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Which is the methyl donor of histone methyltransferases?

['While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA.', 'Based on known SET domain structures, the mutations likely affect either the lysine-substrate binding pocket, the binding site for the adenosylmethionine methyl donor, or a critical tyrosine predicted to interact with the substrate lysine epsilon-amino group', 'Also, S-adenosylhomocysteine or methyl donor deficiency inhibits RIZ1 and other H3 lysine 9 methylation activities.', 'Angiosperms synthesize S-methylmethionine (SMM) from methionine (Met) and S-adenosylmethionine (AdoMet) in a unique reaction catalyzed by Met S-methyltransferase (MMT). SMM serves as methyl donor for Met synthesis from homocysteine, catalyzed by homocysteine S-methyltransferase (HMT).', 'Plants synthesize S-methylmethionine (SMM) from S-adenosylmethionine (AdoMet), and methionine (Met) by a unique reaction and, like other organisms, use SMM as a methyl donor for Met synthesis from homocysteine (Hcy).', 'AtHMT-1 and -2 both utilize l-SMM or (S,S)-AdoMet as a methyl donor in vitro and have higher affinities for SMM.', 'When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity.', 'S-adenosylmethionine (SAMe), the major methyl donor for DNA and histone methylation was fed with ethanol for 1month in order to modify the effects of ethanol on rat liver.', 'To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine.', 'The enzyme was capable of transferring methyl groups to selected lysine residues in a substrate protein using S-adenosyl-l-methionine (SAM) as the methyl donor.', 'SAM is the main methyl group donor for methyltransferases to modify DNA, RNA, protein, metabolites, or phospholipid target substrates.', 'To control the enzymatic activity of vSET in vivo with an engineered S-adenosyl-l-methionine (SAM) analogue as methyl donor cofactor, we have carried out structure-guided design, synthesis, and characterization of orthogonal vSET methyltransferase mutant/SAM analogue pairs using a "bump-and-hole" strategy.', 'Protein lysine methyltransferases are important regulators of epigenetic signaling.', 'One of the well-studied PTMs, arginine methylation, is catalyzed by protein arginine methyltransferases (PRMTs) with SAM as the methyl donor.', 'While SAMe is a methyl donor, MTA is an inhibitor of methylation.', 'The purified cytochrome can act as a methyl acceptor for a methyltransferase activity in the cell extract that uses S-adenosylmethionine as methyl donor.', 'This enzyme utilizes S-adenosyl-L-methionine as the methyl donor.']

['The major methyl donor of histone methyltransferases (HMTs) is S-adenosyl-L–methionine (SAM, AdoMet).']

['S-adenosyl-L–methionine', 'SAM', 'AdoMet', 'S-Adenosylmethionine', 'adenosylmethionine', 'S-Adenosyl methionine']

How is synapsin described as an evolutionarily conserved presynaptic phosphoprotein?

['["Synapsin is an evolutionarily conserved presynaptic phosphoprotein.", "Synapsins as a family of presynaptic terminal phosphoprotein participates in neuronal development", "Synapsin III (SynIII) is a phosphoprotein", "The neuronal phosphoprotein synapsin III", "Synapsin II is a member of the neuronal phosphoprotein family.", "phosphoprotein synapsin"]']

Synapsin is described as an evolutionarily conserved presynaptic phosphoprotein in the context.

[]

List all approved indications for Glivec

['The limited available experience suggests that imatinib could be considered as an individualized treatment approach in severe SSc and underscores the need to identify markers for selecting particular patients, who will safely respond to therapeutic inhibition of tyrosine kinases.', 'Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous neoplasm', 'Moreover, even when surgery is utilized, there are cases where positive margins remain, in which case imatinib would be an option, often in combination with surgery. Imatinib can decrease tumor size preoperatively and help to improve postsurgical aesthetic appearance and minimize functional impairment.', 'for CML we analysed imatinib, dasatinib and nilotinib. RESULTS: Most drugs included in this study had received market authorization in all countries, but the range of indications for which they had been authorized differed by country', 'Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). Treatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST, the most recent FDA-approved indication (December 2008), has been shown to significantly improve recurrence-free survival (RFS) compared with surgical resection alone', 'Currently, there are no clinical recommendations regarding how to incorporate imatinib drug plasma monitoring in patients with either chronic myeloid leukemia or gastrointestinal stromal tumors, indications for which imatinib is approved.', 'Imatinib was effective against GIST that were positive for KIT protein', 'The introduction of alternative therapies, such as imatinib for CML, has challenged well-established indications.', 'More micro-GIST are discovered with the development of investigations, rising the question of wait and see policy for some of them. In locally advanced inoperable patients and metastatic patients, Imatinib is the standard treatment.', 'The introduction of alternative therapies has challenged well-established indications such as imatinib for chronic myeloid leukaemia.', 'Imatinib mesylate (Gleevec, Novartis Pharmaceuticals East Manruer, NJ) received accelerated approval on May 10, 2001 for the treatment of patients with chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN-alpha therapy, (b) accelerated phase, and (c) blast crisis.', 'Gleevec (imatinib mesylate), a highly promising new drug for the treatment of chronic myelogenous leukemia in blast crisis, in accelerated phase, and in chronic phase after interferon failure or intolerance, received orphan drug status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development on January 31, 2001, and accelerated approval from the FDA for the above three indications on May 10, 2001.', 'Imatinib is the first effective systemic therapy for advanced GIST.']

['CML - blast crisis, in accelerated phase, and in chronic phase after interferon failure or intolerance. Glivec received orphan drug status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development on January 31, 2001, and accelerated approval from the FDA for the above three indications on May 10, 2001.\n\nGastrointestinal stromal tumor (GIST\nTreatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST\n In locally advanced inoperable patients and metastatic patients, Imatinib is the standard treatment.', 'Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous neoplasm.']

['Chronic myelogenous leukemia (CML)', 'Gastrointestinal stromal tumor (GIST)', 'Dermatofibrosarcoma protuberans (DFSP)']

What disease is Velcade (bortezomib) mainly used for?

