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Which mutations of alpha-myosin heavy chain gene are implicated in hypertrophic cardiomyopathy?

['Accordingly, pressure overload by transverse aortic constriction (TAC) was induced in 2-month-old, male mice with and without a FHC (R403Q) mutation in α-myosin heavy chain.', 'This model (designated TnI-203/MHC-403) was generated by crossbreeding mice with the Gly203Ser cardiac troponin I (TnI-203) and Arg403Gln alpha-myosin heavy chain (MHC-403) FHC-causing mutations. ', 'Male but not female mice carrying a single R403Q missense allele for cardiac alpha-myosin heavy chain (M-alphaMHC(R403Q/+) and F-alphaMHC(R403Q/+), respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-alphaMHC(+/+) and F-alphaMHC(+/+), respectively) after approximately 30 wk of age.', 'A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring.', 'To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln missense mutation in the alpha-myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing G(s)alpha (G(s)alpha x403). ', 'A mouse model of FHC resulting from a mutation in the alpha-myosin heavy-chain (Arg403Gln) was used to study the electrophysiologic phenotype of this disease.', 'We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alphaMHC403/+).', 'Genetically-manipulated mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+) display a phenotype characteristic of familial hypertrophic cardiomyopathy (FHC).', 'A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. ', 'The introduction of the mouse model for FHC (the mouse expresses predominantly alpha-MHC as opposed to the beta-isoform in larger mammals) created a new paradigm for FHC based on finding enhanced motor function for R403Q alpha-MHC.', 'A mouse model of familial hypertrophic cardiomyopathy (FHC) was generated by the introduction of an Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene.', 'Biochemical analysis of one FHC mutant (Arg-249-->Gln) demonstrates that the structures formed by the mutant are solubilized at a lower ionic strength than those formed by wild-type MHC. We conclude that although the FHC mutant MHC is not labile, its assembly properties may be impaired.']

['The following mutations of alpha-myosin heavy chain gene are implicated in hypertrophic cardiomyopathy: R403Q; Q1065H and Arg-249-->Gln']

['R403Q', 'Arg403Gln', 'Q1065H', 'Arg-249-->Gln']

DX-88 is investigational name of which drug?

['Ecallantide (known as DX-88 previously), a potent and specific inhibitor of plasma kallikrein is an innovative medicinal product. ', 'Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies.', 'Several novel therapies have completed phase III trials in the US, including: (i) plasma-derived C1-INH replacement therapies (Berinert P and Cinryze); (ii) a recombinant C1-INH replacement therapy (conestat alfa; Rhucin); (iii) a kallikrein inhibitor (ecallantide [DX-88]); and (iv) a bradykinin-2-receptor antagonist (icatibant).', 'Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery.', 'OBJECTIVE: Ecallantide (DX-88) is a potent and specific inhibitor of plasma kallikrein. ', 'DX-88 (ecallantide), a 60-amino acid recombinant protein discovered through phage display technology, is a highly specific, potent inhibitor of human plasma kallikrein that has been used successfully in the treatment of patients experiencing acute HAE attacks.', 'DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing.', 'DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously.', 'DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously']

['DX-88 is investigational name of a drug Ecallantide, a 60-amino acid recombinant protein discovered through phage display technology, that is a highly specific, potent inhibitor of human plasma kallikrein that has been used successfully in the treatment of patients experiencing acute hereditary angioedema attacks.']

['Ecallantide']

Which R/bioconductor package utilizes the Hilbert curve in order to visualize genomic data?

["In many genomic studies, one works with genome-position-dependent data, e.g. ChIP-chip or ChIP-Seq scores. Using conventional tools, it can be difficult to get a good feel for the data, especially the distribution of features. This article argues that the so-called Hilbert curve visualization can complement genome browsers and help to get further insights into the structure of one's data. This is demonstrated with examples from different use cases. An open-source application, called HilbertVis, is presented that allows the user to produce and interactively explore such plots.AVAILABILITY: http://www.ebi.ac.uk/huber-srv/hilbert/."]

["The so-called Hilbert curve visualization can complement genome browsers and help to get further insights into the structure of one's data. An open-source application, called HilbertVis, has been developed for R/bioconductor that allows the user to produce and interactively explore such plots."]

['HilbertVis']

Is clathrin involved in E-cadherin endocytosis?

['We demonstrated that GnT-III induced a stabilizing effect on E-cadherin at the cell membrane by inducing a delay in the turnover rate of the protein, contributing for the formation of stable and functional adherens-junctions, and further preventing clathrin-dependent E-cadherin endocytosis.', 'Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell-cell adhesion.', 'Here we show that E-cadherin polarity is controlled by the polarized regulation of clathrin- and dynamin-mediated endocytosis.', 'We delineate a pathway that controls the initiation of E-cadherin endocytosis through the regulation of AP2 and clathrin coat recruitment by E-cadherin.', 'Clathrin dependent endocytosis of E-cadherin is regulated by the Arf6GAP isoform SMAP1', 'E-cadherin is a central component of the adherens junction in epithelial cells and continuously undergoes endocytosis via clathrin-coated vesicles and/or caveolae depending on the cell type.', 'Collectively, SMAP1 likely represents a key Arf6GAP in clathrin dependent endocytosis of E-cadherin in MDCK cells.', 'Consistent with these observations, we found that selective uncoupling of p120 from E-cadherin by introduction of amino acid substitutions in the p120-binding site increased the level of E-cadherin endocytosis. The increased endocytosis was clathrin-dependent, because it was blocked by expression of a dominant-negative form of dynamin or by hypertonic shock.', 'We found that in this experimental system E-cadherin entered a transferrin-negative compartment before transport to the early endosomal compartment, where it merged with classical clathrin-mediated uptake pathways.']

['E-cadherin is a central component of the adherens junction in epithelial cells and continuously undergoes endocytosis via clathrin-coated vesicles and/or caveolae depending on the cell type.']

['yes']

Which myosin isozymes are located within the pericuticular necklace of the hair cell?

['Myosin 1 beta, VI, VIIa and probably XV are all expressed within a single cell in the inner ear, the hair cell.', 'The myosin isozymes expressed in the hair cell all have unique domains of expression and in some areas, such as the pericuticular necklace, several domains overlap.', 'Substantial amounts of myosins-Ibeta, -VI, and -VIIa are located in a pericuticular necklace', 'four unconventional myosin isozymes in the inner ear, a tissue that is particularly reliant on actin-rich structures and unconventional myosin isozymes.', 'The myosin isozymes expressed in the hair cell all have unique domains of expression and in some areas, such as the pericuticular necklace, several domains overlap.', 'Substantial amounts of myosins-Ibeta, -VI, and -VIIa are located in a pericuticular necklace that is largely free of F-actin, squeezed between (but not associated with) actin of the cuticular plate and the circumferential belt.', 'To understand how cells differentially use the dozens of myosin isozymes present in each genome, we examined the distribution of four unconventional myosin isozymes in the inner ear, a tissue that is particularly reliant on actin-rich structures and unconventional myosin isozymes.', 'This study examined the changes of myosin VI and myosin VIIa, two unconventional myosins that are critical for normal hair cell formation and function, during hair cell death and regeneration.', 'Substantial amounts of myosins-Ibeta, -VI, and -VIIa are located in a pericuticular necklace that is largely free of F-actin, squeezed between (but not associated with) actin of the cuticular plate and the circumferential belt.', 'Substantial amounts of myosins-Ibeta, -VI, and -VIIa are located in a pericuticular necklace that is largely free of F-actin, squeezed between (but not associated with) actin of the cuticular plate and the circumferential belt', 'The myosin isozymes expressed in the hair cell all have unique domains of expression and in some areas, such as the pericuticular necklace, several domains overlap', 'To understand how cells differentially use the dozens of myosin isozymes present in each genome, we examined the distribution of four unconventional myosin isozymes in the inner ear, a tissue that is particularly reliant on actin-rich structures and unconventional myosin isozymes']

['The hair cell is located in the inner ear, a tissue that is particularly reliant on actin-rich structures and unconventional myosin isozymes. Within the pericuticular necklace, a domain of the hair cell, certain unconventional myosin isozymes are located, namely myosins-Ibeta, myosin-VI, and myosin-VIIa.']

['myosins-Ibeta', 'myosin-VI', 'myosin-VIIa']

What is the role of neurogranin in Alzheimer's disease patients?

['We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng48-76), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng48-76 is the dominant peptide in human brain tissue.', 'In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. ', 'The results suggest that CSF Ng, in particular Ng48-76, might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.', ' These modifications were associated with impaired spatial memory and reduced hippocampal expression of signaling molecules important for synaptic plasticity and memory, including neurogranin, CaMKII, ERK, GSK3β, CREB, and expression of the transcription factor EGR1/Zif268. ', "Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease.", 'Relative quantification revealed a significant increase of neurogranin in the AD group compared with controls, while the MCI group was not statistically different from either controls or the AD group. ', 'The elevated neurogranin levels in the MCI and AD groups might reflect synaptic degeneration. These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neurogranin.', 'Further, to determine whether presynaptic or postsynaptic compartments of neurons are preferentially affected in AD patients, we studied 3 presynaptic vesicle proteins (synaptotagmin, synaptophysin, and Rab 3A), 2 synaptic membrane proteins (Gap 43 and synaptobrevin), and 2 postsynaptic proteins (neurogranin and synaptopodin) in specimens from AD and age-matched control brains. ', 'Our study suggests that postsynaptic proteins and presynaptic proteins are important for synaptic function and may be related to cognitive impairments in AD.', 'These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neurogranin.', 'Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease', 'We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng48-76), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng48-76 is the dominant peptide in human brain tissue.']

["Dendritic protein neurogranin is markedly increased in cerebrospinal fluid in Alzheimer's disease patients. Neurogranin might reflect the neurodegenerative processes within the brain, indicating a role for neurogranin as a potential novel clinical biomarker for synaptic degeneration in AD.\nNeurogranin is important for synaptic plasticity and memory."]

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What is the role of edaravone in traumatic brain injury?

[' The edaravone-treated animals also exhibited higher rCBF in the contralateral hemisphere compared with that seen in -vehicle-treated animals. It is suggested that edaravone reduces neuronal damage by scavenging reactive oxygen species (ROS) and by maintaining intact the autoregulation of the cerebral vasculature.', 'Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease in O2 (∙-) levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.', 'Edaravone significantly suppressed axonal injury and oxidative stress in the cortex, corpus callosum, and hippocampus 24h after injury. ', 'These results suggest that edaravone protects against memory deficits following TBI and that this protection is mediated by suppression of TAI and oxidative stress.', 'Concordantly, edaravone has been found to have neuroprotective effects in a number of animal models of disease, including stroke, spinal cord injury, traumatic brain injury, neurodegenerative diseases and brain tumors. ', 'Free-radical scavenger edaravone treatment confers neuroprotection against traumatic brain injury in rats.', 'Edaravone treatment significantly decreased hippocampal CA3 neuron loss, reduced oxidative stress, and decreased neuronal programmed cell death compared to vehicle treatment. ', 'Lastly, edaravone treatment significantly reduced the presence of inflammatory cytokines, cerebral edema, blood-brain barrier (BBB) permeability, and, importantly, neurological deficits following TBI. Our results suggest that edaravone exerts a neuroprotective effect in the rat model of TBI. The likely mechanism is via inhibiting oxidative stress, leading to a decreased inflammatory response and glial activation, and thereby reducing neuronal death and improving neurological function.', 'After treatment with edaravone, the degree of morphological injury, p-ERK1/2 level and number of apoptotic neurons decreased, latent period to find the safety platform was significantly shortened (in low-dose edaravone treatment group, p-ERK1/2 expression level at 6, 24, 48 hours was 2.46 + or - 0.22, 4.00 + or - 0.84, 2.38 + or - 0.32, and in high-dose edaravone treatment group was 1.67 + or - 0.15, 1.86 + or - 0.38, 1.27 + or - 0.28; in low-dose edaravone treatment group, the apoptotic cells at 6, 24, 48, 72 hours was 5.20 + or - 1.23, 7.10 + or - 1.72, 9.54 + or - 1.36, 14.12 + or - 3.19, and in high-dose edaravone treatment group was 3.40 + or - 0.49 , 4.39 + or - 0.73, 5.02 + or - 1.12, 8.78 + or - 2.16; in low-dose edaravone treatment group, latent period to find the safety platform at 7-10 days was 94.8 + or - 22.8, 65.2 + or - 19.0, 62.0 + or - 16.7, 59.5 + or - 15.6, and in high-dose edaravone treatment group it was 81.5 + or - 20.7, 55.4 + or - 18.5, 40.0 + or - 12.3, 32.2 + or - 11.0, all P<0.05). High-dose edaravone showed a better effect (all P<0.05).', ' Edaravone gives good therapeutic effect on severe TBI, and the molecular mechanism is related to attenuation of ERK1/2 pathway and neuronal apoptosis following severe brain trauma.', 'Numbers of 8-OHdG-, 4-HNE-, and ssDNA-positive cells around the damaged area after TBI were significantly decreased in the edaravone group compared with the saline group (P < 0.01). There was a significant increase in neuronal cell number and improvement in cerebral dysfunction after TBI in the edaravone group compared with the saline group (P < 0.01). Edaravone administration following TBI inhibited free radical-induced neuronal degeneration and apoptotic cell death around the damaged area. In summary, edaravone treatment improved cerebral dysfunction following TBI, suggesting its potential as an effective clinical therapy.', 'Edaravone administration inhibited production of free radicals known to induce neuronal degeneration and cell death after brain injury, and protected nestin-positive cells, including NSCs, with the potential to differentiate into neurons and glia around the area damaged by TBI.', 'Under specific experimental conditions, edaravone minimized traumatic brain injury by functioning as a synthetic antioxidant. ', 'Thus, edaravone can scavenge OR- and significantly reduce levels of these radicals in TBI patients.']

['Edaravone, a free radical scavenger, has been shown to have neuroprotective effects after traumatic brain injury. In animal models, edaravone has been shown to reduce neuronal damage by scavenging reactive oxygen species (ROS), maintain intact the autoregulation of the cerebral vasculature, decrease neuronal loss, reduce programmed cell death, the presence of inflammatory cytokines, cerebral edema, and blood-brain barrier (BBB) permeability. Edaravone also protects against neurological deficits and memory deficits following traumatic brain injury.']

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Between which probes does the recurrent translocation breakpoint on chromosome 22 of neuroepithelioma lie?

['The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has been localized between two probes, D22S1 and D22S15, by both in situ hybridization and somatic cell hybrids', 'The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has been localized between two probes, D22S1 and D22S15, by both in situ hybridization and somatic cell hybrids.']

['The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has been localized between two probes, D22S1 and D22S15, by both in situ hybridization and somatic cell hybrids', 'The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has been localized between two probes, D22S1 and D22S15, by both in situ hybridization and somatic cell hybrids. ', 'The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has been localized between two probes, D22S1 and D22S15, by both in situ hybridization and somatic cell hybrids.', 'The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has been localized between two probes, D22S1 and D22S15, by both in situ hybridization and somatic cell hybrids ']

['D22S1', 'D22S15']

Which therapeutic interventions for sarcopenia have been applied

['The main bulk of experimental pharmacological interventions addressing the clinical problem of frailty have been focused on the use of hormones, as replacement therapy in subjects with low or normal circulating basal levels of the hormone. Results have been disappointing, except for the case of testosterone that have shown some benefits. The effectiveness of other potential therapeutic interventions (antioxidants, anti-inflammatory agents, nutritional supplements) appears to be limited or has not been explored in detail until now.', 'effective treatment options are still under investigation.', 'Design of therapeutic interventions for geriatric frailty has been challenging and may be because of inadequate understanding of its biological underpinnings']

['The main bulk of experimental pharmacological interventions addressing the clinical problem of frailty have been focused on the use of hormones, as replacement therapy in subjects with low or normal circulating basal levels of the hormone. Results have been disappointing, except for the case of testosterone that have shown some benefits. The effectiveness of other potential therapeutic interventions (antioxidants, anti-inflammatory agents, nutritional supplements) appears to be limited or has not been explored in detail until now.']

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What percentage of rheumatoid arthritis patients are responsive to anti-TNF therapy?

['Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. ', 'Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients.']

['Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. ', 'The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients.', 'Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. A substantial proportion of Rheumatoid Arthritis patients (approximately 30-40%) fail to respond to anti-TNF therapies.', 'Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients.', 'Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. ', 'strategies blocking tumor necrosis factor (anti-tnf) have proven very successful in patients with rheumatoid arthritis (ra) , showing beneficial effects in approximately 50-60% of the patients. . this , a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies . ', 'Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease.', 'treatment strategies blocking tumor necrosis factor (anti-tnf) have proven very successful in patients with rheumatoid arthritis (ra), showing beneficial effects in approximately 50-60% of the patients.', 'Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. ', 'Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients.', 'Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies.']

['50-60%']

What are clinical features of the de Morsier syndrome?

[' SOD was formerly known as de Morsier syndrome, which associated a midline brain defect such as an absent septum pellucidum with optic nerve hypoplasia.', 'The triad consists of optic nerve hypoplasia, pituitary hormone abnormalities, and midline brain defects, although it can vary in the severity of clinical presentation and phenotype. ', 'INTRODUCTION: Previous studies have described septooptic dysplasia (SOD) to describe patients who have optic nerve hypoplasia, the absence of septum pellucidum, and pituitary hypoplasia.', 'BACKGROUND: Septo-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad features: midline brain abnormalities, optic nerve hypoplasia and pituitary endocrine dysfunction. ', 'Septo-optic dysplasia (SOD), otherwise called De Morsier syndrome, is a developmental anomaly of mid-line brain structures and includes optic nerve hypoplasia, absence of the septum pellucidum and hypothalamo-pituitary abnormalities). ', 'The frequently associated features of hypopituitarism and absent septum pellucidum were felt to have embryonic linkage as "septo-optic dysplasia" or "de Morsier\'s syndrome."', 'An MRI of the brain demonstrated the absence of the septum pellucidum, which confirmed a diagnosis of septo-optic dysplasia or de Morsier syndrome.', 'Septo-optic dysplasia (De Morsier syndrome) is a developmental anomaly of mid-line brain structures and includes optic nerve hypoplasia, absence of the septum pellucidum and hypothalamo-pituitary abnormalities.', 'Septo-optic dysplasia, also known as de Morsier syndrome, is a rare congenital entity almost always characterized by hypoplasia/dysplasia of the optical nerve, chiasma or optic radiations and the complete or partial absence of the septum pellucidum.', 'The de Morsier syndrome, or septo-optic dysplasia, is a developmental anomaly characterized by involvement of the optic system, hypothalamic-pituitary axis and septum pellucidum.', 'The term septooptic dysplasia was coined in 1956 by de Morsier, who pointed out the association of optic nerve hypoplasia and absence of the septum pellucidum.', 'Septo-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad features: midline brain abnormalities, optic nerve hypoplasia and pituitary endocrine dysfunction', 'Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction', 'Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction. ', 'Septo-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad features: midline brain abnormalities, optic nerve hypoplasia and pituitary endocrine dysfunction.', 'Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction.', "[Optic nerve hypoplasia and growth hormone deficiency: de Morsier's syndrome]."]

['Classic triad of the De Morsier syndrome (septooptic dysplasia) includes optic nerve hypoplasia, the absence of septum pellucidum, and pituitary hypoplasia.']

['optic nerve hypoplasia', 'absence of septum pellucidum', 'pituitary hypoplasia']

How does Ssu72 mediate gene looping?

['Investigation of chromosome folding in mutants confirms roles for RSC, "gene looping" factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome.', 'Furthermore, different regions of Pta1 interact with the CPF subunits Ssu72, Pti1, and Ysh1, supporting the idea that Pta1 acts as a scaffold to organize CPF.', "The essential N terminus of the Pta1 scaffold protein is required for snoRNA transcription termination and Ssu72 function but is dispensable for pre-mRNA 3'-end processing", 'The first 300 amino acids of Pta1 are sufficient for interactions with Ssu72, which is needed for pre-mRNA cleavage. ', 'These findings suggest that the amino terminus of Pta1 has an inhibitory effect and that this effect can be neutralized through the interaction with Ssu72.', "TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP.", " These interactions are transcription-dependent, require the Ssu72 and Pta1 components of the CPF 3'-end processing complex, and require the phosphatase activity of Ssu72.", 'We propose a model for RNAP II transcription in which promoter and terminator regions are juxtaposed, and that the resulting gene loops facilitate transcription reinitiation by the same molecule of RNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation.', "The essential N terminus of the Pta1 scaffold protein is required for snoRNA transcription termination and Ssu72 function but is dispensable for pre-mRNA 3'-end processing.", "The pta1-Delta75 mutant is defective for snoRNA termination, RNA polymerase II C-terminal domain Ser5-P dephosphorylation, and gene looping but is fully functional for mRNA 3'-end processing. ", 'We conclude that Swd2.2 opposes condensin-mediated chromosome condensation by facilitating the function of the two CPF-associated phosphatases PP1 and Ssu72.', "Based on the interactions of Ssu72 and Sub1 with both the Pta1 of CPF and the TFIIB component of the initiation complex, we present a model describing how these novel connections between the transcription and 3' end processing machineries might facilitate transitions in the RNAP II transcription cycle.", 'By the degron-mediated depletion of Pta1, we show that the removal of this essential region leads to a loss of Ssu72, yet surprisingly, in vitro cleavage and polyadenylation remain efficient.', "The pta1-Delta75 mutant is defective for snoRNA termination, RNA polymerase II C-terminal domain Ser5-P dephosphorylation, and gene looping but is fully functional for mRNA 3'-end processing."]

['Investigation of chromosome folding in mutants confirms roles for RSC, "gene looping" factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. The essential N terminus of the Pta1 scaffold protein is required for snoRNA transcription termination and Ssu72 function but is dispensable for pre-mRNA 3\'-end processing. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3\' end processing complex, and is independent of TBP. We propose a model for RNAP II transcription in which promoter and terminator regions are juxtaposed, and that the resulting gene loops facilitate transcription reinitiation by the same molecule of RNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation. The first 300 amino acids of Pta1 are sufficient for interactions with Ssu72, which is needed for pre-mRNA cleavage. ', "In RNAP II transcription, promoter and terminator regions are juxtaposed and the resulting gene loops facilitate transcription reinitiation by the same molecule of RNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation. These interactions are transcription-dependent, require the Ssu72 and Pta1 components of the CPF 3'-end processing complex, and require the phosphatase activity of Ssu72.", "tfiib crosslinks to both the promoter and terminator regions of the pma1 and blm10 genes, and its association with the terminator, but not the promoter, is adversely affected by e62k and by depletion of the ssu72 component of the cpf 3' end processing complex, and is independent of tbp.", 'Investigation of chromosome folding in mutants confirms roles for RSC, "gene looping" factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3\' end processing complex, and is independent of TBP. We propose a model for RNAP II transcription in which promoter and terminator regions are juxtaposed, and that the resulting gene loops facilitate transcription reinitiation by the same molecule of RNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation. The essential N terminus of the Pta1 scaffold protein is required for snoRNA transcription termination and Ssu72 function but is dispensable for pre-mRNA 3\'-end processing These interactions are transcription-dependent, require the Ssu72 and Pta1 components of the CPF 3\'-end processing complex, and require the phosphatase activity of Ssu72. Furthermore, different regions of Pta1 interact with the CPF subunits Ssu72, Pti1, and Ysh1, supporting the idea that Pta1 acts as a scaffold to organize CPF.', "The essential N terminus of the Pta1 scaffold protein is required for snoRNA transcription termination and Ssu72 function but is dispensable for pre-mRNA 3'-end processing"]

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What is the role of Thyrotropin Releasing Hormone in the treatment of comatose patients?

["Despite the correction of these metabolic disorders, the patient became comatose, and MRI, on T2 weighted image, showed hyperintense signals in the basal ganglia consistent with extra-pontine myelinolysis. The patient's state remained unchanged for six weeks. Since S. Konno and H. Wakui published cases of myelinolysis who dramatically improved after TRH treatment, the patient was given 0.6 mg i.v daily of TRH for six weeks. Improvement began within a few days, and continued until complete recovery.", 'His CNS symptoms improved dramatically after administration of thyrotropin-releasing hormone tartrate (TRH-T).', '[Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice].', 'NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3.', 'Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly.', 'A 46-year-old female motorcyclist, who suffered injuries to the brain stem in a traffic accident, showed hypotensive and bradycardiac responses to thyrotropin-releasing hormone (TRH) given to counter consciousness disturbance.', 'The direct TRH (thyrotropin releasing hormone) stimulation to the anterior lobe was responded to well. ', 'The neuropharmacological activities of TRH include an interesting arousal effect and an analeptic action on generalized depression of the CNS whether this depression is of natural origin, such as hibernation, or induced pharmacologically (barbiturates, ethanol) or of a traumatic origin (coma). This analeptic action is attributable to stimulation of cholinergic neurons in the septo-hippocampal area and to the presence of terminals containing TRH in the lateral septum and TRH receptors concentrated especially in the medial septum and diagonal band of Broca. It has also been suggested that TRH localized in the pineal gland has a part in activating the neuronal mechanisms of arousal. Associated with the arousal effect and especially evident in variously originated shock conditions are the activating effects of TRH on vegetative functions (body temperature, circulation, the gastrointestinal tract). These stimulatory activities on the CNS were the rationale for therapeutic use of TRH in the initial treatment of coma due to brain trauma and for the treatment of endogenous depression. ', 'In the vegetative group, TRH caused significant increases in MBP (from 91 +/- 8 mm Hg to 110 +/- 10 mm Hg) at 2 min after the injection [p < 0.05, analysis of variance (ANOVA) with a Scheffé F-test]. In contrast, five of the seven BD patient showed no alterations in the measured parameter in response to the TRH injection. However, the remaining two BD patients, who had spinal reflexes, exhibited an elevation in MBP. ', 'These results indicate that in comatose patients, the hemodynamic effects of TRH may differ depending on impairments in the central nervous system; the results support previous reports indicating a mediation of the central sympathetic nervous system in the development of pressor effects of TRH. ']

['Thyrotropin Releasing Hormone and its analogs are used for treatment of comatose patients. In animal models, Thyrotropin Releasing Hormone and its analogs have been shown to improve the disturbance of consciousness caused by head concussion and pentobarbital. This analeptic action is attributable to stimulation of cholinergic neurons in the septo-hippocampal area and to the presence of terminals containing TRH in the lateral septum and TRH receptors concentrated especially in the medial septum and diagonal band of Broca. It has also been suggested that TRH localized in the pineal gland has a part in activating the neuronal mechanisms of arousal. Associated with the arousal effect and especially evident in variously originated shock conditions are the activating effects of TRH on vegetative functions (body temperature, circulation, the gastrointestinal tract). These stimulatory activities on the CNS were the rationale for therapeutic use of TRH in the initial treatment of coma due to brain trauma. Thyrotropin Releasing Hormone has been shown to induce recovery in comatose patients with extrapontine and pontine myelinosis syndromes.']

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Have studies shown that there is no link between DNA methylation patterns and Post Traumatic Stress Disorder?

