare and can present as mass abdomen. Resection is the treatment of choice.', 'Surgery remains the only curative treatment for gastrointestinal stromal tumour (GIST).', 'When they are localized, the treatment of choice is surgical excision, but advanced tumors have a limited response to chemo or radiotherapy. Imatinib (STI571 or Glivec) is a selective inhibitor or tyrosine kinase proteins that has been used successfully in the treatment of advanced GIST.', 'Therefore Imatinib can be a therapeutic alternative in patients with metastatic GIST.', 'The surgical resection is a treatment of choice for gastrointestinal stromal tumors. It has been shown that adequate surgical resection correlates with high 5-years survival rates for patients with gastric GIST.', 'Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation. ', 'combination of imatinib therapy and surgery also may be effective in a subset of patients with metastatic or unresectable primary GIST']

['The surgical resection is a treatment of choice for gastrointestinal stromal tumors. It has been shown that adequate surgical resection correlates with high 5-years survival rates for patients with gastric GIST. When they are localized, the treatment of choice is surgical excision, but advanced tumors have a limited response to chemo or radiotherapy. Imatinib (STI571 or Glivec) is a selective inhibitor or tyrosine kinase proteins that has been used successfully in the treatment of advanced GIST. ', 'Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation.']

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Is there any role for long noncoding RNAs in adipogenesis?

['Long noncoding RNAs regulate adipogenesis.', 'Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.', 'Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). ']

['Yes. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, numerous lncRNAs are functionally required for proper adipogenesis.']

['yes']

Name a method for enrichment of arginine-methylated peptides.

['To better study protein methylation, we have developed highly specific antibodies against monomethyl arginine; asymmetric dimethyl arginine; and monomethyl, dimethyl, and trimethyl lysine motifs. These antibodies were used to perform immunoaffinity purification of methyl peptides followed by LC-MS/MS analysis to identify and quantify arginine and lysine methylation sites in several model studies. ']

['Immunoaffinity purification using specific antibodies has been used in order to perform enrichment of methylated peptides.']

['Immunoaffinity purification']

List tele monitoring applications of miniaturised sensors

['Home-polysomnography (HPSG) has been proposed as a cost-effective alternative for obstructive sleep apnea (OSA) diagnosis. We assessed, in a feasibility study, whether telematic transmission using the Dream® and Sleepbox® technologies was associated with low HPSG failure rate', ' In this study, we monitored remotely self-measured body weight and blood pressure, in parallel with the data automatically transmitted by implantable cardioverter-defibrillators.', 'Body weight, patient activity, and the difference between MHR and RHR are mutually correlated and may reasonably contribute to an algorithm for predicting heart failure deterioration. Blood pressure appears to offer no additional value. As both genesis and symptoms of heart failure exacerbation are non-uniform and complex, the telemonitoring concepts for heart failure patients should employ continuous monitoring of multiple diagnostic parameters, rather than rely on a single parameter.', "System and can collect users' vital signs with a set of wireless sensors", 'this terminal is very helpful in special circumstances such as disaster relief, dangerous outdoor sports and adventure monitoring, and antiterrorism activities.', 'A new, phonocardiography-based telemetric fetal home monitoring system.', 'The input element of the system was the home monitor with two sensors for recording the trans-abdominal fetal heart signal and the uterine contractions. T', 'Telemonitoring is currently being used in community-based healthcare, at the scene of medical emergencies, by ambulance services and in hospitals. ', 'Mobile telemonitoring for achieving tighter targets of blood pressure control in patients with complicated diabetes: ', 'Patients in the intervention arm transmitted weekly blood pressure readings wirelessly, using adapted sensors via mobile phones to a central server. ', 'In patients with diabetes, mobile telemonitoring has potential for delivering intensified care to improve blood pressure control, and its use may be associated with reduced exposure to hyperglycemia.', 'A new codivilla-spring prosthesis with sensors for telemonitoring / telerehabilitation has been designed and constructed. It provides step counting', 'This article is a survey of systems, algorithms and sensors, for the automatic early detection of the fall of elderly persons. ', 'We describe a vital sign telemonitor (VST) that acquires, records, displays, and provides readings such as: electrocardiograms (ECGs), temperature (T), and oxygen saturation (SaO2) over the Internet to any site. The design of this system consisted of three parts: sensors, analog signal processing circuits, and a user-friendly graphical user interface (GUI). ', 'The paper describes the development of biomedical clothing for ambulatory telemonitoring of human vital parameters. VTAM (Vetement de Tele-Assistance Medicale) presents a T-shirt made from textile with woven wires and incorporating four smooth dry ECG electrodes, a breath rate sensor, a shock/fall detector and two temperature sensors. ']

['Home-polysomnography (HPSG)\nBody weight\nBlood pressure control\nHeart failure control\nVital signs - disaster relief, dangerous outdoor sports and adventure monitoring, and antiterrorism activities.\nTelemetric fetal home monitoring system for recording the trans-abdominal fetal heart signal and the uterine contractions\nVital signs - electrocardiograms (ECGs), temperature (T), and oxygen saturation (SaO2) , breath rate\nStep-counting for tele-rehabilitation\nDetection of falls in elderly']

['Sleep monitoring', 'Body weight', 'Blood pressure control', 'Heart failure control', 'vital signs', 'fetal heart signal', 'uterine contractions', 'Electrocardiograms', 'ECG', 'Temperature', 'Oxygen saturation', 'SaO2', 'breath rate', 'Step-counting', 'Falls detector']

What is known about the Kub5-Hera/RPRD1B interactome?

['The Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repair', 'Ku70-binding protein 5 (Kub5)-Hera (K-H)/RPRD1B maintains genetic integrity by concomitantly minimizing persistent R-loops and promoting repair of DNA double strand breaks (DSBs)', 'The Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repair.']

['Ku70-binding protein 5 (Kub5)-Hera (K-H)/RPRD1B maintains genetic integrity by concomitantly minimizing persistent R-loops and promoting repair of DNA double strand breaks (DSBs). Thus, the Kub5-Hera/RPRD1B interactome plays a novel role in preserving genetic stability by regulating DNA mismatch repair.']

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What is BioASQ?

['BIOASQ helped obtain a unified view of how techniques from text classification, semantic indexing, document and passage retrieval, question answering, and text summarization can be combined to allow biomedical experts to obtain concise, user-understandable answers to questions reflecting their real information needs.', 'BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies.', 'This article provides an overview of the first BIOASQ challenge, a competition on large-scale biomedical semantic indexing and question answering (QA), which took place between March and September 2013.', 'This article provides an overview of the first BIOASQ challenge, a competition on large-scale biomedical semantic indexing and question answering (QA), which took place between March and September 2013', 'BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies', 'BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies.RESULTS: The 2013 BIOASQ competition comprised two tasks, Task 1a and Task 1b. ', 'The BIOASQ infrastructure, including benchmark datasets, evaluation mechanisms, and the results of the participants and baseline methods, is publicly available.CONCLUSIONS: A publicly available evaluation infrastructure for biomedical semantic indexing and QA has been developed, which includes benchmark datasets, and can be used to evaluate systems that: assign MESH headings to published articles or to English questions; retrieve relevant RDF triples from ontologies, relevant articles and snippets from PUBMED Central; produce "exact" and paragraph-sized "ideal" answers (summaries). The results of the systems that participated in the 2013 BIOASQ competition are promising. ', 'In Task 1b the systems received high scores in the manual evaluation of the "ideal" answers; hence, they produced high quality summaries as answers. Overall, BIOASQ helped obtain a unified view of how techniques from text classification, semantic indexing, document and passage retrieval, question answering, and text summarization can be combined to allow biomedical experts to obtain concise, user-understandable answers to questions reflecting their real information needs.', 'Overall, BIOASQ helped obtain a unified view of how techniques from text classification, semantic indexing, document and passage retrieval, question answering, and text summarization can be combined to allow biomedical experts to obtain concise, user-understandable answers to questions reflecting their real information needs.', 'BACKGROUND: This article provides an overview of the first BIOASQ challenge, a competition on large-scale biomedical semantic indexing and question answering (QA), which took place between March and September 2013. ', 'This article provides an overview of the first BIOASQ challenge, a competition on large-scale biomedical semantic indexing and question answering (QA), which took place between March and September 2013.', 'BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies. The 2013 BIOASQ competition comprised two tasks, Task 1a and Task 1b.', 'This article provides an overview of the first BIOASQ challenge, a competition on large-scale biomedical semantic indexing and question answering (QA), which took place between March and September 2013. BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies.', 'BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies.The 2013 BIOASQ competition comprised two tasks, Task 1a and Task 1b.']

['BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies. ', 'The BioASQ challenge is a competition on large-scale biomedical semantic indexing and question answering (QA). BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies. BIOASQ helped obtain a unified view of how techniques from text classification, semantic indexing, document and passage retrieval, question answering, and text summarization can be combined to allow biomedical experts to obtain concise, user-understandable answers to questions reflecting their real information needs.']

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What is the definition of autophagy?

['autophagy, a process in which de novo formed membrane enclosed vesicles engulf and consume cellular components', 'As a general definition, autophagy encompasses a range of processes in which the cell degrades parts of itself within the lysosome (or the analogous organelle, the vacuole, in yeast and plants), followed by the release and reuse of the breakdown products', 'definition of autophagy is the following: all processes in which intracellular material is degraded within the lysosome/vacuole and where the macromolecular constituents are recycled', 'Autophagic PCD in animals is defined as being accompanied by an increase in the number of autophagosomes, autolysosomes, and small lytic vacuoles produced by autolysosomes', 'utophagy is the endogenous, tightly regulated cellular "housekeeping" process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates', 'utophagy has been predominantly studied as a nonselective self-digestion process that recycles macromolecules and produces energy in response to starvation', 'utophagy is a ubiquitous eukaryotic cytoplasmic quality and quantity control pathway', 'utophagy is a catabolic trafficking pathway for bulk destruction and turnover of long-lived proteins and organelles via regulated lysosomal degradation.', ' non-apoptotic programmed cell death, such as autophagy ', 'utophagy and senescence share a number of characteristics, which suggests that both responses could serve to collaterally protect the cell from the toxicity of external stress such as radiation and chemotherapy and internal forms of stress such as telomere shortening and oncogene activation']

['There are several definitions of autophagy. Among them, autophagy can be defined as a non- apoptotic programmed cell death that consists on a catabolic trafficking pathway for bulk destruction and turnover of long-lived proteins and organelles via regulated lysosomal degradation.']

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Which cells secretes alpha defensin 5?

['The major tissue in which HD5 is expressed is the crypt of the small intestine, an anaerobic niche that should allow for substantial pools of both oxidized and (partly) reduced HD5. ', 'Human α-defensin 5 (HD5) exhibits broad spectrum antimicrobial activity and plays an important role in mucosal immunity of the small intestine.', 'Human enteric α-defensins (HD5 and HD6), major antimicrobial peptides produced by Paneth cells in the intestine, play important roles in intestinal innate immunity.', 'Human α-defensin 5 (HD5), the most abundant enteric antimicrobial peptide,', 'HD5, naturally present at very high concentrations in the mucosa of the small intestine, ', 'Human α-defensin 5 (HD5) is an innate immune effector peptide secreted by epithelial cells in the genitourinary tract', 'Human α-defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits broad-spectrum antimicrobial activity and contributes to innate immunity in the human gut and other organ systems. ', 'The concentrations of lactoferrin and defensins in preterm breast milk have antimicrobial activity against common neonatal pathogens.']

['Human enteric α-defensins (HD5 and HD6), major antimicrobial peptides produced by Paneth cells in the intestine, play important roles in intestinal innate immunity.']

['Intestinal Paneth cells secretes alpha-defensin 5']

Which thyroid hormone transporter is implicated in thyroid hormone resistance syndrome?

['Hemizygous MCT8 mutations in males cause severe psychomotor retardation, known as the Allan-Herndon-Dudley syndrome (AHDS), and abnormal serum TH levels. AHDS thus represents a type of TH resistance caused by a defect in cellular TH transport.', 'Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities.', 'When thyroid hormone production was reduced by PTU, high doses of LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone', 'One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8']

['thyroid hormone transporter MCT8 is implicated in thyroid hormone resistance syndrome', 'Hemizygous MCT8 mutations cuases TH resistance syndrome in males characterized by severe psychomotor retardation, known as the Allan-Herndon-Dudley syndrome (AHDS).']

['monocarboxylate transporter 8', 'TH monocarboxylate transporter 8 (MCT8) mutation is implicated in the TH resistance syndrome', 'MCT8']

Describe Exploding head syndrome.

['Exploding head syndrome is characterized by the perception of loud noises during sleep-wake or wake-sleep transitions.', 'Exploding head syndrome is characterized by the perception of abrupt, loud noises when going to sleep or waking up.', 'BACKGROUND: Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake.', 'INTRODUCTION: Exploding head syndrome (EHS) is a rare parasomnia in which affected individuals awaken from sleep with the sensation of a loud bang.', 'Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake.', 'Exploding head syndrome (EHS) attacks are characterized by the sensation of sudden loud banging noises, and are occasionally accompanied by the sensation of a flash light.', 'Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake.We present six new cases extending the clinical experience with the syndrome', 'Exploding head syndrome (EHS) is a rare parasomnia in which affected individuals awaken from sleep with the sensation of a loud bang', 'Exploding head syndrome (EHS) attacks are characterized by the sensation of sudden loud banging noises, and are occasionally accompanied by the sensation of a flash light. ', 'Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake.We present six new cases extending the clinical experience with the syndrome.']

['Exploding head syndrome is characterized by the perception of abrupt, loud noises when going to sleep or waking up.']

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What are the functions of sorting nexin 27?