['patients with multiple myeloma (MM)', 'bortezomib, and lenalidomide have shown improved outcomes in these patients.', 'Bortezomib, a proteasome inhibitor drug very effective against multiple myeloma, may induce the so-called bortezomib-induced peripheral neuropathy (BIPN), hardly manageable with common analgesic drugs.', 'bortezomib have emerged as effective treatment in patients with multiple myeloma (MM).', 'the use of thalidomide to treat multiple myeloma, and describe problems arising in the Thaled® outpatient department. METHODS: Multiple myeloma patients treated with thalidomide at Hitachi General Hospital.', 'Thalidomide showed some success in treating multiple myeloma either after auto-PBSCT or following treatment with bortezomib. In the case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), grave complications could have very easily developed, thus underscoring the importance of careful monitoring.', "Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3\u2009mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles.", "In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles.", 'we provide data comparing sFLC with M protein as biomarkers of response in newly diagnosed patients with MM undergoing induction therapy with the novel agents thalidomide, lenalidomide and/or bortezomib.', 'Bortezomib, indicated for multiple myeloma (MM) treatment, is available in 3.5-mg vials, a quantity higher than the average dose commonly prescribed.', 'Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors.', 'efficacy and safety of bortezomib (BOR) for treatment of multiple myeloma in comparison with thalidomide (THAL) by reference to adverse events, and searched for laboratory markers that could be used for prognostication of patients.', 'BOR showed a higher rate of effectiveness than THAL for refractory multiple myeloma, and its effects were rapid. BOR treatment prolonged the survival time of THAL-resistant patients. The efficacy of BOR was unrelated to patient age, the number of previous therapeutic regimens, or the disease period.', 'It is suggested that BOR has therapeutic efficacy for multiple myeloma as a first-line medical treatment and/or for patients with THAL resistance, and can improve prognosis and survival. Since serum ALP elevation was observed in many patients for whom BOR was effective, this may be a predictor of BOR efficacy.', 'Bortezomib-treated MM patients whose tumours had high baseline expression of genes suppressed by LCQ195 had significantly shorter progression-free and overall survival than those with low levels of these transcripts in their MM cells. These observations provide insight into the biological relevance of multi-targeted CDK inhibition in MM.', 'bortezomib is the only effective agent in the treatment of plasma cell leukemia (PCL), a type of plasma cell dyscrasia characterized by poor prognosis despite conventional chemotherapy including autologous and allogeneic transplantation.', 'These 3 patients with primary or secondary PCL who received a bortezomib-based regimen as rescue medication did not respond to treatment.', 'To evaluate the effects and safety of the regimen of bortezomib combined with dexamethasone (VD) in the treatment of primary systemic (AL) amyloidosis.', 'VD regimen might be an efficient, rapid effective and safe regimen in the treatment of AL amyloidosis.', 'Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo.', 'Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.', 'Relapsed/refractory myeloma has a poor outcome because of multi-drug resistance, patient low-performance status and toxicity of conventional chemotherapy.', 'Bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to other drugs and overcome drug-resistance. Notably, doxorubicin and bortezomib may reciprocally increase their efficacy. Thus, to improve outcome whilst minimizing therapy-related toxicity, liposomal doxorubicin was added to a bortezomib-based combination.', 'the growth inhibitory and pro-apoptotic effects of the proteasome inhibitor bortezomib in combination with anti-EGFR drugs, such as gefitinib, vandetanib, and cetuximab in EGFR-expressing human cancer cell lines. Bortezomib determined dose-dependent growth inhibition in a nine cancer cell line panel (IC(50) values, range 6-42 nM).', 'overexpression of a constitutively active P-Akt protected A549 cells by cell growth inhibition and apoptosis following treatment with bortezomib and EGFR inhibitors. The combined treatment with bortezomib and EGFR inhibitors has a synergistic growth inhibitory and pro-apoptotic activity in different human cancer cells which possess a functional EGFR-dependent autocrine growth pathway through to a more efficient and sustained inhibition of Akt.', 'Among 19 patients with breast cancer, four had evidence of a clinical benefit.', 'Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.', 'A regimen of bortezomib, 1.3 mg/m(2) on days 1, 4, 8, and 11 with PLD, 30 mg/m(2), on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.', 'Bortezomib, a proteasome inhibitor, has been used for patients with refractory and relapsed multiple myeloma, lymphoma and leukemia.', 'Bortezomib, a first-in-class proteasome inhibitor, has shown clinical activity in relapsed, refractory multiple myeloma in a pivotal Phase II trial, SUMMIT.', 'treatment with bortezomib results in meaningful long-term benefit for patients with relapsed and refractory myeloma.', 'The proteasome inhibitor bortezomib (BTZ), used in antineoplastic chemotherapy, must be diluted in NaCl 0.9% for injection and stored for no more than 3 hours in a syringe or 8 hours in a vial.', 'Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies.', 'Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.', 'These patients were treated with bortezomib variously combined with other drugs outside of clinical trials.']

['Velcade (bortezomid), a proteasome inhibitor drug indicated for multiple myeloma (MM) treatment. Velcade is also approved for the treatment of patients with mantle cell lymphoma.']

['multiple myeloma']

List scales that are used for scoring of patients with spinal metastasis?

['METHODS: Outcomes of surgery, prognostic factors for survival, and relevance of Tomita and Tokuhashi scores were investigated.', 'PURPOSE: To assess variability in the use of Tomita and modified Bauer scores in spine metastases.', 'Only the Tomita scoring system was shown to be an independent prognostic factor for overall survival. ', '.CONCLUSION: The Tomita scoring system represents a practicable and highly predictive prognostic tool. ', 'Analysis of the predictive role and new proposal for surgical strategies based on the modified Tomita and Tokuhashi scoring systems for spinal metastasis.', 'We also aimed to evaluate the validity of the prognostic scores in the Tomita and Tokuhashi systems and discuss several aspects to improve the predictive accuracy of these systems. ', 'CONCLUSIONS: Tomita scores more accurately predicted survival than Tokuhashi scores. ', 'A comparison of the modified Tokuhashi and Tomita scores in determining prognosis for patients afflicted with spinal metastasis.', ' It is for this reason that scoring systems, such as the modified Tokuhashi and Tomita scores, have been created', 'The modified Tokuhashi score had better accuracy in determining actual survival.', 'Tokuhashi, Tomita, Bauer, and Oswestry scores have been devised for survival prediction; however, none of these systems have been evaluated in nasopharyngeal carcinoma (NPC).', 'All four scoring systems could be used to prognosticate these patients. The modified Tokuhashi score is the best in doing so.', 'Primary tumor type and Tokuhashi score independently predicted survival in patients with spinal metastases.', ' Primary tumor type and Tokuhashi scoring independently predicted survival in patients with spinal metastases after surgery.', 'A predictive score was then developed and compared against that of the modified Bauer score alone in terms of prognosticating 1-year survival after surgery.', 'Our predictive score performed better than the modified Bauer alone and may be used to predict survival after surgical intervention for metastatic disease.', 'Tokuhashi Scoring System has limited applicability in the majority of patients with spinal cord compression secondary to vertebral metastasis.', 'Tokuhashi Scoring System has limited applicability in the majority of patients with spinal cord compression secondary to vertebral metastasis', 'Tokuhashi, Tomita, Bauer, and Oswestry scores have been devised for survival prediction; however, none of these systems have been evaluated in nasopharyngeal carcinoma (NPC).To investigate the accuracy of these scoring systems in predicting survival and to identify prognostic factors for survival of the patients with spinal metastases from NPC.Retrospective analysis of the patients with spinal metastases from NPC who were treated in our institution.The study included 87 patients with spinal metastases from NPC.The primary outcome measure was the survival time of these patients', 'Predictive value of survival by modified Tokuhashi score was the highest among all four scoring systems.Patients with spinal metastases from NPC have relatively good survival prognosis', 'The data of the present study emphasize that the original Bauer score and a modified Bauer score without scoring for pathologic fracture seem to be practicable and highly predictive preoperative scoring systems for patients with spinal metastases', 'A retrospective study of 180 patients with lung cancer spinal metastases, wherein prognostic score-predicted survival was compared with actual survival.To evaluate and compare the accuracy of prognostic scoring systems in lung cancer spinal metastases.The modified Tokuhashi, Tomita, modified Bauer, and Oswestry scores are currently used to guide decisions regarding operative treatment of patients with spinal metastases.', 'To evaluate the predictive values of Tokuhashi score, revised Tokuhashi score and Tomita score systems for life expectancy and treatment options in patients with spinal metastasis.', 'A comparison of the modified Tokuhashi and Tomita scores in determining prognosis for patients afflicted with spinal metastasis.', 'The combination of Tokuhashi score and Tomita score may be applied to better predict postoperative survival prognosis and guide the surgical options for patients with spinal metastasis..', 'reported a composite model taking into account a modified Bauer score, preoperative albumin, and ambulatory status of patients with spinal metastasis.']