['Using pre-deployment SKA2 methylation levels and childhood trauma exposure, we found that the previously published suicide prediction rule significantly predicted post-deployment PTSD symptoms (AUC=0.66, 95% CI: 0.53-0.79) with an optimal sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random methylation loci supported these findings. Together, these data establish the importance of SKA2 for cortisol stress responsivity and the development of PTSD and provide further evidence that SKA2 is a promising biomarker for stress-related disorders including PTSD.', ' Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.', 'We investigated serum DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, for post-traumatic stress disorder (PTSD) cases and controls who were US military service members recently deployed to Afghanistan or Iraq.', 'In light of its role in glucocorticoid receptor transactivation, we investigated whether SKA2 DNA methylation influences cortisol stress reactivity and is involved in the development of post-traumatic stress disorder (PTSD).', 'These results suggest that alterations in global methylation pattern are involved in behavioural adaptation to environmental stress and pinpoint Dlgap2 as a possible target in PTSD.', 'Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation', 'We investigated serum DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, for post-traumatic stress disorder (PTSD) cases and controls who were US military service members recently deployed to Afghanistan or Iraq.Cases (n = 75) had a postdeployment diagnosis of PTSD', 'DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members', 'Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation. ', 'DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members.', 'AIM: We investigated serum DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, for post-traumatic stress disorder (PTSD) cases and controls who were US military service members recently deployed to Afghanistan or Iraq. ', 'Together, these results suggest that psychosocial stress may alter global and gene-specific DNA methylation patterns potentially associated with peripheral immune dysregulation.', 'DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2.', 'Subjects with PTSD showed a higher DNA methylation of four CpG sites at the BDNF promoter compared with those without PTSD', 'Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.']

['Studies do show a correlation of PTSD-related accelerated aging in DNA methylation patterns.']

['no']

What is the systemic nickel allergy syndrome?

['patients with "systemic nickel allergy syndrome" (SNAS), characterized by Ni-allergic contact dermatitis and systemic reactions after eating Ni-rich food.', 'Systemic (gastrointestinal and skin) reactions to ingestion of nickel rich foods in patients with nickel allergic contact dermatitis characterize Systemic Nickel Allergy Syndrome (SNAS)', 'Nickel ingested with food can elicit either systemic cutaneous or gastrointestinal symptoms causing a systemic nickel allergy syndrome (SNAS) ', 'Sistemic Nickel Allergy Syndrome (SNAS) consisting of urticaria-like troubles, itch, erythema, cutaneous rush, headache, intestinal symptoms, recurrent vesicular palmar dermatitis.', 'A severe form of this allergy is the Systemic nickel allergy syndrome, clinically characterized by cutaneous manifestions (contact dermatitis, pompholyx, hand dermatitis dyshydrosis, urticaria) with chronic course and systemic symptoms (headache, asthenia, itching, and gastrointestinal disorders related to histopathological alterations of gastrointestinal mucosa, borderline with celiac disease).', 'Some patients with nickel (Ni) allergic contact dermatitis (ACD) suffer from systemic symptoms after ingestion of Ni-rich foods, a condition termed Systemic Nickel Allergy Syndrome (SNAS).', 'Recently a Systemic Nickel Allergy Syndrome (SNAS) has been identified in allergic subjects, with a clinical picture of urticaria, general hitching, headache, gastrointestinal troubles. SNAS may affect allergic occupational or non-occupational ones.', 'Some patients affected by nickel-contact allergy present digestive symptoms in addition to systemic cutaneous manifestations, falling under the condition known as systemic nickel allergy syndrome (SNAS).', 'systemic nickel allergy syndrome (SNAS). The SNAS can have cutaneous signs and symptoms (Systemic Contact Dermatitis or SCD) or extracutaneous signs and symptoms (gastrointestinal, respiratory, neurological, etc.).', 'Some patients with nickel (Ni) allergic contact dermatitis suffer from systemic (intestinal or cutaneous) symptoms after ingestion of Ni-rich foods and experience symptoms reduction with low-Ni diet, a condition termed Systemic Ni Allergy Syndrome (SNAS)', '"systemic nickel allergy syndrome" (SNAS), characterized by urticaria/angioedema and gastrointestinal symptoms correlated to the ingestion of nickel-containing foods. ']

['A severe form of this allergy is the Systemic nickel allergy syndrome, clinically characterized by cutaneous manifestions (contact dermatitis, pompholyx, hand dermatitis dyshydrosis, urticaria) with chronic course and systemic symptoms (headache, asthenia, itching, and gastrointestinal disorders related to histopathological alterations of gastrointestinal mucosa, borderline with celiac disease).']

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Is Doxorubicin cardiotoxic?

['Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. ', 'The results provide direct evidence for the role of catalase in doxorubicin cardiotoxic responses.', 'These results do not support the possibility that mitomycin C potentiates the acute cardiotoxic effects produced by doxorubicin.', 'The anthracycline chemotherapeutic agent doxorubicin is converted by the enzyme carbonyl reductase 1 (CBR1) into its cardiotoxic metabolite doxorubicinol', 'The clinical efficiency of the highly potent antitumor agent doxorubicin is limited by cardiotoxic effects', 'Doxorubicin (DOX), a highly active chemotherapeutic drug, faces limitations in clinical application due to severe cardiotoxic effects (mainly through increased oxidative stress)', 'Clinical uses of doxorubicin (DOX), a highly active anticancer agent, are limited by its severe cardiotoxic side effects associated with increased oxidative stress and apoptosis', 'Doxorubicin (DOX) and trastuzumab (TRZ) are highly effective chemotherapeutic agents in the breast cancer setting, limited by their cardiotoxic side effects', 'Twisting and ironing: doxorubicin cardiotoxicity by mitochondrial DNA damage.', 'Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin.', 'On the other hand, pretreatment of rats with hesperidin protected cardiac tissues against the cardiotoxic effects of doxorubicin as evidenced from amelioration of histopathological changes and normalization of cardiac biochemical parameters.Hesperidin may have a protective effect against DOX-induced cardiotoxicity.', 'However, with cumulative doses, doxorubicin also is known to have cardiotoxic effects, including cardiomyopathy and heart failure.', 'Methods of reducing or preventing doxorubicin-induced cardiotoxicity have been suggested, including an investigational doxorubicin analog, mitoxantrone ( Novantrone ).', 'The most cardiotoxic drug, doxorubicin, is the most potent inducer of superoxide generation, while epirubicin, which is less cardiotoxic, has a relatively limited effect on superoxide production.', 'The mechanism of doxorubicin cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to doxorubicin cardiotoxicity are unknown.', 'As doxorubicin cardiotoxicity is considered irreversible, early detection of cardiotoxicity and prevention of overt heart failure is essential.', 'Although there are monitoring guidelines for cardiotoxicity, optimal timing for early detection of subclinical doxorubicin cardiotoxicity is still obscure.', 'Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression.', 'However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use.', 'Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity.', 'Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application.', 'he clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. ', 'Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo.', 'Doxorubicin is an effective antineoplastic agent, but it frequently causes dose-related cardiotoxic effects. ', 'Among these analogs, idarubicin (4-demethoxy-daunorubicin) was shown to be less cardiotoxic than doxorubicin i', 'Verapamil has also been suggested to potentiate the cardiotoxicity of doxorubicin. ', 'Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. ', 'cardiac effects of diclofenac sodium on doxorubicin-induced cardiomyopathy in rats']

['Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage', 'Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. ']

['yes']

Is there a role for the cylindromatosis tumor suppressor (CYLD) in lung cancer?

['Over-expressing CYLD augments antitumor activity of TRAIL by inhibiting the NF-κB survival signaling in lung cancer cells', 'increased expression of CYLD directly blocks TRAIL-induced NF-κB activation, and consequently increases TRAIL-induced apoptosis in lung cancer cells. CYLD may act as a therapeutic target of lung cancer. Targeting CYLD, in combination with TRAIL, may be a new strategy to treat lung cancer with high NF-κB activity', 'Truncation of the catalytic domain of the cylindromatosis tumor suppressor impairs lung maturation', 'down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer', 'Deletion of exon 9 would cause a carboxyl-terminal truncation of CYLD and inactivation of its deubiquitinating activity. In accordance with previous studies, fibroblasts from Cyld(Delta 9/Delta 9) embryos had hyperactive nuclear factor kappaB and c-Jun kinase pathways compared with control fibroblasts. Cyld(Delta 9/Delta 9) newborn mice were smaller than wild-type littermates with a short and kinky tail and no major developmental defects. However, Cyld(Delta 9/Delta 9) mice died shortly after birth from apparent respiratory dysfunction. Histological examination of E18.5 Cyld(Delta 9/Delta 9) lungs demonstrated an immature phenotype characterized by hyperplasic mesenchyme but apparently normal epithelial, smooth muscle. and endothelial structures. Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer', 'Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer.', 'Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer.', 'Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer']

['To explore a correlation between CYLD expression and responsiveness to TRAIL in lung cancer cell lines, we established lung cancer cell lines that stably express CYLD. Our data provided the first evidence that increased expression of CYLD directly blocks TRAIL-induced NF - B activation, and consequently increases TRAIL-induced apoptosis in lung cancer cells. CYLD may act as a therapeutic target of lung cancer. Targeting CYLD, in combination with TRAIL, may be a new strategy to treat lung cancer with high NF - B activity. Cyld encodes a 956-amino acid deubiquitinating enzyme, which is a negative regulator of nuclear factor kappaB and mitogen-activated protein kinase pathways. Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. To establish an animal model of human CYLD inactivation and characterize the biological role of CYLD in vivo, we generated mice carrying a homozygous deletion of Cyld exon 9 mice ) using a conditional approach. Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer. ', 'To explore a correlation between CYLD expression and responsiveness to TRAIL in lung cancer cell lines, we established lung cancer cell lines that stably express CYLD. Our data provided the first evidence that increased expression of CYLD directly blocks TRAIL-induced NF - B activation, and consequently increases TRAIL-induced apoptosis in lung cancer cells. But studies have demonstrated that many tumor cells were resistant to TRAIL-induced apoptosis. CYLD is recognized as a negative regulator of nuclear factor-kappa B activity. Cyld encodes a 956-amino acid deubiquitinating enzyme, which is a negative regulator of nuclear factor kappaB and mitogen-activated protein kinase pathways. Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. To establish an animal model of human CYLD inactivation and characterize the biological role of CYLD in vivo, we generated mice carrying a homozygous deletion of Cyld exon 9 mice ) using a conditional approach. Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer. ', 'Yes. Down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. Deletion of exon 9 would cause a carboxyl-terminal truncation of CYLD and inactivation of its deubiquitinating activity. Fibroblasts from Cyld(Delta 9/Delta 9) embryos had hyperactive nuclear factor kappaB and c-Jun kinase pathways compared with control fibroblasts. Cyld(Delta 9/Delta 9) newborn mice were smaller than wild-type littermates with a short and kinky tail and no major developmental defects. However, Cyld(Delta 9/Delta 9) mice died shortly after birth from apparent respiratory dysfunction. Histological examination of E18.5 Cyld(Delta 9/Delta 9) lungs demonstrated an immature phenotype characterized by hyperplasic mesenchyme but apparently normal epithelial, smooth muscle and endothelial structures. Thus, it is thought that CYLD has an important role in lung maturation, which may underlie the development of many cases of lung cancer.']

['yes']

Which genes are regulated by TRalpha2 in the heart?

['n FM the reduced mRNA expression of ARB1 (p<0.05, -37%) and ARB2 (p<0.05, -42%) was associated with a reduction of the messenger for TRalpha1 (p<0.05, -85%) and TRalpha2 (p<0.05, -73%).', 'hese data reveal that in human heart failure the reduction of beta-adrenergic receptors is associated with reduced expression of both TRalpha1 and TRalpha2 isoforms of thyroid hormone receptors.', 'Mitigating TRalpha1 effects, both TRalpha2 and TRbeta1 attenuate TRalpha1-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively.', 'Selective ablation of TRalpha2 resulted in an inevitable, concomitant overexpression of TRalpha1.', 'These data reveal that in human heart failure the reduction of beta-adrenergic receptors is associated with reduced expression of both TRalpha1 and TRalpha2 isoforms of thyroid hormone receptors.']

['ARB1, ARB2, TAK1, p38, TRalpha1']

['ARB1', 'ARB2', 'TAK1', 'p38', 'TRalpha1']

Which proteins induce inhibition of LINE-1 and Alu retrotransposition?

['APOBEC3G oligomerization is associated with the inhibition of both Alu and LINE-1 retrotransposition', 'We have previously demonstrated that antiretroviral restriction factors, human APOBEC3 (hA3) proteins (A-H), differentially inhibit L1 retrotransposition', 'In this present study, we found that hA3 members also restrict Alu retrotransposition at differential levels that correlate with those observed previously for L1 inhibition', 'Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1', 'Here, we demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) infectivity and neutralized by the viral Vpx protein, is also a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition', 'We also found that mutant SAMHD1s of Aicardi-Goutières syndrome patients are defective in LINE-1 inhibition', 'SAMHD1 inhibits LINE-1 retrotransposition in dividing cells', 'we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1Δvif, and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition', 'The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1Δvif, and HTLV-1 infection, as well as LINE-1 retrotransposition', 'Expression of cellular A3 proteins is sufficient for inhibition of L1 and Alu retrotransposition, but the effect of A3 proteins transferred in exosomes on retroelement mobilization is unknown.', 'Inhibition of LINE-1 and Alu retrotransposition by exosomes encapsidating APOBEC3G and APOBEC3F.', 'APOBEC3G oligomerization is associated with the inhibition of both Alu and LINE-1 retrotransposition.', 'Previous studies revealed that the overexpression of some A3 proteins could restrict engineered human Long INterspersed Element-1 (LINE-1 or L1) retrotransposition in HeLa cells.', 'APOBEC3 proteins inhibit LINE-1 retrotransposition in the absence of ORF1p binding.', 'We concluded that APOBEC3 proteins interfere indirectly with the LINE-1 retrotransposition pathway, probably through interference with RNA targeting.', 'Expression of cellular A3 proteins is sufficient for inhibition of L1 and Alu retrotransposition, but the effect of A3 proteins transferred in exosomes on retroelement mobilization is unknown', 'Here, we demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) infectivity and neutralized by the viral Vpx protein, is also a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition', 'Human cytidine deaminases, including APOBEC3G (A3G) and A3F, are part of a cellular defense system against retroviruses and retroelements including non-LTR retrotransposons LINE-1 (L1) and Alu', 'SAMHD1 inhibits LINE-1 retrotransposition in dividing cells', 'Expression of cellular A3 proteins is sufficient for inhibition of L1 and Alu retrotransposition, but the effect of A3 proteins transferred in exosomes on retroelement mobilization is unknown', 'Selective inhibition of Alu retrotransposition by APOBEC3G.', 'Our data further indicate that APOBEC3G recognizes 7SL RNA and Alu RNA by its common structure, the Alu domain, suggesting a mechanism for APOBEC3G- mediated inhibition of Alu retrotransposition', 'Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.']

['It was demonstrated that antiretroviral restriction factors, human APOBEC3 proteins A to H, differentially inhibit LINE-1 and Alu retrotransposition. The same effect was shown to be induced by the Aicardi-Goutières syndrome gene product SAMHD1.']

['human APOBEC3 proteins A to H', 'Aicardi-Goutières syndrome gene product SAMHD1']

Is Kanzaki disease associated with deficiency in alpha-N-acetylgalactosaminidase?

['Kanzaki disease (OMIM#104170) is attributable to a deficiency in alpha-N-acetylgalactosaminidase (alpha-NAGA; E.C.3.2.1.49), which hydrolyzes GalNAcalpha1-O-Ser/Thr. ', ' Our findings suggest that the association of alpha-NAGA with its substrates is strongly affected by the amino acid substitution at R329 and that the association with GalNAcalpha1-O-Thr is more highly susceptible to structural changes. The residual mutant enzyme in R329W could not associate with GalNAcalpha1-O-Thr and GalNAcalpha1-O-Ser. However, the residual mutant enzyme in R329Q catalyzed GalNAcalpha1-O-Ser to some extent. Therefore, the urinary ratio of GalNAcalpha1-O-Ser:GalNAcalpha1-O-Thr was lower and the clinical phenotype was milder in the R329Q mutation. ', 'Kanzaki disease (OMIM#104170) is attributable to a deficiency in alpha-N-acetylgalactosaminidase (alpha-NAGA; E.C.3.2.1.49), which hydrolyzes GalNAcalpha1-O-Ser/Thr.', 'Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (Schindler/Kanzaki disease) is a clinically and pathologically heterogeneous genetic disease with a wide spectrum including an early onset neuroaxonal dystrophy (Schindler disease) and late onset angiokeratoma corporis diffusum (Kanzaki disease).', 'Structural and immunocytochemical studies on alpha-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease).', 'We describe the neurologic findings in a patient with alpha-N-acetylgalactosaminidase deficiency (Kanzaki disease).', 'Three dimensional structural studies of alpha-N-acetylgalactosaminidase (alpha-NAGA) in alpha-NAGA deficiency (Kanzaki disease): different gene mutations cause peculiar structural changes in alpha-NAGAs resulting in different substrate specificities and clinical phenotypes.', 'alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described.', 'Schindler disease and Kanzaki disease are caused by a deficient lysosomal enzyme, alpha-N-acetylgalactosaminidase (E.C.3.2.1.49).', 'The 1.9 a structure of human alpha-N-acetylgalactosaminidase: The molecular basis of Schindler and Kanzaki diseases.', 'These data suggest that a prototype of alpha-NAGA deficiency in Kanzaki disease and factors other than the defect of alpha-NAGA may contribute to severe neurological disorders, and Kanzaki disease is thought to be caused by a single enzyme deficiency.', 'Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (Schindler/Kanzaki disease) is a clinically and pathologically heterogeneous genetic disease with a wide spectrum including an early onset neuroaxonal dystrophy (Schindler disease) and late onset angiokeratoma corporis diffusum (Kanzaki disease). ', 'alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described. ', 'Kanzaki disease (OMIM#104170) is attributable to a deficiency in alpha-N-acetylgalactosaminidase (alpha-NAGA; E.C.3.2.1.49), which hydrolyzes GalNAcalpha1-O-Ser/Thr. Missense mutations, R329W or R329Q were identified in two Japanese Kanzaki patients.', 'Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (Schindler/Kanzaki disease) is a clinically and pathologically heterogeneous genetic disease with a wide spectrum including an early onset neuroaxonal dystrophy (Schindler disease) and late onset angiokeratoma corporis diffusum (Kanzaki disease).', 'Kanzaki disease (OMIM#104170) is attributable to a deficiency in alpha-N-acetylgalactosaminidase (alpha-NAGA; E.C.3.2.1.49),', 'Kanzaki disease (OMIM#104170) is attributable to a deficiency in alpha-N-acetylgalactosaminidase (alpha-NAGA; E.C.3.2.1.49), which hydrolyzes GalNAcalpha1-O-Ser/Thr.', 'alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described.']

['Yes, Kanzaki disease is attributable to a deficiency in alpha-N-acetylgalactosaminidase, which hydrolyzes GalNAcalpha1-O-Ser/Thr.']

['yes']

What are the main results of PRKAR1A Knockdown?

['These results show that RIα inactivation leads to multiple, compartment-specific alterations of the cAMP/PKA pathway revealing new aspects of signaling dysregulation in tumorigenesis.', 'Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been proven to inhibit cholangiocarcinoma (CCA) cell growth and enhance apoptosis.', 'Silencing PRKAR1A expression induced growth inhibition and apoptosis of CCA cells, with an associated decrease in mitogen-activated protein kinases, PI3K/Akt, JAK/STAT and Wnt/β-catenin pathway signaling.', 'The inhibition of PKA using a PKA inhibitor and cAMP analogs also led to a significant cell growth inhibition.', 'abrogation of gene expression caused significant CCA cell growth inhibition, oncogenic signaling and coupled apoptosis induction', 'Knockdown of the cAMP-dependent protein kinase (PKA) Type Ialpha regulatory subunit in mouse oocytes disrupts meiotic arrest and results in meiotic spindle defects.', 'These results demonstrate that RIalpha is required for regulating PKA activity in maturing oocytes and that compensatory upregulation of RII does not occur.']

['Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been proven to inhibit cholangiocarcinoma (CCA) cell growth and enhance apoptosis. Also, Knockdown of the cAMP-dependent protein kinase (PKA) Type Ialpha regulatory subunit in mouse oocytes disrupts meiotic arrest and results in meiotic spindle defects.']

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Are selenium supplements recommended for prostate cancer prevention?

['Our meta-analysis in prospective studies demonstrated a significant inverse association between selenium status and CVD risk within a narrow selenium range and a null effect of selenium supplementation on CVD was observed in RCTs. These findings indicate the importance of considering selenium status, dose and safety in health assessment and future study design.', 'Selenium supplementation of 140 or more μg/day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. Caution is warranted regarding usage of such supplements among men with prostate cancer.', 'The SELECT study failed to show any significant risk reduction for prostate cancers ascribable to selenium and vitamin E supplementations.', 'Vitamins and supplements, including selenium or vitamin E, have not been proven in clinical trials to prevent prostate cancer and in the case of Vitamin E has been found to increase the risk of incident prostate cancer. Ongoing and future trials may further elucidate the role of diet and immunotherapy for prevention of prostate cancer.']

['No. The SELECT study failed to show any significant risk reduction for prostate cancers ascribable to selenium and vitamin E supplementations.']

['no']

Which proteins act as factors that promote transcription-coupled repair in bacteria?

['Transcription-coupled repair (TCR) is a cellular process by which some forms of DNA damage are repaired more rapidly from transcribed strands of active genes than from nontranscribed strands or the overall genome. In humans, the TCR coupling factor, CSB, plays a critical role in restoring transcription following both UV-induced and oxidative DNA damage. It also contributes indirectly to the global repair of some forms of oxidative DNA damage. The Escherichia coli homolog, Mfd, is similarly required for TCR of UV-induced lesions.', 'Transcription coupled nucleotide excision repair (TC-NER) is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd) is a transcription repair coupling factor, involved in repair of template strand during transcription.', 'the transcription-repair coupling factor, Mfd, promotes direct restart of the fork following the collision by facilitating displacement of the RNAP.', 'We report observations suggesting that the transcription elongation factor NusA promotes a previously unrecognized class of transcription-coupled repair (TCR) in addition to its previously proposed role in recruiting translesion synthesis (TLS) DNA polymerases to gaps encountered during transcription.', 'NusA participates in an alternative class of TCR involved in the identification and removal of a class of lesion, such as the N(2)-f-dG lesion', 'Bacterial transcription-coupled repair is initiated when RNA polymerase stalled at a DNA lesion is removed by Mfd, an ATP-dependent DNA translocase.', 'Transcription-coupled repair, the targeted repair of the transcribed strands of active genes, is defective in bacteria, yeast, and human cells carrying mutations in mfd, RAD26 and ERCC6, respectively.', 'The effect of the bacterial transcription-repair coupling factor, Mfd, at such lesions is not known: it has been suggested that Mfd may promote mutagenesis by increasing the efficiency with which RNA polymerase bypasses non-bulky lesions, but it has also been reported that 8-oxoguanine, a major product of oxidative DNA damage that is efficiently bypassed by RNA polymerase, is subject to Mfd-dependent transcription-coupled repair in Escherichia coli.', 'The transcription-repair coupling factor (TRCF, the product of the mfd gene) is a widely conserved bacterial protein that mediates transcription-coupled DNA repair.', 'Recent structural studies of the bacterial transcription-repair coupling factor, Mfd, have revealed a modular architecture in which an ATP-dependent DNA-based motor is coupled to protein-protein interaction domains that can attach the motor to RNA polymerase and the DNA repair protein UvrA.', 'The bacterial Mfd protein is a transcription-repair coupling factor that performs two key functions during transcription-coupled DNA repair.', 'Mfd remains bound to the DNA in a long-lived complex that could act as a marker for sites of DNA damage, directing assembly of subsequent DNA repair factors.', 'Transcription and DNA repair are coupled in E. coli by the Mfd protein, which dissociates transcription elongation complexes blocked at nonpairing lesions and mediates recruitment of DNA repair proteins.', 'The first is to remove RNA polymerase (RNAP) complexes that have been stalled by a DNA lesion from the site of damage, and the second is to mediate the recruitment of DNA repair proteins.', 'Coupling of transcription and DNA repair in bacteria is mediated by transcription-repair coupling factor (TRCF, the product of the mfd gene), which removes transcription elongation complexes stalled at DNA lesions and recruits the nucleotide excision repair machinery to the site.', 'Mfd remains bound to the DNA in a long-lived complex that could act as a marker for sites of DNA damage, directing assembly of subsequent DNA repair factors', 'Mfd may act through a translocase activity that rewinds upstream DNA, leading either to translocation or to release of RNA polymerase when the enzyme active site cannot continue elongation.', 'Recent structural studies of the bacterial transcription-repair coupling factor, Mfd, have revealed a modular architecture in which an ATP-dependent DNA-based motor is coupled to protein-protein interaction domains that can attach the motor to RNA polymerase and the DNA repair protein UvrA', 'E. coli Transcription repair coupling factor (Mfd protein) rescues arrested complexes by promoting forward translocation.', 'We also find that the transcription-repair coupling factor, Mfd, promotes direct restart of the fork following the collision by facilitating displacement of the RNAP', 'We also found that the transcription-repair coupling factor Mfd promotes direct restart of the fork after the collision by facilitating displacement of the RNAP', 'We show that Mfd-dependent TCR in bacteria involves the formation of a damage search complex that can detect lesions downstream of a stalled RNAP, and that the strand specificity of the accelerated repair pathway is independent of the requirement for a lesion to stall RNAP', 'coli by the Mfd protein, which dissociates transcription elongation complexes blocked at nonpairing lesions and mediates recruitment of DNA repair proteins']

['Transcription coupled nucleotide excision repair (TC-NER or TCR) is a cellular process by which UV-induced damage and other road-blocks encountered in the transcribed strand are restored. Bacterial transcription-coupled repair is initiated when RNA polymerase stalled at a DNA lesion is removed by Mfd (Mutation frequency decline), an ATP-dependent DNA translocase. Mfd is the major transcription repair coupling factor in bacteria. Also, the transcription elongation factor NusA, in addition to its role in recruiting translesion synthesis (TLS) DNA polymerases to gaps encountered during transcription, promotes an alternative class of TCR involved in the identification and removal of a class of lesion, such as the N(2)-f-dG lesion.']

['Mfd', 'NusA']

What is the function of the spliceosome complex?

['The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. ', 'Splicing and alternate splicing are the two key biological processes that result in the generation of diverse transcript and protein isoforms in Plasmodium falciparum as well as in other eukaryotic organisms. ', ' Spliceosome assembly belongs to the key processes that enable splicing of mRNA and modulate alternative splicing.', 'The excision of introns from nascent eukaryotic transcripts is catalyzed by the spliceosome, a highly complex and dynamic macromolecular machine composed of RNA and protein. ', 'Recent advances have begun to provide exciting new insights into the dynamic interactions that govern the function of the spliceosome, the multi-megadalton complex that performs splicing.']

['The excision of introns from nascent eukaryotic transcripts is catalyzed by the spliceosome, a highly complex and dynamic macromolecular machine composed of RNA and protein.']

['The excision of introns from nascent eukaryotic transcripts is catalyzed by the spliceosome.']

What is the clinical indication of cardiac T1 mapping magnetic resonance?

['More diverse patterns of late enhancement including patchy, mid-wall, subepicardial, or diffuse enhancement are of interest in diagnosing nonischemic cardiomyopathies.', 'Methods for quantification of T1 and extracellular volume fraction are emerging to tackle the issue of discriminating globally diffuse fibrosis from normal healthy tissue which is challenging using conventional late enhancement methods. ', 'Recent T1 mapping techniques aim to overcome the limitations of late gadolinium enhancement to assess diffuse fibrosis.', 'T1 mapping techniques performed both with and without contrast are enabling quantification of diffuse myocardial fibrosis and myocardial infiltration.', 'Noncontrast T1 mapping has high diagnostic accuracy for detecting cardiac AL amyloidosis, correlates well with markers of systolic and diastolic dysfunction, and is potentially more sensitive for detecting early disease than LGE imaging.', 'T1 mapping has been proposed as potentially valuable in the quantitative assessment of diffuse myocardial fibrosis, but no studies to date have systematically evaluated its role in the differentiation of healthy myocardium from diffuse disease in a clinical setting. ', 'This study demonstrates that native and post-contrast T1 values provide indexes with high diagnostic accuracy for the discrimination of normal and diffusely diseased myocardium.', 'T1 values lengthened with greater LVMI and correlated with the degree of biopsy-quantified fibrosis. This may provide a useful clinical assessment of diffuse myocardial fibrosis in the future.', 'Cardiac magnetic resonance (CMR) T1 mapping has been used to characterize myocardial diffuse fibrosis. ', 'In HCM and DCM, noncontrast T1 mapping detects underlying disease processes beyond those assessed by LGE in relatively low-risk individuals.']