['Knockdown of SNX27 by siRNA in HEK293 cells raised MRP4 expression on the plasma membrane, increased the extrusion of 6-[(14)C]mercaptopurine, an MRP4 substrate, and conferred resistance against 6-[(14)C]mercaptopurine.', 'Sorting nexin 27 (SNX27) is a 62-kDa protein localized to early endosomes and known to regulate the intracellular trafficking of ion channels and receptors.', 'Finally, migration assays revealed that depletion of SNX27 from HeLa and mouse principal kidney cortical collecting duct cells significantly decreases cell motility. We propose a model by which SNX27 regulates trafficking of β-Pix to focal adhesions and thereby influences cell motility.', 'We found that SNX27a redirected part of 5-HT4(a)R to early endosomes.', 'sorting nexin 27 (SNX27), a recently described member of a protein family involved in intracellular trafficking,', 'SNX27 co-localized with transferrin receptor-positive vesicles, pointing to its participation in T cell endocytic recycling.', 'This protein is a unique member of the sorting nexin family of proteins, a group generally involved in the endocytic and intracellular sorting machinery', 'These previously unreported results indicate that SNX27 is a participant in NK cell polarization, as a mediator or target of the mechanism.', 'Like most sorting nexins, SNX27 possesses a functional PX domain that selectively binds the membrane phospholipid phosphatidylinositol-3-phosphate (PI3P) and is important for trafficking to the early endosome.', 'This is consistent with a role of SNX27 as a general regulator for sorting of membrane proteins containing a PDZ-binding motif, and its absence may alter the trafficking of these proteins, leading to growth and survival defects.', 'Sorting nexin 27 (SNX27) belongs to the sorting nexin family of proteins, which participate in vesicular and protein trafficking. Similarly to all sorting nexin proteins, SNX27 has a functional PX domain that is important for endosome binding, but it is the only sorting nexin with a PDZ domain.', 'These results identify SNX27 as a PDZ-containing component of the T cell immunological synapse, and demonstrate a role for this protein in the regulation of the Ras-ERK pathway, suggesting a functional relationship between SNX27 and DGKζ.', 'Sorting nexins have been implicated in trafficking of proteins through endosomal compartments.']

['Sorting nexin 27 (SNX27) regulates endocytic sorting/recycling and intracellular trafficking of ion channels and receptors.']

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What is the effect of SAHA treatment in Huntington's disease?

["Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease", 'To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood-brain barrier and increases histone acetylation in the brain', 'SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics.', 'Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage', "Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models", 'The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases', 'SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons', 'neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation']

['Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage. SAHA is predominantly an inhibitor of class I HDACs. However, it can also bind to class IIa HDACs and has been shown to degrade class IIa HDACs at the protein level in vitro. The neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. SAHA can lead to the degradation of class IIa HDACs 4 and 5 via RANBP2 mediated proteasome degradation in vitro.']

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Which is the mechanism used by bacteria to induce tumors in Arabidopsis?

['Agrobacterium tumefaciens causes crown gall disease in a wide range of plant species. The neoplastic growth at the infection sites is caused by transferring, integrating, and expressing transfer DNA (T-DNA) from A. tumefaciens into plant cells', ' gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome', "robacterium tumefaciens is a plant pathogenic bacterium that causes neoplastic growths, called 'crown gall', via the transfer and integration of transferred DNA (T-DNA) from the bacterium into the plant genome.", 'grobacterium tumefaciens causes crown gall disease by transferring and integrating bacterial DNA (T-DNA) into the plant genome', 'ransformation of plant cells with T-DNA of virulent agrobacteria is one of the most extreme triggers of developmental changes in higher plants.', 'grobacterium tumefaciens infects plants and induces the formation of tumors called "crown galls" by integrating the transferred-DNA (T-DNA) region of the Ti-plasmid into the plant nuclear genome', '-DNA nuclear import is a central event in genetic transformation of plant cells by Agrobacterium', 'grobacterium tumefaciens Chry5, which is particularly virulent on soybeans, induces tumors ', ' have identified T-DNA tagged Arabidopsis mutants that are resistant to transformation by Agrobacterium tumefaciens (rat mutants', 'grobacterium tumefaciens induces crown gall tumors on plants by transferring a nucleoprotein complex, the T-complex, from the bacterium to the plant cell', 'The recalcitrance of another ecotype occurs at a late step in T-DNA transfer']

['The bacteria Agrobacterium tumefaciens infects Arabidopsis, as well as other plants, and induces the formation of tumors by integrating the transferred-DNA (T-DNA) region of the Ti-plasmid into the plant nuclear genome.']

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What is the RESID database?

['The RESID Database of Protein Modifications as a resource and annotation tool.', 'The RESID Database of Protein Modifications is a comprehensive collection of annotations and structures for protein modifications and cross-links including pre-, co-, and post-translational modifications', 'The RESID Database is a comprehensive collection of annotations and structures for protein pre-, co- and post-translational modifications including amino-terminal, carboxyl-terminal and peptide chain cross-link modifications.', 'The RESID Database is a comprehensive collection of annotations and structures for protein post-translational modifications including N-terminal, C-terminal and peptide chain cross-link modifications. ', 'The RESID Database contains supplemental information on post-translational modifications for the standardized annotations appearing in the PIR-International Protein Sequence Database. ', 'The RESID Database of protein structure modifications.']

['The RESID Database of Protein Modifications is a comprehensive collection of annotations and structures for protein modifications and cross-links including pre-, co-, and post-translational modifications']

['The RESID Database of Protein Modifications is a comprehensive collection of annotations and structures for protein modifications and cross-links including pre-, co-, and post-translational modifications']

For what indications is thalidomide currently marketed?

['In this retrospective study, pharmacy claims were analyzed for those patients with a diagnosis of MM who received thalidomide, lenalidomide, or pomalidomide from a large specialty pharmacy in the US between January 1, 2011, and December 31, 2013.', 'Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently, the prognosis of POEMS was substantially improved by introduction of therapeutic intervention for myeloma. However, no randomised clinical trial has been performed because of the rarity and severity of the disease.METHODS AND ANALYSIS: The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome', 'Thalidomide could relieve clinical symptoms and intestinal mucosal lesions effectively in children with refractory inflammatory bowel disease (IBD) from the pre-clinical study.', 'In reactional states of leprosy the use of thalidomide is established.', 'The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction.', 'New uses of thalidomide.', 'Currently, it is used for a few indications; in Brazil, where leprosy is endemic, thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of thalidomide embryopathy have been reported.We analyzed the frequency of births with phenotypes consistent with thalidomide embryopathy (TEP) and correlated this with the distribution of thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil.A total of 5,889,210 thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54-1.66) and TEP was 0.11 (CI95%: 0.10-0.13) per 10,000 births.', 'The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL)', 'To explore the inhibitory effect of thalidomide combined with interferon (IFN) on the human acute myeloid leukemia cell line Kasumi- 1 and its mechanism.The inhibitiory effect of Kasumi- 1 cells by thalidomide, interferon or combination was detected by CCK- 8 method, the apoptosis by flow cytometry, the expression of apoptosis related proteins by Western blot, vascular endothelial growth factor (VEGF) concentration in culture supernatant by ELISA.Thalidomide inhibited the proliferation of Kasumi- 1 in a dose- dependent manner from 50 μg/ml to 500 μg/ml with an IC₅₀ of (451.', 'Interferon (INF)-α was the maintenance treatment of choice after autologous stem cell transplantation in multiple myeloma in the past, but currently Thalidomide is commonly used', 'However, no randomised clinical trial has been performed because of the rarity and severity of the disease.The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome, with an additional 48-week open-label safety study', 'Thalidomide, mainly used for the treatment of leprosy, is a current teratogen in South America, and it is reasonable to assume that at present this situation is affecting many births in underdeveloped countries. ', 'Currently, it is used for a few indications; in Brazil, where leprosy is endemic, thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of thalidomide embryopathy have been reported.We analyzed the frequency of births with phenotypes consistent with thalidomide embryopathy (TEP) and correlated this with the distribution of thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil.A total of 5,889,210 thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54-1.66) and TEP was 0.11 (CI95%: 0.10-0.13)', 'A review of the therapeutic indications for thalidomide in dermatology as well as the mechanisms of action and side-effects of this drug are presented.', "Thalidomide first was marketed as a sedative in the 1950s and withdrawn from the market in 1961 following reports of teratogenicity. Later, it was used as an investigational agent for the treatment of Hansen's disease, Kaposi's sarcoma, myelofibrosis, RAUs, and wasting associated with HIV.", 'The drug has since been found effective for several different indications.', 'Based on present publications we review indications of the therapy of dermatoses with thalidomide as well as possible mechanisms of action and side effects of this drug.', 'Use of thalidomide in dermatological indications.', 'Current data demonstrates that thalidomide is clinically promising in multiple myeloma, glioblastoma multiforme and renal cell cancer.', 'Erythema nodosum leprosum is the only registered indication for the use of thalidomide in the United States of America.', 'Thalidomide is currently under investigation for the treatment of a wide variety of diseases, including conditions thought to have an inflammatory or immune basis, malignancies and complications of infection with HIV.', "Gradually, thalidomide was reintroduced for the treatment of a few skin diseases including leprous erythema nodosum, severe mucosal ulcers (e.g., associated with HIV infection or Behçet's disease), lymphocytic skin infiltrations, cutaneous lupus erythematosus, and chronic graft-versus-host disease", 'Thalidomide has been used in several cutaneous inflammatory disorders (such as erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus, severe aphtosis), cancers (relapsed/refractory multiple myeloma) and inflammatory conditions.', 'This drug was more recently rediscovered as a powerful immunomodulatory and antiinflammatory agent and was approved by the FDA in 1998 for treatment of erythema nodosum leprosum.', ' Since, however, it has been found to be an effective drug in erythema nodosum leprosum']

['Drug repositioning, exemplified by sildenafil and thalidomide, is a promising way to explore alternative indications for existing drugs. THE USE OF A DRUG WITH A TEMPORARY MARKETING AUTHORISATION: Thalidomide is currently available in France for nominative or cohort use with a temporary marketing authorisation (TMA). Currently, it is used for a few indications; in Brazil, where leprosy is endemic, thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of thalidomide embryopathy have been reported.We analyzed the frequency of births with phenotypes consistent with thalidomide embryopathy (TEP) and correlated this with the distribution of thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil.A total of 5,889,210 thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54-1.66) and TEP was 0.11 (CI95%: 0.10-0.13) Currently it includes a group of new drugs (immunosuppressives tacrolimus mycophenolate, thalidomide, biologic therapy, probiotics, neuroinflammation blockers), new treatment techniques (cytaphereses, sequential immunosuppression, immunosuppression with high doses), and finally new indications (chemoprophylaxis). A review of the therapeutic indications for thalidomide in dermatology as well as the mechanisms of action and side-effects of this drug are presented.', 'Thalidomide can be used to treat multiple myeloma, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome and possibly Irritable Bowel Syndrome.']

['Multiple myeloma', 'polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes', 'POEMS', 'Irritable Bowels Syndrome ', 'IBS']

What is the biological role of SERCA2 SUMOylation in cardiac physiology and pathophysiology, such as in heart failure?

['SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and PKCα. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation.', 'The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins, and is involved in many cellular processes. Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts.', 'Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function, and provide a platform for the design of novel therapeutic strategies for heart failure.', 'Recently, the impact of small ubiquitin-related modifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2a) function was discovered. The amount of myocardial SUMO-1 is decreased in failing hearts, and its knockdown results in severe heart failure (HF) in mice.', 'SUMO-1 gene transfer therefore improved cardiac function and stabilized LV volumes in a large-animal model of HF. These results support the critical role of SUMO-1 in SERCA2a function and underline the therapeutic potential of SUMO-1 for HF patients.', 'However, the initial simple view of a PLN/SERCA regulatory complex has been modified by our recent identification of SUMO, S100 and the histidine-rich Ca-binding protein as regulators of SERCA activity.', 'The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts', 'Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells', 'Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function, and provide a platform for the design of novel therapeutic strategies for heart failure', 'SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation', 'The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts', 'Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells']

['Recently, the impact of small ubiquitin-related modifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2a) function was discovered. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins, and is involved in many cellular processes. SERCA2a is SUMOylated at lysines 480 and 585 and this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO-1 gene transfer improved cardiac function supporting the critical role of SUMO-1 in SERCA2a function and underlining the therapeutic potential of SUMO-1 for HF patients.']

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Is there evidence for de novo genesis of enhancers in vertebrates?

['De novo genesis of enhancers in vertebrates.', 'Evolutionary innovation relies partially on changes in gene regulation. While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates. For this, we took advantage of the massive gene loss following the last whole genome duplication in teleosts to systematically identify regions that have lost their coding capacity but retain sequence conservation with mammals. We found that these regions show enhancer activity while the orthologous coding regions have no regulatory activity. These results demonstrate that these enhancers have been de novo generated in fish. By revealing that minor changes in non-regulatory sequences are sufficient to generate new enhancers, our study highlights an important playground for creating new regulatory variability and evolutionary innovation.', 'Here we show evidence for the de novo genesis of enhancers in vertebrates.', 'While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated.', 'While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated', 'While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates. For this, we took advantage of the massive gene loss following the last whole genome duplication in teleosts to systematically identify regions that have lost their coding capacity but retain sequence conservation with mammals. ', 'Here we show evidence for the de novo genesis of enhancers in vertebrates. ', 'While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates.']

['Yes.']

['yes']

What genetic alterations are commonly associated with Diffuse Midline Gliomas, aside from IDH1 mutation and EGFR amplification, and often linked to p53 overexpression, ATRX loss, and monosomy 10?

[' transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo.", "In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas.CONCLUSION: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.", "Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles.", "Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas.", "Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations.", "In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.", "The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.", "K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.", "Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\\u00a0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\\u00a0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.", "Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3."]']

The H3.3 K27M mutation is commonly associated with Diffuse Midline Gliomas, aside from IDH1 mutation and EGFR amplification, and often linked to p53 overexpression, ATRX loss, and monosomy 10.

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Which proteins are involved in actin bundling and filopodia formation and function?