['Tokuhashi, Tomita, Bauer, and Oswestry scores are used for survival prediction of patients with spinal metastases.']

['Tokuhashi', 'Tomita', 'Bauer', 'Oswestry']

List sodium glucose co-transporter-2 (SGLT2) inhibitors that have been FDA approved for type 2 diabetes mellitus treatment.

['Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved.', 'To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).', ' Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway.', 'Sodium-glucose cotransporter type 2 (SGLT2) inhibitors such as canagliflozin and dapagliflozin have been approved for the treatment of type 2 diabetes mellitus', 'To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM)', "The present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic drug 'Invokana' (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the treatment of T2DM and Alzheimer's Disease (AD). ", "Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study.", 'This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes. ', ' Inhibitors of the sodium-glucose co-transporter 2 (SGLT2) promote the excretion of glucose to reduce glycated hemoglobin (HbA1c) levels. Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved.', 'a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).', 'To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).', 'Sodium glucose co-transporter 2 (SGLT2) inhibition with canagliflozin in type 2 diabetes mellitus.', 'Canagliflozin (Invokana™), an oral selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, is under global development with Mitsubishi Tanabe Pharma and Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson, for the treatment of type 2 diabetes mellitus.', "Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study.", 'Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved.']

['Canagliflozin, along with dapagliflozin and empagliflozin, are SGLT2 inhibitors approved by the US FDA for use in the treatment of type 2 diabetes.']

['Dapagliflozin', 'Empagliflozin', 'Canagliflozin']

What type of enzyme is peroxiredoxin 2 (PRDX2)?

['Peroxiredoxin-2 (PRDX-2) is an antioxidant and chaperone-like protein critical for cell function.', 'We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells.', 'The aim of this study was to examine gonadotropin regulation of antioxidant enzyme sulfiredoxin (Srx) and peroxiredoxin 2 (PRDX2) expressions and modification during the ovulatory process in rats. ', 'The mRNA profiler array showed more than 2-fold differential expression of 32 oxidative stress-related genes in unstimulated moDCs, including peroxiredoxin-2 (PRDX2), an enzyme reducing hydrogen peroxide and lipid peroxides. ', 'Peroxiredoxin-2 (Prx-2) is an abundant mammalian enzyme that protects against oxidative stress.', 'Peroxiredoxin 2 (PRDX2) has been known to act as an antioxidant enzyme whose main function is H(2)O(2) reduction in cells. ', 'These data indicate that Srx1 activity protects mice from the lethality of endotoxic shock, adding this enzyme to other host factors, as NRF2 and peroxiredoxin 2, which by regulating cellular reactive oxygen species levels act as important modifiers in the pathogenesis of sepsis.', 'One of the identified proteins was peroxiredoxin 2 (Prx2), an anti-oxidant enzyme. ', "Peroxiredoxin-2 (Prdx2), a potent peroxide reductant, is the third most abundant protein in the erythrocyte and might be expected to play a major role in the cell's oxidative defenses. ", 'Importantly, we also demonstrate the antioxidant enzyme Prx2 (peroxiredoxin 2) as a critical cytoplasmic target of cdk5. ', 'Human erythrocyte peroxiredoxin 2 (Prx2) is a typical 2-cys cytosolic peroxiredoxin with thiol-dependent hydrogen peroxide scavenger activity. ', 'Peroxiredoxin 2 (Prx2) is an antioxidant enzyme that uses cysteine residues to decompose peroxides.', 'Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, was the most upregulated while tribbles homolog 3 (TRB3), a pro-apoptotic protein, was the most downregulated, implying a beneficial effect of lithium on neuronal cells.', 'After 5 Gy irradiation, the relative abundance of peroxiredoxin 2, an antioxidant enzyme, and latexin, an inhibitor of carboxypeptidase, increased. ', 'Peroxiredoxin 2 (Prx2), a thiol-dependent peroxidase, is the third most abundant protein in the erythrocyte, and its absence in knock-out mice gives rise to hemolytic anemia. ', 'Suppression subtractive hybridization performed on Down syndrome (DS) versus control fetal brains revealed differential expression of peroxiredoxin 2 (PRDX2), mapped at 13q12. Peroxiredoxins are antioxidant enzymes involved in protein and lipid protection against oxidative injury and in cellular signalling pathways regulating apoptosis. T']

['Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme that uses cysteine residues to decompose peroxides. \nPeroxiredoxin-2 (PRDX2), an enzyme reducing hydrogen peroxide and lipid peroxides \nPeroxiredoxin 2 (Prx2) is a thiol-dependent peroxidase.']

['antioxidant']

Has the gorilla genome been determined?

['Starting with human, chimpanzee, gorilla, and orangutan genomes, our software generated an exhaustive data set of 292 ALs (∼1 kb each) in ∼3 h. ', 'We generated a high-quality assembly of the gorilla genome using single-molecule, real-time sequence technology and a string graph de novo assembly algorithm', 'Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera.', 'DNA sequencing reveals that the genomes of the human, gorilla and chimpanzee share more than 98% homology.']

['Yes, the gorilla genome has been sequenced.']