['T1 mapping can quantitatively characterize myocardial tissue, in particular diffuse and interstitial fibrosis, edema in both overt and subclinical cardiophyopathies. However more research is required before a large-scale application for clinical decision-making can be recommended.', 'The clinical indication of cardiac T1 mapping magnetic resonance is the detection of diffuse myocardial fibrosis in nonischemic cardiomyopathies']

['detection of myocardial fibrosis in nonischemic cardiomyopathies', 'T1 mapping can quantitatively characterize myocardial tissue, i.e. fibrosis and edema.']

What is the mechanism by which HIV-1-encoded Vif protein allows virus replication?

['A naturally occurring Vif mutant (I107T) attenuates anti-APOBEC3G activity and HIV-1 replication', 'The human immunodeficiency virus type 1 (HIV-1) Vif protein counteracts the antiviral activity of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of proteins by targeting the proteins for degradation through the ubiquitin-proteasome pathway', "The host protein APOBEC3G (A3G) can limit HIV-1 replication. Its protective effect is overcome by the HIV-1 'viral infectivity factor' (Vif), which targets A3G for proteosomal degradation", ' Vif is thought to primarily overcome APOBEC3G through an interaction that mediates APOBEC3G ubiquitination and results in its proteasomal degradation', 'However, Vif may also inhibit APOBEC3G mRNA translation, virion encapsidation, and deamination activity', 'Vif counteracts the packaging of two cellular cytidine deaminases named APOBEC3G (A3G) and A3F by diverse mechanisms including the recruitment of an E3 ubiquitin ligase complex and the proteasomal degradation of A3G/A3F, the inhibition of A3G mRNA translation or by a direct competition mechanism', 'In addition, Vif appears to be an active partner of the late steps of viral replication by participating in virus assembly and Gag processing, thus regulating the final stage of virion formation notably genomic RNA dimerization and by inhibiting the initiation of reverse transcription', 'Human apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) 3G (A3G) is an antiviral protein that blocks HIV-1 replication. However, the antiviral activity of A3G is overcome by the HIV-1 protein Vif. This inhibitory function of Vif is related to its ability to degrade A3G in the proteasome', 'Polyubiquitination of APOBEC3G is essential for its degradation by HIV-1 Vif', 'These data suggest that polyubiquitination of APOBEC3G, not that of HIV-1 Vif, is crucial for APOBEC3G degradation', 'During coevolution with the host, HIV-1 developed the ability to hijack the cellular ubiquitin/proteasome degradation pathway to counteract the antiviral activity of APOBEC3G (A3G), a host cytidine deaminase that can block HIV-1 replication. Abrogation of A3G function involves the HIV-1 Vif protein, which binds A3G and serves as an adapter molecule to recruit A3G to a Cullin5-based E3 ubiquitin ligase complex', 'HIV-1 counteracts APOBEC3 proteins by encoding the viral protein Vif, which contains distinct domains that specifically interact with these APOBEC3 proteins to ensure their proteasomal degradation, allowing virus replication to proceed']

['The HIV-1 Vif protein counteracts the antiviral activity of the APOBEC3 family by targeting the proteins for degradation through the ubiquitin-proteasome pathway. More specifically, Vif, serving as a substrate receptor, facilitates ubiquitination of APOBEC3 proteins by forming a Cullin5-based E3 ubiquitin ligase complex, which targets APOBEC3 proteins for rapid proteasomal degradation.']

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What is the genetic basis of the disease attributed to mutations in the TSC1 and TSC2 genes?

['["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."]']

The genetic basis of the disease is attributed to mutations in the TSC1 and TSC2 genes.

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Where in the cell does the proteins S100A4 and p53 interact ?

['S100A4 interacts with p53 in the nucleus', 'we show that endogenous S100A4 and p53 interact in complex samples', 'using proximity ligation assay, we show that the interaction takes place in the cell nucleus.', 'Coexpression and nuclear colocalization of metastasis-promoting protein S100A4 and p53 without mutual regulation in colorectal carcinoma.']

['S100A4 interacts with p53 in the cell nucleus.']

['nucleus']

Can life style changes reduce oxidative stress

['The CFS group had an unfavorable lipid profile and signs of oxidative stress induced damage to lipids and proteins. These results might be indicative of early proatherogenic processes in this group of patients who are otherwise at low risk for atherosclerosis. Antioxidant treatment and life style changes are indicated for women with CFS, as well as closer observation in order to assess the degree of atherosclerosis.', 'Once detected, these patients may be offered more aggressive treatment strategies such as early pharmacotherapy in addition to life style changes targeted to maintaining pericyte integrity.', 'Our results suggested that life style changes which related to migration might reduce DNA damage in Hasake nationalities.', 'Low levels of antioxidants and increased oxidative stress with insulin resistance in metabolic syndrome suggests that besides therapeutic life style changes (TLC) as suggested in ATP III guidelines inclusion of antioxidant vitamins, fruits and vegetable could be beneficial to ward off the consequences of metabolic syndrome.']

['Our results suggested that life style changes which related to migration might reduce DNA damage in Hasake nationalities.']

['yes']

Can adult humans be induced to produce fetal hemoglobin?

[' At the time of birth, HbF accounts for approximately 70% of the total Hb. ', ' whereas in the trace amounts of HbF that is found in the adult it reverses to 40:60 because of a gamma- to beta-globin gene switch', 'With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients.', 'The data suggest that TGF-beta reactivates gamma-globin expression, combined with a sequential stimulation and suppression of erythropoiesis. ']

["Fetal hemoglobin, or foetal haemoglobin, is the main oxygen transport protein in the human fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months old. Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother's bloodstream.\nUnusually high levels of fetal haemoglobin production can ameliorate sickle cell disease and β thalassaemia. Although efforts directed at the pharmacological stimulation of fetal haemoglobin as an approach to managing these conditions have met with limited success, there is wide variation in individual responses. \nBased on results, adults humans could be induced to produce fetal hemoglobin."]

['yes']

Is the length of the poly(A) tail involved in human disease?

['In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails.']

['Yes. Severely truncated poly(A) tails of mitochondrial mRNAs were found to be involved in an autosomal recessive spastic ataxia with optic atrophy.']

['yes']

Can cffDNA be used for non-invasive testing?

['Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation', 'The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible.', 'In recent years, technical advances in the molecular analysis of fetal DNA (e.g., digital PCR and massively parallel sequencing (MPS)) has enabled the successful implementation of noninvasive testing into clinical practice, such as fetal sex assessment, RhD genotyping, and fetal chromosomal aneuploidy detection.With the ability to decipher the entire fetal genome from maternal plasma DNA, we foresee that an increased number of non-invasive prenatal tests will be available for detecting many single-gene disorders in the near future. This review briefly summarizes the technical aspects of the NIPT and application of NIPT in clinical practice.', 'First identified in 1997, cell-free fetal DNA (cffDNA) has just recently been used to detect fetal aneuploidy of chromosomes 13, 18, and 21, showing its potential to revolutionize prenatal genetic testing as a non-invasive screening tool', 'To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake', 'Non-invasive prenatal testing of cell-free fetal DNA (cffDNA) in maternal plasma can predict the fetal RhD type in D negative pregnant women', 'The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible', 'The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing', 'The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field', 'Non-invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation', 'Analysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders', 'Non-invasive prenatal diagnosis (NIPD) using cell-free fetal DNA (cffDNA) in maternal plasma is an alternative to invasive prenatal diagnosis (IPD), which carries a 1% risk of miscarriage. ', 'The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. ', 'The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing. ', 'NIFTY (Non-invasive Fetal Trisomy Test) is a non-invasive prenatal test which is used for diagnosing fetal trisomy. The test is based on the analysis of cell free fetal DNA (cffDNA) present in the plasma and serum of a pregnant woman.', 'Using non-invasive method of cffDNAs in the shortest time possible, as well as avoiding invasive tests for early determination of fetal gender, provides the opportunity of deciding and employing early treatment for fetuses at risk of genetic diseases.', 'The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible.', 'To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake.', 'Nowadays, new advances in the use of cell free fetal DNA (cffDNA) in maternal plasma of pregnant women has provided the possibility of applying cffDNA in prenatal diagnosis as a non-invasive method.', 'Non-invasive prenatal testing of cell-free fetal DNA (cffDNA) in maternal plasma can predict the fetal RhD type in D negative pregnant women.', 'Prevention of contamination following our anti-contamination criteria is a good practice for certain non-invasive sex determination, using cffDNA.']

['Yes, cell-free fetal DNA (cffDNA) has made non-invasive prenatal testing possible.']

['yes']

Which proteins are the different members of the NF-kappaB family of transcription factors?

['The transcription factor NF-kappaB is composed of homodimeric and heterodimeric complexes of Rel/NF-kappaB-family polypeptides, which include Rel-A, c-Rel, Rel-B, NF-kappaB/p50 and NF-kappaB2/p52 .', 'Nuclear factor kappa B (NFκB) is a dimeric transcription factor comprised of five family members RelA (p65), RelB, c-Rel, p50 and p52.', 'In mammals, the genes rela, relb, crel, nfkappaΒ1, and nfkappaB encode the five NF-kB protein family members RelA (p65), RelB, c-Rel, p50, and p52, respectively, which form homo- and heterodimeric DNA-binding complexes capable of regulating target gene transcription of specific biological responses differentially.', 'These results suggest that the Rel-homology domain can act as an allosteric effector to promote transcription by p50/NFkappaB1 and that the configuration of p50 is important for its activity.']

['Nuclear factor kappa B (NFκB) is a dimeric transcription factor comprised of five family members RelA (p65), RelB, c-Rel, NF-kB1/p50 and NF-kB2/p52.']

['RelA', 'p65', 'RelB', 'c-Rel', 'NF-kB1/p50', 'NF-kB2/p52']

How many Viliuisk encephalomyelitis patients were found in Yakut Republic, Russia from 1940-1999?

['["BACKGROUND: Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.", "Communicating hydrocephalus following eosinophilic meningitis is pathogenic for chronic Viliuisk encephalomyelitis in Northeastern Siberia.", "Epidemiology of Viliuisk encephalomyelitis in Eastern Siberia.", ". An epidemic of this disease has been spreading throughout the Yakut Republic of the Russian Federation.", "METHODS: Detailed clinical, pathologic, laboratory, and epidemiologic studies have identified 414 patients with definite Viliuisk encephalomyelitis in 15 of 33 administrative regions of the Yakut Republic between 1940 and 1999.", "Viliuisk encephalomyelitis in Eastern Siberia - analysis of 390 cases.", "Viliuisk encephalomyelitis (VE) is a unique disease occurring in the Yakut (Sakha) population of Eastern Siberia. ", "Viliuisk encephalomyelitis in Northeastern Siberia is not caused by Borrelia burgdorferi infection.", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin. ", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin.", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.", "Viliuisk encephalomyelitis in the Iakut people of Siberia.", "Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.", "Viliuisk encephalomyelitis (VE) is an unique neurological disease occurring in the Iakut (Sakha) people of Siberia.", "Viliuisk encephalomyelitis (VEM) appears to be endemic disease, affecting native population in Yakutia (Yakut, Even, Evenk).", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006", "Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease", "Viliuisk encephalomyelitis (VE) is a unique disease occurring in the Yakut (Sakha) population of Eastern Siberia", "Viliuisk encephalomyelitis in Northeastern Siberia is not caused by Borrelia burgdorferi infection", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin", "Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.", "Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic.In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006.", "IgG antibodies to HTLV-I were measured in the sera and/or cerebrospinal fluid from 82 Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia, 164 Guamanian normal controls, 10 patients with kuru from']

414 patients

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Is apremilast effective for psoriatic arthritis?

['Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3).', 'OBJECTIVE: To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents.', 'CONCLUSIONS: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52\u2005weeks. ', 'Apremilast: A Novel Drug for Treatment of Psoriasis and Psoriatic Arthritis.', 'OBJECTIVE: To review the pharmacology, efficacy, and safety of apremilast and determine its role relative to other agents in the treatment of psoriasis and psoriatic arthritis.', 'CONCLUSIONS: Apremilast has a novel mechanism of action and is safe and effective for the management of psoriasis and psoriatic arthritis. ', ' In particular, apremilast has been recently approved for the treatment of psoriasis and psoriatic arthritis.', 'Apremilast, an oral phosphodiesterase 4 inhibitor, has an acceptable safety profile and is effective for treatment of plaque psoriasis and psoriatic arthritis.', 'As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of apremilast was invited to submit evidence for its clinical and cost effectiveness for the treatment of active psoriatic arthritis (PsA) for whom disease-modifying anti-rheumatic drugs (DMARDs) have been inadequately effective, not tolerated or contraindicated.', 'Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.', 'In patients with psoriatic arthritis, there are no clinical trials comparing apremilast with TNF alpha antagonists, and no interpretable trials of apremilast after failure of a TNF alpha antagonist.', 'Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID', 'No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function', 'Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis.Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P&lt;0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus', 'The purpose of this study is to give an overview of the new treatments approved by the U.S. Food and Drug Administration (FDA) for use in psoriatic arthritis (PsA).FDA has approved three new drugs for PsA: Certolizumab-pegol: a PEGylated Fc-free tumour necrosis factor inhibitor (TNFi); ustekinumab: an anti interleukin (IL)-12 and IL-23 mAb; and apremilast and oral phosphodiesterase 4 inhibitor.', 'In all trials, the drug had an acceptable safety profile, with the most common adverse effects of diarrhea, nausea, and headache.Apremilast has a novel mechanism of action and is safe and effective for the management of psoriasis and psoriatic arthritis.', 'Apremilast is a well-tolerated and effective phosphodiesterase type 4 inhibitor that is indicated for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis.', 'Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID.', 'Newer drugs in the treatment armamentarium that have shown efficacy for both psoriasis and psoriatic arthritis consist of the anti-IL-17 agent, secukinumab, and a phosphodiesterase-4 inhibitor, apremilast.', 'To review the pharmacology, efficacy, and safety of apremilast and determine its role relative to other agents in the treatment of psoriasis and psoriatic arthritis.A PubMed search (1946 to December 2015) using the terms apremilast and CC-10004 was conducted to identify relevant articles.In vitro or in vivo evaluations of apremilast published in the English language were eligible for inclusion.', 'In patients with psoriatic arthritis, there are no clinical trials comparing apremilast with TNF alpha antagonists, and no interpretable trials of apremilast after failure of a TNF alpha antagonist.', 'No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function.', 'Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis.Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P<0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus.', 'Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function.', 'Apremilast has a novel mechanism of action and is safe and effective for the management of psoriasis and psoriatic arthritis.', 'Apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated effectiveness (versus placebo) for treatment of active psoriatic arthritis in the psoriatic arthritis long-term assessment of clinical efficacy (PALACE) phase III clinical trial program.', 'Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.', 'Apremilast: A Review in Psoriasis and Psoriatic Arthritis.', 'Drug safety evaluation of apremilast for treating psoriatic arthritis.', 'Apremilast for the treatment of psoriatic arthritis.', 'Apremilast mechanism of action and application to psoriasis and psoriatic arthritis.', 'Apremilast: A Phosphodiesterase 4 Inhibitor for the Treatment of Psoriatic Arthritis.']

['Yes, apremilast, an oral phosphodiesterase 4 inhibitor, is effective for psoriatic arthritis.']

['yes']

Is CHEK2 involved in cell cycle control?

['Moreover, cell-cycle progression genes [i.e. E2F transcription factor (E2F) family and histone deacetylase ( HDAC )] and DNA-repair genes [i.e. growth arrest and DNA-damage-inducible, gamma ( GADD45G ) family and serine/threonine-protein kinase Chk2 ( CHEK2)] were also increased.', 'As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma.', 'In the current study, we evaluated the possible associations of seven common variants of the DNA repair and cell cycle control genes BRCA2 and CHEK2 with malignant melanoma (MM).', 'Promotor methylation analysis of key regulatory genes involved in cell cycle control (p14, p15, p16, CHK2), DNA repair (hMLH1), apoptosis (p73, survivin, DAPK), and differentiation (RARb, WT1) was performed by methylation-specific polymerase chain reaction.', 'CHEK2 is a key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage.', 'High-fidelity maintenance of genomic integrity in eukaryotes is ensured by cell cycle checkpoints and DNA repair. The checkpoint kinase, Chk2, has been implicated in both of these responses. In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. The fully activated Chk2 then phosphorylates downstream substrates of cell cycle control.', 'Checkpoint kinase 2 (hCHK2/hCds1) is a tumor suppressor gene involved in cell-cycle control.']

['CHEK2 is a key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage.']

['yes']

What is the prognostic role of thyroid hormone in patients with heart failure?

[' Cumulative survival was significantly lower among patients with free triiodothyronine < 2.12 pg/mL and among patients with brain natriuretic peptide > 686 pg/mL. In multivariate analysis, the significant independent predictors of major cardiac events were age, free triiodothyronine, and brain natriuretic peptide', 'The T3 was more meaningful than the BNP in the prognosis of CHF. The BNP and T3 combination detection was more valuable in determining the severity of CHF and prognosis.', 'fT3 and BNP hold an independent and additive prognostic value in HF.', 'Univariate regression analysis showed that TSH (p<0.0001), fT3 (p<0.0001), fT4 (p=0.016) and fT3/fT4 (p<0.0001) were associated with heart failure progression but multivariate analysis showed that only TSH considered as a continuous variable (p = 0.001) as well as subclinical hypothyroidism (TSH > 5.5 mUI/l; p=0.014) remained significantly associated with the events.', 'Low T(3) levels are an independent predictor of mortality in patients with chronic heart failure, adding prognostic information to conventional clinical and functional cardiac parameters.', 'Sixteen patients (14%) died during the follow-up period; their fT3/fT4 ratio was significantly lower than the patients who survived (1.31+/-0.37 vs. 2.01+/-0.72, p<0.001).', 'The authors conclude that among elderly patients with heart failure, lower triiodothyronine concentrations are more prevalent and are associated with a worse prognosis.', 'A low free T3 index/reverse T3 ratio is associated with poor ventricular function and nutritional status and is the strongest predictor yet identified for short-term outcome in patients with advanced heart failure.']

['Altered thyroid profile, particularly sick euthyroid syndrome, is an independent predictor of mortality in patients with chronic heart failure, adding prognostic information to conventional clinical and functional cardiac parameters.']

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What are 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin'?

['The present metaanalysis was designed to assess the effect of DPP-4 inhibitors on blood lipids, verifying possible differences across compounds of this class.METHODS: An extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words "sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and/or "dutogliptin." ', 'Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237).', 'Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2).', 'Testing the therapeutic equivalence of alogliptin, linagliptin, saxagliptin, sitagliptin or vildagliptin as monotherapy or in combination with metformin in patients with type 2 diabetes.', 'The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities.', 'The reader will gain detailed pharmacological and clinical information on alogliptin, dutogliptin and linagliptin and will learn how these DPP IV inhibitors may widen the whole drug class.', 'When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.', 'Currently, there are four DPP IV inhibitors available in various countries-alogliptin, sitagliptin, vildagliptin and saxagliptin (1).', 'The various marketed or under developmental status, potential gliptins have been opted to build a pharmacophore model, e.g. Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237)', 'Currently, there are four DPP IV inhibitors available in various countries-alogliptin, sitagliptin, vildagliptin and saxagliptin (1)', 'Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2)', 'Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus--Thrombolysis in Myocardial Infarction-53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo', 'Of these, two have been approved for clinical use in the United States: sitagliptin and saxagliptin', 'Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes', 'To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes', "METHODS: DATA SOURCES: an extensive Medline, Embase and Cochrane Database search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin' and 'dutogliptin' was performed up to 1 March 2013. ", "RESEARCH DESIGN AND METHODS: An extensive Medline and Embase search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin' was performed, collecting all randomized clinical trials on humans up to March 1, 2011. ", "METHODS: We conducted a search on MEDLINE, Embase and Cochrane Collaborative database for randomized controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words 'alogliptin', 'dutogliptin', 'linagliptin', 'saxagliptin', 'sitagliptin', 'vildagliptin' and 'metformin'. ", 'Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237). ', 'Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4.DATA SOURCES: An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. ', 'Quantitative model of the relationship between dipeptidyl peptidase-4 (DPP-4) inhibition and response: meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results.', 'The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. ', 'The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). ', 'Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin.', 'The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses.', 'In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.', 'Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. ', 'AIM: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. ', 'Whether the DPP-IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. ', 'OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibitors, including sitagliptin, saxagliptin, vildagliptin, and linagliptin, in type 2 diabetes. ', 'Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another.', 'Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.', "an extensive Medline, Embase and Cochrane Database search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin' and 'dutogliptin' was performed up to 1 March 2013.", "An extensive Medline and Embase search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin' was performed, collecting all randomized clinical trials on humans up to March 1, 2011.", 'An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013.', 'Saxagliptin.', 'Vildagliptin.', "an extensive Medline, Embase and Cochrane Database search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin' and 'dutogliptin' was performed up to 1 March 2013.", "An extensive Medline and Embase search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin' was performed, collecting all randomized clinical trials on humans up to March 1, 2011.", 'An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013.', 'the words "sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and/or "dutogliptin." Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website,', 'Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237).', 'Of these, two have been approved for clinical use in the United States: sitagliptin and saxagliptin. Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2).', "We conducted a search on MEDLINE, Embase and Cochrane Collaborative database for randomized controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words 'alogliptin', 'dutogliptin', 'linagliptin', 'saxagliptin', 'sitagliptin', 'vildagliptin' and 'metformin'.", 'Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another. Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.', 'Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2). Alogliptin was approved for use in Japan under the trade name Nesina® in April 2010 (3).', 'Any DPP-4 inhibitor (vildagliptin, sitagliptin, saxagliptin, linagliptin or alogliptin).', 'An extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words "sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and/or "dutogliptin." Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website, using the same keywords as above.', 'A systematic review and meta-analysis of randomised controlled trials (RCTs) of DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin and alogliptin) on HbA1c were conducted.', 'Several clinical trials have studied the addition of GLP-1 receptor agonists [exenatide BID (twice daily), lixisenatide, albiglutide] or DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, alogliptin, linagliptin) to ongoing insulin therapy or adding insulin to ongoing therapy with a GLP-1 receptor agonist (liraglutide).', 'Testing the therapeutic equivalence of alogliptin, linagliptin, saxagliptin, sitagliptin or vildagliptin as monotherapy or in combination with metformin in patients with type 2 diabetes.', 'Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2).', 'This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin.']

['"Sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and "dutogliptin" are dipeptidyl peptidase-4 (DPP-4) inhibitors.']

['dipeptidyl peptidase-4 (DPP-4) inhibitors']

Which protein pathway is regulating SGK1-mediated phosphorylation of FOXO3a to control cell proliferation?

['The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase', 'the FoxO3a transcription factor is coordinately regulated by mTORC1 and mTORC2, and plays a crucial role in controlling cell proliferation', 'mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314', 'These results suggest that mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314', 'SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation. These results suggest that mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314.']

['mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FOXO3a at Ser314.']

['The mTOR pathway']

Is Musclin a secretory peptide?

['Musclin is a novel skeletal muscle-derived secretory factor,', 'Musclin has been described as a muscle-derived secretory peptide, responsive to insulin in vivo, and inducing insulin resistance in vitro.', 'Musclin is a type of muscle-secreted cytokine and its increased gene expression induces insulin resistance in type 2 diabetes. ', 'Musclin is a novel skeletal muscle-derived factor found in the signal sequence trap of mouse skeletal muscle cDNAs.', 'Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. ', 'Musclin is a novel skeletal muscle-derived secretory factor that was isolated by our group. ']

['Yes, musclin has been described as a muscle-derived secretory peptide.']

['yes']

Elaborate on the potential efficacy of gemcitabine for the treatment of recurrent, platinum-resistant epithelial ovarian cancer.

['Gemcitabine and carboplatin demonstrate moderate toxicity with similar efficacy in both platinum-sensitive and platinum-resistant epithelial ovarian cancer, suggesting reversal of platinum resistance by gemcitabine', 'The combination of gemcitabine and carboplatin shows similar efficacy in the treatment of platinum-resistant and platinum-sensitive recurrent epithelial ovarian cancer patients', 'Gemcitabine-oxaliplatin (GEMOX) as salvage treatment in pretreated epithelial ovarian cancer patients', 'GEMOX showed encouraging activity and manageable toxicity. Under circumstances requiring a rapid disease control, this combination regimen may offer a particularly viable option, particularly in heavily pretreated patients', 'Salvage therapy of gemcitabine plus endostar significantly improves progression-free survival (PFS) with platinum-resistant recurrent epithelial ovarian cancer', 'Gemcitabine plus endostar significantly improved the prognosis in patients with platinum-resistant recurrent ovarian cancer, especially in those with malignant effusion', 'Though the endostar cohort also improved median OS by 2.1 months, there was no statistically significant difference compared with gemcitabine alone cohort in this case', 'Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer', 'The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer', ' the combination of gemcitabine and carboplatin is now approved for patients with platinum-sensitive recurrent ovarian cancer', 'Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer', 'Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer', 'The combination of gemcitabine and PLD is an effective and tolerable treatment option, with 74.3 % disease control rate for patients with platinum resistant/refractory ovarian cancer', 'Both gemcitabine and pegylated liposomal doxorubicin (PLD) are antineoplastic drugs with clinical activity in patients with platinum-resistant ovarian cancer', 'A biweekly schedule of gemcitabine combined with PLD is an active and safe chemotherapy regimen with acceptable and easily manageable toxicities in women with recurrent platinum-resistant ovarian cancer', 'the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone', 'Gemcitabine is a novel agent that has shown consistent activity as a single agent in the treatment of platinum-resistant ovarian cancer and a favorable toxicity profile', 'Because of its clinical and preclinical synergism with platinum analogs, gemcitabine has been combined with carboplatin as a convincing approach in the treatment of platinum-sensitive recurrent ovarian cancer patients', 'Gemcitabine is a new antimetabolite selected for clinical trials based on its activity in preclinical studies. With response rates ranging from 11% to 22% in monotherapy in resistant or platinum refractory diseases, gemcitabine has quickly been shown to be an active agent in the treatment of patients with refractory recurrent ovarian cancer', ' Gemcitabine and prolonged oral etoposide have shown reproducible single-agent activity in patients with platinum/paclitaxel-resistant ovarian cancer', 'Gemcitabine combined with platinum chemotherapy appears to be an effective and well-tolerant treatment for recurrent epithelial ovarian cancer, including platinum-resistant or -refractory diseases', '[Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer].', 'Gemcitabine and carboplatin demonstrate moderate toxicity with similar efficacy in both platinum-sensitive and platinum-resistant epithelial ovarian cancer, suggesting reversal of platinum resistance by gemcitabine.', 'The combination of gemcitabine and carboplatin shows similar efficacy in the treatment of platinum-resistant and platinum-sensitive recurrent epithelial ovarian cancer patients.', 'Efficacy and toxicity of gemcitabine and pegylated liposomal Doxorubicin in recurrent platinum-resistant/refractory epithelial ovarian cancer.', 'Gemcitabine combined with platinum chemotherapy appears to be an effective and well-tolerant treatment for recurrent epithelial ovarian cancer, including platinum-resistant or -refractory diseases.', 'Salvage therapy of gemcitabine plus endostar significantly improves progression-free survival (PFS) with platinum-resistant recurrent epithelial ovarian cancer.', 'The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer.', 'To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer.', 'A pilot study evaluating the efficacy and toxicity of biweekly gemcitabine and pegylated liposomal doxorubicin in recurrent platinum-resistant epithelial ovarian cancer.', 'CONCLUSION: The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer.', 'Gemcitabine combined with platinum chemotherapy appears to be an effective and well-tolerant treatment for recurrent epithelial ovarian cancer, including platinum-resistant or -refractory diseases.', 'The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer.', 'Gemcitabine combined with oxaliplatin (GEMOX) as salvage treatment in elderly patients with advanced ovarian cancer refractory or resistant to platinum: a single institution experience.', 'Gemcitabine combined with platinum chemotherapy appears to be an effective and well-tolerant treatment for recurrent epithelial ovarian cancer, including platinum-resistant or -refractory diseases.']