['CRP1, a protein localized in filopodia of growth cones, is involved in dendritic growth', 'CRP1, which cross-links actin filaments to make actin bundles, is the only CRP family member expressed in the CNS with little known about its function in nerve cells.', 'Here, we report that CRP1 colocalizes with actin in the filopodia of growth cones in cultured rat hippocampal neurons.', 'Knockdown of CRP1 expression by short hairpin RNA interference results in inhibition of filopodia formation and dendritic growth in neurons.', 'Overexpression of CRP1 increases filopodia formation and neurite branching, which require its actin-bundling activity.', 'F-ascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types.', 'In this study, we investigated the role of fascin, a cytoskeleton actin-bundling protein involved in the formation of filopodia and cell migration, in prostate cancer progression.', 'In cellular models, fascin gene silencing using small interfering RNA in the androgen-independent prostate cancer cell line DU145 decreased cell motility and invasiveness while increasing cell adhesive properties.', 'Fascin is an actin-bundling protein that induces membrane protrusions and cell motility after the formation of lamellipodia or filopodia.', 'The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages', 'Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis.', 'The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration.', 'Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro.', 'In addition, MAYP colocalized with cortical and filopodial F-actin in vivo.', 'Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.', 'We report an unexpected direct association between fascin, an actin-bundling component of filopodia, microspikes and lamellipodial ribs, and protein kinase Calpha (PKCalpha), a regulator of focal adhesions.', 'Fascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types.', 'Actin-crosslinking proteins organize actin into highly dynamic and architecturally diverse subcellular scaffolds that orchestrate a variety of mechanical processes, including lamellipodial and filopodial protrusions in motile cells.', 'IRSp53, a multi-domain protein that can associate with the Rho-GTPases Rac and Cdc42, participates in these processes mainly through its amino-terminal IMD (IRSp53 and MIM domain). The isolated IMD has actin-bundling activity in vitro and is sufficient to induce filopodia in vivo.', 'Eps8 activates and synergizes with IRSp53 in mediating actin bundling in vitro, enhancing IRSp53-dependent membrane extensions in vivo.', 'Consistently, Cdc42-induced filopodia are inhibited following individual removal of either IRSp53 or Eps8.', 'Collectively, these results support a model whereby the synergic bundling activity of the IRSp53-Eps8 complex, regulated by Cdc42, contributes to the generation of actin bundles, thus promoting filopodial protrusions.', 'The bundling activity of vasodilator-stimulated phosphoprotein is required for filopodium formation', 'Filopodia are highly dynamic finger-like cell protrusions filled with parallel bundles of actin filaments. Previously we have shown that Diaphanous-related formin dDia2 is involved in the formation of filopodia. Another key player for the formation of filopodia across many species is vasodilator-stimulated phosphoprotein (VASP).', 'It has been proposed that the essential role of VASP for formation of filopodia is its competition with capping proteins for filament barbed-end interaction.', 'Only WT DdVASP, but not a mutant lacking the F-actin bundling activity, could rescue the ability of these cells to form WT-like filopodia.', 'Our data suggest that DdVASP is complexed with dDia2 in filopodial tips and support formin-mediated filament elongation by bundling nascent actin filaments.', 'Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia.', 'Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation.', 'The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro.', 'These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family.', 'Role of the actin bundling protein fascin in growth cone morphogenesis: localization in filopodia and lamellipodia', 'Fascin localized to radially oriented actin bundles in lamellipodia (ribs) and filopodia.', 'Using a fascin antibody and a GFP fascin construct, we found that fascin incorporated into actin bundles from the beginning of growth cone formation at the cut end of axons.', 'Later, during growth cone morphogenesis when actin ribs shortened, the proximal fascin-free zone of bundles increased, but fascin was retained in the distal, filopodial portion of bundles.', 'Treatment with tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), which phosphorylates fascin and decreases its affinity for actin, resulted in loss of all actin bundles from growth cones.', 'Our findings suggest that fascin may be particularly important for the linear structure and dynamics of filopodia and for lamellipodial rib dynamics by regulating filament organization in bundles.']

['A number of proteins have been found to regulate F-actin bundling and enhance filopodia formation and motility. Among these are Cysteine-rich protein 1 (CRP1), Fascin, Macrophage actin-associated tyrosine phosphorylated protein (MAYP/PSTPIP2), Insulin receptor tyrosine kinase substrate p53 (IRSp53), Missing in metastasis protein (MIM), Eps8, Diaphanous-related formin (dDia2) and Vasodilator-stimulated phosphoprotein (VASP).']

['Cysteine-rich protein 1 (CRP1)', 'Fascin', 'Macrophage actin-associated tyrosine phosphorylated protein (MAYP/PSTPIP2)', 'Insulin receptor tyrosine kinase substrate p53 (IRSp53)', 'Missing in metastasis protein (MIM)', 'Eps8', 'Diaphanous-related formin (dDia2)', 'Vasodilator-stimulated phosphoprotein (VASP)']

Is ABCE1 involved in ribosomal recycling?

['Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final-or the first-step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation.', ' Recent studies have identified ABCE1 as a ribosome-recycling factor important for translation termination in mammalian cells, yeast and also archaea.', 'd a termination/prerecycling complex containing eRF1-ABCE1', 'ABCE1, a eukaryotic ribosome recycling factor']

['Yes, recent studies have identified ABCE1 as a ribosome-recycling factor important for translation termination in mammalian cells, yeast and also archaea']

['yes']

How does adrenergic signaling affect thyroid hormone receptors?

['PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05.', 'nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process.']

['alpha1- adrenergic signalling increases TRalpha1 expression in nucleus and decreases TRalpha1 expression in cytosol.']

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What is the association between number of pregnancies and rheumatoid arthritis

['In this unique population, greater parity significantly reduced the odds of RA;', 'an early age at first birth increased the odds, and the postpartum period was confirmed as high risk for RA onset. The protective effect of repeated exposure to the ameliorating hormonal and immunological changes of pregnancy may counterbalance the effect of early exposure to the postpartum reversal of these changes.', 'We found an inverse correlation between the number of pregnancies and age at onset of RA', 'A larger number of pregnancies and late menopause show a protective effect, delaying the onset of the disease.', 'Since the landmark study on rheumatoid arthritis, many reports have suggested that physiological changes during pregnancy often induce remission of systemic and cutaneous inflammatory diseases.', 'Literature review shows that at best, there are weak negative associations between current estrogen use and RA, and no association with nulliparity and infertility.', 'It appears that infertility, the number of pregnancies, and pregnancy outcome are not strongly associated with the risk of developing RA in women of childbearing age. However, in this study there may have been selection biases in the women with RA and the controls that differentially could have affected their reproductive outcomes. Thus, a true association could have been missed. Most other published studies find no association between nulliparity and RA.', 'Number of pregnancies and children, however, were significantly higher in controls']

['Greater parity significantly reduced the odds of RA. A larger number of pregnancies and late menopause show a protective effect, delaying the onset of the disease.']

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Can valproic acid act as an activator of AMPK?

['Here we demonstrate that VPA is a novel activator of AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism, using primary mouse and human hepatocytes.', 'These studies are the first to establish VPA and its metabolites as in vitro activators of AMPK.']

['Yes, valproic acid canact as an activator of AMPK.', 'VPA is a novel activator of AMP-activated protein kinase (AMPK)']

['yes']

What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.

['Dyke-Davidoff-Masson syndrome is a rare condition characterized by cerebral hemiatrophy, calvarial thickening, skull and facial asymmetry, contralateral hemiparesis, cognitive impairment and seizures.', 'Dyke-Davidoff-Masson syndrome refers to atrophy of one cerebral hemisphere (hemiatrophy) due to an insult to the brain in fetal or early childhood period. ', 'Acquired cerebral hemiatrophy: Dyke-Davidoff-Masson Syndrome - a case report.', 'CT and MRI scan of the head showed hemiatrophic cerebral parenchyma with prominent sulci and encephalomalacia.', 'CT of the brain revealed characteristic features diagnostic of infantile type of cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome.', 'Magnetic resonance imaging (MRI) of brain revealed atrophic of left cerebral hemisphere with mildly ventricular dilatation, prominent paranasal and mastoid air cells, suggestive of Dyke-Davidoff-Masson syndrome (DDMS).', 'Imaging showed resolution of the infection and features of Dyke-Davidoff-Masson syndrome (cerebral hemiatrophy). ', 'Dyke-Davidoff-Masson syndrome (DDMS) is a rare epilepsy syndrome that is characterized by cerebral hemiatrophy, homolateral skull hyperplasia, hyperpneumatization of the paranasal sinuses, seizures with or without mental retardation, and contralateral hemiparesis. ', 'Brain MRI showed prominent atrophy in the left frontal dorsal and lateral regions and mild atrophy of the left superior temporal gyrus and left parietal gyri.', 'A 15-year-old female presented with seizures, right-sided hemiparesis, hemiatrophy of the right side of the body and mental retardation. ', 'Described here is the case of a girl with a reticulated capillary malformation on the right side of her face, along with Dyke-Davidoff-Masson syndrome, as evidenced by microphthalmia and severe associated anomalies in the right eye, and right cerebral hemispheric atrophy and cerebral arteries malformations.', 'The purpose of this study was to retrospectively evaluate the cognitive and electroclinical characteristics of right cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome [DDMS]). ', 'The CHA of childhood or Dyke-Davidoff-Masson syndrome, is originated by intrauterine or perinatal insults that affect the perfusion of a single cerebral hemisphere, manifesting clinically by variable mental retardation, refractory epilepsy, facial asymmetry, hemiplegia/hemiparesis or abnormal movements of the contralateral extremities and by imaging studies, loss of volume in one cerebral hemisphere and ipsilateral compensatory cranial changes such as skull vault thickening, elevation of the orbital roof and petreous ridge, also hyperpneumatization of the frontal sinus and mastoid cells.', 'Dyke-Davidoff-Masson syndrome is a disorder involving hemiatrophy or hypoplasia of 1 cerebral hemisphere secondary to an insult in the developing brain. Often this will manifest with seizures, hemiparesis, mental retardation, and facial changes. Associated with this pathology are the radiologically evident changes, such as thickening of the calvarium, hyperpneumatization of the sinuses, and dilation of the ipsilateral lateral ventricle among others.', 'Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally acquired entity characterized by predominantly neurologic symptoms, such as seizures, facial asymmetry, contralateral hemiplegia, and mental retardation. ', 'The Dyke-Davidoff-Masson syndrome is characterized by various symptoms related to hemiatrophy of the cerebrum and hypertrophy of the ipsilateral calvarium and paranasal sinuses. Clinical findings include hemiparesis or hemiplegia, seizures and/or mental retardation. ', 'Asymmetry of cerebral hemispheric growth with atrophy on one side, ipsilateral osseous hypertrophy and hyper-pneumatization of sinuses with contralateral paresis are features of Dyke Davidoff Masson Syndrome (DDMS). ', 'Dyke Davidoff Masson syndrome (DDMS) is characterized by seizures, facial asymmetry, contralateral hemiplegia and mental retardation. The characteristic radiologic features are cerebral hemiatrophy with homolateral hypertrophy of the skull and sinuses. We report a case of DDMS in an 18-month-old girl who presented with right sided focal seizures, hemiparesis of the same side, and delayed milestones.', 'Cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome) in childhood: clinicoradiological analysis of 19 cases.', 'The so-called Dyke-Davidoff-Masson syndrome (DDMS) is a rare disorder of cerebral hemiatrophy. The clinical presentation may consist of facial asymmetry, contralateral atrophy (including the trunk, and the extremities) and hemiparesis, speech difficulties, mental retardation, and epilepsy.', 'Dyke-Davidoff-Masson syndrome is clinically characterized by hemiparesis, hemiplegia, seizures, mental retardation, and facial asymmetry secondary to congenital or early childhood vascular insult. A 21-year-old man with Dyke-Davidoff-Masson syndrome presented with uncontrolled seizures.', 'Dyke-Davidoff-Masson syndrome is a condition characterized by seizures, facial asymmetry, contralateral hemiplegia or hemiparesis and mental retardation.', 'Brain MRI showed unilateral loss of cerebral volume with hypertrophy and hyperpneumatization of the paranasal sinuses and mastoid cells. ', 'Although radiological findings of cerebral hemiatrophy (Dyke-Davidoff-Masson Syndrome) are well known, there is no systematic study about the gender and the affected side in this syndrome.', 'The patient was a 19-year-old woman who presented with hemiatrophy and diminished superficial sensation on the left side of her body including her face. She had a past history of tonic-clonic seizures accompanied by left hemiparesis in late childhood. Brain CT demonstrated dilatation of the frontal sinus, calvarial thickening, cerebral hemiatrophy and dilatation of the lateral ventricle on the right side. Brain MRI showed atrophy of the right cerebrum and midbrain and dilatation of the lateral ventricle on T1-weighted images, as well as a high signal intensity area from the parietal to the occipital lobe on T2-weighted images. ', 'Cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome is a condition characterized by seizures, facial asymmetry, contralateral hemiplegia or hemiparesis, and mental retardation. ', 'The radiological features are unilateral loss of cerebral volume and associated compensatory bone alterations in the calvarium, like thickening, hyperpneumatization of the paranasal sinuses and mastoid cells and elevation of the petrous ridge. ', 'We reported a 39-year-old man with Dyke-Davidoff-Masson syndrome presenting with total hemiatrophy. ', 'This paper presents an 18-year-old mentally retarded patient with cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome) associated with a growing skull fracture in the ipsilateral hemicranium, in whom not only a dural tear but also the ipsilaterally displaced and dilated lateral ventricle due to the original disease apparently contributed to the development of growing skull fracture.', 'The magnetic resonance (MR) findings of three patients with cerebral hemiatrophy, the so-called Dyke-Davidoff-Masson syndrome, which is characterized by variable degrees of unilateral loss of cerebral volume and compensatory changes of the calvarium are presented.', 'MRI brain revealed characteristic features diagnostic of congenital type of cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome.', 'Imaging showed resolution of the infection and features of Dyke-Davidoff-Masson syndrome (cerebral hemiatrophy).', 'Asymmetry of cerebral hemispheric growth with atrophy on one side, ipsilateral osseous hypertrophy and hyper-pneumatization of sinuses with contralateral paresis are features of Dyke Davidoff Masson Syndrome (DDMS).', 'CT of the brain revealed characteristic features diagnostic of infantile type of cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome', 'Dyke-Davidoff-Masson syndrome refers to atrophy of one cerebral hemisphere (hemiatrophy) due to an insult to the brain in fetal or early childhood period', 'Magnetic resonance imaging (MRI) of brain revealed atrophic of left cerebral hemisphere with mildly ventricular dilatation, prominent paranasal and mastoid air cells, suggestive of Dyke-Davidoff-Masson syndrome (DDMS)', 'Dyke-Davidoff-Masson syndrome is a relatively rare syndrome with its typical clinical and radiological features including facial asymmetry, hemiplegia, cerebral hemiatrophy, mental retardation with calvarial thickening, hypertrophy of sinuses and elevated petrous ridge on imaging', 'Dyke Davidoff Masson syndrome (DDMS) refers to atrophy or hypoplasia of one cerebral hemisphere following a prior fetal or childhood insult', 'The purpose of this study was to retrospectively evaluate the cognitive and electroclinical characteristics of right cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome [DDMS])', 'We describe a female infant with prenatal diagnosis of unilateral left ventriculomegaly in which early brain MRI and contrast enhanced-MRI angiography, showed cerebral left hemiatrophy associated with reduced caliber of the left middle cerebral artery revealing the characteristic findings of the Dyke-Davidoff-Masson syndrome']

['Cerebral hemiatrophy (atrophy of one cerebral hemisphere) is the characteristic feature of the Dyke-Davidoff-Masson syndrome. It develops due to an insult to the brain in fetal or early childhood period. Calvarial thickening, skull and facial asymmetry, contralateral hemiparesis, cognitive impairment and seizures are also characteristic to the Dyke-Davidoff-Masson syndrome.\n.']