['yes']

Is sumoylation implicated in myogenesis?

['Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) has broad de-SUMOylation activities in vitro, which is essential for embryonic heart development.', 'Silencing SENP2 can reduce myostatin expression and, therefore, promote myogenesis of skeletal muscle. These results reveal the important role of SENP2 in the regulation of myostatin expression and myogenesis.', 'Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown.', 'Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation.', 'Although this modification has little effect on SnoN repression of the plasminogen activator inhibitor-1 promoter and only modestly potentiates SnoN repression of the p21 promoter, SnoN sumoylation robustly augments the ability of SnoN to suppress transcription of the myogenesis master regulatory gene myogenin', 'Our study also points to a physiological role for SnoN sumoylation in the control of myogenin expression in differentiating muscle cells.', 'Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. ', 'An essential role of small ubiquitin-like modifier (SUMO)-specific Protease 2 in myostatin expression and myogenesis.', 'These results reveal the important role of SENP2 in the regulation of myostatin expression and myogenesis.', 'The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC-Smyd1 in myogenesis.', 'Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis.', ' We show that the overall load of sumoylated proteins present in myoblasts diminishes progressively throughout myogenesis', 'These novel results suggest that protein sumoylation plays a pivotal role in myoblast differentiation and is required to regulate the activity of key targets downstream of MyoD and myogenin.', 'a composite sequence motif has recently been identified that couples phosphorylation, sumoylation, and perhaps also deacetylation to control transcriptional repression in stress response, mitogen and nuclear hormone signaling, myogenesis, and neuronal differentiation.', 'Mutation of these SUMO acceptor sites in Sharp-1 does not impact its subcellular localization but attenuates its ability to act as a transcriptional repressor and inhibit myogenic differentiation. Consistently, co-expression of the SUMO protease SENP1 with wild type Sharp-1 abrogates Sharp-1-dependent inhibition of myogenesis. ', 'Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation.', 'Ubiquitin Specific Protease 25 (USP25), a member of the deubiquitinase family, is involved in several disease-related signal pathways including myogenesis, immunity and protein degradation. ', ' In addition, we show that the skNAC interaction partner Smyd1 contains a putative sumoylation motif and is sumoylated in muscle cells, with depletion of Mms21/Nse2 leading to reduced concentrations of sumoylated Smyd1. Taken together, our data suggest that the function, specifically the balance between the nuclear and cytosolic roles, of the skNAC-Smyd1 complex might be regulated by sumoylation.']

['Yes, sumoylation is implicated in myogenesis.', 'Yes, protein sumoylation present in myoblasts is regulated in myogenesis.']

['yes']

Which drugs affect insulin resistance in obesity?

['enistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance.', 'he positive effects of ACE inhibitor drugs, particularly on hypertriglyceridemia and insulin resistance, might bring them forth as first-line drugs in the treatment of obese and hypertensive children. ']

['Enistein treatment could help reduce insulin resistance\nACE inhibitor drugs may improve insulin resistance']

['Enistein', 'ACE inhibitors']

What components make up the major light-harvesting complex in cyanobacteria and red algae, and what is their role in photosynthesis?

[' "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",']

The major light-harvesting complex in cyanobacteria and red algae is the phycobilisome, which is a water-soluble complex located on the outer surface of the photosynthetic membranes. It is composed of both pigmented phycobiliproteins (85%) and non-pigmented linker (15%) polypeptides. The phycobiliproteins, including phycocyanin, phycoerythrin, and allophycocyanin, absorb light energy and transfer it to the photosynthetic reaction center, enhancing the efficiency of photosynthesis in these organisms.

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Which gene is associated with Muenke syndrome?

['Abstract Muenke is a fibroblast growth factor receptor 3 (FGFR-3) associated syndrome, which was first described in late 1990s. ', 'The syndrome is defined molecularly by a unique point mutation c.749C>G in exon 7 of the FGFR3 gene which results to an amino acid substitution p.Pro250Arg of the protein product. ', 'Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the Fibroblast Growth Factor Receptor3 (FGFR3) gene. ', 'Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene.', 'Muenke syndrome is characterized by various craniofacial deformities and is caused by an autosomal-dominant activating mutation in fibroblast growth factor receptor 3 (FGFR3(P250R) ).', 'The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes. ', 'The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene.', 'Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. ', ' Fibroblasts from 10 individuals each with Apert syndrome (FGFR2 substitution S252W), Muenke syndrome (FGFR3 substitution P250R), Saethre-Chotzen syndrome (various mutations in TWIST1) and non-syndromic sagittal synostosis (no mutation detected) were cultured.', 'We report on a set of identical twins with a de novo C749G mutation in the FGFR3 gene codon 250 after a pregnancy complicated by prenatal exposure to Nortriptyline.', 'Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730).', 'The identification of the P250R mutation allowed the confirmation of the Muenke Syndrome in 9 out of the 52 cases referred. ', 'Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mu', 'Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. ', 'To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. ', 'The patients were either placed into the "Muenke" group (n=11) or the "non-Muenke" control group (n=12) on the basis of a test for the P250R mutation in the FGFR3 gene.', 'P250R mutation in the FGFR3 gene also known as Muenke syndrome is associated with coronal craniosynostosis, sensorineural deafness, craniofacial, and digital abnormalities.', 'However, Muenke et al. [(1997); Am J Hum Genet 91: 555-564] described a new subgroup carrying the Pro250Arg mutation in the fibroblast growth factor receptor (FGFR) 3 gene on chromosome 4p16.', 'Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). ', 'In spite of a variable phenotype, Muenke syndrome has been related to a unique mutation on the FGFR3 gene, Pro 250 to Arg, which is characteristic of this disease. ', 'Hypochondroplasia (HCH) and Muenke syndrome (MS) are caused by mutations on FGFR3 gene.']

['Muenke syndrome has been related to a mutation on the Fibroblast Growth Factor Receptor (FGFR3) gene.']

['Fibroblast Growth Factor Receptor 3 (FGFR3)']

Which antibiotics target peptidoglycan biosynthesis?