['Gemcitabine is a novel agent that has shown consistent activity as a single agent in the treatment of platinum-resistant ovarian cancer and a favorable toxicity profile. Because of its clinical and preclinical synergism with platinum analogs, gemcitabine has been combined with carboplatin as a convincing approach in the treatment of platinum-sensitive recurrent ovarian cancer patients. Gemcitabine and prolonged oral etoposide have shown reproducible single-agent activity in patients with platinum/paclitaxel-resistant ovarian cancer. The combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. A biweekly schedule of gemcitabine combined with PLD is an active and safe chemotherapy regimen with acceptable and easily manageable toxicities in women with recurrent platinum-resistant ovarian cancer. Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer. Gemcitabine plus endostar significantly improved the prognosis in patients with platinum-resistant recurrent ovarian cancer, especially in those with malignant effusion. Though the endostar cohort also improved median OS by 2.1 months, there was no statistically significant difference compared with gemcitabine alone cohort in this case.']

[]

Which is the main cause of the Patau syndrome?

['Trisomy 13, or Patau syndrome is a rare chromosomal disorder characterized by a triad of cleft lip and palate, postaxial polydactyly and microcephaly.', 'Mosaic trisomy 13 is very rare, it occurs in only 5% of all patients with trisomy 13 phenotype.', 'Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome) are compatible with postnatal survival. ', "We describe the management of the eyelid anomaly associated with Patau syndrome. Trisomy 13 is the genotype of the syndrome's phenotype. ", 'This article identifies the causes and manifestations of most of these trisomies: trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), and trisomy 21 (Down syndrome). ', 'WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13.', 'Patau syndrome is a chromosomal disorder associated with multiple malformations caused by inheritance of an extra chromosome (trisomy 13).', 'Survival of trisomy 18 (Edwards syndrome) and trisomy 13 (Patau Syndrome) in England and Wales: 2004-2011', 'To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome.Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months.Data from 22 EUROCAT congenital anomaly registers in 12 European countries.Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age ≥ 20 weeks and terminations after prenatal diagnosis of the anomaly.', 'Congenital diaphragmatic hernia (CDH) occurs in 5-10% associated with chromosomal abnormalities like, Pallister Killian syndrome, Trisomy 18, and certain deletions.. Association of CDH with trisomy 13 (Patau syndromes) is very rare', 'WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13. ', 'Patau syndrome is a chromosomal disorder associated with multiple malformations caused by inheritance of an extra chromosome (trisomy 13). ', 'Ocular abnormalities in Patau syndrome (chromosome 13 trisomy syndrome).', "Trisomy 13 (Patau's syndrome): a rare case of survival into adulthood.", 'BACKGROUND: Whilst maternal age is an established risk factor for Patau syndrome (trisomy 13), Edwards syndrome (trisomy 18) and Down syndrome (trisomy 21), the aetiology and contribution of genetic and environmental factors remains unclear.', 'WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13.', 'Patau syndrome, trisomy 13, is the third commonest autosomal trisomy.', 'Patau syndrome (trisomy 13) is very rare in live-born babies.']

['Patau syndrome is caused by trisomy 13.']

['Trisome 13']

What is dovitinib?

['This phase 2 study investigated the efficacy and safety of dovitinib (TKI258), a receptor tyrosine kinase inhibitor with potent activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR), in locally advanced or metastatic thyroid cancer patients', 'Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.', 'Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma.', 'Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma.', 'The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.']

['Dovitinib (TKI258) is a tyrosine kinase receptor inhibitor with potent activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR).']

['tyrosine kinase receptor inhibitor']

Is the monoclonal antibody Trastuzumab (Herceptin) of potential use in the treatment of prostate cancer?

['Herceptin is widely used in treating Her2-overexpressing breast cancer. However, the application of Herceptin in prostate cancer is still controversial.', 'Our data demonstrate that Re-188-labeled Herceptin effectively inhibited the growth of DU145 cells compared to the Herceptin- and Re-188-treated cohorts. This implies that targeting Her2 by both radio- and immuno- therapy might be a potential strategy for treating patients with androgen-independent prostate cancer.', 'epidermal growth factor receptor (EGFR) family members are potential targets for therapy using extra-cellular domain receptor binding agents, such as the antibodies trastuzumab and cetuximab', ' there were tendencies for upregulation of HER2, increased co-expression of EGFR and HER2 and downregulation of HER3 in the prostate cancer lymph node metastases in comparison to the primary tumors. ', 'We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4.', 'These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer.', 'Human epidermal growth factor receptor type 2 (HER2) overexpression supports proliferation of androgen-independent prostate cancer (PC)', 'Radiolabeled ABY-025 Affibody molecule provides higher contrast in imaging of HER2-expressing PC xenografts than radiolabeled trastuzumab. ', 'These studies indicate that dual EGFR/HER2 inhibition, administered together with AWT, sensitize prostate cancer cells to apoptosis during AWT', 'The overall goal of these studies is to determine whether dual inhibition of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness of this treatment in prostate cancer. ', 'The expression of HER2 was demonstrated and quantified in all three tested prostate cancer cell-lines.', 'Such features would definitely favor the use of radiometal labels for trastuzumab and, most likely, for affibody molecules', 'our data demonstrate that Her2 plays an important role in the support of AR protein stability in the transition of androgen requirement in prostate cancer cells. We hope these findings will provide novel insight into the treatment of hormone-refractory prostate cancer.', 'These two cell lines exhibited distinct responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation', ' While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody', 'Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate', 'Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin', 'The data from these in vitro and in vivo studies supported advancement of radiolabeled trastuzumab into two clinical studies', 'Tumor targeting was evaluated in mice bearing subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian, and prostate carcinomas.', 'we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody', 'detection of prostate cancer (PCa) and advances in hormonal and chemotherapy treatments have provided great clinical benefits to patients with early stages of the disease.', 'MAbs directed to established targets include those approved for other solid tumors, including anti-human epidermal growth factor receptor-2 (HER2) MAb trastuzumab', 'We conclude that Her2/neu expression in the peripheral blood mononuclear cell fraction of prostate cancer patients is frequent and therefore this assay may potentially be useful to detect the presence of micrometastatic disease in men with prostate cancer and for monitoring patients enrolled in trastuzumab-based therapeutic protocols.', 'This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer.', 'there was no significant difference in antimetastatic activity between the emulsion and the immunoemulsion despite the affinity of the immunoemulsion towards the HER2 receptor. ', 'a targeted drug delivery system based on cationic emulsion covalently linked to anti-HER2 monoclonal antibody (Herceptin), in a well-established in vivo pharmacologic model of metastatic prostate cancer that overexpresses the HER2 receptor', 'The finding of strong, consistent HER-2/neu expression in ACBCC suggests that treatment with Herceptin (trastuzumab) may be effective in patients with this rare tumour.', 'Although HER2 can be over-expressed in prostate cancer, there is no clinical data to support the use of trastuzumab for prostate cancer patients.', 'whereas the effect of the trastuzumab-RT combination was inferior to that predicted by the individual effects.', 'HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab', 'Trastuzumab (Herceptin) as a single agent demonstrated poor efficacy in treating HRPC.', 'To investigate the efficacy and toxicity of the antibody to the HER-2/neu receptor (trastuzumab, Herceptin) in the treatment of advanced hormone-refractory prostate cancer (HRPC)', 'Conclusions regarding the predictive value of HER-2 status on outcome after trastuzumab-based therapy were not reached and were only drawn after larger-scale screening efforts. ', 'rastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma', 'clinical trials are currently in progress in patients with prostate cancer testing novel agents that selectively interfere with these receptors, such as trastuzumab,', 'ytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate', 'The clinical interpretation of c-erbB-2 abnormalities should reflect the complexity of c-erbB-2 mediated regulatory pathway and explain why tumours with overexpression/amplification of c-erbB-2 very often do not respond to therapy using Herceptin', 'HER-2 overexpression also has been reported in up to 60% of patients with hormone-refractory prostate carcinoma (HRPC) and was correlated with shortened survival', 'Unlike breast carcinoma and contrary to prior reports, HER-2 overexpression by IHC in archival prostate tissue from patients who eventually developed hormone-refractory disease was infrequent. There did not appear to be any correlation between HER-2 overexpression by IHC and shed HER-2 antigen levels in serum by ELISA in this tumor type.', 'Further development of trastuzumab for the treatment of patients with metastatic prostate carcinoma is not feasible until more reliable and practical methods of sampling metastatic disease are developed to identify patients with HER-2 positive tumors.', 'the expression of ERBB2 in prostate cancer is relatively low, and is not altered during disease progression. Thus, it is unlikely that treatment modalities relying on the overexpression of ERBB2 gene will be useful in treating prostate cancer.', 'A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC)', 'Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine', 'trastuzumab, a monoclonal antibody binding to the HER2 receptor; immunotoxin conjugates use an antibody directed against EGFR joined to a cell toxin. All are in clinical trials for a number of cancers, including prostate cancer', 'we investigated the antitumor efficacy of Herceptin, a new recombinant humanized anti-HER2/neu antibody, which exhibits cytostatic activity on breast and prostate cancer cells that overexpress the HER2 oncogene.', 'trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents', 'ER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer', 'in these prostate cancer model systems, Herceptin alone has clinical activity only in the androgen-dependent tumor and has at least an additive effect on growth,', 'anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells.']

['Although is still controversial, Trastuzumab (Herceptin) can be of potential use in the treatment of prostate cancer overexpressing HER2, either alone or in combination with other drugs.']

['yes']

Is there a crystal structure of the full-length of the flaviviridae NS5(Methyltransferase - RNA depended RNA Polymerase) ?

[' flavivirus NS5 harbors a methyltransferase (MTase) in its N-terminal ≈ 265 residues and an RNA-dependent RNA polymerase (RdRP) within the C-terminal part. One of the major interests and challenges in NS5 is to understand the interplay between RdRP and MTase as a unique natural fusion protein in viral genome replication and cap formation. Here, we report the first crystal structure of the full-length flavivirus NS5 from Japanese encephalitis virus. ', "(DENV) nonstructural protein 5 (NS5) is composed of two globular domains separated by a 10-residue linker. The N-terminal domain participates in the synthesis of a mRNA cap 1 structure ((7Me)GpppA(2'OMe)) at the 5' end of the viral genome and possesses guanylyltransferase, guanine-N7-methyltransferase, and nucleoside-2'O-methyltransferase activities. The C-terminal domain is an RNA-dependent RNA polymerase responsible for viral RNA synthesis. Although crystal structures of the two isolated domains have been obtained, there are no structural data for full-length NS5. It is also unclear whether the two NS5 domains interact with each other to form a stable structure in which the relative orientation of the two domains is fixed. To investigate the structure and dynamics of DENV type 3 NS5 in solution, we conducted small-angle X-ray scattering experiments with the full-length protein. NS5 was found to be monomeric and well-folded under the conditions tested.", 'West Nile virus (WNV) NS5 protein contains a methyltransferase (MTase) domain involved in RNA capping and an RNA-dependent RNA polymerase (RdRp) domain essential for virus replication. Crystal structures of individual WNV MTase and RdRp domains have been solved; however, the structure of full-length NS5 has not been determined. To gain more insight into the structure of NS5 and interactions between the MTase and RdRp domains, we generated a panel of seven monoclonal antibodies (mAbs) to the NS5 protein of WNV (Kunjin strain) and mapped their binding sites using a series of truncated NS5 proteins and synthetic peptides. Binding sites of four mAbs (5D4, 4B6, 5C11 and 6A10) were mapped to residues 354-389 in the fingers subdomain of the RdRp. This is consistent with the ability of these mAbs to inhibit RdRp activity in vitro and suggests that this region represents a potential target for RdRp inhibitors. Using a series of synthetic peptides, we also identified a linear epitope (bound by mAb 5H1) that mapped to a 13 aa stretch surrounding residues 47 and 49 in the MTase domain, a region predicted to interact with the palm subdomain of the RdRp. The failure of one mAb (7G6) to bind both N- and C-terminally truncated NS5 recombinants indicates that the antibody recognizes a conformational epitope that requires the presence of residues in both the MTase and RdRp domains. ']

['Yes, there is the crystal Structure of the full-length Japanese encephalitis virus (Flaviviridae) NS5 - PDB:4K6M']

['yes']

What is the lipid droplet used for in the cell?

['Eukaryotic cells store excess fatty acids as neutral lipids, predominantly triacylglycerols and sterol esters, in organelles termed lipid droplets (LDs) that bulge out from the endoplasmic reticulum. ', 'Lipid droplets (LD) are spherical cellular inclusion devoted to lipids storage.', 'Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). ', 'Lipid droplets are found in all cell types', 'Lipid droplets (LDs) are ubiquitous and physiologically active organelles regulating storage and mobilization of lipids in response to metabolic demands. ', 'Lipids accumulate in spherical cellular inclusions called lipid droplets (LDs) whose sizes range from fraction to one hundred of micrometers in adipocytes.']

['Lipid droplets (LDs) are ubiquitous and physiologically active organelles regulating storage and mobilization of lipids in response to metabolic demands.']

['lipid storage and lipid mobilization']

What is the inheritance of hypophosphatemic rickets?

['Among 35 candidate genes in this region, the dentin matrix protein 1 gene (DMP1) was sequenced to reveal a nonsense mutation 250C/T on exon 6. ', 'Previous research has shown that mutations in the DMP1 gene are responsible for autosomal recessive hypophosphatemic rickets in humans.', 'A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.', 'Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting. ', 'Prenatal diagnosis for a novel splice mutation of PHEX gene in a large Han Chinese family affected with X-linked hypophosphatemic rickets.', 'X-linked hypophosphatemia (XLH) is the most common form of heritable rickets characterized by X-linked dominant inheritance, renal phosphate wasting, hypophosphatemia, and defective bone mineralization.', 'Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.', 'We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated fibroblast growth factor-23 (FGF23).', 'First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. ', 'Discordance for X-linked hypophosphataemic rickets in identical twin girls.', 'We report monozygotic twin girls with a family history consistent with X-linked hypophosphataemic rickets (XLH). ', 'Microsatellite analysis was performed to confirm monozygosity and bi-parental inheritance of the X chromosome. ', 'Hypophosphatemia due to isolated renal phosphate wasting is a genetically heterogeneous disease. Two new genes linked to two different forms of hereditary hypophosphatemias have recently been described. Autosomal recessive form of hypophosphatemic rickets was mapped to chromosome 4q21 and identified homozygous mutations in dentin matrix protein 1 (DMP1) gene, which encodes a non-collagenous bone matrix protein.', 'Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.', 'Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively.', 'Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. ', 'Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.', 'We report two cases of x-linked dominant hypophosphatemic rickets involving a man and his daughter. ', 'X-linked hypophosphatemic rickets--a report of 2 cases and review of literature.', 'The study of this family tree strongly suggests an x-linked dominant inheritance.', 'Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder.', 'We performed clinical and biochemical evaluations of individuals from a large kindred with autosomal dominant hypophosphatemic rickets/osteomalacia.', ' In conclusion, autosomal dominant hypophosphatemic rickets/osteomalacia is an inherited disorder of isolated renal phosphate wasting. ', '[Scriver type autosomal hypophosphatemic rachitis: a family case].', 'A familial observation of hypophosphatemic rickets with unusual inheritance and evolution, different from that of X linked hypophosphatemia, is reported. ', "This observation is quite similar to the 'autosomal hypophosphatemic bone disease' described by Scriver et al. ", 'The HHRH is transmitted by autosomal recessive inheritance and is an extremely rare form of hypophosphatemic rickets.', 'First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance.', 'A familial observation of hypophosphatemic rickets with unusual inheritance and evolution, different from that of X linked hypophosphatemia, is reported.', 'Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting.', 'Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred.', 'Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting', 'A familial observation of hypophosphatemic rickets with unusual inheritance and evolution, different from that of X linked hypophosphatemia, is reported', 'The HHRH is transmitted by autosomal recessive inheritance and is an extremely rare form of hypophosphatemic rickets', 'First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance', 'Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred', 'Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively.The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance.We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets', 'Hereditary hypophosphatemic rickets with hypercalciuria is another rare disorder of autosomal recessive inheritance', 'First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance.', 'Autosomal recessive form of hypophosphatemic rickets was mapped to chromosome 4q21 and identified homozygous mutations in dentin matrix protein 1 (DMP1) gene, which encodes a non-collagenous bone matrix protein.', 'In addition, such CLCN5 mutations that would result in a functional loss have also been demonstrated in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and an Italian kindred with X-linked recessive hypophosphatemic rickets (XLRH) and hypercalciuria.', 'Inactivating mutations of phosphate-regulating gene with homologies to endopeptidases on the X chromosome, dentin matrix acidic phosphoprotein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1 are associated with X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets 1, and autosomal recessive hypophosphatemic rickets 2, respectively.', 'The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance.', 'The HHRH is transmitted by autosomal recessive inheritance and is an extremely rare form of hypophosphatemic rickets.', 'X-linked familial hypophosphatemic rickets (X.L.F.H.R.) is one of the D resistant rickets.', 'Iron deficiency may affect autosomal dominant hypophosphatemic rickets phenotype by regulating FGF23 production.Current treatment with activated vitamin D metabolites and oral inorganic phosphate salts may partially correct skeletal lesions and linear growth in patients with hypophosphatemic rickets.', "[X-linked familial hypophosphatemic rickets report of six cases (author's transl)]."]

['Hypophosphatemic rickets are transmitted with:\n1) autosomal recessive\n2) autosomal dominant\n3) X-linked recessive and\n4) X-linked dominant inheritance.']

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

What are the different classes of orally administered drugs used to treat diabetes

[' achieved by selectively inhibiting sodium-glucose co-transporter 2 (SGLT2).', 'After a decade-long effort to improve the pharmacokinetics of GLP1, a number of GLP1 analogues are currently available on the market', ' short-acting glucagon-like peptide-1 receptor agonists exenatide and lixisenatide. ', ' Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates;', 'In 2013, sulfonylureas were the most common second-line treatment after metformin i', 'this position was taken by DPP-4 inhibitors', '[Studies on resorption of orally administered antibiotics and chemotherapeutic agents in children and its modification.', 'The drugs used to treat diabetes mellitus are diverse and include several classes.', 'Many of the therapeutic agents used to treat diabetes mellitus have the ability to lower blood glucose to dangerous concentrations; these include the sulfonylurea, meglitinide, and thiazolidinedione drug classes.', 'The most common therapeutic classes of drugs used in all participating regions, in the previous week, were cardiovascular, gastrointestinal, metabolic (including drugs to treat diabetes) and nervous system.', 'Use of oral antidiabetic agents, by drug class, did not differ significantly by race/ethnicity (p = 0.33 for TZDs, p = 0.43 for metformin, p = 0.38 for sulfonylureas). ', 'The use of these drugs was also common among insulin treated diabetics but did not differ significantly from among non-diabetics. ', 'Drug use among those treated with insulin and those treated orally was substantially higher than among non-diabetics while the difference between diabetics on dietary regimen and non-diabetics was much smaller. ', 'UNLABELLED: The aims of the study were to evaluate differences in dietary, oral hygiene habits and social class in children with Type I diabetes mellitus (DM), compared to non-diabetics, and to investigate relationship between selected caries-risk factors and caries experience in diabetics. ', 'Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function.', 'The literature covered includes original studies and meta-analyses identified in PubMed, recent abstracts presented at major diabetes scientific conferences, and clinical trials registered at ClinicalTrials.gov.Although there are some differences in the pharmacokinetic and pharmacodynamic profiles of the different DPP-4 inhibitors, all are small orally active compounds with broadly similar HbA1c-lowering efficacy.', 'The authors conclude that rosiglitazone can be safely administered with metformin and, due to the different mechanisms of action of these agents, may offer a therapeutic advantage in patients with type 2 diabetes mellitus.', 'There are different classes of anti-diabetic drugs reported to treat diabetes.', 'There are now four different classes of oral medications which are available to treat diabetes-sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors.', 'During followup, incident treated diabetes was defined as a self-report of a new physician diagnosis of diabetes treated with insulin or oral drugs.', 'This systematic review will compare adherence and persistence rates across the different classes of medication available to people with type 2 diabetes.', 'Five classes of oral hypoglycaemic drugs and two trace minerals used to treat diabetes mellitus in humans are reviewed and current knowledge on the use of these drugs in diabetic dogs and cats is presented.', 'Sulfonylureas, biguanides, alpha-glucosidase, meglitinides, DPP-4 inhibitors and thiazolidinediones are among the classes of oral hypoglycemic drugs available to treat Type II diabetes, but concerns exist regarding safety and efficacy of these drugs.', 'Currently, four classes of orally administered antidiabetic agents are available for use in patients with type 2 diabetes: insulin secretagogues, biguanides, a-glucosidase inhibitors, and thiazolidinediones.']

['There are a number of classes of medications tha are used to treat Type 2 diabetes. These include biguanides like metformin, which decreased hepatic glucose release; sulfonyureas like Glimepride, metglitinides like repaglin and d-phenylalanine derivatives, all of which stimulate pancreatic insulin release; Glitizones or thiazolidinediones which make the body more sensitive to insulin; DPP-4 inhibitors which lower the amount of glucose made in the body; alpha-glucosidase inhibitors which slow the absorbtion of carbohydrate in the blood; and bile acid sequestrants that lower blood glucose']

['Biguanides', 'Sulfonylureas', 'Meglitinides', 'D-Phenylalanine Derivatives', 'glitazones', 'DPP-4 Inhibitors', 'Alpha-glucosidase inhibitors', 'bile acid sequestrants']

What type of cancers and inherited diseases have been associated to mutations in the Notch pathway?

['Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients.', 'Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines.', 'We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers.', 'We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain).', 'Importantly, mutations of the Notch protein and components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis).', 'Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome.', 'In this study, analysis of 21 Vietnamese ALGS individuals led to the identification of 19 different mutations (18 JAG1 and 1 NOTCH2), 17 of which are novel, including the third reported NOTCH2 mutation in Alagille Syndrome.', 'Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization redundant 6qter deletions, DELTA Like 1 (DLL1), which is a ligand of NOTCH.', 'Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family,', 'Here we have used autozygosity mapping to identify a mutation in a fourth Notch pathway gene, Hairy-and-Enhancer-of-Split-7 (HES7), in an autosomal recessive SCD family.', 'Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals.', 'Mutations in the JAG1 (Jagged 1) gene, coding a ligand in the evolutionarily conserved Notch signaling pathway, are responsible for AGS. Here we present sixteen different JAG1 gene mutations, among them twelve novel, not described previously.', 'Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations.', 'Previous studies have demonstrated that a wide spectrum of JAG1 mutations result in AGS. These include total gene deletions, protein truncating, splicing and missense mutations which are distributed across the coding region of the gene. Here we present results of JAG1 mutation screening by SSCP and FISH in 105 patients with AGS. For these studies, new primers were designed for 12 exons. Mutations were identified in 63/105 patients (60%)', 'We have screened 54 AGS probands and family members to determine the frequency of mutations in JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis. Of the 35 identified intragenic mutations, all were unique, with the exceptions of a 5-bp deletion in exon 16, seen in two unrelated patients, and a C insertion at base 1618 in exon 9, also seen in two unrelated patients.', 'Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12.']

['So far, mutations in Notch and other components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis), but more pathologies are likely to be associated with Notch in the future due to its network complexity.']

['Alagille syndrome', 'spondylocostal dysostosis', 'CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)', 'T-cell acute lymphoblastic leukemia']

What are the treatment options for SUI after 12 months, considering cost and effectiveness?

['["The initial treatment for SUI that persists after 12 months consists of conservative measures such as pelvic floor muscle exercises and behavioral therapy. Properly selected and informed patients can also be treated efficiently with minimally invasive procedures such as the implantation of a male suburethral sling, although the experience with such devices is not extensive. However, the implantation of artificial urinary sphincter is the gold standard therapy.", "treatments such as periurethral injection of bulking agents, artificial urinary sphincter (AUS) implantation, and sub-urethral sling positioning. The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options.", "Today, three different sling procedures are commonly performed: bone-anchored, readjustable, and trans-obturator slings systems.", "The bone anchored suburethral synthetic sling is a simple and attractive procedure that can produce immediate good results with low morbidity, especially when strictly selected patients are treated. ", "BAUS implantation is a safe, effective, minimally invasive option for iatrogenic male incontinence due to ISD. It compares favourably with AUS."]']

The initial treatment for SUI that persists after 12 months consists of conservative measures such as pelvic floor muscle exercises and behavioral therapy. Properly selected and informed patients can also be treated efficiently with minimally invasive procedures such as the implantation of a male suburethral sling, although the experience with such devices is not extensive. However, the implantation of artificial urinary sphincter is the gold standard therapy.

[]

What does iBAQ stand for in proteomic analysis?

['intensity-based absolute quantification (iBAQ)', 'Intensity-Based Absolute Quantification Index,']

['iBAQ stands for intensity-based absolute quantification.']

['intensity-based absolute quantification']

Which disease is characterized by congenital absence of intrinsic ganglion cells of the gastrointestinal tract?

["Hirschsprung's disease (HSCR), also known as aganglionic megacolon, derives from a congenital malformation of the enteric nervous system (ENS).", 'This severe congenital condition is caused by the absence of colonic neural ganglia and thus lack of intrinsic innervation of the colon due in turn to improper colonization of the developing intestines by ENS progenitor cells.', 'Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon.', 'Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract.', 'Hirschsprung disease (HSCR) is a congenital disorder associated with the absence of intrinsic ganglion cells in the distal gastrointestinal tract.', 'Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon.', 'Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon.', "Hirschsprung's disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerves forming the plexus of the lower intestine.", 'Hirschsprung disease (HSCR) is an inherited disorder characterised by absence of intrinsic ganglion cells in the distal gastrointestinal tract.', 'Hirschsprung disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut.', 'Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract.', 'BACKGROUND: Hirschsprungs Disease (HD) is a developmental disorder of enteric nervous system characterised by the absence of ganglion cells in submucosal (Meissners) and myenteric (Aurbachs) plexuses of distal bowel.', "Hirschsprung's disease is an inherited disorder characterized by the absence of ganglion cells in the distal bowel.", 'Hirschsprung disease (HSCR) is a congenital disease characterized by the absence of ganglion cells in various length of distal digestive tract', 'Hirschsprung disease (HSCR) is a congenital disorder associated with the absence of intrinsic ganglion cells in the distal gastrointestinal tract', "Hirschsprung's disease (HSCR) is a congenital intestinal disease, characterized by the absence of ganglion cells in the distal portion of the intestinal tract", 'Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of intramural ganglion cells along with variable lengths of the gastrointestinal tract', 'Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon', 'Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon', "Hirschsprung's disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerves forming the plexus of the lower intestine", 'Hirschsprung disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut', 'Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract', 'Hirschsprung disease (HSCR) is an inherited disorder characterised by absence of intrinsic ganglion cells in the distal gastrointestinal tract', 'Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract']

['Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. ', 'The medical condition characterized by the congenital absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract is called aganlionic megacolon or Hirschsprung disease.', 'Hirschsprung disease (HSCR) is a congenital disorder associated with the absence of intrinsic ganglion cells in the distal gastrointestinal tract.This severe congenital condition is caused by the absence of colonic neural ganglia and thus lack of intrinsic innervation of the colon due in turn to improper colonization of the developing intestines by ENS progenitor cells.', 'Hirschsprungs disease (HSCR), also known as aganglionic megacolon, derives from a congenital malformation of the enteric nervous system (ENS). This severe congenital condition is caused by the absence of colonic neural ganglia and thus lack of intrinsic innervation of the colon due in turn to improper colonization of the developing intestines by ENS progenitor cells.']