['cerebral hemiatrophy']

What genes are associated with mutations that result in the tuberous sclerosis complex phenotype?

['["The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2.", "The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently", "Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors", "Ten years ago, a mutation in the TSC2 gene was identified in the Eker rat at Fox Chase Cancer Center by Yeung and Knudson, and in Tokyo by Kobayashi and Hino.", "Here, we will review the clinical association of RCC in TSC, consider the factors that have led to its under-emphasis within the RCC field, address the cellular and biochemical mechanisms that may contribute to RCC in cells with TSC1 or TSC2 mutations, and finally discuss the ways in which the TSC signaling pathways may be linked to sporadic RCC in the general population.", "Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype.", "The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways", "Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. ", "TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease.", "We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis.", "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis", "The disease can be caused by mutations in either of two genes, TSC2, identified in 1993, and TSC1, only recently identified.", "Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis (Tsc2)", "We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat", "Tuberous sclerosis complex is a genetic disorder caused by mutations in either the TSC1 or TSC2 gene that can result in the growth of hamartomas in multiple organ systems", "Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway. ", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway.", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13."]']

TSC1 and TSC2 genes are associated with mutations that result in the tuberous sclerosis complex phenotype.

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Which gene is associated with the Mitchell-Riley syndrome?

['Mutations in rfx6 were recently associated with Mitchell-Riley syndrome, which involves neonatal diabetes, and other digestive system defects. ', 'bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia.']

['Mutations in the gene coding for the transcription factor RFX6 (regulatory factor X,6) have been described as the cause of the Mitchell-Riley syndrome.']

['RFX6']

What is the basis of the methodology of "functional class scoring" (FCS) for the analysis of gene expression data?

['The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step.', 'We aimed at examining such discrepancies on the level of apparently affected biologically related groups of genes, e.g. metabolic or signalling pathways. This can be achieved by group testing procedures, e.g. over-representation analysis, functional class scoring (FCS), or global tests.', 'They also suggest that functional class scoring methods appear to perform better and more consistently than overrepresentation analysis and distributional score methods.', 'With the use of functional class scoring, a semi-supervised method exploring both the expression pattern and the functional annotation of the genes, the Gene Ontology classes were ranked according to the significance of the impact of D3T treatment.', 'Most of the existing pathway analysis methods focus on either the number of DE genes observed in a given pathway (enrichment analysis methods), or on the correlation between the pathway genes and the class of the samples (functional class scoring methods)', ' There are three main classes of these methods: over-representation analysis, functional class scoring, and pathway topology based methods.', 'Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena', 'Proteomics Expansion Pipeline (PEP), Functional Class Scoring (FCS), and Maxlink, in a test scenario of valproic acid (VPA)-treated mice.', 'We propose and examine personalized extensions of pathway statistics, overrepresentation analysis and functional class scoring, to generate individualized pathway aberrance score.', 'The comparison of two analytical approaches, based on either Over Representation Analysis or Functional Class Scoring, by a meta-analysis-based approach, led to the retrieval of known information about the biological situation - thus validating the model - but also more importantly to the discovery of the previously unknown implication of the spliceosome, the cellular machinery responsible for mRNA splicing, in the development of metastasis.', 'The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step.', 'The second method, &quot;functional class scoring&quot; (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step', 'The first method, &quot;overrepresentation analysis&quot; (ORA), is based on statistically evaluating the fraction of genes in a particular gene ontology class found among the set of genes showing age-related changes in expression', 'Using the gene ontology for microarray data mining: a comparison of methods and application to age effects in human prefrontal cortex', 'The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. ', 'The first method, &quot;overrepresentation analysis&quot; (ORA), is based on statistically evaluating the fraction of genes in a particular gene ontology class found among the set of genes showing age-related changes in expression. The second method, &quot;functional class scoring&quot; (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step.', 'The second method, &quot;functional class scoring&quot; (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. We find that FCS yields more consistent results than ORA, and the results of ORA depended strongly on the gene selection threshold.']

['The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step.', 'Functional class scoring (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. It consists of a semi-supervised method exploring both the expression pattern and the functional annotation of the genes.', 'The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. ']

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What is GDF10?

['We have identified a new member of the transforming growth factor-beta (TGF-beta) superfamily, growth/differentiation factor-10 (GDF-10), which is highly related to bone morphogenetic protein-3 (BMP-3). The nucleotide sequence of GDF-10 encodes a predicted protein of 476 amino acids with a molecular weight of approximately 52,000. The GDF-10 polypeptide contains a potential signal sequence for secretion, a putative RXXR proteolytic processing site, and a carboxy-terminal domain with considerable homology to other known members of the TGF-beta superfamily. In the mature carboxy-terminal domain GDF-10 is more homologous to BMP-3 (83% amino acid sequence identity) than to any other previously identified TGF-beta family member. GDF-10 also shows significant homology to BMP-3 (approximately 30% amino acid sequence identity) in the pro- region of the molecule. Based on these sequence comparisons, GDF-10 and BMP-3 define a new subgroup within the larger TGF-beta superfamily. By Northern analysis, GDF-10 mRNA was detected primarily in murine uterus, adipose tissue, and brain and to a lesser extent in liver and spleen. In addition, GDF-10 mRNA was present in both neonatal and adult bone samples, with higher levels being detected in calvaria than in long bone. These results suggest that GDF10 may play multiple roles in regulating cell differentiation events, including those involved in skeletal morphogenesis. Gdf10 was mapped to the proximal region of mouse chromosome 14 close to a region known to contain a spontaneous recessive mutation that is associated with a craniofacial defect.', 'Growth differentiation factor 10 (Gdf10), also known as Bmp3b, is a member of the transforming growth factor (TGF)-ß superfamily', 'Thus, we show for the first time, that Gdf10, expressed in Bergmann glial cells, is affected by the loss of Shh as early as E18.5, suggesting a regulation of glial development by Shh.', 'These results suggest that GDF10 may play multiple roles in regulating cell differentiation events, including those involved in skeletal morphogenesis. Gdf10 was mapped to the proximal region of mouse chromosome 14 close to a region known to contain a spontaneous recessive mutation that is associated with a craniofacial defect.']

['The growth/differentiation factor-10 (GDF-10) is a new member of the transforming growth factor-beta (TGF-beta) superfamily. It is highly related to bone morphogenetic protein-3 (BMP-3) and often referred to as BMP3b. The nucleotide sequence of GDF-10 encodes a predicted protein of 476 amino acids with a molecular weight of approximately 52,000. The GDF-10 polypeptide contains a potential signal sequence for secretion, a putative RXXR proteolytic processing site, and a carboxy-terminal domain with considerable homology to other known members of the TGF-beta superfamily. GDF10 is found primarily in murine uterus, adipose tissue, and brain and to a lesser extent in liver and spleen. In addition, GDF-10 mRNA was present in both neonatal and adult bone samples, with higher levels being detected in calvaria than in long bone. These results suggest that GDF10 may play multiple roles in regulating cell differentiation events, including those involved in skeletal morphogenesis. Gdf10 was mapped to the proximal region of mouse chromosome 14 close to a region known to contain a spontaneous recessive mutation that is associated with a craniofacial defect.']

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What is Achondroplasia?

['Achondrogenesis type II is an autosomal-dominant disease leading to severe micromelic dwarfism.', 'Physical basis behind achondroplasia, the most common form of human dwarfism', 'Achondroplasia is the best described and most common form of the congenital short-limbed dwarfing conditions. ']

['Achondrogenesis type II also known as Achondroplasia is an autosomal-dominant disease leading to severe micromelic dwarfism', 'Achondrogenesis type II is an autosomal-dominant disease leading to severe micromelic dwarfism. ', 'Achondrogenesis type II is an autosomal-dominant disease leading to severe micromelic dwarfism.', 'achondrogenesis type ii is an autosomal-dominant disease leading to severe micromelic dwarfism.', 'achondrogenesis type ii is an autosomal-dominant disease to severe micromelic dwarfism. . ']

['An autosomal dominant form of dwarfism']

Which transcription factor is considered as a master regulator of lysosomal genes?

['In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression', 'Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB', 'Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes', 'The identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lysosome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease', 'TFEB regulates lysosomal proteostasis', 'Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs', 'our findings identify TFEB as a specific regulator of lysosomal proteostasis', 'the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism', 'A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.', 'the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane', 'the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR', 'These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.', 'We showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes.', 'In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression.', 'In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy.', 'Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane.', 'Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs.', 'Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α.', 'Transcription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity.', 'These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.', 'We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system.', 'The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. ', 'In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. ', 'We showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes. ', 'In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. ', 'We recently discovered the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network and its master gene transcription factor EB (TFEB), which regulates lysosomal biogenesis and function. ', 'Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. ', 'In contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core.', 'Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane.', 'We showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes.', 'In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression.', 'We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF (micropthalmia-associated transcription factor) and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes.', 'Transcription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity.', 'Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs.', 'Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied.', 'These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.', 'In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy.']

['Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, driving lysosome adaptation to environmental cues, such as starvation, and therefore targeting of TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease.']

['Transcription factor EB (TFEB)']

Which is the main function of "RNA sponges"?

['Pseudogene OCT4-pg4 functions as a natural micro RNA sponge to regulate OCT4 expression by competing for miR-145 in hepatocellular carcinoma', 'Mechanistic analysis revealed that OCT4-pg4 functions as a natural micro RNA sponge to protect OCT4 transcript from being inhibited by miR-145.', 'Natural RNA circles function as efficient microRNA sponges', 'Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants.', 'Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ', 'We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. ', 'Natural RNA sponges sequestering cellular noncoding RNA molecules have been found in diverse organisms.', 'n this issue, Lalaouna et al. (2015) report another type of RNA sponge, showing that stable intermediates of bacterial tRNA processing control endogenous small RNAs.', 'Circular RNAs can function as templates for viroid and viral replication, as intermediates in RNA processing reactions, as regulators of transcription in cis, as snoRNAs, and as miRNA sponges', 'Recent research has revealed that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing and transcription, and modifiers of parental gene expression', 'This can involve RNA sponges that sequester regulatory RNAs of mRNAs in the same regulon, but the underlying molecular mechanism of such mRNA cross talk remains little understood. Here, we report sponge-mediated mRNA cross talk in the posttranscriptional network of GcvB, a conserved Hfq-dependent small RNA with one of the largest regulons known in bacteria. We show that mRNA decay from the gltIJKL locus encoding an amino acid ABC transporter generates a stable fragment (SroC) that base-pairs with GcvB. ', 'the sex determining region Y ( Sry) and the cerebellar degeneration-related protein 1 ( CDR1as) RNA transcripts have been described to function as a new class of post-transcriptional regulatory RNAs that behave as circular endogenous RNA sponges for the micro RNAs (miRNAs) miR-138 and miR-7,']

['Natural RNA circles function as efficient microRNA sponges. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants.', 'Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. Natural RNA sponges sequestering cellular noncoding RNA molecules have been found in diverse organisms. In this issue, Lalaouna et al. (2015) report another type of RNA sponge, showing that stable intermediates of bacterial tRNA processing control endogenous small RNAs. Furthermore, survival analysis suggests that high OCT4-pg4 level is significantly correlated with poor prognosis of HCC patients.']

[]

List five applications of machine learning algorithms in medical diagnosis.

['The ability to differentiate between brain tumor progression and radiation therapy induced necrosis is critical for appropriate patient management. I', 'Experimental results on public leukemia, prostate, and colon cancer datasets show that fuzzy support vector machine applied in combination with filter or wrapper feature selection methods develops a robust model with higher accuracy than the conventional microarray classification models such as support vector machine, artificial neural network, decision trees, k nearest neighbors, and diagonal linear discriminant analysis', 'Mass spectrometry based proteomics technologies have allowed for a great progress in identifying disease biomarkers for clinical diagnosis and prognosis. However, they face acute challenges from a data reproducibility standpoint, in that no two independent studies have been found to produce the same proteomic patterns. Such reproducibility issues cause the identified biomarker patterns to lose repeatability and prevent real clinical usage. In this work, we propose a profile biomarker approach to overcome this problem from a machine-learning viewpoint by developing a novel derivative component analysis (DCA)', 'In this paper, a random forest classifier (RFC) approach is proposed to diagnose lymph diseases', 'The algorithm provides excellent discrimination of PD patients from PSP patients at an individual level, thus encouraging the application of computer-based diagnosis in clinical practice.', 'The objective of this project was the development and validation of a multiparameter machine learning algorithm and system capable of predicting the need for life-saving interventions (LSIs) in trauma patients.']

["Machine learning technology is well suited for the induction of diagnostic and prognostic rules and solving of small and specialized diagnostic and prognostic problems. The medical diagnostic knowledge can be automatically derived from the description of cases solved in the past. In several medical domains we actually applied machine learning algorithms. Typically, the automatically generated diagnostic rules achieved the same or slightly better diagnostic accuracy than physicians specialists. There many several application of machine learning algorithms in medical diagnosis such as Brain glioma progression, Microarray classification, Mass spectral proteomics, Lymph disease classification and Parkinson's disease."]

['Brain glioma progression', 'Microarray classification', 'Mass spectral proteomics', 'Lymph disease classification', "Parkinson's disease"]

Are genes symmetrically distributed between leading and lagging DNA strand in bacteria?