['Treatment with antibiotics that interfere with peptidoglycan biosynthesis inhibits chloroplast division in the desmid Closterium', 'To detect cells just after division, we used colchicine, which inhibits Closterium cell elongation after division', 'The antibiotics bacitracin and vancomycin showed no obvious effect.', 'cells treated with ampicillin, D-cycloserine, or fosfomycin had only one chloroplast after cell division, suggesting that the cells divided without chloroplast division', 'We investigated the effects of antibiotics that interfere with peptidoglycan biosynthesis on chloroplast division in the desmid Closterium peracerosum-strigosum-littorale complex', 'Recent advances in pneumococcal peptidoglycan biosynthesis suggest new vaccine and antimicrobial targets.', 'Of late, the peptidoglycan (PG) layer, the most important component of the bacterial cell wall has been the subject of drug targeting because, first, it is essential for the survivability of eubacteria and secondly, it is absent in humans.', 'Antibiotics which inhibit bacterial peptidoglycan biosynthesis are the most widely used in current clinical practice.', 'A dose-response experiment with an E. coli strain susceptible to ampicillin demonstrated a weak effect before the MIC dose.', ' In an initial approach, the procedure accurately discriminates susceptible, intermediate and resistant strains of Escherichia coli to amoxicillin/clavulanic acid.', 'Surprisingly, also cinnamycin of Streptomyces cinnamoneus cinnamoneus), previously known to bind specifically to phosphatidylethanolamin of biological membranes, provoked strong cell wall biosynthetic stress.', 'Here, we compare the staining patterns observed in Bacillus subtilis using fluorescent derivatives of two PG-binding antibiotics, vancomycin and ramoplanin.', 'Ramoplanin probes may be better imaging agents than vancomycin probes because they yield clear staining patterns at concentrations well below their minimum inhibitory concentrations.', 'Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors.', 'The muraymycins constitute a new antibiotic family whose core structure contains a glycosylated uronic acid derivative joined by an aminopropane group to a hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing dipeptide that is further extended by a urea-valine moiety.', 'The muraymycins inhibited peptidoglycan biosynthesis. ', 'Rethinking ramoplanin: the role of substrate binding in inhibition of peptidoglycan biosynthesis.', 'Ramoplanin is a cyclicdepsipeptide antibiotic that inhibits peptidoglycan biosynthesis.', 'Vancomycin binds to bacterial cell-wall intermediates to achieve its antibiotic effect.', 'The lantibiotic mersacidin inhibits peptidoglycan biosynthesis at the level of transglycosylation.', 'The lantibiotic mersacidin has been previously reported to interfere with bacterial peptidoglycan biosynthesis', 'Here, we focus on the target reaction and describe a mersacidin-induced accumulation of UDP-N-acetylmuramoyl-pentapeptide, indicating that inhibition of peptidoglycan synthesis occurs after the formation of cytoplasmic precursors', 'The analogy to the glycopeptides may hint at an interaction of mersacidin with the peptidoglycan precursor rather than with the enzyme. Unlike vancomycin however, mersacidin inhibits peptidoglycan formation from UDP-N-acetylmuramoyl-tripeptide and is active against Enterococcus faecium expressing the vanA resistance gene cluster.', 'Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic.', 'LY191145 is a p-chlorobenzyl derivative of LY264826 (A82846B) with activity against both vancomycin-susceptible and -resistant enterococci. Incorporation of L-[14C]lysine into peptidoglycan of intact vancomycin-susceptible and -resistant Enterococcus faecium was inhibited by LY191145 (50% inhibitory concentrations of 1 and 5 microgram/ml, respectively). Inhibition was accompanied by accumulation of UDP-muramyl-peptide precursors in the cytoplasm', 'The fact that inhibition of peptidoglycan biosynthesis by LY191145 was not readily antagonized by an excess of free acyl-D-alanyl-D-alanine or acyl-D-alanyl-D-lactate ligands indicates that the manner in which this compound inhibits transglycosylation may not be identical to that of vancomycin.', 'Comparison with tunicamycin-treated cells indicated that peptidoglycan rather than teichoic acid metabolism is primarily affected', 'Mersacidin caused the excretion of a putative cell wall precursor into the culture supernatant', 'Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism?', 'Mersacidin is an antibiotic peptide produced by Bacillus sp. strain HIL Y-85,54728 that belongs to the group of lantibiotics. Its activity in vivo against methicillin-resistant Staphylococcus aureus strains compares with that of the glycopeptide antibiotic vancomycin', 'Incubation of Staphylococcus simulans 22 with mersacidin resulted in the cessation of growth and slow lysis.', 'n contrast to vancomycin, the activity of mersacidin was not antagonized by the tripeptide diacetyl-L-Lys-D-Ala-D-Ala, indicating that on the molecular level its mode of action differs from those of glycopeptide antibiotics.', 'Inhibition of peptidoglycan biosynthesis by ramoplanin.', 'Ramoplanin, a new lipoglycopeptide antibiotic, inhibits cell wall peptidoglycan biosynthesis in gram-positive bacteria.', 'Bacitracin and other antibiotics that inhibit late stages in peptidoglycan biosynthesis induce vancomycin resistance in a high-level, inducibly vancomycin-resistant strain of Enterococcus faecium.', 'This effect does not involve a change in the permeability of the cell wall by this drug and is consistent with the identification of D-alanine racemase as a target of D-cycloserine. ', 'CONCLUSIONS: Several pathways and genes downregulated by fosfomycin have been identified, in contrast to previously described cell wall active antibiotics, and was explained by starvation response induced by phosphoenolpyruvate accumulation. ', 'The target pathway - peptidoglycan biosynthesis - was upregulated following fosfomycin treatment. ', 'Ramoplanin, a new lipoglycopeptide antibiotic, inhibits cell wall peptidoglycan biosynthesis in gram-positive bacteria. ', 'Fosfomycin inhibited the first enzymatic step of peptidoglycan synthesis, which was followed by decreased levels of peptidoglycan precursors but enhanced levels of substrates such as UDP-GlcNAc and alanine-alanine.', 'In contrast, vancomycin and ampicillin inhibited the last stage of peptidoglycan construction on the outer cell surface.', 'The target pathway - peptidoglycan biosynthesis - was upregulated following fosfomycin treatment. Modulation of transport processes, cofactor biosynthesis, energy metabolism and nucleic acid biosynthesis was also observed.', 'Ramoplanin, a new lipoglycopeptide antibiotic, inhibits cell wall peptidoglycan biosynthesis in gram-positive bacteria.']