['Aganlionic megacolon or Hirschsprung disease']

Is there increased incidence of incontinence in athletes?

['Urinary incontinence affects women of all ages, including top female athletes, but is often under-reported. The highest prevalence of urinary incontinence is reported in those participating in high impact sports.', 'The prevalence of female stress urinary incontinence is high, and young adults are also affected, including athletes, especially those involved in "high-impact" sports', 'Analysis of these data suggests that perineal pressure is decreased in female athletes compared with nonathlete women. A lower perineal pressure correlates with increased symptoms of urinary incontinence and pelvic floor dysfunction.', 'Urinary incontinence is a prevalent condition among athletes that is not openly discussed.', 'High-level sport appears to be a significant independent risk factor for AI in healthy young women. ', 'The prevalence of LUTS was 54.7%, and 30% for urinary incontinence.', 'LUTS and incontinence are prevalent in female athletes.', 'A relationship between sport or fitness activities and urinary incontinence (UI) previously has been described in women. ', 'studies have also shown a high prevalence of SUI in young, physically fit female athletes. ', 'There was urinary incontinence in female long-distance runners and a correlation with eating disorders.', 'young female athletes participating in high-impact sports may be at higher risk for urinary incontinence.', 'Results indicated that more than 25% of those completing surveys experienced incontinence and that more than 90% had never told anyone about their problem and had no knowledge of preventive measures; 16% reported incontinence negatively impacted their quality of life.', 'There is a very high prevalence of urinary incontinence in women athletes.', 'Women athletes should be counseled about the increased risk of urinary incontinence with ultra high-impact sports and eating disorders.', "Stress urinary incontinence is a barrier to women's participation in sport and fitness activities and, therefore, it may be a threat to women's health, self-esteem and well-being. The prevalence during sports among young, nulliparous elite athletes varies between 0% (golf) and 80% (trampolinists). The highest prevalence is found in sports involving high impact activities such as gymnastics, track and field, and some ball games", 'Urinary leakage is common among elite athletes and dancers, particularly during training, but also during daily life activities.', 'There is a high prevalence of stress and urge incontinence in female elite athletes. The frequency of SUI and urge incontinence was significantly higher in eating disordered athletes compared with healthy athletes.', 'High impact sports activities may produce urinary incontinence.', 'Urinary incontinence during physical stresses is common in young nulliparous wome', 'Incontinence during physical stresses is common in young, highly fit, nulliparous women.']

['There is a very high prevalence of urinary incontinence in women athletes.']

['yes']

List diseases associated with the Dopamine Receptor D4 (DRD4).

['The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of attention deficit hyperactivity disorder (ADHD) and substantially exists in Asian populations, which have a lower ADHD prevalence.', 'The variable number of tandem repeats (VNTR) of the dopamine receptor D4 (DRD4) gene among humans may elucidate individual differences in susceptibility to neuropsychiatric diseases. Dopamine dysfunction may be involved with Attention Deficit Hyperactivity Disorder (ADHD) symptoms.', 'This review summarized the ongoing research of DA receptor genes in ADHD pathogenesis and gathered the past published data with meta-analysis and revealed the high risk of DRD5, DRD2, and DRD4 polymorphisms in ADHD.']

['The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of attention deficit hyperactivity disorder (ADHD).']

['attention deficit hyperactivity disorder', 'ADHD', 'susceptibility to neuropsychiatric diseases']

Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?

['To identify additional proteins that may interact with PLN, we used the yeast-two-hybrid system to screen an adult human cardiac cDNA library. HS-1 associated protein X-1 (HAX-1) was identified as a PLN-binding partner.', 'Analysis of the anti-apoptotic function of HAX-1 revealed that the presence of PLN enhanced the HAX-1 protective effects from hypoxia/reoxygenation-induced cell death. These findings suggest a possible link between the Ca(2+) handling by the sarcoplasmic reticulum and cell survival mediated by the PLN/HAX-1 interaction.', 'The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2.', 'The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.', 'The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis.', 'On triple transfections with PLN, however, HAX-1 massively translocated to the ER membranes, where it codistributed with PLN and SERCA2.', 'These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca(2+) stores.', 'Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function.', 'The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed protein that protects cardiomyocytes from programmed cell death. Here we identify 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.', 'The inhibitory effects of HAX-1 were abolished upon phosphorylation of phospholamban, which plays a fundamental role in controlling basal contractility and constitutes a key downstream effector of the beta-adrenergic signaling cascade.', ' Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1.', ' Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2.', 'Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1']

['Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function.The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.', 'The HS-1 associated protein X-1 (HAX-1) is a mitochondrial protein with anti-apoptotic function and presents with numerous similarities to Bcl-2. and was identified as a phospholamban-binding partner. Using the yeast-two-hybrid system, HS-1 associated protein X-1 (HAX-1) was identified as a PLN-binding partner.', 'The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis.Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function.']

['The HS-1 associated protein X-1', '(HAX-1)']

What are phycobiliproteins and what role do they play in cyanobacteria and algae?

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

Phycobiliproteins are pigmented proteins found in cyanobacteria and algae that are part of the photosynthetic apparatus. They play a crucial role in light harvesting and energy transfer processes in these organisms. Phycobiliproteins include phycocyanin, phycoerythrin, and allophycocyanin, among others, and are essential for efficient photosynthesis in cyanobacteria and algae.

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Is butterfly rash a symptom of Systemic lupus erythematosus?

['Diagnosing SLE can be challenging because of the myriad of clinical features and substantial variability between patients. Cutaneous involvement is present in about 60% of cases and typically manifests as a malar or butterfly rash.', 'The prevalence of systemic lupus erythematosus (SLE) is 28 per 100,000. ', 'We report a 12 years old female patient with an overlap syndrome involving autoimmune hepatitis (AIH) and systemic lupus erythematosus (SLE). The patient presented with jaundice, hepatosplenomegaly, malaise, polyarthralgia, arthritis and butterfly rash on the face.', 'Some of the clinical characteristics of SLE patients observed were nephritis (53.7%), fever (53.26%), neuropsychological disorder (36.18%), malar/butterfly rash (27.6%), pulmonary disorder (22.6%), photosensitivity (21.6%), cardiac involvement (21.1%) and oral ulcers (19.09%). ', 'Systemic lupus erythematosus and infections: a retrospective study in Saudis.', 'The prevalence of the following manifestations was significantly higher for pediatric than for adult-onset disease including: lupus nephritis (43% pediatric vs 26.4% for adult-onset), hematological disorders (57% vs 36.4%), photosensitivity (20% vs 9%), butterfly rash (61% vs 35.5%) and mucosal ulceration (11.4% vs 4%). ', 'Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with highest prevalence among women of childbearing age. ', 'We described a unique case of a 25-year-old Arab young woman who was diagnosed with SLE, depending on clinical, laboratory investigations and after she had fulfilled the diagnostic criteria for SLE and had presented the following findings: constitutional findings (fatigue, fever, and arthralgia); dermatologic finding (photosensitivity and butterfly rash); chronic renal failure (proteinuria up to 400 mg in 24 hours); hematologic and antinuclear antibodies (positivity for antinuclear factor (ANF), anti-double-stranded DNA antibodies, direct Coombs, ANA and anti-DNA, low C4 and C3, aCL by IgG and IgM). ', 'Grade 1 and 2-3 inflammatory process occurred in 53 (63%) and 31 (37%) patients respectively. Symptom complexes "systemic inflammation", "butterfly rash", "wrist petechiae", "enanthema of the oral mucous membrane", and other lesions were regarded as the markers of SLE activity. ', 'Systemic lupus erythematosus (SLE) remains a challenging medical problem. ', "Rembrandt's Maria Bockenolle has a butterfly rash and digital deformities: overlapping syndrome of rheumatoid arthritis and systemic lupus erythematosus.", "A butterfly rash on the patient's face suggested a diagnosis of systemic lupus erythematosus (SLE).", 'A butterfly rash on the patients face suggested a diagnosis of systemic lupus erythematosus (SLE)', 'The diagnosis of SLE could be excluded and the butterfly rash attributed to a laminar hemorrhage, an ecchymosis due to the autoimmune thrombocytopenia.', 'We describe a case of KD who developed a typical butterfly rash, reminiscent of SLE. ', "The diagnosis of SLE was made 22 years ago based on Raynaud's phenomenon, butterfly rash, hair loss, photosensitivity and positive antinuclear antibody. ", 'Symptom complexes "systemic inflammation", "butterfly rash", "wrist petechiae", "enanthema of the oral mucous membrane", and other lesions were regarded as the markers of SLE activity.', "Rembrandt's Maria Bockenolle has a butterfly rash and digital deformities: overlapping syndrome of rheumatoid arthritis and systemic lupus erythematosus.", 'To investigate, various unspecific, but otherwise typical clinical symptoms of skin and mucous membranes that arise in SLE patients other than those defined as SLE criteria such as butterfly rash, chronic cutaneous lupus erythematosus, oral ulcers, and increased photosensitivity.']

['Yes, butterfly rash is symptom of Systemic lupus erythematosus.']

['yes']

What is the frequency of mutations induced spontaneously through Ethylnitrosourea (ENU) mutagenesis?

['The mutation frequency increased linearly with MNU or ENU concentration (0.01--2.0 mM); mean values were 2800 and 840 mutants per 10(6) clonable cells per mM, respectively', 'The mutation frequency induced by a 400 mg/kg dosage of ethylnitrosourea is 12 times the maximal mutation frequency achievable with a single exposure to x-rays and 36 times that reported for procarbazine, the most effective chemical mutagen previously known for mouse stem-cell spermatogonia', 'Specific locus tests designed to detect recessive mutations showed that ENU is the most efficient mutagen in mouse with an approximate mutation rate of 1 in 1,000 gametes.', 'Theoretical considerations and empirical analysis suggest that the per-base mutation frequency for a fractionated-dose treatment protocol is on the order of 1 sequence change per 10(5) bp', 'Unlike spontaneous chromosome damage, spontaneous mutant frequencies did not differ significantly among homozygous, heterozygous, and wild-type mice (3.2 x 10(-5), 3.1 x 10(-5), and 3.1 x 10(-5), respectively; P > 0.05)', 'The ENU-induced mutation frequency in Blmtm3Brd homozygous, heterozygous, and wild mice were 54 x 10(-5), 35 x 10(-5), and 25 x 10(-5) mutants/plaques, respectively', 'mutation frequencies per nucleotide based on mutant spectra from this study and published literature. We found this frequency in control spleen to be similar for lacI (3.8 +/- 0.7 x 10(-8)) and PhiX174 (3.1 +/- 1.2 x 10(-8)) at 6 weeks of age']

['Theoretical considerations and empirical analysis suggest that the per-base mutation frequency for a fractionated-dose treatment protocol is on the order of 1 sequence change per 10(5) bp.']

['1/100000']

Which protein complexes contain mitofilin?

[' and the mitochondrial structural proteins-components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), ', 'Mitofilin/MINOS protein complex ', ' APOOL physically interacts with several subunits of the MINOS complex, namely Mitofilin, MINOS1, and SAMM50. ', 'Mitofilin/MINOS protein complex ', 'MINOS subunits (mitofilin, MINOS1, and CHCHD3)', 'mitofilin, a core MINOS subunit,', 'The mitochondrial inner membrane organizing system (MINOS) is a large protein complex required for maintaining inner membrane architecture. ', 'Mitochondria lacking mitofilin, the large core subunit of MINOS,', 'The mitochondrial inner membrane contains a large protein complex crucial for membrane architecture, the mitochondrial inner membrane organizing system (MINOS).', ' To study if outer membrane interactions and maintenance of cristae morphology are directly coupled, we generated mutant forms of mitofilin/Fcj1 (formation of crista junction protein 1), a core component of MINOS. ', 'The C-terminal domain of Fcj1 is required for formation of crista junctions and interacts with the TOB/SAM complex in mitochondria.', 'Mitofilin/Fcj1, the central component of the MINOS complex,', 'We provide evidence that the SAM components exist in a large protein complex together with the IMM proteins mitofilin and CHCHD3, which we term the mitochondrial intermembrane space bridging (MIB) complex.', 'which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components. ', 'Mitofilin is part of a large inner membrane complex, and we identify five partner proteins as constituents of the mitochondrial inner membrane organizing system (MINOS) that is required for keeping cristae membranes connected to the inner boundary membrane.', ' Our findings indicate that mitofilin is a central component\xa0of MINOS']

['mitochondrial inter-membrane space bridging (MIB) complex \nmitochondrial inner membrane organizing system (MINOS)\nMitOS for mitochondrial organizing structure']

['MIB', 'mitochondrial inter-membrane space bridging complex', 'MINOS', 'mitochondrial inner membrane organizing system', 'MitOS']

What is the average diameter of intermediate filaments?

['Negative staining showed that supernatants from the centrifugation assays contained protofilaments, protofibrils and short particles (less than 300 nm), but pellets contained long filaments (greater than 1 micron) with an average diameter of 10 nm.', 'Ultrastructurally, rhabdoid cells showed paranuclear aggregates and whorls of intermediate filaments with a 9-10 nm diameter.', 'After removing IFs by calcination, electron microscopy revealed hollow silica nanotubes several micrometers long, with outer diameters of 35-55 nm and an average inner diameter of 10 nm (comparable to that of IFs)', 'Intermediate filaments are filaments 10\u2009nm in diameter that make up an important component of the cytoskeleton in most metazoan taxa.', 'Neurofilaments (NFs) are essential cytoskeletal filaments that impart mechanical integrity to nerve cells. They are assembled from three distinct molecular mass proteins that bind to each other to form a 10-nm-diameter filamentous rod with sidearm extensions.', 'Scanning tunneling microscope (STM) and transmission electron microscope (TEM) micrographs showed that acidic keratins and basic keratins can assemble into dimers and further into 10 nm filamentsin vitro.', 'Intermediate in diameter between microtubules and microfilaments, IFs constitute the third cytoskeletal filament system of metazoan cells.', 'Just above the bulb, the filaments are characterized by a diameter of 100 Angstroms and a low-density core.', 'Further, using cryo-transmission electron microscopy on native, fully hydrated, vitreous epidermis we show that the subfilametous keratin electron density pattern consists, both in corneocytes and in viable keratinocytes, of one axial subfilament surrounded by an undetermined number of peripheral subfilaments forming filaments with a diameter of approximately 8 nm.']

['Intermediate filaments have an average diameter of 10 nanometers (nm).']

['10 nanometers', '10 nm']

What are Kupffer cells and what is their role?

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

['Kupffer cells (KCs)are hepatic macrophages which can secrete matrix metalloproteinases (MMPs), and can contribute to decreased hepatic insulin sensitivity. KCs may play a role in the development of drug induced liver injury (DILI)', 'Kupffer cells (KCs) play a role in the development of drug induced liver injury (DILI). Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. ']

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Does fibronectin constitute a serum biomarker for Duchenne muscular dystrophy?

['Fibronectin is a serum biomarker for Duchenne muscular dystrophy', 'There was a significant increase in fibronectin levels in DMD patients compared to age-matched controls. Fibronectin levels in patients with Becker muscular dystrophy, Bethlem myopathy, or myasthenia gravis were comparable to control levels. Progressive elevation in fibronectin levels was observed in longitudinal samples from 22 DMD patients followed up for a period of 6 months up to 4 years', 'This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients', 'Fibronectin is a serum biomarker for Duchenne muscular dystrophy.', 'Progressive elevation in fibronectin levels was observed in longitudinal samples from 22 DMD patients followed up for a period of 6 months up to 4 years.CONCLUSION AND CLINICAL RELEVANCE: This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients.', 'There was a significant increase in fibronectin levels in DMD patients compared to age-matched controls.', 'Progressive elevation in fibronectin levels was observed in longitudinal samples from 22 DMD patients followed up for a period of 6 months up to 4 years.', 'This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients.', 'Progressive elevation in fibronectin levels was observed in longitudinal samples from 22 DMD patients followed up for a period of 6 months up to 4 years. This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients.', 'This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients. © 2014 The Authors PROTEOMICS - Clinical Applications Published by Wiley-VCH Verlag GmbH & Co.', 'There was a significant increase in fibronectin levels in DMD patients compared to age-matched controls. Fibronectin levels in patients with Becker muscular dystrophy, Bethlem myopathy, or myasthenia gravis were comparable to control levels.', 'Fibronectin levels in patients with Becker muscular dystrophy, Bethlem myopathy, or myasthenia gravis were comparable to control levels. Progressive elevation in fibronectin levels was observed in longitudinal samples from 22 DMD patients followed up for a period of 6 months up to 4 years.', 'Fibronectin is a serum biomarker for Duchenne muscular dystrophy.', 'This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients.']

['Compared to age-matched controls, fibronectin levels in DMD patients were found to be significantly increased, whereas in patients with Becker muscular dystrophy, Bethlem myopathy, or myasthenia gravis were close to the control levels. Additionally, progressive elevation in fibronectin levels was observed in longitudinal samples from DMD patients followed up for a period of 6 months up to 4 years. Therefore, fibronectin is a serum biomarker for Duchenne muscular dystrophy.', 'Fibronectin is a serum biomarker for Duchenne muscular dystrophy']

['yes']

How does long-range epigenetic silencing (LRES) occur?

['Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types.', 'We demonstrate that LRES also occurs in murine cancer in vivo and mimics the molecular features of the human phenomenon, namely, downregulation of gene expression, acquisition of inactive histone marks, and DNA hypermethylation of specific CpG islands.', 'Malignant regression of cancer cells by in vitro differentiation resulted in partial reversion of LRES and gain of CTCF binding. ', 'genes in LRES regions are plastically regulated in cell differentiation and hyperproliferation, but are constrained to a coordinated repression by abolishing boundaries and the autonomous regulation of chromatin domains in cancer cells.', 'Loss of tumour suppressor gene function can occur as a result of epigenetic silencing of large chromosomal regions, referred to as long-range epigenetic silencing (LRES), and genome-wide analyses have revealed that LRES is present in many cancer types', ' Epigenetic gene silencing has always been envisaged as a local event silencing discrete genes, but recent data now indicates that large regions of chromosomes can be co-coordinately suppressed; a process termed long range epigenetic silencing (LRES)', 'LRES can span megabases of DNA and involves broad heterochromatin formation accompanied by hypermethylation of clusters of contiguous CpG islands within the region. It is not clear if LRES is initiated by one critical gene target that spreads and conscripts innocent bystanders, analogous to large genetic deletions or if coordinate silencing of multiple genes is important in carcinogenesis', 'This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors.', 'Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain.', 'The long-range epigenetic silencing (LRES) can be a frequent occurrence throughout the human genome. ', 'Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.', 'By creating an integrated prostate cancer epigenome map using tiling arrays, we show that contiguous regions of gene suppression commonly occur through long-range epigenetic silencing (LRES).', 'We identified 47 LRES regions in prostate cancer, typically spanning about 2 Mb and harbouring approximately 12 genes, with a prevalence of tumour suppressor and miRNA genes.', 'We propose that consolidation or effective reduction of the cancer genome commonly occurs in domains through a combination of LRES and LOH or genomic deletion, resulting in reduced transcriptional plasticity within these regions.', 'It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing.', 'Ikaros hypermethylation occurred in the context of a novel long-range epigenetic silencing (LRES) region.', 'Our results not only provide the first evidence that LRES can have functional specific effects in cancer but also identify several deregulated Ikaros targets that may contribute to progression in colorectal adenocarcinoma.', 'Previously, we showed that gene suppression commonly occurs across chromosome 2q14.2 in colorectal cancer, through a process of long-range epigenetic silencing (LRES), involving a combination of DNA methylation and repressive histone modifications.', 'We now investigate whether LRES also occurs in prostate cancer across this 4-Mb region and whether differential DNA methylation of 2q14.2 genes could provide a regional panel of prostate cancer biomarkers.', 'Consistent with LRES in colorectal cancer, we found regional epigenetic remodeling across 2q14.2 in prostate cancer. ', 'We were able to gain a comprehensive view of promoters with various CpG densities, including CpG Islands (CGIs), transcript bodies, and various repeat classes.', 'Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types.', 'The CpG island methylator phenotype correlates with long-range epigenetic silencing in colorectal cancer.', 'We now know that tumour suppressor genes, with CpG island-associated promoters, are commonly hypermethylated and silenced in cancer, but we do not understood what triggers this process or when it occurs during carcinogenesis. Epigenetic gene silencing has always been envisaged as a local event silencing discrete genes, but recent data now indicates that large regions of chromosomes can be co-coordinately suppressed; a process termed long range epigenetic silencing (LRES).', 'Epigenetic gene silencing has always been envisaged as a local event silencing discrete genes, but recent data now indicates that large regions of chromosomes can be co-coordinately suppressed; a process termed long range epigenetic silencing (LRES). LRES can span megabases of DNA and involves broad heterochromatin formation accompanied by hypermethylation of clusters of contiguous CpG islands within the region.']

['Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types.', 'Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types. Loss of tumour suppressor gene function can occur as a result of epigenetic silencing of large chromosomal regions, referred to as long-range epigenetic silencing (LRES), and genome-wide analyses have revealed that LRES is present in many cancer types. LRES can span megabases of DNA and involves broad heterochromatin formation accompanied by hypermethylation of clusters of contiguous CpG islands within the region. It is not clear if LRES is initiated by one critical gene target that spreads and conscripts innocent bystanders, analogous to large genetic deletions or if coordinate silencing of multiple genes is important in carcinogenesis. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.']

[]

Is GAGA associated with nucleosome-free regions (NFR)?

['One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin.', 'The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1.', 'The interactions of GAGA factor and heat shock factor with their binding sites in chromatin occurred in two modes. Their interaction with binding sites in the nucleosome-free regions did not require ATP. In the presence of ATP both factors interacted also with nucleosomal binding sites, causing nucleosome rearrangements and a refinement of nucleosome positions', 'While chromatin remodeling upon transcription factor interaction has previously been interpreted to involve nucleosome disruption, the data suggest energy-dependent nucleosome sliding as main principle of chromatin reorganization.', ' These (CT)n repeats are associated with a nonhistone protein(s) in vivo and are bound by a purified Drosophila protein, the GAGA factor, in vitro.', 'This (CT)n element appears to contribute to formation of the wild-type chromatin structure of hsp26, an organized nucleosome array that leaves the HSEs in nucleosome-free, DNase I-hypersensitive (DH) site', 'The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1.', 'One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin.', 'The iab-7 polycomb response element maps to a nucleosome-free region of chromatin and requires both GAGA and pleiohomeotic for silencing activity.', 'The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. ']

['The GAGA factor is a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin. The interactions of GAGA factor and heat shock factor with their binding sites in chromatin occurred in two modes. Their interaction with binding sites in the nucleosome-free regions did not require ATP. In the presence of ATP both factors interacted also with nucleosomal binding sites, causing nucleosome rearrangements and a refinement of nucleosome positions. While chromatin remodeling upon transcription factor interaction has previously been interpreted to involve nucleosome disruption, the data suggest energy-dependent nucleosome sliding as main principle of chromatin reorganization.', 'The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. To study the contribution of transcription factors to the establishment of this specific chromatin configuration we assembled nucleosomes on the hsp26 promoter using a cell-free reconstitution system derived from fly embryos. This (CT)n element appears to contribute to formation of the wild-type chromatin structure of hsp26, an organized nucleosome array that leaves the HSEs in nucleosome-free, DNase I-hypersensitive (DH) sites (Q. Lu, L.L. Wallrath, B.D. Allan, R.L. Glaser, J.T. Lis, and S.C.R. Elgin, J. Mol. Biol. Both DH sites were readily reconstituted from extract components.', 'One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin.']

['yes']

List symptoms of the IFAP syndrome.

['The IFAP syndrome is a rare X-linked genetic disorder characterized by the triad of follicular ichthyosis, atrichia, and photophobia.', 'Mutations in MBTPS2 have been reported to cause a broad phenotypic spectrum of X-linked genodermatoses, including IFAP (ichthyosis follicularis; atrichia and photophobia) syndrome (OMIM 308205) with or without BRESHECK (brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia) syndrome, keratosis follicularis spinulosa decalvans (KFSD; OMIM 308800) and an X-linked form of Olmsted syndrome. We report a recurrent intronic mutation in MBTPS2 (c.671-9T>G) in a Chinese patient with the typical triad of IFAP syndrome (i.e. ichthyosis, atrichia and photophobia), along with pachyonychia, palmoplantar and periorificial keratoderma, which were reminiscent of Olmsted syndrome. ', 'The ichthyosis follicular with atrichia and photophobia syndrome (IFAP) is a rare X-linked multiple congenital malformation syndrome.', 'This patient presented with a severe IFAP/BRESHECK phenotype including ichthyosis follicular, atrichia, photophobia, brain anomalies, global developmental delay, Hirschsprung disease and kidney hypoplasia. ', 'The clinical findings include all the features that dermotrichic and ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome have in common and in addition those that characterize IFAP syndrome (photophobia, recurrent respiratory infections, etc.', 'Photoletter to the editor: A new variant of ichthyosis follicularis with alopecia and photophobia (IFAP) syndrome with coexisting psoriasiform lesions and palmoplantar keratoderma. IFAP-PPK syndrome?', 'Ichthyosis follicularis, atrichia, and photophobia (IFAP) are typical features of a rare neuroichthyosis termed IFAP syndrome.', 'Child with manifestations of dermotrichic syndrome and ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome.', 'These features correspond to the ichthyosis follicularis, alopecia, photophobia (IFAP) syndrome.', 'Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare congenital disorder.', 'Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome in two unrelated female patients.', 'Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome (ichthyosis follicularis with atrichia and photophobia).', 'Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome due to mutation of the gene MBTPS2 in a large Australian kindred.', 'Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin.', 'Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis, seizures, mental retardation and inguinal hernia: a severe manifestation of IFAP syndrome?', 'Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome.', 'We describe an 18-month-old male infant suffering from the ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome and further delineate the clinical phenotype.', 'The clinical findings include all the features that dermotrichic and ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome have in common and in addition those that characterize IFAP syndrome (photophobia, recurrent respiratory infections, etc.), those that are present only in dermotrichic syndrome (nail anomalies, hypohydrosis, megacolon, vertebral defects, etc.) and additional ones (enamel dysplasia, renal anomalies, inguinal hernia, etc.).', 'The clinical findings include all the features that dermotrichic and ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome have in common and in addition those that characterize IFAP syndrome (photophobia,', 'Ichthyosis follicularis, atrichia, and photophobia (IFAP) are typical features of a rare neuroichthyosis termed IFAP syndrome.', 'These features correspond to the ichthyosis follicularis, alopecia, photophobia (IFAP) syndrome.', 'Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare congenital disorder.', 'The ichthyosis follicular with atrichia and photophobia syndrome (IFAP) is a rare X-linked multiple congenital malformation syndrome.']

['The IFAP syndrome is a rare X-linked genetic disorder characterized by the triad of follicular ichthyosis, atrichia, and photophobia.']

['follicular ichthyosis', 'atrichia', 'photophobia']

Describe what is athelia syndrome?

['Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. ', 'Absence of the nipple, areola (athelia), or the breast tissue (amastia) is less frequent.', 'The absence of nipple-areola complex is a rare entity and is always associated with other anomalies. This paper described a case of bilateral athelia without other alterations.', 'Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp-ear-nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape.', 'Athelia is a very rare entity that is defined by the absence of the nipple-areola complex.']

['Athelia is a very rare entity that is defined by the absence of the nipple-areola complex.']

[]

Was modafinil tested for schizophrenia treatment?

['Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: a randomized, double-blind, placebo-controlled study.', 'CONCLUSION: The data suggest that modafinil was a safe adjunctive treatment which improved parkinsonian symptoms and signs in patients with schizophrenia or schizoaffective disorder. ', 'A review of its effects in schizophrenia suggests that modafinil facilitates cognitive functions, with pro-mnemonic effects and problem solving improvements. Emotional processing also appears to be enhanced by the drug, although to date there are only a limited number of studies.', 'BACKGROUND: Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions. ', 'A review of modafinil and armodafinil as add-on therapy in antipsychotic-treated patients with schizophrenia.', 'It has been suggested that modafinil and its isomer armodafinil as an add-on strategy to antipsychotic treatment in patients with schizophrenia may improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions as well as weight gain.', 'Evidence for the use of modafinil or armodafinil as add-on therapy to antipsychotic drugs to alleviate fatigue, sleepiness and inactivity is inconclusive. One cohort study and one out of two single-dose crossover RCTs in which modafinil addition was studied could demonstrate a positive effect. All five RCTs of modafinil (three RCTs) and armodafinil (two RCTs) addition with a longer study duration could not demonstrate a positive effect. ', 'In RCTs with a treatment duration of 4 weeks or more, however, no positive effect could be demonstrated on cognitive functioning with modafinil and armodafinil addition. Yet, four single-dose crossover RCTs of modafinil addition show significant positive effects on executive functioning, verbal memory span, visual memory, working memory, spatial planning, slowing in latency, impulse control and recognition of faces expressing sadness and sadness misattribution in the context of disgust recognition. The addition of modafinil or armodafinil to an antipsychotic regime, despite theoretical and preclinical considerations, has not been proved to enhance cognitive function, attenuate fatigue, enhance activity, improve negative symptoms and reduce weight in patients with schizophrenia.', 'RATIONAL: In recent years, evidence suggests that modafinil may be useful for certain symptom domains of schizophrenia, especially for the negative and cognitive symptoms. ', 'CONCLUSION: The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. ', 'Modafinil is a wake-promoting drug that has been shown to improve attention, memory and executive function in the healthy population and in patients with schizophrenia.', 'CONCLUSIONS: Results of this pilot trial do not support routine use of modafinil to counteract increased weight and metabolic diseases in patients taking clozapine.', 'Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear.', 'Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy individuals and attention and executive function in schizophrenia. ', 'CONCLUSIONS: These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction.', 'Modafinil improves working memory in healthy subjects and individuals diagnosed with schizophrenia and Attention Deficit/Hyperactivity Disorder, though the effects of modafinil have not been evaluated on working memory in methamphetamine-dependent subjects.', 'Modafinil is a psychostimulant approved for treating excessive sleepiness in adults; off-label uses (e.g., treatment of cognitive impairment in schizophrenia, ADHD and age-related dementias) are currently being explored. ', 'CONCLUSIONS: Results of this pilot trial do not support routine use of modafinil to treat negative symptoms, cognitive deficits, or wakefulness/fatigue in patients on clozapine.', 'We have previously shown that the amount of movement exhibited by patients with schizophrenia is positively correlated with the volume of left anterior cingulate cortex and that this quantity of movement can be increased by modafinil. ', 'OBJECTIVE: Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability. ', 'RESULTS: One of 4 reviewed studies found a significant effect of modafinil as an alerting agent for antipsychotic-induced fatigue and sedation. Neither of 2 reviewed studies found modafinil to improve negative symptoms of schizophrenia. Three of 6 reviewed studies showed that modafinil may improve short-term memory, attention, and the ability to shift mental sets. ', 'CONCLUSIONS: While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. ', 'Hence, before prescribing modafinil to a schizophrenia patient, the possible risks and benefits of each particular case should be evaluated.', 'Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness and depression in patients with traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue and multiple sclerosis; however, it did not provide any benefit greater than placebo.', 'RATIONALE: The wake-promoting agent modafinil selectively improves neuropsychological task performance in healthy volunteers, in adults with attention deficit hyperactivity disorder (ADHD) and in schizophrenia. ', 'Recently, however, modafinil has been shown to improve attentional set-shifting performance in patients with schizophrenia.', 'In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia.', 'There is increasing interest in the use of modafinil to improve cognition in schizophrenia as well as in other disorders such as attention-deficit/hyperactivity disorder.', 'Initial findings indicate that modafinil may lead to better executive functioning and attentional performance in patients with schizophrenia. ', 'CONCLUSIONS: Although no effect on negative symptoms was found, adjunctive therapy with modafinil may result in global improvements in patients with schizophrenia who have prominent negative symptoms.', 'CONCLUSIONS: Modafinil did not improve cognitive control in all schizophrenia patients.', '. These data suggest that modafinil increases quantifiable motor behaviour in schizophrenia and may have an impact on avolition.', 'One patient was on treatment with both modafinil and trazodone and reported no change after tapering each in separate discontinuation trials, while another 3 patients were taking sleeping medications and also noted no change after discontinuation.', ' Neuroprotective agents as add-on therapies (e.g., modafinil, erythropoietin, glycine, D-serine, memantine and celecoxib) are currently being evaluated in schizophrenia and related disorders. ', 'In the modafinil (N = 10) and placebo (N = 10) groups, fatigue improved significantly over time (p < .01), but there were no differences between groups on changes in fatigue, positive and negative symptoms, or cognition. ', 'CONCLUSIONS: Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation.', 'Modafinil significantly improved overall clinical condition, with 64% and 82% of patients rated as clinically improved at week 4 by a blinded clinician and the investigator respectively.', 'Modafinil significantly improved fatigue (P = 0.025, week 3) and tended to improve cognitive functioning scores. ', 'Although preliminary, these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition, and reduces fatigue in patients with schizophrenia or schizoaffective disorder. ', 'Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. ', 'Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.', 'While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia.', 'Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability.', 'The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms.', ' It has been suggested that modafinil and its isomer armodafinil as an add-on strategy to antipsychotic treatment in patients with schizophrenia may improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions as well as weight gain.', 'CONCLUSION: The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms.', 'OBJECTIVE: Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability.', 'CONCLUSIONS: While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia.', 'The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms.', 'Although preliminary, these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition, and reduces fatigue in patients with schizophrenia or schizoaffective disorder.', 'While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia', 'The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms', 'Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions']

['Yes. Modafinil has been shown to improve attention, memory, executive function and antipsychotic-induced parkinsonism in patients with schizophrenia. However, some authors have failed to demonstrate beneficial action of modafinil for schizophrenia.']

['yes']

Can glyburide reduce cerebral edema?

['Preclinical studies have shown that a continuous infusion of glyburide blocks edema formation and improves outcome. We hypothesize that treatment with RP-1127 (Glyburide for Injection) reduces formation of brain edema in patients after large anterior circulation infarction.', 'CONCLUSIONS: GAMES-RP was designed to provide critical information regarding glyburide for injection in patients with large hemispheric stroke and will inform the design of future studies.', 'Glyburide is associated with attenuated vasogenic edema in stroke patients.', 'Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. ', 'RESULTS: We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level.CONCLUSIONS: Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. ', 'Pilot study of intravenous glyburide in patients with a large ischemic stroke.', 'BACKGROUND AND PURPOSE: Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. ', 'Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema.', 'Glyburide in Treating Malignant Cerebral Edema. ', 'Glyburide in Treating Malignant Cerebral Edema. Blocking Sulfonyl Urea One (SUR1) Receptors.', 'The sulfonylurea receptor 1-regulated NC(Ca-ATP) channel is upregulated in rodent models of stroke with block of the channel by the sulfonylurea, glibenclamide (glyburide), significantly reducing mortality, cerebral edema, and infarct volume.', 'Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema.', 'In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema.', 'Potential of glyburide to reduce intracerebral edema in brain metastases.', 'Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial: Rationale and Design.', 'Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema.', 'Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage.', 'Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema', 'RESULTS: We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level. ', 'Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. ', 'Exploratory analysis of glyburide as a novel therapy for preventing brain swelling.', 'Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. ', 'In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema.', 'Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema.', 'Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4.', 'Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke.', 'We hypothesize that treatment with RP-1127 (Glyburide for Injection) reduces formation of brain edema in patients after large anterior circulation infarction.', 'Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema..', 'Glyburide is associated with attenuated vasogenic edema in stroke patients.']

['Yes. Glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing and attenuating cerebral edema.']

['yes']

What is the function of Neu5Gc (N-Glycolylneuraminic acid)?

['Humans lack a functional cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate mammalian signal of self', 'N-glycolylneuraminic acid (Neu5Gc) is an immunogenic sugar of dietary origin that metabolically incorporates into diverse native glycoconjugates in humans. ', 'N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by animals, but not by humans or birds. However, it can be incorporated in human cells and can trigger immune response.', 'Human heterophile antibodies that agglutinate animal erythrocytes are known to detect the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc). ', ' the human anti-Neu5Gc antibody response is diverse and polyclonal.', 'As dietary Neu5Gc is primarily found in red meat and milk products, we suggest that this ongoing antigen-antibody reaction may generate chronic inflammation, possibly contributing to the high frequency of diet-related carcinomas and other diseases in humans.', 'These data suggest that anti-Neu5Gc Abs represent a barrier for long-term acceptance of porcine xenografts. Because anti-Neu5Gc Abs can promote chronic inflammation, the long-term safety of living and acellular pig tissue implants in recipients warrants further evaluation.']

['N-glycolylneuraminic acid (Neu5Gc) is an immunogenic sugar of dietary origin that metabolically incorporates into diverse native glycoconjugates in humans. Humans lack a functional cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate mammalian signal of self. N-Glycolylneuraminic acid (Neu5Gc) can be incorporated in human cells and can trigger immune response, a response that is diverse and polyclonal. As dietary Neu5Gc is primarily found in red meat and milk products, it is suggested that this ongoing antigen-antibody reaction may generate chronic inflammation, possibly contributing to the high frequency of diet-related carcinomas and other diseases in humans.']

['Neu5Gc is an immune message to self']

Is Hirschsprung disease a mendelian or a multifactorial disorder?

['Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes', "In this study, we review the identification of genes and loci involved in the non-syndromic common form and syndromic Mendelian forms of Hirschsprung's disease. The majority of the identified genes are related to Mendelian syndromic forms of Hirschsprung's disease. The non-Mendelian inheritance of sporadic non-syndromic Hirschsprung's disease proved to be complex; involvement of multiple loci was demonstrated in a multiplicative model", 'Coding sequence mutations in e.g. RET, GDNF, EDNRB, EDN3, and SOX10 lead to long-segment (L-HSCR) as well as syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). Furthermore, mutations in the RET gene are responsible for approximately half of the familial and some sporadic cases, strongly suggesting, on the one hand, the importance of non-coding variations and, on the other hand, that additional genes involved in the development of the enteric nervous system still await their discovery', 'For almost all of the identified HSCR genes incomplete penetrance of the HSCR phenotype has been reported, probably due to modifier loci. Therefore, HSCR has become a model for a complex oligo-/polygenic disorder in which the relationship between different genes creating a non-mendelian inheritance pattern still remains to be elucidated', ' Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes.', ' The inheritance of Hirschsprung disease is generally consistent with sex-modified multifactorial inheritance with a lower threshold of expression in males.', 'Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes.', 'Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.', 'BACKGROUND: RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology.', 'In the etiology of Hirschsprung disease various genes play a role; these are: RET, EDNRB, GDNF, EDN3 and SOX10, NTN3, ECE1, Mutations in these genes may result in dominant, recessive or multifactorial patterns of inheritance.', "Chromosomal and related Mendelian syndromes associated with Hirschsprung's disease.", "The majority of the identified genes are related to Mendelian syndromic forms of Hirschsprung's disease", 'In the etiology of Hirschsprung disease various genes play a role; these are: RET, EDNRB, GDNF, EDN3 and SOX10, NTN3, ECE1, Mutations in these genes may result in dominant, recessive or multifactorial patterns of inheritance', 'On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder', 'The inheritance of Hirschsprung disease is generally consistent with sex-modified multifactorial inheritance with a lower threshold of expression in males', "The non-Mendelian inheritance of sporadic non-syndromic Hirschsprung's disease proved to be complex; involvement of multiple loci was demonstrated in a multiplicative model"]

["Coding sequence mutations in RET, GDNF, EDNRB, EDN3, and SOX10 are involved in the development of Hirschsprung disease. The majority of these genes was shown to be related to Mendelian syndromic forms of Hirschsprung's disease, whereas the non-Mendelian inheritance of sporadic non-syndromic Hirschsprung disease proved to be complex; involvement of multiple loci was demonstrated in a multiplicative model."]

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Which is the most prevalent form of arrhythmia worldwide?

['Atrial fibrillation remains the most prevalent cardiac arrhythmia, and its incidence is increasing as the population ages. ', 'Atrial fibrillation is the most prevalent sustained arrhythmia. ', 'Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and has a significant impact on morbidity and mortality.', 'Atrial fibrillation is the most common heart rhythm disorder in the world, with major public health impact especially due to increased risk of stroke and hospitalizations.', 'Atrial fibrillation is the most common arrhythmia affecting patients today.', 'Atrial fibrillation (AF) is the most common arrhythmia worldwide, and it has a significant effect on morbidity and mortality. It is a significant risk factor for stroke and peripheral embolization, and it has an effect on cardiac function.', 'Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting up to 1-1.5% of the population.', 'Atrial fibrillation is the most prevalent form of cardiac arrhythmia.', 'Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality.', 'Atrial fibrillation (AF) is associated with increased morbidity and is in addition the most prevalent cardiac arrhythmia.', 'Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in clinical practice associated with significant morbidity and mortality', 'Atrial fibrillation is the most prevalent form of cardiac arrhythmia']

['Atrial fibrillation (AF) is the most common arrhythmia worldwide, and it has a significant effect on morbidity and mortality. It is a significant risk factor for stroke and peripheral embolization, and it has an effect on cardiac function. Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting up to 1-1.5% of the population.']

['atrial fibrilation', 'AF']

Why graphics processing units (GPU) are more suitable for biological tasks than central processing units (CPU)?

['The global speedups of 22.11, 38.80, and 44.80 are found comparing the parallel computation of one GPU, two GPUs by exact rotational operator, and two GPU versions by an approximate rotational operator with serial computation of the CPU', 'evaluate the use of general-purpose graphics processing units (GPGPUs) to improve the performance of MODFLOW, an unstructured preconditioned conjugate gradient (UPCG) solver has been developed', 'UPCG solver uses a compressed sparse row storage scheme and includes Jacobi, zero fill-in incomplete, and modified-incomplete lower-upper (LU) factorization, and generalized least-squares polynomial preconditioners. The UPCG solver also includes options for sequential and parallel solution on the central processing unit (CPU) using OpenMP', 'Testing indicates GPGPU speedups on the order of 2 to 8, relative to the standard MODFLOW preconditioned conjugate gradient (PCG) solver, can be achieved when (1) memory copies between the CPU and GPGPU are optimized, (2) the percentage of time performing memory copies between the CPU and GPGPU is small relative to the calculation time, (3) high-performance GPGPU cards are utilized, and (4) CPU-GPGPU combinations are used to execute sequential operations that are difficult to parallelize', 'A list-mode ToF OSEM library was developed on the GPU-CUDA platform. Our studies show that the GPU reformulation is considerably faster than a single-threaded reference CPU method especially for ToF processing, while producing virtually identical images', 'When applied to line projection operations for non-ToF list-mode PET, this new GPU-CUDA method is >200 times faster than a single-threaded reference CPU implementation', 'The GPU-based parallel implementation of the Gillespie stochastic simulation algorithm (SSA), the logarithmic direct method (LDM) and the next reaction method (NRM) is approximately 85 times faster than the sequential implementation of the NRM on a central processing unit (CPU', 'exploration of fundamental biological processes involving the forced unraveling of multimeric proteins, the sliding motion in protein fibers and the mechanical deformation of biomolecular assemblies under physiological force loads is challenging even for distributed computing systems', 'We assessed the computational performance of an end-to-end application of the program, where all the steps of the algorithm are running on a GPU, by profiling the simulation time and memory usage for a number of test systems', 'Our results show that the GPGPUs can provide significant speedup over conventional processors', 'explore the power and feasibility of using programmable graphics processing units (GPUs) for real-time rendering and displaying large 3D medical datasets for stereoscopic display workstation', 'The performance of rendering and displaying was measured and compared between GPU-based and central processing unit (CPU)-based programming. The results indicate that GPU-based programming was capable of rendering large 3D datasets at real-time interactive rates with stereographic displays']

['Traditional central processing unist (CPUs) are reaching their limit in processing power and are not designed primarily for multithreaded applications. Graphics processing units (GPUs) on the other hand are affordable, scalable computer powerhouses that, thanks to the ever increasing demand for higher quality graphics, have yet to reach their limit. Typically high-end CPUs have 8-16 cores, whereas GPUs can have more than 2,500 cores. GPUs are also, by design, highly parallel, multicore and multithreaded, able of handling thousands of threads doing the same calculation on different subsets of a large data set. This ability is what makes them perfectly suited for biological analysis tasks. Lately this potential has been realized by many bioinformatics researches and a huge variety of tools and algorithms have been ported to GPUs, or designed from the ground up to maximize the usage \nof available cores.']

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List representatives of the major fungal hypoxanthine-adenine-guanine transporter families.

['Comparative kinetic analysis of AzgA and Fcy21p, prototypes of the two major fungal hypoxanthine-adenine-guanine transporter families', 'We carried out a comparative kinetic analysis of two prototypes of these transporter families. The first was Fcy21p, a herein characterized protein of Candida albicans, and the second was AzgA, a transporter of Aspergillus nidulans', 'The azgA gene of Aspergillus nidulans encodes a hypoxanthine-adenine-guanine transporter', 'In Aspergillus nidulans, loss-of-function mutations in the uapA and azgA genes, encoding the major uric acid-xanthine and hypoxanthine-adenine-guanine permeases, respectively, result in impaired utilization of these purines as sole nitrogen sources', 'Comparative kinetic analysis of AzgA and Fcy21p, prototypes of the two major fungal hypoxanthine-adenine-guanine transporter families.', 'The azgA gene of Aspergillus nidulans encodes a hypoxanthine-adenine-guanine transporter.', 'In Aspergillus nidulans, loss-of-function mutations in the uapA and azgA genes, encoding the major uric acid-xanthine and hypoxanthine-adenine-guanine permeases, respectively, result in impaired utilization of these purines as sole nitrogen sources.', 'Modelling, substrate docking and mutational analysis identify residues essential for function and specificity of the major fungal purine transporter AzgA.', 'In Arabidopsis two proteins, AtAzg1 and AtAzg2, show substantial amino acid sequence similarity to the adenine-guanine-hypoxanthine transporter AzgA of Aspergillus nidulans']

['AzgA and Fcy21p are prototypes of the two major fungal hypoxanthine-adenine-guanine transporter families.']

['AzgA', 'Fcy21p']

Is K-63 linked protein ubiquitination related to proteasomal degradation?

['In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes.', 'Modification of proteins by the addition of lysine (K)-63-linked polyubiquitin (polyUb) chains is suggested to play important roles in a variety of cellular events, including DNA repair, signal transduction, and receptor endocytosis. ', 'Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor kappaB (NF-kappaB) through IkappaB kinase beta (IKKbeta), but a negative role in the noncanonical pathway that activates NF-kappaB through IKKalpha. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K(63) polyubiquitin chains, but is targeted to degradation by the proteasome when it is K(48)-polyubiquitinted by the NF-kappaB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways.', 'Importantly, although Lys-48-linked ubiquitin chains appear to trigger proteasomal degradation, the presence of Lys-63-linked ubiquitin chains suggests that ubiquitination of IP(3)Rs may have physiological consequences beyond signaling for degradation.', 'Chains of ubiquitin linked via lysine 48 (K48) are associated with protein degradation while chains linked via lysine 63 (K63) are associated with intracellular signaling.', 'Lys(48)-linked chains target proteins for proteasomal degradation, and Lys(63)-linked chains function in signal transduction, endocytosis and DNA repair', 'Remarkably, the attached Lys-48- and Lys-63-linked ubiquitin chains are homogeneous and are segregated to separate IP(3)R subunits, and Lys-48-linked ubiquitin chains, but not Lys-63-linked chains, are required for IP(3)R degradation', 'Activated inositol 1,4,5-trisphosphate receptors are modified by homogeneous Lys-48- and Lys-63-linked ubiquitin chains, but only Lys-48-linked chains are required for degradation.']

['Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor kappaB (NF-kappaB) through IkappaB kinase beta (IKKbeta), but a negative role in the noncanonical pathway that activates NF-kappaB through IKKalpha. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K(63) polyubiquitin chains, but is targeted to degradation by the proteasome when it is K(48)-polyubiquitinted by the NF-kappaB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways.In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes.', 'In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes. Modification of proteins by the addition of lysine (K)-63-linked polyubiquitin (polyUb) chains is suggested to play important roles in a variety of cellular events, including DNA repair, signal transduction, and receptor endocytosis. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism.', 'One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism', 'Modification of proteins by the addition of lysine (K)-63-linked polyubiquitin (polyUb) chains is suggested to play important roles in a variety of cellular events, including DNA repair, signal transduction, and receptor endocytosis. In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes.']

['no']

Which cell type has the protein Chromogranin A as marker?

['Neuroendocrine differentiation (chromogranin A and/or synaptophysin positivity) ', 'All paragangliomas were universally positive for chromogranin A ', 'chromogranin A (CGA) is a useful marker for pancreatic neuroendocrine tumors (pNET)', 'Together with Chromogranin B and Secretogranins, Chromogranin A (CGA) is stored in secretory (chromaffin) granules of the diffuse neuroendocrine system', 'Chromogranin A (CgA) is the most important general tumour marker used in the diagnosis and follow-up of patients with neuroendocrine tumours (NET).', 'Chromogranin A (CgA) not only plays an important role in pathologic diagnosis, but is also used as a circulating biomarker in patients with gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN).', 'numbers of chromogranin A (CHGA)-positive enteroendocrine cells (EEC', ' CgA is a reliable serum diagnostic biomarker for PNETs', 'Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients.', 'the neuroendocrine markers chromogranin A and synaptophysin;']

['Chromogranin A is a marker for neuroendocrine cells']

['neuroendocrine cells']

What is ATAC-seq?

["We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.", 'We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis.', 'ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution.', "Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.", 'We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ', 'When TFs are bound to active regulatory regions, they displace canonical nucleosomes, making these regions biochemically detectable as nucleosome-depleted regions or accessible/open chromatin. Here we ask whether open chromatin profiling can be used to identify the entire repertoire of active promoters and enhancers underlying tissue-specific gene expression during normal development and oncogenesis in vivo. To this end, we first compare two different approaches to detect open chromatin in vivo using the Drosophila eye primordium as a model system: FAIRE-seq, based on physical separation of open versus closed chromatin; and ATAC-seq, based on preferential integration of a transposon into open chromatin. ', 'We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution.']

['ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. ', 'An assay for transposase-accessible chromatin using sequencing (ATAC-seq) is based on in vitro transposition of sequencing adaptors into native chromatin. It is described as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution.']

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Is the protein FAK (Focal Adhesion Kinase) phosphorylated?

['Overexpression of NEDD9 led to tyrosine phosphorylation of FAK and SRC oncoproteins, ', 'yrosine phosphorylated FAK', 'TNFα contributes for attenuating both Y397FAK and Y416Src phosphorylations in osteoblasts.', ' It was possible to show that TNFα provokes attenuation at Y-phosphorylation of both FAK (at Y397 )', 'ownregulation of G3BP significantly inhibited the phosphorylation of Src, FAK', 'Periodic mechanical stress significantly induced sustained phosphorylation of FAK at Tyr(397) and Tyr(576/577). ', 'oss of αSNAP impaired Golgi-dependent glycosylation and trafficking of β1 integrin and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin resulting in FA disassembly.', "functional characterization of many of today's best-known Src substrates (for example, p85-Cortactin, p110-AFAP1, p130Cas, p125FAK and p120-catenin)", 'Western blots were used for P-FAK', 'e first time, that the EGF-dependent EGFR activation led to increased P-FAKSer732', '. P-FAKSer732 presence was crucial for the maintenance of the proliferation rate and its levels were inversely related to the levels of acetylated α-tubulin. P-FAKSer732 localized at the microtubules (MTs) of the spindle, biochemically associated with MTs and contributed to MT depolymerization.', 'specially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1nM of methyl violet 2B in A375P cancer cells. ', ' The protein expression of PTPN13, focal adhesion kinase (FAK) and phosphorylated FAK (P-FAK) was evaluated using immunohistochemical staining and western blotting.', 'Curcumin inhibits focal adhesion kinase (FAK) phosphorylation and enhances the expressions of several extracellular matrix components which play a critical role in invasion and metastasis. ', 'uppressed both the phosphorylation of FAK ', ' A GEF-inactive Rgnef mutant rescues FAK-Y397 phosphorylation ']

['yes, the protein FAK (Focal Adhesion Kinase) is phosphorylated.']

['yes']

What do mepolizumab and reslizumab have in common?

['The most promising agents are targeted against cytokines of Th2 pattern and related receptors, such as IL-2 (daclizumab) and IL-13 (lebrikizumab) or IL-5 in patients with hypereosinophilia (mepolizumab, reslizumab and benralizumab).', 'Patients with severe asthma or COPD have often a suboptimal symptom control due to inadequate treatment. ', 'For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6 years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL-5 receptor α-chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated.', 'IL-5 antagonist therapies in current development include two monoclonal anti-IL-5 antibodies (mepolizumab, reslizumab), a monoclonal antibody directed at the IL-5 receptor (benralizumab), and anti-sense oligonucleotide therapy (TPI ASM8).', 'In patients with severe, refractory asthma associated with eosinophilia, however, clinical trials have demonstrated significant reductions in asthma exacerbations. Clinical studies in other disorders, particularly eosinophilic esophagitis and hypereosinophilic syndrome, have also shown significant improvements in blood and/or tissue eosinophilia and variable alterations in clinical disease activity. Strategies aimed at the inhibition of IL-5 may hold great promise in the treatment of eosinophilic diseases.', 'Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability to reduce blood and tissue eosinophil counts. ', 'Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab).', 'To date, two humanized monoclonal antibodies, mepolizumab and reslizumab, have been developed that bind to human IL-5.', 'Monoclonal antibodies directed towards interleukin-5, such as mepolizumab or reslizumab, were shown to be very effective at reducing blood and airways eosinophilia.', 'IL-5 antagonist therapies in current development include two monoclonal anti-IL-5 antibodies (mepolizumab, reslizumab), a monoclonal antibody directed at the IL-5 receptor (benralizumab), and anti-sense oligonucleotide therapy (TPI ASM8).', 'The most promising agents are targeted against cytokines of Th2 pattern and related receptors, such as IL-2 (daclizumab) and IL-13 (lebrikizumab) or IL-5 in patients with hypereosinophilia (mepolizumab, reslizumab and benralizumab).', 'Asthma is a chronic inflammatory disease that often features eosinophilia, especially in its most severe forms. Monoclonal antibodies directed towards interleukin-5, such as mepolizumab or reslizumab, were shown to be very effective at reducing blood and airways eosinophilia. ']

['Mepolizumab and reslizumab are monoclonal antibodies that target and neutralize interleukin 5. They have been shown to reduce eosinophil counts and they are used for the treatment of refractory asthma (associated with eosiniphilia) and other eosinophilic diseases.']

['monoclonal antibodies', 'treatment for refractory asthma', 'treatment for eosinophilic disease', 'neutralize interleukin 5', 'reduce eosinophil counts']

Describe a diet that reduces the chance of kidney stones.