['Genomic DNA is used as the template for both replication and transcription, whose machineries may collide and result in mutagenesis, among other damages. Because head-on collisions are more deleterious than codirectional collisions, genes should be preferentially encoded on the leading strand to avoid head-on collisions, as is observed in most bacterial genomes examined.', 'Most genes in bacteria are encoded on the leading strand of replication. This presumably avoids the potentially detrimental head-on collisions that occur between the replication and transcription machineries when genes are encoded on the lagging strand.', 'The majority of bacterial genes are located on the leading strand', 'genes of some functional categories such as ribosome have higher preferences to be on the leading strands', 'genes of some functional categories such as transcription factor have higher preferences on the lagging strands', 'essential genes are more preferentially situated at the leading strand than at the lagging strand', 'remarkable strand-bias of the distribution of essential genes', 'Head-on encounters between the replication and transcription machineries on the lagging DNA strand can lead to replication fork arrest and genomic instability. To avoid head-on encounters, most genes, especially essential and highly transcribed genes, are encoded on the leading strand such that transcription and replication are co-directional.', 'Replication-associated purine asymmetry may contribute to strand-biased gene distribution.', 'strand-biased gene distribution (SGD)', 'SGD correlates not only with polC, but also with purine asymmetry (PAS)', 'In bacteria, most genes are on the leading strand of replication, a phenomenon attributed to collisions between the DNA and RNA polymerases.', 'genes whose expression is important for fitness are selected to the leading strand because this reduces the duration of these interruptions', 'Among prokaryotic genomes, the distribution of genes on the leading and lagging strands of the replication fork is known to be biased. ', 'We show that the evidence they provided is invalid and that the existence of lagging strand encoded genes is explainable by a balance between deleterious mutations that bring genes from the leading to the lagging strand and purifying selection purging such mutants.', 'Based on those experimentally determined for 10 bacteria, we find that essential genes are more preferentially situated at the leading strand than at the lagging strand, for all the 10 genomes studied, confirming previous findings based on either smaller datasets or putatively assigned ones by homology search.', 'The majority of bacterial genes are located on the leading strand, and the percentage of such genes has a large variation across different bacteria.', 'Most genes in bacteria are encoded on the leading strand of replication.', 'This paradox could be explained by assuming that the stronger mutation pressure and selection after inversion preferentially eliminate genes transferred from the leading to the lagging DNA strand.', 'We have shown that the relative number of translocations which have switched positions of genes from the leading to the lagging DNA strand is lower than the number of translocations which have transferred genes from the lagging strand to the leading strand of prokaryotic genomes.', 'Most genes in bacteria are encoded on the leading strand of replication', 'The majority of bacterial genes are located on the leading strand, and the percentage of such genes has a large variation across different bacteria', 'We have shown that the relative number of translocations which have switched positions of genes from the leading to the lagging DNA strand is lower than the number of translocations which have transferred genes from the lagging strand to the leading strand of prokaryotic genomes', 'Using Monte Carlo methods, we have simulated, under experimentally determined directional mutation pressure, the divergence rate and the elimination rate of genes depending on their location in respect to the leading/lagging DNA strands in the asymmetric prokaryotic genome']

['In most bacteria, genes are preferentially encoded on the leading strand than on the lagging strand. This avoids the potentially detrimental head-on collisions that occur between the replication and transcription machineries when genes are encoded on the lagging strand. Head-on collisions are more deleterious than codirectional collisions, and may lead to replication fork arrest and genomic instability. Genes of some functional categories such as ribosome have higher preferences to be on the leading strands, while genes of other functional categories such as transcription factor have higher preferences on the lagging strands. Strand-biased gene distribution correlates with replication-associated purine asymmetry and the presence or absence of polC. Especially essential and highly transcribed genes and genes whose expression is important for fitness are more preferentially situated at the leading strand in bacteria.']

['no']

Is Calcium homeostasis important in cardiac physiology and pathophysiology?

['Maintenance of cellular calcium homeostasis is critical to regulating mitochondrial ATP production and cardiac contraction. ', 'the Ca(2+) signal regulates the most important activities of the cell, from the expression of genes, to heart and muscle contraction and other motility processes, to diverse metabolic pathways involved in the generation of cell fuels', 'Pharmacologic modification of cellular calcium handling recently moved into focus as an alternative for prevention and treatment of ventricular tachyarrhythmias', 'diabetic rats displayed abnormal cardiac structure and systolic and diastolic dysfunction, and spermine (CaSR agonist) could prevent or slow its progression. These results indicate that the CaSR expression of myocardium is reduced in the progress of DCM, and its potential mechanism is related to the impaired intracellular calcium homeostasis.', 'calcium-sensing receptor (CaSR)', 'Na(+)/Ca(2+) exchanger (NCX) plays important roles in cardiac electrical activity and calcium homeostasis.', 'NCX current (I(NCX)) shows transmural gradient across left ventricle in many species. Previous studies demonstrated that NCX expression was increased and transmural gradient of I(NCX) was disrupted in failing heart', 'calcium homeostasis, the key process underlying excitation-contraction coupling', 'The results indicate the calcium handling properties of hiPSC-derived cardiomyocytes are relatively immature to hESC counterparts', 'Our understanding of the molecular processes which regulate cardiac function has grown immeasurably in recent years. Even with the advent of β-blockers, angiotensin inhibitors and calcium modulating agents, heart failure (HF) still remains a seriously debilitating and life-threatening condition. Here, we review the molecular changes which occur in the heart in response to increased load and the pathways which control cardiac hypertrophy, calcium homeostasis, and immune activation during HF.', 'Calcium-sensing receptors (CaSRs) are G-protein coupled receptors which maintain systemic calcium homeostasis and participate in hormone secretion, activation of ion channels, cell apoptosis, proliferation, and differentiation.', 'CaSRs are associated with I/R injury and apoptosis in neonatal rat ventricular cardiomyocytes via suppressing Bcl-2 and promoting caspase-3 expression.', 'Important insights into the molecular basis of hypertrophic cardiomyopathy and related diseases have been gained by studying families with inherited cardiac hypertrophy. Integrated clinical and genetic investigations have demonstrated that different genetic defects can give rise to the common phenotype of cardiac hypertrophy. Diverse pathways have been identified, implicating perturbations in force generation, force transmission, intracellular calcium homeostasis, myocardial energetics, and cardiac metabolism in causing disease', 'HAX-1 as a regulator of contractility and calcium cycling in the heart. HAX-1 overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity in isolated cardiomyocytes and in vivo, leading to depressed myocyte calcium kinetics and mechanics.', 'Thus, HAX-1 represents a regulatory mechanism in cardiac calcium cycling and its responses to sympathetic stimulation, implicating its importance in calcium homeostasis and cell survival.', 'Calcium ions are the most ubiquitous and versatile signaling molecules in eukaryotic cells. Calcium homeostasis and signaling systems are crucial for both the normal growth of the budding yeast Saccharomyces cerevisiae and the intricate working of the mammalian heart.', 'this knowledge can be used to help treat relevant human diseases such as pathological cardiac hypertrophy and heart failure', 'With aging, the heart develops myocyte hypertrophy associated with impaired relaxation indices. To define the cellular basis of this adaptation, we examined the physiological changes that arise in calcium handling in the aging heart and contrasted the adaptations that occur following the imposition of a stimulus that alters calcium homeostasis in a young and an old heart', 'alterations in the calcium-handling machinery of the cardiocyte differ in the context of age and as such may predispose the older heart to the development of a hypertrophic phenotype.', 'The cardiac sodium-calcium exchanger (NCX1) is a key sarcolemmal protein for the maintenance of calcium homeostasis in the heart. ', 'Thus exchanger overexpression in mice leads to abnormal calcium handling and a decompensatory transition to heart failure with stress', 'Central to controlling intracellular calcium concentration ([Ca(2+)](i)) are a number of Ca(2+) transporters and channels with the L-type Ca(2+) channel, Na(+)-Ca(2+) exchanger and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) being of particular note in the heart. This review concentrates on the regulation of [Ca(2+)](i) in cardiac muscle and the homeostatic mechanisms employed to ensure that the heart can operate under steady-state conditions on a beat by beat basis.', 'the tight regulation of SR Ca(2+) content is also required to prevent the abnormal, spontaneous or diastolic release of Ca(2+) from the SR. Such diastolic events are a major factor contributing to the genesis of cardiac arrhythmias in disease situations and in recently identified familial mutations in the SR Ca(2+) release channel (ryanodine receptor, RyR).', 'Calcium channels have a unique functional role, because not only do they participate in this activity, they form the means by which electrical signals are converted to responses within the cell. Calcium channels play an integral role in excitation in the heart and shaping the cardiac action potential. In addition, calcium influx through calcium channels is responsible for initiating contraction. Abnormalities in calcium homeostasis underlie cardiac arrhythmia, contractile dysfunction and cardiac remodelling. ', 'Cardiac calcium (Ca(2+)) handling subsumes the mechanisms maintaining the myocardial Ca(2+) homeostasis that contribute essentially to cardiac performance.', 'Calcium is an important mediator in cardiac excitation and disorders in cardiac Ca(2+) homeostasis have great influence on the cardiac action potential.', 'We review the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling.', 'We review the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling', 'Calcium is an important mediator in cardiac excitation and disorders in cardiac Ca(2+) homeostasis have great influence on the cardiac action potential', 'The role of calcium in cardiac and vascular smooth muscle physiology was reviewed, highlighting the major mechanisms responsible for maintaining calcium homeostasis in these cells', 'Energy metabolism and Ca(2+) handling serve critical roles in cardiac physiology and pathophysiology']

['Calcium homeostasis is very important in cardiac physiology and pathophysiology. Maintenance of cellular calcium homeostasis is critical to regulating cardiac contraction. Abnormalities in calcium homeostasis underlie cardiac arrhythmia, contractile dysfunction and cardiac remodelling.']

['yes']

Is there a relationship between B cells and Multiple Sclerosis?

['These results suggest that RRMS patients with radiological phenotypes showing high neurodegeneration have changes in B cells characterized by down-regulation of B-cell-specific genes and increased activation status', 'Although the exact etiology is still obscure, the leading hypothesis behind MS relapses is acute inflammatory attacks on CNS myelin and axons. This complex process involves B and T cells together with macrophages and microglia.', 'It is currently known that CD24 serves as a costimulatory factor of T cells that regulate their homeostasis and proliferation, while in B cells, CD24 is functionally involved in cell activation and differentiation. CD24 can enhance autoimmune diseases in terms of its protective role in the clonal deletion of autoreactive thymocytes', 'Multiple B cell-dependent mechanisms contributing to inflammatory demyelination of the CNS have been explored using experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for multiple sclerosis. ', 'The role of B cells in multiple sclerosis: rationale for B-cell-targeted therapies.', 'Interest in CD8+ T cells and B cells was initially inspired by observations in multiple sclerosis rather than in animal models: CD8+ T cells predominate in multiple sclerosis lesions, oligoclonal immunoglobulin bands in CSF have long been recognised as diagnostic and prognostic markers, and anti-B-cell therapies showed considerable efficacy in multiple sclerosis.', 'Differential effects of fingolimod on B-cell populations in multiple sclerosis.', 'Unaltered regulatory B-cell frequency and function in patients with multiple sclerosis.', 'B cells are increasingly recognized as major players in multiple sclerosis pathogenesis.', "These observations underscore the B cell's contribution to the putative underpinnings of multiple sclerosis.", 'Data suggesting that B cells play a role in the pathogenesis of multiple sclerosis have been accumulating for the past five decades, demonstrating that the cerebrospinal fluid and central nervous system tissues of multiple sclerosis patients contain B cells, plasma cells, antibodies, and immunoglobulins.', 'B-cell-targeted treatment for multiple sclerosis: mechanism of action and clinical data.', 'Subset composition and cytokine production of B cells derived from peripheral blood mononuclear cells from multiple sclerosis patients under Fingolimod treatment, untreated multiple sclerosis patients and healthy controls were analyzed by flow cytometry and ELISA.', 'In particular, antigen presentation between B cells and T cells, increased trafficking of B cells across the blood-brain barrier, and autoantibodies produced by plasma cells may contribute to the pathophysiology of autoimmune disorders such as multiple sclerosis.', 'Accumulating evidence supports a major role of B cells in multiple sclerosis (MS) pathogenesis.', 'Further research is needed to elucidate the pathology of B cells and their role in central nervous system autoimmune diseases, including multiple sclerosis.', 'Targeting B cells in the treatment of multiple sclerosis: recent advances and remaining challenges', 'phingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis']

['MS patients with high neurodegeneration have changes in B cells characterized by down-regulation of B-cell-specific genes and increased activation status']

['yes']

Which syndromes are associated with mutations in the EZH2 gene?

['Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML)', 'We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH result', ' Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure.', 'Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome', 'Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.', 'EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined', 'Weaver syndrome and EZH2 mutations', 'In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome', 'The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. ', 'Mutations in EZH2 cause Weaver syndrome', 'These data show that mutations in EZH2 cause Weaver syndrome', 'The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies', 'EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.', 'Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL)', 'The EZH2 gene was previously reported to be located on chromosome 21q22 and was proposed as a candidate gene for some characteristics of the Down syndrome phenotype', 'Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN).', 'EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.', 'In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome.', 'Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively.', 'Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.', 'Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.', 'The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.', 'We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities.', 'Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). ', 'Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features. ', 'Recently, the advent of next generation sequencing (NGS) techniques has helped identify somatic gene mutations in 75-80% of MDS, that cluster mainly in four functional groups, i.e. cytokine signaling (RAS genes), DNA methylation, (TET2, IDH1/2, DNMT3a genes) histone modifications (ASXL1 and EZH2 genes), and spliceosome (SF3B1 and SRSF2 genes) along with mutations of RUNX1 and TP 53 genes.', 'Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains.', 'EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.', 'Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.', 'EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.', 'Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.', 'The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML.', 'Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features.']

['EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. These data show that mutations in EZH2 cause Weaver syndrome. The EZH2 gene is a homolog of the Drosophila Polycomb group (PcG) gene enhancer of zest, a crucial regulator of homeotic gene expression.', 'Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL). The EZH2 gene is involved in the pathogenesis of 7q35-q36 aberrations in myeloid leukaemia.']