['Under some conditions, both ramoplanin and vancomycin probes produce helicoid staining patterns along the cylindrical walls of B. subtilis cells. This work has implications for the design of ramoplanin derivatives and may influence how other proposed substrate binding antibiotics are studied. This was confirmed by in vitro studies involving a wall-membrane particulate fraction from Gaffkya homari in which peptidoglycan synthesis from UDP-MurNAc-tetrapeptide was inhibited by ramoplanin but not by vancomycin. New results support a two-state model for septal and peripheral PG synthesis at mid-cell, involvement of essential cell division proteins in PG remodeling, and mid-cell localization of proteins that organize PG biosynthesis and that form the protein translocation apparatus.', 'Antibiotics which inhibit bacterial peptidoglycan biosynthesis are the most widely used in current clinical practice. Cells treated with ampicillin, D-cycloserine, or fosfomycin had only one chloroplast after cell division, suggesting that the cells divided without chloroplast division. The antibiotics bacitracin and vancomycin showed no obvious effect. Colchicine inhibits Closterium cell elongation after division. Surprisingly, also cinnamycin of Streptomyces cinnamoneus cinnamoneus), previously known to bind specifically to phosphatidylethanolamin of biological membranes, provoked strong cell wall biosynthetic stress. Other substances include fluorescent derivatives of two PG-binding antibiotics, vancomycin and ramoplanin. The muraymycins constitute a new antibiotic family whose core structure contains a glycosylated uronic acid derivative joined by an aminopropane group to a hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing dipeptide that is further extended by a urea-valine moiety. The muraymycins inhibited peptidoglycan biosynthesis. Ramoplanin is a cyclicdepsipeptide antibiotic that inhibits peptidoglycan biosynthesis. The lantibiotic mersacidin inhibits peptidoglycan biosynthesis at the level of transglycosylation. Ramoplanin, a new lipoglycopeptide antibiotic, inhibits cell wall peptidoglycan biosynthesis in gram-positive bacteria.']

['colchicine', 'fosfomycin', 'bacitracin', 'vancomycin', 'D-cycloserine', 'seromycin', 'ampicillin', 'cinnamycin', 'ramoplanin', 'muraymycin', 'mersacidin']

What is the association between cell phone use and glioblastoma?

['Decreased survival of glioma cases with long-term and high cumulative use of wireless phones was found. ', 'There was no significant association between glioma and alcohol consumption, smoking and mobile phone use.', 'Regular cell phone use was not associated with an increased risk of neuroma (OR=0,92; 95% confidence interval=[0.53-1.59]), meningioma (OR=0,74; 95% confidence interval=[0.43-1.28]) or glioma (OR=1.15; 95% confidence interval=[0.65-2.05]). Although these results are not statistically significant, a general tendency was observed for an increased risk of glioma among the heaviest users: long-term users, heavy users, users with the largest numbers of telephones. ', 'No significant increased risk for glioma, meningioma or neuroma was observed among cell phone users participating in Interphone. ', ' Our results, suggesting the possibility of an increased risk among the heaviest users, therefore need to be verified in the international INTERPHONE analyses.', 'The risk for ipsilateral use was significantly increased for astrocytoma for all studied phone types, analogue phones OR=1.8,95% CI=1.1-3.2, digital phones OR=1.8, 95% CI=1.1-2.8, cordless phones OR=1.8, 95% CI=1.1-2.9.', 'For astrocytoma and ipsilateral use the trend was for analogue phones OR=1.10, 95% CI=1.02-1.19, digital phones OR=1.11, 95% CI=1.01-1.22, and cordless phones OR=1.09, 95% CI=1.01-1.19. There was a tendency of a shorter tumour induction period for ipsilateral exposure to microwaves than for contralateral, which may indicate a tumour promotor effect.', 'Case reports of brain tumours in users initiated this case-control study on brain tumours and use of cellular telephones.', 'Increased risk was found only for use of the NMT system. ', 'This increased HR was based on results for astrocytoma WHO grade IV (glioblastoma multiforme).', 'Some studies show increasing incidence of brain tumours whereas other studies do not.', 'The meta-analysis gave for glioma in the most exposed part of the brain, the temporal lobe, odds ratio (OR)=1.71, 95% confidence interval (CI)=1.04-2.81 in the ≥10 years (>10 years in the Hardell group) latency group. Ipsilateral mobile phone use ≥1640h in total gave OR=2.29, 95% CI=1.56-3.37. ', 'After 1983 and during the period with increasing prevalence of mobile phone users, the incidence has remained relatively stable for both men and women.']

['The association between cell phone use and incident glioblastoma remains unclear. Some studies have reported that cell phone use was associated with incident glioblastoma, and with reduced survival of patients diagnosed with glioblastoma. However, other studies have repeatedly replicated to find an association between cell phone use and glioblastoma.']

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What histone modification is recognized by the bromodomain?

['acetyllysine-specific protein-protein interaction with bromodomain reader modules', 'Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code', ' three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization.', 'acetyl-lysine binding bromodomain (BRD)', 'bromodomain proteins bind to acetylated lysines in histones', 'romodomains are present in many chromatin-associated proteins such as the SWI/SNF and RSC chromatin remodelling and the SAGA HAT (histone acetyltransferase) complexes, and can bind to acetylated lysine residues in the N-terminal tails of the histones', 'recognition of acetylated histones by bromodomains', 'BRD7, a novel bromodomain gene', 'BRD7 interacted with H3 peptide acetylated', 'bromodomain-containing proteins that recognize histone acetylation sites', 'bromodomains of Gcn5, PCAF, TAF1 and CBP are able to recognize acetyllysine residues in histones', 'romodomain factor 1 (Bdf1', ' Bdf1 binds preferentially to acetylated histone H4', 'chromatin remodeling complex RSC bears multiple bromodomains, motifs for acetyl-lysine and histone tail interaction', ' in vitro binding of a HAT bromodomain with acetylated lysines within H3 and H4 amino-terminal peptides', 'bromodomain, that recognizes acetylated residues']

['Acetylated lysines in histones (generally H3 and H4)']

['Acetylated lysines']

Why does the prodrug amifostine (ethyol) create hypoxia?