['calcium oxalate remains the dominant type accounting for 64% of stones in our dataset,', 'Uric acid stones contributed 16% of contemporary stone compositions,', 'Struvite stones showed a decreasing trend from 14% in the 1970s, to 12% in the 1980s and 7% in the current data.', '. Given recent concerns that calcium supplements may raise risk for cardiovascular disease and kidney stones,']

['People can help prevent kidney stones by making changes in fluid intake and, depending on the type of kidney stone, changes in consumption of sodium, animal protein, calcium, and oxalate.\nDrinking enough fluids each day is the best way to help prevent most types of kidney stones. Health care providers recommend that a person drink 2 to 3 liters of fluid a day. People with cystine stones may need to drink even more. Though water is best, other fluids may also help prevent kidney stones, such as citrus drinks.']

['reducing sodium']

How long, in kb (kilobases), is a "Long interspersed nuclear element"?

[' A combination of molecular hybridization studies and long-range polymerase chain reaction was used to isolate a 6-kb full-length long interspersed nuclear element (LINE or L1)', 'LINE (7kb long interspersed nuclear element),', 'The retrotransposon known as long interspersed nuclear element-1 (L1) is 6 kb long, although most L1s in mammalian and other eukaryotic cells are truncated.']

['The retrotransposon known as long interspersed nuclear element-1 (L1) is 6-7 kb long,']

['6-7 kb']

Which protein is the main inhibitor of protein phosphatase 1 (PP1)?

["The type 1 protein phosphatase (PP1) is a critical negative regulator of Ca(2+) cycling and contractility in the cardiomyocyte. In particular, it mediates restoration of cardiac function to basal levels, after beta-adrenergic stimulation, by dephosphorylating key phospho-proteins. PP1 is a holoenzyme comprised of its catalytic and auxiliary subunits. These regulatory proteins dictate PP1's subcellular localization, substrate specificity and activity. Amongst them, inhibitor-1 is of particular importance since it has been implicated as an integrator of multiple neurohormonal pathways, which finely regulate PP1 activity, at the level of the sarcoplasmic reticulum (SR). In fact, perturbations in the regulation of PP1 by inhibitor-1 have been implicated in the pathogenesis of heart failure, suggesting that inhibitor-1-based therapeutic interventions may ameliorate cardiac dysfunction and remodeling in the failing heart. ", 'Aberrant beta-adrenergic signaling and depressed calcium homeostasis, associated with an imbalance of protein kinase A and phosphatase-1 activities, are hallmarks of heart failure. Phosphatase-1 is restrained by its endogenous inhibitor, protein phosphatase inhibitor-1 (PPI-1)', 'Using this technology, we showed that inhibition of the protein phosphatase 1, by its constitutively active inhibitor-1, significantly increases cardiac contractility and calcium handling. ', 'Thus, long-term cardiac specific overexpression of the protein phosphatase 1 inhibitor-1 and the associated increases in cardiac contractility appear to herald changes in a rather small number of proteins, which may reflect important compensatory adaptations in a hyperdynamic heart [corrected]', 'Inhibitor-1 becomes a potent inhibitor of protein phosphatase 1 when phosphorylated by cAMP-dependent protein kinase at Thr(35). Moreover, Ser(67) of inhibitor-1 serves as a substrate for cyclin-dependent kinase 5 in the brain.', 'Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), a major eukaryotic Ser/Thr phosphatase. Nonphosphorylated I-1 is inactive, whereas phosphorylated I-1 is a potent PP1 inhibitor. ', 'Ser67-phosphorylated inhibitor 1 is a potent protein phosphatase 1 inhibitor.', 'PP1 activity was inhibited by protamine, heparin, okadaic acid (IC50 50 nM) and mammalian inhibitor-1 (IC50 2 nM). On the other hand. ', 'The cDNA encoding human brain protein phosphatase inhibitor-1 (I-1) was expressed in Escherichia coli. Following PKA phosphorylation at a threonine, recombinant human I-1 was indistinguishable from rabbit skeletal muscle I-1 as a potent and specific inhibitor of the type-1 protein serine/threonine phosphatase (PP1). N-Terminal phosphopeptides of I-1 that retained the selectivity of intact human I-1 highlighted a functional domain that mediates PP1 inhibition.', "Protein phosphatase inhibitor-1 was purified from bovine adipose tissue. The protein had an apparent molecular mass of 32 kDa by SDS/PAGE and a Stokes' radius of 3.4 nm. It was phosphorylated by cAMP-dependent protein kinase on a threonyl residue; this phosphorylation was necessary for inhibition of protein phosphatase-1.", 'Bovine adipose tissue inhibitor-1 was compared directly with rabbit skeletal muscle inhibitor-1 and with a 32000-Mr, dopamine- and cAMP-regulated phosphoprotein from bovine brain (DARPP-32), also an inhibitor of protein phosphatase-1. ', 'Protein inhibitor-1 (I-1) specifically inhibits protein phosphatase 1 (PP1), the predominant PLB phosphatase in heart.', 'Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), the predominating Ser/Thr phosphatase in the heart.', 'Inhibitor-1 (I-1) is a selective inhibitor of protein phosphatase-1 (PP1) and regulates several PP1-dependent signaling pathways, including cardiac contractility and regulation of learning and memory.', 'Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), a major eukaryotic Ser/Thr phosphatase.', 'Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), the predominating Ser/Thr phosphatase in the heart', 'Protein inhibitor-1 (I-1) specifically inhibits protein phosphatase 1 (PP1), the predominant PLB phosphatase in heart']

['Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), a major eukaryotic Ser/Thr phosphatase. Nonphosphorylated I-1 is inactive, whereas phosphorylated I-1 is a potent PP1 inhibitor. ', 'Protein Phosphatase-1 is restrained by its endogenous inhibitor, protein phosphatase inhibitor-1 (PPI-1). Inhibition of the protein phosphatase 1, by inhibitor-1, significantly increases cardiac contractility and calcium handling. Inhibitor-1 becomes a potent inhibitor of protein phosphatase 1 when phosphorylated by cAMP-dependent protein kinase.']

['protein phosphatase inhibitor 1', 'inhibitor 1', 'PPI-1', 'I1']

Which heat shock protein is found to be upregulated during Hsp90 inhibition?

['HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phospho-rylation and the induction of HSP70 expression.', 'Inhibition of Hsp90 upregulated the expression of Hsp70 and Hsp70-bound Nox2, 5 and promoted degradation.', 'Conversely, inhibition of HSP90 significantly increased the expression of both VEGF and HGF mRNA, and induced HSP70 protein in PHH cultures in vitro.']

['HSP90 inhibition was found to be associated with induction of HSP70 expression.']

['HSP70']

What is known about maternal smoking and brain tumor risk?

['BACKGROUND: A recent meta-analysis suggested an association between exposure to paternal smoking during pregnancy and childhood brain tumor risk, but no studies have evaluated whether this association differs by polymorphisms in genes that metabolize tobacco-smoke chemicals.', 'OBJECTIVE: Studies of the effect of maternal smoking during pregnancy on development of brain tumors in the offspring generally have found no increase in risk but most have mainly relied on retrospective exposure assessment. ', 'Children of women who smoked during pregnancy had an increased incidence of brain tumors (hazard ratio = 1.24; 95% confidence interval: 1.01-1.53). The increase in risk was similar for benign and malignant tumors, and was most apparent for astrocytoma. ', 'CONCLUSIONS: These results support a role for maternal smoking during pregnancy in the etiology of childhood brain tumors.', 'Maternal occupational exposure to PAH before conception or during pregnancy was rare, and this exposure was not associated with any type of childhood brain tumor. ', "There was no association between the risk of brain tumors in the child and parental smoking prior to pregnancy, maternal smoking or regular exposure to others' cigarette smoke during pregnancy at home or at work, or passive smoking by the child during the first year of life.", 'Maternal smoking during pregnancy and the risk of childhood brain tumors: a meta-analysis of 6566 subjects from twelve epidemiological studies.', 'OBJECTIVE: Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood brain tumors.', 'Pooling all twelve reports yielded an RRs of 1.05 (0.90-1.21), a non-statistically significant result suggesting no clear association between maternal smoking during pregnancy and risk of childhood brain tumor development.', '.CONCLUSION: The available epidemiological data do not support a clear association between maternal smoking during pregnancy and pediatric brain tumor development. ', 'We observed only few positive associations, namely, between CNS tumors and low birth weight [<2,500 g; odds ratio (OR), 1.73; 95% confidence interval (CI), 1.06-2.84], between ependymoma and maternal smoking during pregnancy (>10 cigarettes per day: OR, 4.71; 95% CI, 1.69-13.1), and between astrocytoma and exposure to wood preservatives (OR, 1.91; 95% CI, 1.22-3.01). ', 'The results on exposure to paternal tobacco smoke suggest an association with brain tumors (RR 1.22; CI, 1.05-1. 40; based on 10 studies) and lymphomas (RR 2.08; CI, 1.08-3.98; 4 studies). ', 'No association was found between the risk of CBTs and maternal or paternal smoking before pregnancy and there was no association between CBTs and maternal smoking during pregnancy [odds ratio (OR) = 0.98; 95% confidence interval (CI) = 0.72-1.3]. A slightly increased OR for CBTs was found for paternal smoking during pregnancy in the absence of maternal smoking (OR = 1.2; 95% CI = 0.90-1.5) and for maternal exposure to passive smoke from any source (OR = 1.2; 95% CI = 0.95-1.6). The results of this analysis are consistent with results from several prior epidemiological studies that showed no significant association between CBTs and maternal smoking before or during pregnancy or maternal exposure to passive smoke during pregnancy.', 'No significant differences in risks were found to be associated with maternal or paternal smoking at any time (odds ratio (OR) = 0.92 for mothers and 1.06 for fathers), during the year of birth of the child (which included both the prenatal and postnatal periods) (ORs = 0.84 for<1 pack/day and 1.0 for>or = 1 pack/day for mothers, and 0.68 for<1 pack/day and 1.07 for>or = 1 pack/day for fathers), or 2 years before the child was born, i.e., the pre-conception period (ORs = 0.75 for<1 pack/day and 1.01 for>or = 1 pack/day for mothers, and 0.90 for<1 pack/day and 1.15 for>or = 1 pack/day for fathers). Mothers were also specifically asked if they smoked during the pregnancy, and no association was found compared with never smokers (OR = 1.08, 95% confidence interval (CI) 0.80-1.45) or for ever-smokers who continued to smoke during pregnancy compared with those who stopped smoking during pregnancy (OR = 1.15, 95% CI 0.75-1.78). ', 'The lack of an effect of parental smoking was observed for both the major histologic types and locations of brain tumors. These findings and those from earlier studies provide no support for the hypothesis that parental cigarette smoking influences the risk of brain tumors in children.', 'Increased risk was associated with maternal contact with nitrosamine-containing substances such as burning incense (odds ratio, 3.3; p = 0.005), sidestream cigarette smoke (odds ratio, 1.5; p = 0.03), and face makeup (odds ratio, 1.6; p = 0.02); with maternal use of diuretics (odds ratio, 2.0; p = 0.03) and antihistamines (odds ratio, 3.4; p = 0.002); and with the level of maternal consumption of cured meats (p = 0.008).', 'Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood brain tumors.', 'Studies of the effect of maternal smoking during pregnancy on development of brain tumors in the offspring generally have found no increase in risk but most have mainly relied on retrospective exposure assessment.', 'No association was found between the risk of CBTs and maternal or paternal smoking before pregnancy and there was no association between CBTs and maternal smoking during pregnancy [odds ratio (OR) = 0.98; 95% confidence interval (CI) = 0.72-1.3].', "There was no association between the risk of brain tumors in the child and parental smoking prior to pregnancy, maternal smoking or regular exposure to others' cigarette smoke during pregnancy at home or at work, or passive smoking by the child during the first year of life.", 'RESULTS: We found positive interaction odds ratios (ORs) for both maternal and paternal smoking during pregnancy, EPHX1 H139R, and childhood brain tumors (P(interaction)\u200a=\u200a0.02; 0.10), such that children with the high-risk (greater PAH activation) genotype were at a higher risk of brain tumors relative to children with the low-risk genotype when exposed to tobacco smoke during pregnancy. ', "Finally, no significant increase in risk of brain tumors was found for the child's passive exposure to parental smoking during the period from birth to diagnosis of the brain tumor in the case.", 'Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood brain tumors.', 'a non-statistically significant result suggesting no clear association between maternal smoking during pregnancy and risk of childhood brain tumor development.', 'These results support a role for maternal smoking during pregnancy in the etiology of childhood brain tumors.']

['Findings regarding association of maternal smoking and brain tumor risk are mixed. It was shown that children of women who smoked during pregnancy had an increased incidence of brain tumors (hazard ratio = 1.24; 95% confidence interval: 1.01-1.53). The increase in risk was similar for benign and malignant tumors, and was most apparent for astrocytoma. However, other authors did not find association between maternal smoking and brain tumor risk.']

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Is autism one of the characteristics of Moebius syndrome?

['The diagnosis of Moebius syndrome, a rare congenital disorder, is primarily based on congenital facial and abducent nerve palsy. Involvement of other cranial nerves is also common. Occasionally the V, X, XI, and XII cranial nerves are involved, resulting in a difficulty to chew, swallow, and cough, which often leads to respiratory complications. Mental retardation and autism have been reported in some cases', 'Moebius sequence is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. A strong association of Moebius sequence with autism spectrum disorders (ASDs) has been suggested in earlier studies with heterogenous age groups', "Certain genetic syndromes are providing us with extremely valuable information about the role played by genetics in autism. This is the case of the following syndromes: Angelman syndrome, Prader-Willi syndrome, 15q11-q13 duplication, fragile X syndrome, fragile X premutation, deletion of chromosome 2q, XYY syndrome, Smith-Lemli-Opitz syndrome, Apert syndrome, mutations in the ARX gene, De Lange syndrome, Smith-Magenis syndrome, Williams syndrome, Rett syndrome, Noonan syndrome, Down syndrome, velo-cardio-facial syndrome, myotonic dystrophy, Steinert disease, tuberous sclerosis, Duchenne's disease, Timothy syndrome, 10p terminal deletion, Cowden syndrome, 45,X/46,XY mosaicism, Myhre syndrome, Sotos syndrome, Cohen syndrome, Goldenhar syndrome, Joubert syndrome, Lujan-Fryns syndrome, Moebius syndrome, hypomelanosis of Ito, neurofibromatosis type 1, CHARGE syndrome and HEADD syndrome.", 'Seventeen children and young adults with Moebius syndrome were examined with a view to finding symptoms of autism. Some 40% of the group showed all or many of the symptoms typical of autistic disorder', "Fifty-nine cases with infantile autism/autistic disorder were subclassified according to associated medical condition (fragile-X, tuberous sclerosis, neurofibromatosis, hypo-melanosis of Ito, Moebius syndrome, Rett syndrome, and a 'new' syndrome associated with a marker chromosome).", 'Autism spectrum disorders in children and adolescents with Moebius sequence.', 'Moebius sequence and autism spectrum disorders--less frequently associated than formerly thought.', 'A strong association of Moebius sequence with autism spectrum disorders (ASDs) has been suggested in earlier studies with heterogenous age groups.', 'Autistic behaviour in Moebius syndrome.', 'The high frequency of autistic symptoms in Moebius syndrome might be a marked overrepresentation and could be suggestive of a common underlying neurobiological deficit at the brainstem level.', 'Autism spectrum disorders in children and adolescents with Moebius sequence.', 'Moebius sequence and autism spectrum disorders--less frequently associated than formerly thought.', 'Autistic behaviour in Moebius syndrome.']

['Moebius syndrome is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. A strong association of Moebius syndrome with autism spectrum disorders (ASDs) has been suggested in early studies with heterogenous age groups.']

['yes']

What is the number of protein coding genes in the human genome?

['Here, seven membrane protein topology prediction methods based on different underlying algorithms, such as hidden Markov models, neural networks and support vector machines, have been used for analysis of the protein sequences from the 21,416 annotated genes in the human genome.', 'he GENCODE 7 release contains 20,687 protein-coding and 9640 long noncoding RNA loci and has 33,977 coding transcripts not represented in UCSC genes and RefSeq', 'Current catalogs list a total of approximately 24,500 putative protein-coding genes.', 'Clustering of these sequences using cross-species relationships suggests that millions of expressed sequences may correspond to only approximately 20,000 distinct protein-coding transcripts.']

['The number of protein coding genes in the human genome is currently estimated between 20,000 and 25,000']

['Between 20,000 and 25,000']

What is known about food intolerance and gluten ?

['At present, there is no specific bio-marker of gluten sensitivity.', 'Emerging research into a syndrome known as nonceliac gluten sensitivity suggests a heterogeneous condition with some features of celiac disease but often categorized as FGIDs, including IBS.', 'Celiac disease, with a prevalence around 1% of the general population, is the most common genetically-induced food intolerance in the world. Triggered by the ingestion of gluten in genetically predisposed individuals,', 'Gluten intolerance is a unique model of autoimmune disease in which we can recognize the main environmental factor (gluten) and the more complex genetic background.', 'Coeliac disease is a multifactorial disease characterized by a dysregulated immune response to ingested wheat gluten and related cereal proteins. With an incidence of about 1% of the general population, it is considered the most common food intolerance disorder.', 'Coeliac disease is a lifelong intolerance to the gluten found in wheat, barley and rye, and some patients are also sensitive to oats. The disease is genetically determined, with 10% of the first-degree relatives affected and 75% of monozygotic twins being concordant.']

['Celiac disease, with a prevalence around 1% of the general population, is the most common genetically-induced food intolerance in the world. Triggered by the ingestion of gluten in genetically predisposed individuals.\nEmerging research into a syndrome known as nonceliac gluten sensitivity suggests a heterogeneous condition with some features of celiac disease but often categorized as FGIDs, including IBS.', 'Coeliac disease is a multifactorial disease characterized by a dysregulated immune response to ingested wheat gluten and related cereal proteins. With an incidence of about 1% of the general population, it is considered the most common food intolerance disorder.Emerging research into a syndrome known as nonceliac gluten sensitivity suggests a heterogeneous condition with some features of celiac disease but often categorized as FGIDs, including IBS.']

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Is protein CXCR4 used as a prognostic marker of cancer?

['Aberrant overexpression of CXCR4 is associated with worse overall survival, adenocarcinoma histology, distant metastasis, lymph node involvement in NSCLC.', 'CXCR4 belongs to a family of G protein-coupled cell surface receptors and has been proved to a prognostic marker in a various tumors, including esophageal squamous cell cancer. ', 'The chemokine C-X-C motif receptor 4 (CXCR4) has been found to be a prognostic marker in various types of cancer, being involved in chemotaxis, stemness and drug resistance. ', 'The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse).', 'XCR4 promotes tumor growth, angiogenesis and metastasis, and is a prognostic marker in a number of different types of tumors.', 'CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. ', 'The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. ', 'Upregulated expression of C-X-C chemokine receptor 4 is an independent prognostic predictor for patients with gastric cancer.', 'detection of CXCR4 expression will be helpful for predicting prognosis for patients with gastric cancer.', 'The chemokine receptor CXCR4 is a marker of metastatic disease.', 'High CXCR4 level in cancer specimens independently predicts a poor outcome for patients with node-positive breast cancer.', 'Univariate and multivariate analyses demonstrated that the high levels of nuclear CXCR4 and CXCL12 expression in hepatocytes were significantly better prognostic factors for overall and hepatic disease-free survival in patients with CLM.', 'The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. ', 'high CXCR4 expression is correlated to shorter DFS and could be used as a prognostic marker in order to stratify melanoma patients at higher progression risk.']

['Yes, the chemokine C-X-C motif receptor 4 (CXCR4) has been found to be a prognostic marker in various types of cancer.']

['yes']

Are chromomethylases present in animal genomes?

['Many plant, animal, and fungal genomes contain cytosine DNA methylation in asymmetric sequence contexts (CpHpH, H = A, T, C).', 'However, at the SUPERMAN locus, asymmetric methylation was only completely abolished in drm1 drm2 chromomethylase 3 (cmt3) triple mutant plants.', 'Although neither the drm1 drm2 double mutants nor the cmt3 single mutants show morphological defects, drm1 drm2 cmt3 triple mutant plants show pleiotropic effects on plant development.', 'Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene.', 'The lack of CMT homologs in animal genomes could account for the observation that in contrast to plants, animals maintain primarily CG methylation.', 'Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants.', 'A role for CHROMOMETHYLASE3 in mediating transposon and euchromatin silencing during egg cell reprogramming in Arabidopsis.', 'During embryogenesis there is a major switch from dependence upon maternally-deposited products to reliance on products of the zygotic genome.', 'Expression analysis of eight putative tomato DNA methyltransferases encoding genes showed that one chromomethylase (CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed in the pericarp during fruit growth and could be involved in the locus-specific increase of methylation observed at this developmental phase in the pericarp.', 'Natural variation for alleles under epigenetic control by the maize chromomethylase zmet2.', 'Arabidopsis has two types of methyltransferases with demonstrated maintenance activity: MET1, which maintains CpG methylation and is homologous to mammalian DNMT1, and CHROMOMETHYLASE 3 (CMT3), which maintains CpNpG (N = A, T, C, or G) methylation and is unique to the plant kingdom.', 'Maize chromomethylase Zea methyltransferase2 is required for CpNpG methylation.', 'A cytosine DNA methyltransferase containing a chromodomain, Zea methyltransferase2 (Zmet2), was cloned from maize. The sequence of ZMET2 is similar to that of the Arabidopsis chromomethylases CMT1 and CMT3, with C-terminal motifs characteristic of eukaryotic and prokaryotic DNA methyltransferases.', 'We have detected a chromodomain embedded within the catalytic region of a predicted Arabidopsis DNA methyltransferase that is diverged from other eukaryotic enzymes. The 791 residue "chromomethylase" (CMT1) is encoded by a floral transcript that is spliced from 20 exons and is present at only approximately 1/10(-7) of total mRNA.']

['No. Multiple lines of experimental evidence suggest that chromomethylases (CMTs) have been hitherto identified in plant genomes(Arabidopsis, maize, tomato). CMTs maintain CpNpG (N = A, T, C, or G) methylation and they are unique to the plant kingdom. The lack of CMT homologs in animal genomes could be explained based on the fact that, in contrast to plants, animals maintain primarily CG methylation. Therefore, the presence of CMTs is not required in the animal genomes.']

['no']

What is the role of Ubiquitin-conjugating enzyme 9 in the sumoylation pathway?

['["Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation. ", "We also found a marked rise in levels of Ubc9, the only SUMO conjugation enzyme identified so far. ", "Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways.", "We observed steady-state expression of SUMO1-3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes - SENPs, throughout normal gestation. ", "The small ubiquitin-like modifier (SUMO) pathway in eukaryotes is an essential post-translational modification required for a variety of cellular processes, development and organelle biogenesis. SUMO-conjugating enzyme (Ubc9) is an important conjunction enzyme in the SUMO pathway. ", "Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1), Ubc9 (the only known conjugating enzyme for the sumoylation pathway) or HIF-1\\u03b1, augmented sumoylation of HIF-1\\u03b1, nucleus-bound translocation and enhanced transcriptional activity of HIF-1\\u03b1 in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. ", "Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation.", "UBC9 is the only E2 conjugating enzyme involved in this process, and loss of UBC9 completely abolishes the SUMOylation pathway.", "Here we have identified host cell proteins involved with the cellular SUMOylation pathway, SUMO-1 (small ubiquitin-like modifier) and UBC9, a SUMO-1 conjugating enzyme that interact with classical swine fever virus (CSFV) Core protein.", "Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways.", "In this study, we found that the SUMOylation pathway was involved in the DENV life cycle, since DENV replication was reduced by silencing the cellular gene Ubc9, which encodes the sole E2-conjugating enzyme required for SUMOylation.", "Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity.", "The SUMO pathway parallels the classical ubiquitinylation pathway with three discrete steps: activation involving the enzyme E1, conjugation involving the E2 enzyme UBC9, and substrate modification through the cooperative association of UBC9 and E3 ligases.", "RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation.", "Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation.", "Although there are multiple E2 enzymes required for ubiquitination, there is only one E2-conjugating enzyme for sumoylation, which is Ubc9.", "Consistent with a role of sumoylation in inhibiting Tec1 activity, specifically increasing sumoylation of Tec1 by fusing it to the sumoylating enzyme Ubc9 leads to a dramatic decrease of Tec1 transcriptional activity.", "Ubc9 is an E2-conjugating enzyme required for sumoylation and has been implicated in regulating several critical cellular pathways.", "We also exposed placental explants to hypoxia to study the effect on the SUMOylation pathway.We observed steady-state expression of SUMO1-3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes - SENPs, throughout normal gestation", "It has been reported that ubiquitin-conjugating enzyme 9 (Ubc9), the unique enzyme2 in the sumoylation pathway, is up-regulated in many cancers", "Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sum']

Ubiquitin-conjugating enzyme 9 (Ubc9) is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation.

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Which is the molecular weight of the protein angiogenin?

['Angiogenin is a potent blood-vessel-inducing polypeptide with a molecular weight of 14,000 that has a unique ribonucleolytic activity.', ' Bovine angiogenin is a single-chain protein of 125 amino acids; it contains six cysteines and has a calculated molecular weight of 14,595.', 'The amino acid composition of this basic (isoelectric point greater than 9.5), single-chain protein of molecular weight approximately 14 400 has been determined.', 'was found to have a molecular weight of 15 kDa on SDS-PAGE, and the sequence of the N-terminal 25 amino acid residues was identical to that of bovine angiogenin', 'Human angiogenin is a 14-kDa plasma protein with angiogenic and ribonucleolytic activities. ', ' angiogenin-1 (15 kDa). ', 'This protein is 14 kD in molecular weight, and is identical to the angioplastic factor angiogenin. ', ' angiogenin (M(r) = 14,120),']

['The molecular weight of angiogenin is 14,120 Da. The bovine angiogenin is 14,595 Da']

['14,120 Da']

How does thyroid hormone regulate SR-Ca2+ ATPase (SERCA) protein in the heart?