['myelodysplastic syndrome (MDS)', 'Acquired aplastic anemia (AA)', 'Weaver syndrome', 'non-Hodgkin lymphoma (NHL)', 'myeloid leukaemia']

What is the treatment of Riedel disease (thyroiditis)?

['IFT often is associated with a systemic extracervical fibrotic process and tobacco use. Attempted thyroid resection often results in postoperative complications. Long-term follow-up showed no deaths fro', "Riedel's invasive fibrous thyroiditis is a rare disorder of unknown origin with progressive extension and invasion of adjacent structures.", "Clinically it is impossible to distinguish between Riedel's/thyroiditis and other diseases as undifferentiated carcinoma, Hashimoto's disease etc...", "Surgical treatment depends on the stage of the disease, when both lobes are involved generous wedge resection of the isthmus may be the treatment of choice to relieve tracheal compression; in earlier stages radical operation are considered. Corticosteroid treatment in Riedel's thyroiditis, as multifocal disease has been successfully used. Other drugs with antifibrosing actions have also utilised in small groups of patients with encouraging results."]

['Riedel thyroiditis is a rare disorder related to a systemic extracervical fibrotic process of unknown origin. The tratment of choice is the surgical treatment: Corticosteroids may be also useful']

[]

Which disease is treated with taliglucerase alfa?

['Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.', 'Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. ', 'The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study.', 'Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.', 'Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD.', ' These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns.', 'Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease.', 'Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD).', 'Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase.', 'A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.', 'These results support safety and efficacy of taliglucerase alfa for Gaucher disease.', 'Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease.', "Taliglucerase alfa for the treatment of Gaucher's disease.", 'Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease.', 'These results support safety and efficacy of taliglucerase alfa for Gaucher disease.', 'These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase.', 'This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD.', 'A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase', 'A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years', 'These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase', 'Clinical trials have demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in adult, ERT-naïve patients with symptomatic GD1, and for such patients previously treated with imiglucerase', 'One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy.Treatment-naïve participants had similar increases in haemoglobin when comparing those receiving imiglucerase or alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17)', 'These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. ', 'Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). ', 'These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns.', 'A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years.', 'Clinical trials have demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in adult, ERT-naïve patients with symptomatic GD1, and for such patients previously treated with imiglucerase.', 'These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD.', 'Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.', 'Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase.', 'A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.']

['Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease.']

['Gaucher disease']

Mutation of which gene is implicated in the Christianson syndrome?

['X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities.', 'CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. ', 'A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death.', 'BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. ', 'BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia.', 'OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). ', 'Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6.', 'Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities. ', 'We report on two children with CS and confirmed mutations in SLC9A6 focusing on neuroimaging findings and review the available literature. ', 'Mutations in the SLC9A6 gene cause Christianson syndrome in boys.', 'Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.', 'This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome.', 'Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum', 'Mutations in the SLC9A6 gene cause Christianson syndrome in boys. ', 'A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES).', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. ', 'Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. ', 'This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. ', 'The single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.', 'In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6.', 'Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia.', 'Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures.', 'Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6.', 'A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.', 'CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes.', 'Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.', 'A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES).', 'X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities.']

['Christianson syndrome is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities.']

['SLC9A6']

What is the role of AMPK in diabetic cardiomyopathy?

['We recently reported that diabetes depresses AMP-activated protein kinase (AMPK) activity, inhibits MAPK8/JNK1-BCL2 signaling', 'Activation of AMPK directly phosphorylates MAPK8, which mediates BCL2 phosphorylation and subsequent BECN1-BCL2 dissociation, leading to restoration of cardiac autophagy, protection against cardiac apoptosis, and ultimately improvement in cardiac structure and function.', 'studies were shown that p38 MAPK stimulates glucose uptake through the AMPK activation.', 'Taken together, it is suggested that the modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy.', 'We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart.', 'Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice.', 'Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha).', 'Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice.', 'The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process.', 'Our findings highlight a role of PP2C and AMPK in the derangements of cardiac lipid metabolism in obesity and provide new insights as to the mechanisms of the liporegulatory disorder leading to lipotoxic cardiomyopathy.', 'We conclude that dissociation of BCL2 from BECN1 through activation of MAPK8-BCL2 signaling may be an important mechanism by which AMPK activation restores autophagy, protects against cardiac apoptosis, and prevents diabetic cardiomyopathy.', 'Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes.', 'UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism.']

['AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart. Decreased AMPK activity and the subsequent reduction in cardiac autophagy are central to the development of diabetic cardiomyopathy. In fact, dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis. In addition, genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. The modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy. Stimulation of AMPK by metformin or trimetazidine administration may represent a novel approach to treat diabetic cardiomyopathy.']

[]

Is Melioidosis caused by the bacterium Burkholderia pseudomallei?

['Burkholderia pseudomallei, the causative agent of melioidosis,', 'What drives the occurrence of the melioidosis bacterium Burkholderia pseudomallei in domestic gardens?', 'Landscape changes influence the occurrence of the melioidosis bacterium Burkholderia pseudomallei in soil in northern Australia.', 'Out of the ground: aerial and exotic habitats of the melioidosis bacterium Burkholderia pseudomallei in grasses in Australia.', 'Melioidosis, caused by the gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia.', 'Melioidosis is a suppurative chronic infection caused by a gramnegative bacterium, Burkholderia pseudomallei.', 'Melioidosis is an infection caused by the gram-negative bacterium Burkholderia pseudomallei.', 'Melioidosis is an infectious disease caused by a saprophytic bacterium, Burkholderia pseudomallei.', 'Melioidosis is an infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei.', 'Melioidosis is a pyogenic infection with high mortality caused by the bacterium Burkholderia pseudomallei.', 'Melioidosis is a tropical infectious disease caused by the gram-negative bacterium Burkholderia pseudomallei.', 'Melioidosis is a potentially fatal disease caused by the bacterium Burkholderia pseudomallei.', 'Melioidosis is a rare tropical disease caused by infection with the bacterium Burkholderia pseudomallei.', 'The mechanisms involved in the pathogenesis of melioidosis, caused by the intracellular bacterium Burkholderia pseudomallei, are unclear.', 'Melioidosis is an emerging tropical infection caused by the intracellular bacterium Burkholderia pseudomallei, and is associated with high mortality rates.', 'Melioidosis is an increasingly recognised cause of sepsis and death across South East Asia and Northern Australia, caused by the bacterium Burkholderia pseudomallei', 'Melioidosis, an infection caused by the gram-negative bacterium Burkholderia pseudomallei, is an important cause of pneumonia, skin infection, sepsis, and death in Southeast Asia and Australia, but is exceedingly rare in North America', 'The Gram-negative bacterium Burkholderia pseudomallei is able to survive and replicate within leukocytes and causes melioidosis, an important cause of pneumonia-derived community-acquired sepsis in Southeast Asia', 'Melioidosis, a lethal tropical infection that is endemic in southeast Asia and northern Australia, is caused by the saprophytic Gram-negative bacterium Burkholderia pseudomallei', 'Melioidosis is an emerging infectious disease caused by the soil bacterium Burkholderia pseudomallei', 'Melioidosis is a tropical disease of high mortality caused by the environmental bacterium, Burkholderia pseudomallei', 'Melioidosis is an infectious disease caused by Burkholderia pseudomallei, a bacterium endemic in Southeast Asia and northern Australia', 'Melioidosis is a life-threatening infection caused by the Gram-negative bacterium Burkholderia pseudomallei, mainly found in Southeast Asia', 'Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a dreadful disease common in South-East Asia and Northern Australia and is characterized by chronic suppurative lesions and pneumonia', 'Melioidosis is caused by the environmental bacterium Burkholderia pseudomallei and can present with severe sepsis', 'Melioidosis is an emerging infectious disease of humans and animals in the tropics caused by the soil bacterium Burkholderia pseudomallei. ', 'Melioidosis is a potentially fatal disease caused by the bacterium Burkholderia pseudomallei. ', 'Melioidosis, infection caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of sepsis in northeast Thailand. ', 'Melioidosis is a potentially fatal disease caused by the bacterium, Burkholderia pseudomallei. ', 'BACKGROUND: The soil-dwelling saprophyte bacterium Burkholderia pseudomallei is the cause of melioidosis, a severe disease of humans and animals in southeast Asia and northern Australia. ', 'Melioidosis is an endemic disease caused by the bacterium Burkholderia pseudomallei. ', 'Melioidosis is a severe infection caused by the gram-negative bacterium, Burkholderia pseudomallei, that is endemic in Southeast Asia. ', 'Melioidosis, infection caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of sepsis in northeast Thailand.', 'Melioidosis is a clinically diverse disease caused by the facultative intracellular Gram-negative bacterium, Burkholderia pseudomallei.', 'Melioidosis is caused by the environmental bacterium Burkholderia pseudomallei and can present with severe sepsis.', 'Melioidosis is a severe infection caused by the gram-negative bacterium, Burkholderia pseudomallei, that is endemic in Southeast Asia.', 'Melioidosis, a lethal tropical infection that is endemic in southeast Asia and northern Australia, is caused by the saprophytic Gram-negative bacterium Burkholderia pseudomallei.', 'Melioidosis, a severe human disease caused by the bacterium Burkholderia pseudomallei, has a wide spectrum of clinical manifestations ranging from acute septicemia to chronic localized illness or latent infection.', 'Melioidosis, an often fatal infectious disease in Northeast Thailand, is caused by skin inoculation, inhalation or ingestion of the environmental bacterium, Burkholderia pseudomallei.', 'Melioidosis is an infection caused by Gram-negative bacterium, Burkholderia pseudomallei.', 'Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a dreadful disease common in South-East Asia and Northern Australia and is characterized by chronic suppurative lesions and pneumonia.', 'Largely due to its recognition as a biological threat agent, current knowledge on melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, has increased tremendously over the last years.', 'Melioidosis is an endemic disease caused by the bacterium Burkholderia pseudomallei.', 'Melioidosis is a potentially fatal disease caused by the bacterium Burkholderia pseudomallei.', 'Melioidosis is a potentially fatal disease caused by the bacterium, Burkholderia pseudomallei.', 'Melioidosis is a disease of humans and animals that is caused by the saprophytic bacterium Burkholderia pseudomallei.', 'Melioidosis is an emerging infectious disease of humans and animals in the tropics caused by the soil bacterium Burkholderia pseudomallei.', 'The soil-dwelling saprophyte bacterium Burkholderia pseudomallei is the cause of melioidosis, a severe disease of humans and animals in southeast Asia and northern Australia.', 'Melioidosis is an often fatal infectious disease affecting humans and animals in tropical regions and is caused by the saprophytic environmental bacterium Burkholderia pseudomallei.', 'We have recently shown that during melioidosis, a severe infection caused by the gram-negative bacterium Burkholderia pseudomallei, TLR2 but not TLR4 impacts the immune response of the intact host in vivo.', 'It is caused by the bacterium Burkholderia pseudomallei, which can infect many organs of the body, including the brain, and results in neurological symptoms.', 'Melioidosis is a frequent cause of severe sepsis in Southeast Asia caused by the gram-negative bacterium Burkholderia pseudomallei.', 'What drives the occurrence of the melioidosis bacterium Burkholderia pseudomallei in domestic gardens?', 'The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosi', 'The environmental bacterium Burkholderia pseudomallei causes the infectious disease melioidosis with a high case-fatality rate in tropical and subtropical regions.', 'Burkholderia pseudomallei is a soil-dwelling bacterium and the cause of melioidosis', 'Melioidosis, an infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei,', 'Melioidosis is a frequently fatal infectious disease caused by the soil dwelling Gram-negative bacterium Burkholderia pseudomallei. ', 'Burkholderia pseudomallei, an environmental bacterium that causes the deadly disease melioidosis, ', 'Melioidosis is an important public health problem in Southeast Asia and Northern Australia. This disease is caused by the gram-negative bacilli, Burkholderia pseudomallei', 'Melioidosis, caused by Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast-Asi', 'Melioidosis is a potentially fatal disease caused by the saprophytic bacterium Burkholderia pseudomallei', 'Melioidosis is a disease of humans caused by opportunistic infection with the soil and water bacterium Burkholderia pseudomallei.']

['Burkholderia pseudomallei is the causative agent of melioidosis']

['yes']

Is paroxetine effective for treatment of premenstrual dysphoric disorder?