['Amifostine (WR-2721, delivered as Ethyol) is a phosphorylated aminothiol compound clinically used in addition to cis-platinum to reduce the toxic side effects of therapeutic treatment on normal cells without reducing their efficacy on tumour cells. ', 'However, amifostine has also been described as a potent hypoxia-mimetic compound and as a strong p53 inducer; both effects are known to potently modulate vascular endothelial growth factor (VEGF-A) expression. The angiogenic properties of this drug have not been clearly defined.', 'Both dose fractionation and amifostine protect osteoblasts from the growth inhibitory effects of ionizing radiation. Fractionation but not amifostine was protective for hypoxia-induced vascular endothelial growth factor production (used as a surrogate marker of normal osteoblast function)', 'Radioprotective modalities such as dose fractionation and pharmacologic agents such as amifostine have been used to protect bone and other types of normal tissue from the damaging effects of ionizing radiation without significantly impacting tumor kill. To better understand the cellular mechanism of radioprotection of osseous tissue, the authors sought to determine the effect of dose fractionation and amifostine on isolated osteoblasts', 'Tumor hypoxia and low intrinsic radiosensitivity may counteract the efficacy of standard radiotherapy for locally advanced head and neck cancer (HNC). We investigated the involvement of hypoxia-regulated proteins (Hypoxia inducible factors HIF1alpha, HIF2alpha and carbonic anhydrase CA9) in HNC resistance to accelerated and hypofractionated radiotherapy', ' Immunohistochemical analysis of hypoxia-regulated proteins, namely HIF1alpha, HIF2alpha and CA9, was performed in formalin-fixed paraffin-embedded tissues obtained prior to radio-chemotherapy.', 'In accord with previously reported studies, high levels of the hypoxia regulated proteins HIF1alpha and CA9 in HNC predict resistance to platinum based radio-chemotherapy. Whether HIF2alpha expressing tumors are more sensitive to larger radiotherapy fractions, compared to standard radiotherapy fractionation, is an issue that deserves further investigation.', 'Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia.', 'We investigated additional cytoprotective pathways involving intracellular hypoxia and the activation of the hypoxia-inducible factor (HIF) pathway, a key transcription factor regulating glycolysis, angiogenesis and apoptosis, which is also linked with radioresistance', ' tumor hypoxia and ability of cancer cells to undergo rapid repopulation during radiotherapy are associated with failure of radiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable to undergo re-oxygenation, are unlikely to be eradicated with standard radiotherapy. Although the therapeutic efficacy of accelerated regimens based on low-dose per fraction may be high since they minimize the adverse role of rapid tumor repopulation, the cellular compartment with low alpha/beta-ratio values (i.e. hypoxic cells) remains a limiting factor. ', 'Amifostine (Ethyol) is a prodrug that must be dephosphorylated to the free thiol in which form it can detoxify free oxygen radicals generated by radiation, hypoxia and by drugs such anthracyclines, platinum analogues and alkylating agents. Amifostine as inactive prodrug is primarily metabolized at the tissue site by membrane alkaline phosphatase, which is highly active in the cell membranes of normal endothelial cells and biliary tree cells but not in the cell membranes and neovascular capillaries of tumor']

['After the administration of Prodrug amifostine the cells of the tissue prefer anaerobic glycolysis rather than regular cellular aerobic respiration. By the beggining of anaerobic glycolysis the inducible by hypoxia proteins are induced and by all these molecules the hypoxic conditions consist of.']

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Which disease has been associated to a disruptive ALX1 protein?

['Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia.', 'In the second family we identified a homozygous donor-splice-site mutation (c.531+1G>A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. ', 'expression of Alx1, an effector of scapula blade patterning, is absent in all compound mutants.', 'Mutations in each of the transcriptional co-activator genes - CBP, p300, Cited2, Cart1 and Carm1 - result in neural tube defects in mice.', 'Scapular truncation in triple mutants of Tbx15, Alx4 and Cart1 indicates essential functions for Alx4 and Cart1 in the anterior part of the scapula', ' Ectopic expression of Cart1 in transgenic mice does not disturb development, whereas expression of a Cart1 form from which the aristaless domain has been deleted results in severe cranial and vertebral malformations.', 'Cart1, is essential for correct morphogenesis of the limbs and cranium.', 'Cart1 encodes the paired-like homeodomain in the central portion of the gene, and plays a crucial role in the developmental lineage of bone and cartilage, especially in head formation.', 'we show that Cart1-homozygous mutant mice are born alive with acrania and meroanencephaly but die soon after birth-a phenotype that strikingly resembles a corresponding human syndrome caused by a neural tube closure defect.', ' 240\xa0kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial development', 'ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively']

['Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia.']

['frontonasal dysplasia']

What is the inheritance of the glucose-6-phosphate dehydrogenase (G6PD) deficiency?

['Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has an X-linked inheritance.', " The high manifestation of G6PD deficiency in women may be due to the preferential expression of the G6PD-deficient gene and X-inactivation of the normal gene, and/or to the presence of an 'enhancer' gene that makes the expression of the G6PD deficiency more likely. ", 'Study of the deficiency pattern amongst family members of the enzyme deficient subjects confirmed the X-linked inheritance of G-6-PD deficiency.', " The investigation of the patient's whole family showed the typical recessive X-linked inheritance of this enzyme-defect. ", 'After having described in detail the pathophysiology, symptomatology, X-chromosomal inheritance and some laboratory methods in detecting G-6-PD-deficiency by demonstrating a case of favism (Schulz et al. 1977), the authors now discuss the particularities of the enzyme deficiency in the newborn. T', 'The genetic pattern is consistent with x-linked recessive inheritance and the defect is associated with drug (primaquine) induced haemolysis. ', 'UNLABELLED: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder in which haemolytic anaemia is the major symptom.', 'Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, and it has a significant prevalence in the male population (X chromosome linked).', 'Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has an X-linked inheritance', 'Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic defect that can cause hemolytic crisis.', 'Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hemolytic anemia caused by a mutation in the G6PD gene on Xq28.', 'Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of G6PD.']

['Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has a recessive X-linked inheritance.']

['recessive X-linked inheritance']

Which medical diagnostic tests are used to test kidney function?

['kidney dysfunction and decreased glomerular filtration rate (GFR) are diagnosed by the evaluation of changes in the serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations. ', 'Renal biomarkers, especially those present in urine, may be useful for the study of both acute and chronic nephropathies.', 'The International Renal Interest Society (IRIS) canine AKI grading system and the implementation of urinary biomarkers', 'Decreased tryptophan (TRP) and increased kynurenine (KYN) and kynurenic acid (KYNA) in blood have been reported in patients and experimental animals with renal diseases.', 'Acute kidney injury was defined as a decrease in estimated glomerular filtration rate of 50% or more from the beginning of vancomycin therapy. ', ' In critically ill children, the development of reversible AKI during vancomycin therapy is associated with administration of nephrotoxic drugs and an elevated BUN: Scr ratio.', 'The physiologic determination of renal status is the measured glomerular filtration rate (mGFR). Serum creatinine, blood urea nitrogen, cystatin C, and estimated GFR (eGFR), based on serum creatinine have failed to replace mGFR.', 'After kidney donation, renal function measured by blood urea nitrogen (BUN) and serum creatinine of all donors returned to normal within one week, and no serious complications were noticed.', ' In living kidney donors GFR is not significantly correlated with age or sex.', 'Increased proteinuria would lead to a larger risk for renal failure in the long term', 'A reduction of proteinuria in patients with non-diabetic renal disease was observed during the 4-month treatment with pioglitazone which continued for 2 months after the cessation of the treatment. However, 4 months after the cessation of the treatment, a little increase was detected in the level of proteinuria.', 'We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD.']

['Most common tests used in diagnosing normal kidney function include blood tests such as serum creatinine levels, glomerular filtration rate (GFR) and blood urea nitrogen (BUN) levels, also medical imaging tests like ultrasound and CT Scan. Additionally kidney biopsy is used in more direct but invasive approach. Lastly, and probably the most relevant tests to kidney function are urine tests along the lines of urinalysis, urine protein levels and microalbuminuria creatinine clearance.']