['Furthermore, using specific inhibitors of the TH-activated kinases, we show that the long-term effects of TH on the expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), alpha- and beta-myosin heavy chain (MHC) and cell growth are reverted, implying that what is initiated as a non-genomic action of the hormone interfaces with genomic effects.', 'Hypothyroid neonates showed increased cholesterol levels and decreased expression of D1 in liver and of Serca-2 in heart, which were normalized with T3 treatment.', 'ERCA2 transcript and protein levels were reduced in FOG-2 transgenic hearts, and FOG-2 overexpression impaired T3-mediated SERCA2 expression in cultured cardiomyocytes. FOG-2 physically interacts with thyroid hormone receptor-alpha1 and abrogated even high levels of T3-mediated SERCA2 promoter activity.', 'A marked elevation of the expression of beta-MHC and a reduced ratio of SERCA/Phospholamban were found in viable myocardium of AMI hearts, which was prevented by TH', 'After TH treatment, AMI-THYR hearts expressed 71% alpha-MHC and 29% beta-MHC, P<0.05 versus SHAM and AMI and the ratio of SERCA/PLB was increased by 2.0-fold, P<0.05 versus SHAM and AMI.', 'Because the binding of T(3) occupied receptors to the thyroid response elements in the SERCA promotor can increase gene expression', 'These results demonstrate that increasing TR expression in the hypertrophied heart is associated with an improvement in contractile function and increased SERCA expression.', 'Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression', 'Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function', 'Hypothyroid heart displays a phenotype of cardioprotection against ischemia and this study investigated whether administration of dronedarone, an amiodarone-like compound that has been shown to preferentially antagonize thyroid hormone binding to thyroid hormone receptor alpha1 (TRalpha1), results in a similar effect. Dronedarone was given in Wistar rats (90 mg/kg, once daily (od) for 2 weeks) (DRON), while untreated animals served as controls (CONT). Hypothyroidism (HYPO) was induced by propylthiouracil administration.', 'while beta-myosin heavy chain (beta-MHC) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) expression (SERCA) was similar to CONT. In HYPO, alpha-MHC and SERCA were decreased while beta-MHC was increased.', 'the postnatal switch from beta- to alpha-myosin heavy chain (beta- and alpha-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers', 'In addition, TR cotransfection and treatment with the TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1,', 'dditionally, in T3-deprived samples alpha-sarcomeric actinin and SERCA-2 protein levels were reduced to 65.6 +/- 3% (P < 0.0001) and 74.1 +/- 4% (P=0.005), respectively, when compared with the T3-supplemented group.', 'even mild chronic myocardial thyrotoxicosis, such as may occur in human hyperthyroidism, can cause tachycardia and associated changes in high energy phosphate compounds independent of an increase in SERCA II and alpha-MHC.', 'Myocytes from banded hearts treated with T4 were hypertrophied but had increased concentrations of alpha-MHC and SERCA proteins', 'Thyroid hormone (T3) increases the transcription of the sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) gene (SERCA 2) through three thyroid hormone response elements.', 'MEF-2a in combination with either T3R alpha 1 or T3R beta 1 isoforms resulted in a 2.5-fold increase in SERCA 2 transgene expression in the absence of T3. Addition of T3 did not induce any further increase in SERCA 2 expression when T3R alpha 1 and MEF-2a expression vectors were cotransfected. In contrast, in the presence of T3R beta 1 and MEF-2, the addition of T3 increased chlorampenicol acetyltransferase activity by an additional 2.2-fold to a total 5.5-fold increase.', 'Our findings point to T3R isoform-specific interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression.', 'These data are consistent with pretranslational and possibly transcriptional level effect of thyroid hormone on the cardiac SR Ca2+ pump gene (SERCA 2)', 'These data demonstrate that T3 increases expression of the cardiac SR Ca2+ pump, that the effect can be localized to the cardiomyocyte, and that the effect is dependent on thyroid hormone receptors.', 'Thyroid hormone receptor (TR), a transcriptional activator, affected the regulation of gene expression of MHC and SR Ca(2+)-ATPase.', 'The thyroid hormone responsiveness of SR Ca2(+)-ATPase mRNA has been previously established.', 'The mRNA encoding the sarcoplasmic reticulum (SR) Ca2+ ATPase is highly influenced by thyroid hormone (T3) in the hearts of intact animals.', 'Direct cellular effects of thyroid hormone have been implicated in modulating the expression of the myosin heavy chain (MHC) genes and the slow sarcoplasmic reticulum calcium adenosine triphosphatase (SR Ca(2+)-ATPase) gene.']

['The thyroid hormone (TH) induced regulation of SERCA is mediated both by non-genomic and genomic actions.\nGenomic actions are mediated by the binding of T(3) receptors (TRs) to the thyroid response elements in the SERCA promotor and result in increased gene expression. \nThyroid hormone increases the transcription of SERCA 2 through three thyroid hormone response elements. \nData show that the regulation of cardiac SERCA by thyroid hormone is made at the pretranslational and possibly transcriptional level \nTRβ1 is shown to be coupled to the expression of SERCA in the heart\nAn increase of TR expression in the hypertrophied heart has been show to result in increased SERCA expression.\nInhibition of TRα1 by dronedarone does not change the expression of SERCA in the heart\nFindings show that SERCA 2 gene expression is regulated by TR isoform-specific interactions with transcription factor (MEF-2) \nHypothyroidism is accompanied by decreased expression of SERCA in the heart. T3 increases expression of the cardiac SERCA\nTH treatment can reverse the reduction in the ratio of SERCA to phospholamban expression which is found in postinfarcted hearts\nTH treatment results in increased expression of SERCA in hearts from banded rats']

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Do thyroid hormone receptors change after brain injury?

['For example, the T3 receptor alpha was predominantly expressed in stroke-tissue, indicating that regeneration of nerves in stroke tissue may be facilitated by increased T3 receptor alpha expression.', 'TRα expression was also increased in human infants with IVH. ', 'Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. ', 'A rapid increase of the total number of binding sites for T3 appeared within 30 min of ischemia and reached over 40% by 3 h. During the same 3-h period, the relative binding affinity was reduced by 25%. Upon recirculation after 30 min or 3 h of ischemia, a rapid reversal of measured T3 binding sites occurred, which progressed to 20-30% below the control value by the recirculation period of 3 h. ']

['thyroid hormone receptors increase after brain injury']

['yes']

What is membrane scission?

['To promote membrane scission, dynamin proteins polymerize, wrap around, and constrict the membrane; however, the mechanism underlying their role in membrane fusion remains unclear.', ' Its role in endocytosis may be mediated by its reported interaction with dynamin 2, a 100 kDa GTPase that polymerizes around the necks of budding vesicles and catalyzes membrane scission', "Because the neck's radius is, in general, finite, membrane scission and the consequent pinching off of the vesicle can only occur if it is narrowed to permit the necessary membrane topological reformation.", 'Dynamin recruitment and membrane scission at the neck of a clathrin-coated pit.', 'ESCRT-III is the final complex in the pathway that assembles on endosomes and executes membrane scission of intraluminal vesicles.', 'The scission of biological membranes is facilitated by a variety of protein complexes that bind and manipulate lipid bilayers. ', 'Dynamin-2 is a pleiotropic GTPase whose best-known function is related to membrane scission during vesicle budding from the plasma or Golgi membranes. ', ' Force produced by actin similarly contributes in membrane scission in endocytosis or Golgi remodeling.', 'Dynamin 2 (Dyn2) is a ~100kDa GTPase that assembles around the necks of nascent endocytic and Golgi vesicles and catalyzes membrane scission. ', 'membrane scission protein dynamin-2.', ' Finally, a membrane scission event must occur to release the free virion', ' Furthermore, GTP-dependent membrane scission by dynamin was dramatically elevated by BAR domain proteins. ', 'few can mediate membrane scission to complete the budding process.']

['Membrane scission is the final step in order to complete the budding process, pinching off of the vesicle. To promote membrane scission, dynamin proteins polymerize, wrap around, and constrict the membrane. The scission of biological membranes is facilitated by a variety of protein complexes that bind and manipulate lipid bilayers.']

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Can you define iatrogenic disease?

['Iatrogenic neurologic deficits after lumbar spine surgery are rare complications, but important to recognize and manage.', 'However, we analyze its etiology in order to determine if it is from iatrogenic causes. This syndrome can be categorized as follows: mistaken diagnoses, transoperative error, technique error, poor application, poor indication', 'However, the clinical events that occur during iatrogenic immunosuppression (transplantation and cancer therapy) and as a result of immunocompromise due to human immunodeficiency virus infection are currently promoting our understanding of the epidemiology of CMV disease and the definition of its clinical spectrum', 'The authors observed one case of an iatrogenic subarachnoid-pleural fistula secondary to the resection of an upper lobe carcinoma of the lung.', 'Radiological procedures require the intravascular administration of iodinated contrast media, which are becoming a great source of an iatrogenic disease known as contrast-induced nephropathy. ', 'Many studies have reported that AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures.', ' The aetiology of arrhythmias can be either iatrogenic, such as postsurgical,', 'Iatrogenic diseases are defined as illnesses due to diagnostic or therapeutic procedures.', 'BACKGROUND: Iatrogenic illness, defined as a disease that results from a diagnostic procedure or from any form of therapy, is a well-recognized phenomenon in clinical practice. ', 'Iatrogenic diseases are defined as illnesses due to diagnostic or therapeutic procedures. ', 'Iatrogenic illness, defined as a disease that results from a diagnostic procedure or from any form of therapy, is a well-recognized phenomenon in clinical practice.To study and evaluate major cardiac iatrogenic disease as the cause of admission to the intensive cardiac care unit in the modern era.We assessed 64 critically ill patients suffering from major cardiac iatrogenic problems among a total of 2,559 patients admitted to the intensive cardiac care unit during 3 years.', 'Iatrogenic disease was defined as adverse drug reactions according to the World Health Organization Definition and complications induced by non-drug medical interventions.', 'Iatrogenic illness, defined as a disease that results from a diagnostic procedure or from any form of therapy, is a well-recognized phenomenon in clinical practice.', 'Iatrogenic illness was defined as any problem that resulted from therapy.', 'An iatrogenic event was defined as "an adverse event related to a medical procedure".', 'Patients with colorectal cancer who had splenectomy as a result of iatrogenic damage of the spleen while undergoing resection of the sigmoid or rectum for adenocarcinoma had a significantly worse prognosis.', 'Intraoperative aortic dissection remains a rare and unpredictable complication of cardiac surgery, with worse outcomes than spontaneous aortic dissection. Increased age and atheromatous disease at the site of cannulation are significant risk factors for iatrogenic dissection. In this series, off-pump coronary artery bypass did not appear to be a risk factor for iatrogenic aortic dissection', ' Iatrogenic injury to the spleen is not an uncommon complication. Left nephrectomy has been reported as the second commonest cause of iatrogenic splenectomy with a reported incidence between 1.3 and 24%. Iatrogenic splenectomy is associated with significant morbidity and mortality.AIMS: We reviewed the occurrence of iatrogenic splenectomy during left nephrectomy at our centre.', 'Hallux valgus is a common forefoot pathology often requiring surgical intervention for symptomatic relief. One complication of hallux valgus correction is flexible hallux varus. Iatrogenic flexible hallux varus often requires surgical repair; however, the most advantageous surgical procedure for repair of iatrogenic flexible hallux varus and their sustainability remains unclear', 'The possible interrelationship between such deposition and cranial irradiation and/or i.t. MTX suggests a new iatrogenic disorder.', ' report of a patient with granulomatous peritonitis following general surgery is presented. Laparoscopy was performed as the final diagnostic procedure. Prevention is the remedy for this iatrogenic problem.', 'This report reviews both the medical and surgical literature during the past 15 years of patients treated for pseudomembranous colitis. Analysis of this clinical data has provided us with the opportunity to both define the role of surgery in this disorder and illustrate the necessity for a combined medical and surgical cooperative approach in the early management of this iatrogenic disease.', 'Iatrogenic problems following gastric surgery.', 'difficult to truly define iatrogenic complications in the postsurgical state in that the surgery is a condition originated by physician intervention and thus any problems that occur may be technically considered as physician created', 'he most severe iatrogenic events were nosocomial infections (49/62 [79%]) and respiratory events (nine of 26 [35%]). Cutaneous injuries were frequent (n=94) but generally minor (89 [95%]), as were medication errors (15/19 [76%]). Most medication errors occurred during administration stage (12/19 [63%]) and were ten-fold errors (nine of 19 [47%]). The major risk factors were low birthweight and gestational age (both p<0.0001), length of stay (p<0.0001), a central venous line (p<0.0001), mechanical ventilation (p=0.0021), and support with continuous positive airwary pressure']

['An iatrogenic disease is one that arises from treatment of another illness, such as an arrythmia that results from surgery or and hospital aquired infection in an immunocompromised patient.']

['illness caused by treatment']

Which is the enzyme that degrades decapped mRNAs?

["The removal of the 5'-cap structure by the decapping enzyme DCP2 and its coactivator DCP1 shuts down translation and exposes the mRNA to 5'-to-3' exonucleolytic degradation by XRN1", "DCP2 activation by DCP1 occurs preferentially on the EDC4 scaffold, which may serve to couple DCP2 activation by DCP1 with 5'-to-3' mRNA degradation by XRN1 in human cells", "XRN1 is a 5' → 3' processive exoribonuclease that degrades mRNAs after they have been decapped"]

["The removal of the 5'-cap structure by the decapping enzyme DCP2 and its coactivator DCP1 shuts down translation and exposes the mRNA to 5'-to-3' exonucleolytic degradation by XRN1", "The removal of the 5'-cap structure by the decapping enzyme DCP2 and its coactivator DCP1 shuts down translation and exposes the mRNA to 5'-to-3' exonucleolytic degradation by XRN1."]

['XRN1']

Which diseases that can be treated using the focused ultrasound thalamotomy.

['Besides DBS and standard thalamotomy, novel surgical approaches for ET are on the horizon. The development of MRI-guided focused ultrasound technique has been the new frontier of deep brain lesional therapies.', '132\u2003A Randomized, Sham-Controlled Trial of Transcranial Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Trial for the Treatment of Tremor-Dominant, Idiopathic Parkinson Disease.', 'Recently, transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been used to successfully perform thalamotomy for essential tremor. We designed a double-blinded, randomized controlled trial to investigate the effectiveness of MRgFUS thalamotomy in tremor-dominant PD.', 'Thalamotomy at the ventralis intermedius nucleus has been an effective treatment method for essential tremor, but how the brain network changes immediately responding to this deliberate lesion and then reorganizes afterwards are not clear. Taking advantage of a non-cranium-opening MRI-guided focused ultrasound ablation technique, we investigated functional network changes due to a focal lesion. ', 'Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes.', 'CONCLUSIONS: Our results demonstrate that MRgFUS thalamotomy is a safe, effective and less-invasive surgical method for treating medication-refractory ET. ', 'OBJECT: The authors report different MRI patterns in patients with essential tremor (ET) or obsessive-compulsive disorder (OCD) after transcranial MR-guided focused ultrasound (MRgFUS) and discuss possible causes of occasional MRgFUS failure.METHODS: Between March 2012 and August 2013, MRgFUS was used to perform unilateral thalamotomy in 11 ET patients and bilateral anterior limb capsulotomy in 6 OCD patients; in all patients symptoms were refractory to drug therapy. ', 'To discern the neurophysiologic correlates of its therapeutic effects, we applied MRgHIFU to an intractable neurologic disorder, essential tremor, while measuring magnetoencephalogram mu rhythms from the motor cortex. ', "MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson's Disease.", 'Methods. Seven PD patients, mean age 59.4 ± 9.8 years (range, 46-74) with a mean disease duration of 5.4 ± 2.8 years (range, 2-10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery. ', 'Thalamotomy using MRgFUS is safe and effective in PD patients.', 'Evolution of Movement Disorders Surgery Leading to Contemporary Focused Ultrasound Therapy for Tremor.', 'A noninvasive approach using transcranial high-energy focused ultrasound has emerged for the treatment of intractable tremor.', 'This article describes the evolution of magnetic resonance-guided focused ultrasound for ventrolateral thalamotomy for tremor.', 'Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.', 'PURPOSE: To use diffusion-tensor (DT) magnetic resonance (MR) imaging in patients with essential tremor who were treated with transcranial MR imaging-guided focused ultrasound lesion inducement to identify the structural connectivity of the ventralis intermedius nucleus of the thalamus and determine how DT imaging changes correlated with tremor changes after lesion inducement.MATERIALS AND METHODS: With institutional review board approval, and with prospective informed consent, 15 patients with medication-refractory essential tremor were enrolled in a HIPAA-compliant pilot study and were treated with transcranial MR imaging-guided focused ultrasound surgery targeting the ventralis intermedius nucleus of the thalamus contralateral to their dominant hand.', 'A pilot study of focused ultrasound thalamotomy for essential tremor.', 'This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor.METHODS: From February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor.', 'CONCLUSIONS: In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy.', 'MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study.', 'MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor', 'Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus.', 'INTERPRETATION: MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor.', 'Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain.', 'The goal of this study was to apply the new transcranial magnetic resonance imaging-guided focused ultrasound (tcMRgFUS) technology to perform noninvasive central lateral thalamotomies (CLTs) as a treatment for chronic neuropathic pain.METHODS: In 12 patients suffering from chronic therapy-resistant neuropathic pain, tcMRgFUS CLT was proposed. ', 'CONCLUSIONS: The authors assert that tcMRgFUS represents a noninvasive, precise, and radiation-free neurosurgical technique for the treatment of neuropathic pain.', 'A new less invasive treatment of tremor using MR guided focused ultrasound has started and is promising.', 'Quality-of-life scores improved from 37% to 11% (P=0.001).CONCLUSIONS: In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy.', 'Seven PD patients, mean age 59.4 ± 9.8 years (range, 46-74) with a mean disease duration of 5.4 ± 2.8 years (range, 2-10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery', 'We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire.This is a retrospective study of medication-refractory essential tremor patients treated at the University of Virginia with bilateral Vim DBS (n\u2009=\u200957), unilateral Vim DBS (n\u2009=\u200913), or unilateral focused ultrasound Vim thalamotomy (n\u2009=\u200915)', 'Quality-of-life scores improved from 37% to 11% (P=0.001).In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy', 'MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinsons Disease', 'Seven PD patients, mean age 59.4 ± 9.8 years (range, 46-74) with a mean disease duration of 5.4 ± 2.8 years (range, 2-10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery.', 'Transcranial magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) is gaining attention as a potent substitute for surgical intervention in the treatment of neurologic disorders. To discern the neurophysiologic correlates of its therapeutic effects, we applied MRgHIFU to an intractable neurologic disorder, essential tremor, while measuring magnetoencephalogram mu rhythms from the motor cortex. Focused ultrasound sonication destroyed tissues by focusing a high-energy beam on the ventralis intermedius nucleus of the thalamus.', 'BACKGROUND: Recent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor.METHODS: From February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor.', "MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson's Disease.", '132\u2003A Randomized, Sham-Controlled Trial of Transcranial Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Trial for the Treatment of Tremor-Dominant, Idiopathic Parkinson Disease.', 'In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy.', 'A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.', 'MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study.', 'Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes.', 'Functional assessment and quality of life in essential tremor with bilateral or unilateral DBS and focused ultrasound thalamotomy.', 'Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain.', 'This is a retrospective study of medication-refractory essential tremor patients treated at the University of Virginia with bilateral Vim DBS (n\u2009=\u200957), unilateral Vim DBS (n\u2009=\u200913), or unilateral focused ultrasound Vim thalamotomy (n\u2009=\u200915).', 'Twenty-one consecutive patients suffering from chronic (mean disease duration 29.9\xa0years), therapy-resistant ET were treated with MRgFUS CTT.']

['Focused ultrasound thalamotomy is used for treatment of Parkinson disease, essential tremor, obsessive-compulsive disorder and chronic neuropathic pain.']

['Parkinson disease', 'essential tremor', 'obsessive-compulsive disorder', 'chronic neuropathic pain']

How can DUF families be deciphered?

[' These families include proteins with domain of unknown function (DUF) DUF23, DUF246, and DUF266. The evidence for these proteins being GTs and their possible roles in cell wall biosynthesis is discussed.', 'The genome projects have unearthed an enormous diversity of genes of unknown function that are still awaiting biological and biochemical characterization. These genes, as most others, can be grouped into families based on sequence similarity. The PFAM database currently contains over 2,200 such families, referred to as domains of unknown function (DUF)', 'In a coordinated effort, the four large-scale centers of the NIH Protein Structure Initiative have determined the first three-dimensional structures for more than 250 of these DUF families.', 'Critically examining domain covariation across metagenomic datasets can grant new perspectives on the roles and associations of DUFs in an ecological setting. Targeted attempts at DUF characterization in the laboratory or in silico may draw from these insights and opportunities to discover new associations and corroborate existing ones will arise as more large-scale metagenomic datasets emerge.', 'Crystal structures of three members (BACOVA_00364 from Bacteroides ovatus, BACUNI_03039 from Bacteroides uniformis and BACEGG_00036 from Bacteroides eggerthii) of the Pfam domain of unknown function (DUF4488) were determined to 1.95, 1.66, and 1.81 Å resolutions, respectively', 'Bacterial species in the Enterobacteriaceae typically contain multiple paralogues of a small domain of unknown function (DUF1471) from a family of conserved proteins also known as YhcN or BhsA/McbA. Proteins containing DUF1471 may have a single or three copies of this domain. Representatives of this family have been demonstrated to play roles in several cellular processes including stress response, biofilm formation, and pathogenesis. We have conducted NMR and X-ray crystallographic studies of four DUF1471 domains from Salmonella representing three different paralogous DUF1471 subfamilies: SrfN, YahO, and SssB/YdgH (two of its three DUF1471 domains: the N-terminal domain I (residues 21-91), and the C-terminal domain III (residues 244-314)). Notably, SrfN has been shown to have a role in intracellular infection by Salmonella Typhimurium', 'Domain of unknown function (DUF) proteins represent a number of gene families that encode functionally uncharacterized proteins in eukaryotes. For example, DUF1618 family members in plants possess a 56-199-amino acid conserved domain and this family has not been described previously. Here, we report the characterization of 121 DUF1618 genes identified in the rice genome. Based on phylogenetic analysis, the rice DUF1618 family was divided into two major groups, each group consisting of two clades. ', 'In this study we identified that a plant specific domain of unknown function, DUF581 is a zf-FCS type zinc finger. ', 'DUF2233, a domain of unknown function (DUF), is present in many bacterial and several viral proteins and was also identified in the mammalian transmembrane glycoprotein N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase ("uncovering enzyme" (UCE)). ']

['The genome projects have unearthed an enormous diversity of genes of unknown function that are still awaiting biological and biochemical characterization. These genes, as most others, can be grouped into families based on sequence similarity. The PFAM database currently contains over 2,200 such families, referred to as domains of unknown function (DUF). \nCritically examining domain covariation across metagenomic datasets can grant new perspectives on the roles and associations of DUFs in an ecological setting. Targeted attempts at DUF characterization in the laboratory or in silico may draw from these insights and opportunities to discover new associations and corroborate existing ones will arise as more large-scale metagenomic datasets emerge. \nIn a coordinated effort, the four large-scale centers of the NIH Protein Structure Initiative have determined the first three-dimensional structures for more than 250 of these DUF families.']

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Is the long non- coding RNA malat-1 up or downregulated in cancer?

['lncRNA MALAT-1 expression is upregulated in some tumors.', 'Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) is an ncRNA that is highly expressed in several tumor types', 'metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is known to be consistently upregulated in several epithelial malignancies', 'MALAT-1 was up-regulated in human prostate cancer tissues and cell lines.', 'Genome-wide profiling revealed that MALAT-1 and prostate cancer gene 3 (PCA3) are overexpressed in PCa tissues', 'The level of MALAT-1 in LSCC was significantly higher than that in the corresponding adjacent non-neoplastic tissues', 'metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant,', '(MALAT1), a long non-coding RNA (lncRNA), is up-regulated in many solid tumors and associated with cancer metastasis and recurrence', ' Quantitative analyses indicated a 6-7-fold increased RNA level in HCCs versus uninvolved liver,', '(hcn), encoding a 7-kb mRNA-like transcript. The gene appears to be the murine ortholog of the human alpha gene, that is, MALAT-1.', 'After suppression subtractive hybridization and differential screening, we detected the metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene as one of the major genes upregulated in ESS', 'a novel non-coding RNA (MALAT-1) to be expressed at significantly higher levels in stage-I and stage-II NSCLC primary tumours that subsequently metastasised', 'quantitative RT-PCR verified overexpression in metastasizing samples. Several of the identified genes (eIF4A1, thymosin beta4 and a novel transcript named MALAT-1) were demonstrated to be significantly associated with metastasis in NSCLC patients ', 'Σ RNA is a class of conserved large non-coding RNAs (murine Hepcarcin; human MALAT-1) up-regulated in carcinomas', 'To date, most known NCTs studied have been relatively short, but several important regulatory NCTs, including XIST, MALAT-1, BC1 and BC200, are considerably larger in length', 'These NCTs were among the most abundantly expressed transcripts detected', 'The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion']

['Malat-1 expression is upregulated in several tumor types']

['upregulated']

What is Uhl's anomaly?

["Uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle.", "Uhl's anomaly is an evolutive disease leading to terminal right ventricular failure", 'Uhl anomaly is a rare form of congenital hypoplasia of the right ventricular myocardium.', "Uhl's anomaly was first reported by Uhl in 1952 and is characterized by congenital partial or complete absence of right ventricular myocardium.", 'Uhls anomaly was first reported by Uhl in 1952 and is characterized by congenital partial or complete absence of right ventricular myocardium']

["uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle.", "Uhl's anomaly is an evolutive disease leading to terminal right ventricular failure. Uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle.", "Uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle. Uhl's anomaly is an evolutive disease leading to terminal right ventricular failure. ", "Uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle. Uhl's anomaly is an evolutive disease leading to terminal right ventricular failure", "Uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle."]

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What histone variants play a role in the DNA damage reponse?

['H2A.Z is an evolutionarily ancient and highly conserved H2A variant that regulates processes ranging from gene expression to the DNA damage response', 'activation of DNA damage checkpoints (ataxia telangiectasia mutated (ATM) and H2A histone family, member X (H2AFX (H2AFX)))', 'the specialization imparted by histone H2A (H2A.X and H2A.Z) variants to the nucleosome core particle constitutes the earliest response to DNA damage in the cell', 'histone variants (H2AX and H2A.Z), histone post-translational modifications (acetylation, phosphorylation, methylation and ubiquitination) and chromatin-remodeling complexes (INO80, SWR1, SWI/SNF, RSC and NuRD) are important and direct players in the DNA double-strand break (DSB)', 'H2A.Z incorporation in the coding regions of genes encoding proteins involved in the regulation of meiosis and genotoxic stress responses', ' phosphorylation of H2AX, a DNA damage signal', 'DSB) are generally considered the most critical lesion induced by ionizing radiation (IR', 'phosphorylated forms of histone H2AX ', 'H2AX has a complete SQ(E/D)varphi (where varphi denotes a hydrophobic residue) known to be phosphorylated in response to DNA damage', 'H2A.X, plays a very important role in the cellular response to DNA damage', 'H2A.X is an H2A variant present in multicellular organisms that is specifically phosphorylated on the serine in the C-terminal consensus sequence, canonically "SQEY," in response to DNA damage.', 'H2AFX) is important in maintaining chromatin structure and genetic stability', 'Saccharomyces cerevisiae, the linker histone HHO1 is involved in DNA repair', 'H1 variant, H1R is involved in DNA damage response', 'high levels of histone H2AX phosphorylation and an increased incorporation of the Htz1p histone variant into chromatin surrounding the DSB', 'TRF2 upregulation was more dramatic in drug-resistant cells and occurred before the expression of ATM, gammaH2AX and p53', 'DNA double-strand breaks induced by anticancer drugs or irradiation increase TRF2 expression', 'Histone variant H2AX and core histone H2A are phosphorylated in mammals and budding yeast, respectively. We demonstrate the DSB-induced phosphorylation of histone variant H2Av in Drosophila melanogaster', 'formation of a double-strand break (DSB) in chromosomal DNA is highly conserved', 'H2A variants, H2AX and H2AZ. H2AX is phosphorylated on a serine four residues from the carboxyl terminus in response to the introduction of DNA double-strand breaks', 'In response to IR, ZNF668 knockdown reduces Tip60-H2AX interaction and impairs IR-induced histone H2AX hyperacetylation, thus impairing chromatin relaxation.', 'RPA foci formation were reduced in parallel with increasing levels of H2AX phosphorylation', 'H2AX phosphorylation on a C-terminal serine residue to form "γ-H2AX" is a critical early event in the chromatin response to chromosomal DNA double strand breaks in eukaryotes', 'The phosphorylation of the histone variant H2AX (gammaH2AX) is one of the best examples of histone PTMs in response to DNA damage induction', 'One of the most well-characterized modifications is caused by the formation of DNA double strand breaks (DSBs), resulting in phosphorylation of histone H2AX (the so-called gamma-H2AX) on the chromatin surrounding the DNA lesion', 'H2AX appears to be mainly associated with maintaining the genome integrity by participating in the repair of the double-stranded DNA breaks exogenously introduced by environmental damage (ionizing radiation, chemicals) or in the process of homologous recombination during meiosis', 'The sustained localization of BMI1 to damage sites is dependent on intact ATM and ATR and requires H2AX phosphorylatio', 'unique functional interactions among various chromatin modifiers, suggesting new regulatory pathways, such as a heterochromatin-specific modulation of DNA damage response involving H2A.X and WICH, both enriched in silent domains']

['Mostly H2A.X, but H2A.Z and H1R have also been associated to DNA damage']

['H2A.X', 'H2A.Z', 'H1R']