['To evaluate the cost effectiveness of the four medications with a US FDA-approved indication for PMDD: fluoxetine, sertraline, paroxetine and drospirenone plus ethinyl estradiol (DRSP/EE).', 'All SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and clomipramine) were effective in reducing premenstrual symptoms.', 'Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults.', 'Selective serotonin-reuptake inhibitors (SSRIs) have been proven safe and effective for the treatment of PMDD and are recommended as first-line agents when pharmacotherapy is warranted. Currently fluoxetine, controlled-release paroxetine, and sertraline are the only Food and Drug Administration-approved agents for this indication.', 'When compared with placebo, patients treated with paroxetine 20 mg attained a significant reduction in irritability (difference in median percent change: -23.9, 95% CI = -51.3 to -6.2, p = .014; difference in mean absolute change: -18.6, 95% CI = -32.5 to -4.6, p = .007). A statistically significant difference was not observed when the patients treated with the lower dose of paroxetine (10 mg) were compared with placebo. Treatment was well tolerated with no unexpected side effects.', 'Intermittent administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD.', 'All these women had significant improvements in the HAMA, HAMD, CGI, and PRISM calendar. The rate of response to paroxetine treatment lay between 50% and 78.6% in the continuous-treatment group, and 37.5-93.8% in the intermittent-treatment group, as determined at the study end-point.', 'The present results indicate that paroxetine is effective in both continuous and intermittent treatment of oriental PMDD women, and that the effects of active treatment lasted for six consecutive treatment menstrual cycles.', 'Paroxetine CR is approved for the treatment of major depression, social anxiety disorder, panic disorder and premenstrual dysphoric disorder in adults.', 'Continuous treatment with paroxetine reduced premenstrual symptoms effectively with a response rate of 85%.', 'Intermittent treatment was as effective as continuous treatment in reducing irritability, affect lability, and mood swings, but had a somewhat weaker effect on depressed mood and somatic symptoms.', 'Daily Record of Severity of Problems scores were lower in the paroxetine group compared with the placebo group, although the differences were not statistically significant.', 'However, the mean on-treatment Inventory of Depressive Symptomatology (clinician-rated) score for the paroxetine group was 17.9 +/- 8.3 compared with 31.5 +/- 11.2 in the placebo group (adjusted mean difference = 13.6, P = 0.009).', 'Response (Clinical Global Impressions Scale score of 1 or 2) occurred in 70% of subjects randomized to paroxetine CR and 10% of those assigned to placebo (chi2(1) = 7.5, P = 0.006).', 'The US Food and Drug Administration and Health Canada recently approved paroxetine for the treatment of premenstrual dysphoric disorder.', 'Patients treated with either dose of paroxetine CR demonstrated significantly greater improvements on the primary efficacy measure (change from baseline in mean luteal phase VAS-Mood scores) and on the majority of secondary efficacy measures compared with patients randomly assigned to placebo.', 'For the treatment of PMDD, luteal phase dosing with 12.5 mg and 25 mg of paroxetine CR is effective and generally well tolerated.', 'A statistically significant difference was observed in favor of paroxetine CR 25 mg versus placebo on the VAS-Mood (adjusted mean difference = -12.58 mm, 95% CI = -18.40 to -6.76; p < .001) and for paroxetine CR 12.5 mg versus placebo (adjusted mean difference = -7.51 mm, 95% CI = -13.40 to -1.62; p = .013).', 'Paroxetine CR doses of 12.5 mg/day and 25 mg/day are effective in treating PMDD and are well tolerated.', 'At end point, subjects treated with paroxetine CR (12.5 mg and 25 mg) demonstrated significant improvement in VAS-Mood scores compared with those who received placebo (paroxetine CR 12.5 mg mean treatment difference vs. placebo, -8.7 mm; 95% CI, -15.7, -1.7; p =.015; paroxetine CR 25 mg mean treatment difference vs. placebo, -12.1 mm; 95% CI, -18.9, -5.3; p <.001).', 'Both doses of paroxetine CR 12.5 mg and 25 mg daily are effective and well tolerated in patients who suffer from PMDD.', 'Of these agents, sertraline, fluoxetine and paroxetine (as an extended-release formulation) are approved by the US FDA for luteal phase, as well as continuous, administration.', 'In well designed placebo-controlled trials in patients with major depressive disorder (including a study in the elderly), social anxiety disorder or premenstrual dysphoric disorder (PMDD), paroxetine CR was consistently superior to placebo with regards to primary endpoints (i.e. mean Hamilton Rating Scale for Depression total score [major depressive disorder], Liebowitz social anxiety scale total score and Clinical Global Impressions-Global Improvement score [social anxiety disorder] and Visual Analogue Scale-Mood score [PMDD]).', 'Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI) with indications for the treatment of depression, obsessive- compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder and chronic headache.', 'Studies having compared the efficiency of antidepressants according to their serotonin activity (paroxetine or sertraline versus maprotiline, that is a selective noradrenaline re-uptake inhibitor), showed that serotonin re-uptake inhibitors were significantly more efficient on all symptoms than maprotiline, that was not more efficient than placebo.', 'Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache.', 'Preliminary data suggest that paroxetine has potential in the treatment of social phobia, premenstrual dysphoric disorder and chronic headache.', 'The effects of active treatment were marked by the first active cycle with luteal phase 17-item Hamilton Rating Scale for Depression scores decreasing from 14.9 (+/- 5.3) to 8.2 (+/- 4.9) in the first, 7.8 (+/- 5.1) in the second, and 7.8 (+/- 6.8) in the third active treatment cycles (F[1,13] = 17.6; p < 0.0001).', 'The most conservative measure, the Clinical Global Impression (CGI), revealed that 7 of 14 patients had a complete response (CGI = 1 or 2) whereas 4 patients had a partial response (CGI = 3).', 'These open trial findings are consistent with the notion that paroxetine is effective in the acute phase for the treatment of PDD.', 'The rating of premenstrual irritability, depressed mood, increase in appetite, and anxiety/tension was markedly lower during treatment with paroxetine than before, and this reduction in symptomatology appeared unabated for the entire treatment period.']

['Yes, paroxetine is effective and FDA approved treatment of women with premenstrual dysphoric disorder. A number of well designed clinical trials have confirmed efficacy and safety of both continuous or intermittent regiments of paroxetine for treatment of premenstrual dysphoric disorder. A number of other antidepressants and hormaonal therapies were also shown to be effective and are FDA approved for treatment of women with premenstrual dysphoric disorder.']

['yes']

What symptoms characterize the Muenke syndrome?

['Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. ', 'Muenke syndrome caused by the FGFR3 Pro250Arg mutation is associated with craniosynostosis, hearing loss, and various bony anomalies.', 'Muenke syndrome caused by the FGFR3(P250R) mutation is an autosomal dominant disorder mostly identified with coronal suture synostosis, but it also presents with other craniofacial phenotypes that include mild to moderate midface hypoplasia. ', 'Sensorineural hearing loss at lower frequencies was found only in patients with Muenke syndrome. ', ' Sensorineural hearing loss can occur in all 4 syndromes studied but is the primary cause of hearing loss in children and young adults with Muenke syndrome.', 'The facial features of children with FGFR3Pro250Arg mutation (Muenke syndrome) differ from those with the other eponymous craniosynostotic disorders. We documented midfacial growth and position of the forehead after fronto-orbital advancement (FOA) in patients with the FGFR3 mutation. ', '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. ', 'Muenke syndrome is characterized by considerable phenotypic variability: features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pansynostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly (broad skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Other craniofacial findings typically include: ocular hypertelorism, ptosis or proptosis (usually mild), midface hypoplasia, temporal bossing, and a highly arched palate. Strabismus is common. Extracranial findings can include: hearing loss (in 33%-100% of affected individuals); developmental delay (~33%); intellectual disability; carpal bone and/or tarsal bone fusions; brachydactyly, broad toes, broad thumbs, and/or clinodactyly; and radiographic findings of thimble-like (short and broad) middle phalanges and/or cone-shaped epiphyses. Phenotypic variability is considerable even within the same family. ', '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. ', 'A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss.', 'Increased digital markings were more severe posteriorly in Muenke patients than in non-Muenke patients. The Muenke patients with unilateral coronal synostosis showed a somewhat more severe asymmetry in the anterior part of the skull than the non-Muenke patients.', 'Muenke syndrome is a genetically determined craniosynostosis that involves one or both coronal sutures. In some patients it is associated with skeletal abnormalities such as thimble-like middle phalanges, coned epiphysis, and/or neurological impairment, namely sensorineural hearing loss or mental retardation.', '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 is characterized by various craniofacial deformities and is caused by an autosomal-dominant activating mutation in fibroblast growth factor receptor 3 (FGFR3(P250R) ).', '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.', 'Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.', 'Muenke syndrome is an autosomal-dominant craniosynostosis syndrome characterized by unilateral or bilateral coronal craniosynostosis, hearing loss, intellectual disability, and relatively subtle limb findings such as carpal bone fusion and tarsal bone fusion.', '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 caused by the FGFR3 Pro250Arg mutation is associated with craniosynostosis, hearing loss, and various bony anomalies', 'Muenke syndrome is characterized by coronal suture synostosis, midface hypoplasia, subtle limb anomalies, and hearing loss', 'Muenke syndrome is an autosomal-dominant craniosynostosis syndrome characterized by unilateral or bilateral coronal craniosynostosis, hearing loss, intellectual disability, and relatively subtle limb findings such as carpal bone fusion and tarsal bone fusion', 'Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition', 'Muenke syndrome is characterized by various craniofacial deformities and is caused by an autosomal-dominant activating mutation in fibroblast growth factor receptor 3 (FGFR3(P250R) )', '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 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 is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. ', 'Muenke syndrome is characterized by considerable phenotypic variability: features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pansynostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly (broad skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Other craniofacial findings typically include: ocular hypertelorism, ptosis or proptosis (usually mild), midface hypoplasia, temporal bossing, and a highly arched palate. Strabismus is common. Extracranial findings can include: hearing loss (in 33%-100% of affected individuals); developmental delay (~33%); intellectual disability; carpal bone and/or tarsal bone fusions; brachydactyly, broad toes, broad thumbs, and/or clinodactyly; and radiographic findings of thimble-like (short and broad) middle phalanges and/or cone-shaped epiphyses. Phenotypic variability is considerable even within the same family.']

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Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?

['Tofacitinib: The First Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthritis.', 'Tofacitinib is the first oral Janus kinase inhibitor indicated for treatment of moderate to severe RA.', 'Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis.', 'The preclinical pharmacokinetic (PK)/pharmacodynamic (PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA).', 'With tofacitinib, the first Janus kinase (JAK) inhibitor has been approved in the USA, as well as in Switzerland and other countries. ', 'Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. ', 'Tofacitinib is an oral janus kinase (JAK) inhibitor that inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving a broad limitation of inflammation by interfering with several cytokine receptors. It first proved its efficacy as an immunosuppressive regimen after renal transplantation, and was recently approved by the FDA for rheumatoid arthritis. ', ' In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. ', 'After two decades of research and development activity focussed on orally active kinase inhibitors, the first such drug (the JAK inhibitor Xeljanz, tofacitinib) was approved by the FDA in November 2012 for the treatment of rheumatoid arthritis (RA). ', 'JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical.', 'An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. ', 'Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR.', 'Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.', 'A non-selective JAK inhibitor, ruxolitinib, has recently been approved to treat myelofibrosis whereas tofacitinib is poised for approval to treat rheumatoid arthritis. ', 'The recent disclosure of the clinical efficacy of a selective JAK1 inhibitor (GLPG-0634) in rheumatoid arthritis and detailed disclosure of the some potent and highly selective JAK1 inhibitors provide a clear stimulus for further activity in this area. ', 'These results suggest that the JAK inhibitor tofacitinib suppresses osteoclast-mediated structural damage to arthritic joints, and this effect is secondary to decreased RANKL production.', 'More recently, the Janus kinase (JAK) inhibitor tofacitinib has been evaluated as a potential new treatment option in RA and is awaiting approval.', 'A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo twice daily and the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12, a primary end point, was significant for all tofacitinib treatment groups. Thus, an orally available tofacitinib in combination with MTX was efficacious and had a manageable safety profile. Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation to optimise the treatment of RA.', 'Moreover, induction of IL-10 production by DCs can be one mechanism of action of the JAK inhibitor (tofacitinib) which have shown high efficiency on active rheumatoid arthritis in clinical trials.', 'Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. ', ' Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). ', 'To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. ', 'In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.', 'OBJECTIVE: To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.', 'Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.', 'The new JAK3 inhibitor, CP690,550, has shown efficacy in the treatment of rheumatoid arthritis.', 'CP-690,550 is a potent and selective JAK inhibitor currently in clinical trials for rheumatoid arthritis (RA) and other autoimmune disease indications.', 'Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment.', 'To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. ', 'Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial.', 'CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.', 'Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA.', 'INCB18424 targeting Jak1/2 and CP690,550 targeting Jak3 has been developed and is now on phase II clinical study for RA.']

['Tofacitinib (or CP690.550) is an oral JAK (Janus kinase) inhibitor that is approved for treatment of rheumatoid arthritis. Tofacitinib inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving a broad limitation of inflammation by interfering with several cytokine receptors. Tofacitinib has also a proven efficacy as an immunosuppressive regimen after renal transplantation. \nGLPG-0634 and INCB18424 are other JAK kinase inhibitors that are being studied for treatment of rheumatoid arthritis.']

['tofacitinib']

How does hyperprolactinaemia related to prolactinoma increase the risk of osteoporosis?

['Hyperprolactinaemia related to prolactinoma significantly (more than functional hyperprolactiaemia) increases the risk of osteopenia, osteoporosis and bone fractures.", "INTRODUCTION Osteopenia and osteoporosis because of hyperprolactinaemia caused by prolactinoma may be followed by an increased risk of fracture.", "In conclusion, men with prolactinoma have high prevalence of osteopenia and osteoporosis.", "Humans with prolactinoma are at risk for osteoporosis.", "Osteopenia and osteoporosis because of hyperprolactinaemia caused by prolactinoma may be followed by an increased risk of fracture.", "The relative risk for developing osteoporosis in women with prolactinoma was found to be 4.5, indicating that hyperprolactinemia in women is a major risk factor for osteoporosis..", "In the premenopausal women, patients with prolactinoma or craniopharyngioma are often accompanied with osteopenia or osteoporosis, and disease duration and hypogonadism are the risk factors of bone loss in prolactinoma."]']

Hyperprolactinaemia related to prolactinoma significantly increases the risk of osteopenia, osteoporosis, and bone fractures. Men with prolactinoma have a high prevalence of osteopenia and osteoporosis. Humans with prolactinoma are at risk for osteoporosis. The relative risk for developing osteoporosis in women with prolactinoma was found to be 4.5, indicating that hyperprolactinemia in women is a major risk factor for osteoporosis. In premenopausal women, patients with prolactinoma or craniopharyngioma are often accompanied by osteopenia or osteoporosis, with disease duration and hypogonadism being risk factors for bone loss in prolactinoma.

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What is ectopia lentis?

['bilateral lens dislocation', 'Clinical manifestations include mental retardation, dislocation of the optic lens (ectopia lentis)', 'Ectopia lentis is a genetically heterogeneous condition that is characterized by the subluxation of the lens resulting from the disruption of the zonular fibers. ']

['Ectopia Lentis is dislocation of the optic lens in the eye.']

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Which is the most common cause of sudden cardiac death in young athletes?

['The most common cause of death was hypertrophic cardiomyopathy (30 %), followed by coronary artery anomalies (9 %), and myocarditis (9 %). ', 'The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable.', 'HCM is the most common cause of sudden death in young competitive athletes and preparticipation screening programs have to be implemented to avoid these tragic fatalities. ', 'Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young people, including trained athletes.', 'Hypertrophic cardiomyopathy (HCM) is regarded as the most common cause of sudden cardiac death in young people (including trained athletes). ', 'Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young people, including trained athletes. ', 'Hypertrophic cardiomyopathy is regarded as the most common cause of sudden cardiac death in young people (including trained athletes).', 'The most common cause of sudden cardiac death in athletes is hypertrophic cardiomyopathy. ', 'Hypertrophic cardiomyopathy (HCM) is one of the most common inherited primary cardiac disorders and the most common cause of sudden cardiac death in young athletes.', 'The most common cause of sudden cardiac death in individuals aged less than 35 years, including competitive athletes, is the inherited disorder hypertrophic cardiomyopathy (HCM). ', 'udden death in young competitive athletes is due to a variety of cardiovascular diseases (CVDs) and, most commonly, HCM. ', 'Hypertrophic cardiomyopathy (HCM) is the most common cause of death in the young, particularly in young competitive athletes.', 'Hypertrophic cardiomyopathy (HC) is probably the most common cause of sudden cardiac death in youthful athletes, and this diagnosis has represented a contraindication to continued participation in competitive sports. ']

['the most common cause of sudden cardiac death in young athletes is hypertrophic cardiomyopathy']

['hypertrophic cardiomyopathy']

Hy's law measures failure for what organ?

[" Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. ", "Enzyme elevations alone may not be harmful, but if caused by a drug and followed by jaundice (called 'Hy's law') there is a high possibility of serious DILI.", "No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria.", "We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample.We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease.", "Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model.", "Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF).", "Hy's law is a method used to identify drug-induced liver injury (DILI)", "Potential severe liver injury is identified in clinical trials by ALT>3\u2009×\u2009upper limits of normal (ULN) and total bilirubin>2\u2009×\u2009ULN, and termed 'Hy's Law' by the US FDA.", "Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT)>3× upper limit of normal (ULN) and bilirubin>2× ULN, termed Hy's law by the Food and Drug Administration. "]

["Hy's law correlates enzyme elevations with liver injury ad subsequent failure."]

['liver']

Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death?

['Here we refine our approach, and apply it to novel variants found in 2266 patients across two large cohorts with inherited sudden death syndromes, namely catecholaminergic polymorphic ventricular tachycardia (CPVT) or Brugada syndrome (BrS).', 'Calsequestrin-associated catecholaminergic polymorphic ventricular tachycardia (CPVT2) can cause sudden death in young individuals in response to stress. ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood', 'In many cases the cause of death can be elucidated by medico-legal autopsy, however, a significant number of these cases remain unexplained despite a detailed postmortem investigation and are labeled as sudden unexplained death (SUD). Post-mortem genetic testing, so called molecular autopsy, revealed that primary arrhythmogenic disorders including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a certain number of these cases.', 'We report a family with repeat events of sudden cardiac death and recurrent ventricular fibrillation in a teenage girl, where autopsy data and clinical investigations were inconclusive. The diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was established only following finding a gene mutation in the cardiac ryano', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. ', 'In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective.', ' Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) yield no evidence to be found at autopsy, leaving coroners, medical examiners, and forensic pathologists only to speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD).', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood.', 'We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome.', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF).', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease that manifests as syncope or sudden death during high adrenergic tone in the absence of structural heart defects.', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy characterized by altered intracellular calcium handling resulting in ventricular arrhythmias and high risk of cardiac sudden death in young cases with normal structural hearts', 'Early detection of CPVT is crucial because opportune medical intervention prevents sudden cardiac death. ', ' If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease. ', 'Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young', 'Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms.', 'Although structural cardiovascular abnormalities explain most cases of sudden cardiac death in young people, the cause of death remains unexplained after autopsy in 10% to 30% of cases. Potentially lethal ion channel disorders (channelopathies) such as the long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and the Brugada syndrome (BrS) may account for at least one-third of these unexplained cases. ', 'Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.', 'The inherited arrhythmogenic diseases associated with the transmembranous ionic channels, anchoring proteins or intracellular calcium regulating proteins are thought to be responsible for sudden cardiac death in infants, children, and young adults who have structurally normal hearts. Recent genetic analyses have identified congenital diseases such as the long-QT syndrome (LQTS), the Jervell and Lange-Nielsen syndrome (JLNS), the Brugada syndrome (BrS), the short-QT syndrome (SQTS), the arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2), and the catecholamine-induced polymorphic ventricular tachycardia (CPVT) /familial polymorphic ventricular tachycardia (FPVT). ', 'At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT']

['Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death.']

['yes']

What congenital anomalies are linked to Mowat-Wilson syndrome?

[' genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies.", "Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum. ", "Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). ", "Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). ", "Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease.", "ACC is found in 40% of the cases of Mowat-Wilson syndrome (MWS), a polytopic embryonic defect including a distinctive facial gestalt, severe mental retardation, epilepsy and postnatal microcephaly as constant features. ", "However, analysis of MWS should be considered in the differential diagnosis of ACC, especially when the facial features raise the possibility of MWS.", "Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome).", "We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome).", "Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common. "]', ' genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies.", "Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum. ", "Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). ", "Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). ", "Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease.", "ACC is found in 40% of the cases of Mowat-Wilson syndrome (MWS), a polytopic embryonic defect including a distinctive facial gestalt, severe mental retardation, epilepsy and postnatal microcephaly as constant features. ", "However, analysis of MWS should be considered in the differential diagnosis of ACC, especially when the facial features raise the possibility of MWS.", "Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome).", "We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome).", "Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common. "]']

Congenital anomalies linked to Mowat-Wilson syndrome include Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum.

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Which kinase is regulating stress granule biogenesis?

["5'-AMP-activated protein kinase alpha regulates stress granule biogenesis", 'Multiple lines of evidence link AMPK activity to SG biogenesis. First, pharmacological kinase inhibition interfered with SG formation. Second, AMPK-α knockdown combined with in-depth quantitative SG analysis revealed isoform-specific changes of SG characteristics. Third, overexpression of mutant α-subunits further substantiated that AMPK regulates SG parameters. Finally, we identified the SG-nucleating protein G3BP1 as an AMPK-α2 binding partner. This interaction is stimulated by stress and notably occurs in SGs', 'our data define the master metabolic regulator AMPK as a novel SG constituent that also controls their biogenesis', "5'-AMP-activated protein kinase alpha regulates stress granule biogenesis.", 'Collectively, our data define the master metabolic regulator AMPK as a novel SG constituent that also controls their biogenesis.', 'This interaction is stimulated by stress and notably occurs in SGs. Collectively, our data define the master metabolic regulator AMPK as a novel SG constituent that also controls their biogenesis.', '5&apos;-AMP-activated protein kinase alpha regulates stress granule biogenesis..']

["5'-AMP-activated protein kinase alpha regulates stress granule biogenesis", "Multiple lines of evidence define the master metabolic regulator 5'-AMP-activated protein kinase alpha (AMPK-alpha) as a novel component of stress granules (SGs) that also controls their biogenesis."]

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Is it feasible to obtain DNA read lengths that exceed 30 Kb?

['Single-molecule, real-time sequencing (SMRT) developed by Pacific BioSciences produces longer reads than secondary generation sequencing technologies such as Illumina. The long read length enables PacBio sequencing to close gaps in genome assembly, reveal structural variations, and identify gene isoforms with higher accuracy in transcriptomic sequencing.', ' Third-generation sequencing, with read lengths>10 kb, will improve the assembly of complex genomes, but these techniques require high-molecular-weight genomic DNA (gDNA), and gDNA extraction protocols used for obtaining smaller fragments for short-read sequencing are not suitable for this purpose.', 'The emergence and development of so called third generation sequencing platforms such as PacBio has permitted exceptionally long reads (over 20\u2009kb) to be generated.']

['The emergence and development of so called third generation sequencing platforms such as PacBio has permitted exceptionally long reads (over 20\u2009kb) to be generated but not yet read length >30 Kb.']

['no']

Why is lock mass used in Orbitrap measurements?

['Benzyldimethylphenylammonium was used as an internal lock mass.', "To compensate for drifts in instrument calibration, a compound of known mass is often employed. This 'lock mass' provides an internal mass standard in every spectrum.", 'The use of mass calibrants (lock masses) to reduce the systematic error of mass-to-charge measurements has also been reported and, in some cases, incorporated in the instrument control software by the instrument manufacturers.', 'We achieved absolute mass accuracies for intact proteins between 0.92 and 2.8 ppm using the "lock mass" mode of operation.', 'Real time recalibration on the "lock mass" by corrections of mass shift removes mass error associated with calibration of the mass scale.']

['The lock mass is a compound of known mass and is used to compensate for drifts in instrument calibration.']

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From which sequence does the Alu repeat originate from?

['The origin of Alu-derived minisatellites appears to have been mediated by short flanking repeats, as first proposed by Haber and Louis', 'Finally, we propose that the origin of Alu subfamilies in human populations may be related to evolution of chromosome Y.', 'Our analysis indicates that about 60 Myr ago, before the prosimian divergence, free left and right monomers formed an Alu heterodimer connected by a 19-nucleotide-long A-rich linker.', 'the presence of Alu-like structural motifs supports the hypothesis of the monophyletic origin of Alu and B1 repeats, i.e., from a common 7SL RNA-derived retroposing monomeric element', 'Alu elements are each a dimer of similar, but not identical, fragments of total size about 300 bp, and originate from the 7SL RNA gene.']

['The presence of Alu-like structural motifs supports the hypothesis of the monophyletic origin of Alu and B1 repeats, i.e., from a common 7SL RNA-derived retroposing monomeric element, The origin of Alu subfamilies in human populations may be related to evolution of chromosome Y.']

['7SL RNA']

What is the mode of inheritance of Acromicric dysplasia?

['AD has an autosomal dominant mode of inheritance, distinct facial and skeleton features (a hoarse voice and internal notch of the femoral head).', 'Finally, WMS is transmitted either by an autosomal dominant or an autosomal recessive (AR) mode of inheritance, GD by an autosomal recessive mode of inheritance and AD by an autosomal dominant mode of inheritance. ', 'The condition appeared to be sporadic in 16 cases but the observation of vertical transmission in three families was consistent with an autosomal dominant mode of inheritance.']

['Acromicric dysplasia has an autosomal dominant mode of inheritance']

['autosomal dominant']

What is MPE-seq?

['MPE-seq, a new method for the genome-wide analysis of chromatin structure.', 'The analysis of chromatin structure is essential for the understanding of transcriptional regulation in eukaryotes. Here we describe methidiumpropyl-EDTA sequencing (MPE-seq), a method for the genome-wide characterization of chromatin that involves the digestion of nuclei withMPE-Fe(II) followed by massively parallel sequencing. Like micrococcal nuclease (MNase), MPE-Fe(II) preferentially cleaves the linker DNA between nucleosomes. However, there are differences in the cleavage of nuclear chromatin by MPE-Fe(II) relative to MNase. Most notably, immediately upstream of the transcription start site of active promoters, we frequently observed nucleosome-sized (141-190 bp) and subnucleosome-sized (such as 101-140 bp) peaks of digested chromatin fragments with MPE-seq but not with MNase-seq. These peaks also correlate with the presence of core histones and could thus be due, at least in part, to noncanonical chromatin structures such as labile nucleosome-like particles that have been observed in other contexts.', 'These findings collectively indicate that MPE-seq provides a unique and straightforward means for the genome-wide analysis of chromatin structure with minimal DNA sequence bias. In particular, the combined use of MPE-seq and MNase-seq enables the identification of noncanonical chromatin structures that are likely to be important for the regulation of gene expression.', 'These findings collectively indicate that MPE-seq provides a unique and straightforward means for the genome-wide analysis of chromatin structure with minimal DNA sequence bias.', 'In particular, the combined use of MPE-seq and MNase-seq enables the identification of noncanonical chromatin structures that are likely to be important for the regulation of gene expression.', 'Here we describe methidiumpropyl-EDTA sequencing (MPE-seq), a method for the genome-wide characterization of chromatin that involves the digestion of nuclei withMPE-Fe(II) followed by massively parallel sequencing.', 'In particular, the combined use of MPE-seq and MNase-seq enables the identification of noncanonical chromatin structures that are likely to be important for the regulation of gene expression.', 'MPE-seq, a new method for the genome-wide analysis of chromatin structure.', 'These findings collectively indicate that MPE-seq provides a unique and straightforward means for the genome-wide analysis of chromatin structure with minimal DNA sequence bias.', 'Here we describe methidiumpropyl-EDTA sequencing (MPE-seq), a method for the genome-wide characterization of chromatin that involves the digestion of nuclei withMPE-Fe(II) followed by massively parallel sequencing.']

['MPE-seq (methidiumpropyl-EDTA sequencing) is a new method for the genome-wide characterization of chromatin that involves the digestion of nuclei with MPE-Fe(II) followed by massively parallel sequencing. Like micrococcal nuclease (MNase), MPE-Fe(II) preferentially cleaves the linker DNA between nucleosomes. However, there are differences in the cleavage of nuclear chromatin by MPE-Fe(II) relative to MNase. MPE-seq provides a unique and straightforward means for the genome-wide analysis of chromatin structure with minimal DNA sequence bias. In particular, the combined use of MPE-seq and MNase-seq enables the identification of noncanonical chromatin structures that are likely to be important for the regulation of gene expression.']

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The drug JTV519 is derivative of which group of chemical compounds?

['In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca²⁺ leak.', 'The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex.', 'In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties.', 'K201 (JTV519), a benzothiazepine derivative, has been shown to possess anti-arrhythmic and cardioprotective properties, but the mechanism of its action is both complex and controversial.', 'K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker.', 'A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias.', 'We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury.', 'In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.', 'A newly synthesized 1,4-benzothiazipine derivate, 4-[3-(4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2,3,4,5-tetrahydro-1, 4-benzothiazepine monohydrochloride (JTV-519) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) mediated multidrug resistance (MDR) in K562/MDR and KB/MRP cells, respectively. ', 'JTV-519, which has potential use as an antiarrhythmic [285800]. The drug is a novel cardioprotectant derivative of 1,4-benzothiazepine for which phase I trials were completed in the third quarter of 1998', 'The 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion channel modulator.', 'A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. ', 'A newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective.', 'Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation', 'A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury.', ' We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process.', 'Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation.', 'A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury.', 'A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury.', ' In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca?⁺ leak.', 'The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts.', 'We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process']

['The 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion channel modulator.JTV-519, which has potential use as an antiarrhythmic [285800]. The drug is a novel cardioprotectant derivative of 1,4-benzothiazepine for which phase I trials were completed in the third quarter of 1998', 'JTV519 (K201), is a 1,4-benzothiazepine derivative and multi-channel blocker, which has been found to stabilize RyR2s and decrease SR Ca²⁺ leak.']

['1,4-benzothiazepine', 'benzothiazepine']