['Blood Tests', 'Imaging Tests', 'Kidney Biopsy', 'Urine Tests', 'estimated GFR (eGFR)', 'Decreased tryptophan (TRP)']

How does TNF affect thyroid hormone receptors?

['treatment of the cells with T(3) for 2 d induced the expression of thyroid hormone receptor-beta and caspase-3, and this thyroid hormone receptor-beta induction was drastically repressed by xTNF-alpha.']

['TNF-alpha inhibits the T3-induced expression of thyroid hormone receptor-beta']

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How many disulfide bridges has the protein hepcidin got?

[' hepcidin, containing four disulfide bridges', "Cshepc has eight cysteines formed four conserved disulfide bridges, similarly to that of human's", 'The native peptide of 25 amino acids (Hepc25) contains four disulfide bridges that maintain a β-hairpin motif.', 'Hepcidin, a 25 amino acid peptide hormone containing a complex network of four disulfide bonds is the hormone regulator of iron homeostasis', 'Molecular mass measurements of the native peptide and the reduced and alkylated peptide confirmed the sequence with four intramolecular disulfide bridges. ', 'Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets.']

['Hepcidin contains eight cysteine residues that form four disulfide bridges.']

['Hepcidin contains eight cysteine residues that form four disulfide bridges']

What is the treatment of triiodothyronine toxicosis?

['Three patients met the criteria for free T3 toxicosis and three had subclinical hyperthyroidism. All six patients had either multinodular glands or a single nodule on thyroid exam. Four patients were treated with radioactive iodine or surgery, resulting in reversal of the TSH suppression in three cases.', '6 months treatment with propranolol (160 mg/day) in eight patients with T3 (triiodothyronine) toxicosis. Serum total T3 concentrations showed a significant (p less than 0.01) and sustained fall to approximately 80% of pre-treatment values.', 'Both patients responded to therapy with propylthiouracil.']

['Treatment of T3 toxicosis is a complex medical problem because not well responsive to the various options. Usual treatment includes antithyroid drugs such as propyltiouracil, radioactive iodine or beta blockers like propanol; surgery may be also necessary in some cases.']

['Propyltiouracil', 'Radioiodine', 'beta blockers', 'thyroidectomy']

What is the role of the constitutive photomorphogenesis 9 signalosome (CSN)?

['The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. ', 'The COP9 (constitutive photomorphogenesis 9) signalosome (CSN) is a protein complex involved in the ubiquitin proteasome system and a common host target of diverse pathogens in Arabidopsis. ', 'The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN), a large multiprotein complex that resembles the 19S lid of the 26S proteasome, plays a central role in the regulation of the E3-cullin RING ubiquitin ligases (CRLs).', 'The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. Its role in tumor development, however, remains unclear.', 'COP9 plays a role in plant innate immunity. ', 'The constitutive photomorphogenesis\xa09 signalosome (COP9 or CSN) is an evolutionarily conserved multiprotein complex found in plants and animals. Because of the homology between the COP9 signalosome and the 19S lid complex of the proteosome, COP9 has been postulated to play a role in regulating the degradation of polyubiquitinated proteins. ', 'Therefore, it is conceivable that COP9 plays a significant role in cancer, regulating processes relevant to carcinogenesis and cancer progression (e.g., cell cycle control, signal transduction and apoptosis). ', 'The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-κB activation in mammals.', 'The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this has not been tested in a critical vertebrate organ.', 'The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response.', 'Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN).', 'The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood.', 'CSN6 is one subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is an evolutionarily conserved multiprotein complex found in plants and animals and originally described as a repressor of light-dependent growth and transcription in Arabidopsis.', 'CSN6, a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has received attention as a regulator of the degradation of cancer-related proteins such as p53, c-myc and c-Jun, through the ubiquitin-proteasome system, suggesting its importance in cancerogenesis.', 'The COP9 signalosome (CSN) is a complex of eight proteins first identified as a repressor of plant photomorphogenesis.', 'COP10 is a ubiquitin-conjugating enzyme variant (UEV), which is thought to act together with COP1, DET1, and the COP9 signalosome (CSN) in Arabidopsis to repress photomorphogenesis.', 'The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this has not been tested in a critical vertebrate organ.', 'The COP9 signalosome (CSN) is an evolutionarily conserved multiprotein complex that mediates the repression of photomorphogenesis in the dark in Arabidopsis through the degradation of transcription factors such as HY5 and HYH.', 'The COP9 signalosome (CSN), a suppressor of plant photomorphogenesis, associated with multiple cullins and promoted cleavage of the ubiquitin-like protein NEDD8 from Schizosaccharomyces pombe CUL1 in vivo and in vitro.', 'The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-êB activation in mammals.', 'Repression of photomorphogenesis in Arabidopsis thaliana requires activity of the COP9 signalosome (CSN), CDD, and COP1 complexes, but how these three complexes work in concert to accomplish this important developmental switch has remained unknown.', 'The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-κB activation in mammals', 'Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN)', 'The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN), a large multiprotein complex that resembles the 19S lid of the 26S proteasome, plays a central role in the regulation of the E3-cullin RING ubiquitin ligases (CRLs)', 'CSN6 is one subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is an evolutionarily conserved multiprotein complex found in plants and animals and originally described as a repressor of light-dependent growth and transcription in Arabidopsis', 'The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response', 'The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this has not been tested in a critical vertebrate organ', 'The COP9 Signalosome (CSN) is a multiprotein complex that was originally identified in Arabidopsis thaliana as a negative regulator of photomorphogenesis and subsequently shown to be a general eukaryotic regulator of developmental signaling', 'Repression of photomorphogenesis in Arabidopsis thaliana requires activity of the COP9 signalosome (CSN), CDD, and COP1 complexes, but how these three complexes work in concert to accomplish this important developmental switch has remained unknown', 'COP10 is a ubiquitin-conjugating enzyme variant (UEV), which is thought to act together with COP1, DET1, and the COP9 signalosome (CSN) in Arabidopsis to repress photomorphogenesis', 'The constitutive photomorphogenesis 9 signalosome directs vascular endothelial growth factor production in tumor cells.', 'Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN). ', 'The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-κB activation in mammals. ', 'The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN), a large multiprotein complex that resembles the 19S lid of the 26S proteasome, plays a central role in the regulation of the E3-cullin RING ubiquitin ligases (CRLs). ', 'Plant homologue constitutive photomorphogenesis 9 (COP9) signalosome subunit CSN5 regulates innate immune responses in macrophages.', 'The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this has not been tested in a critical vertebrate organ. ', 'The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. ', 'Recent studies indicate that Int6 is a multifaceted protein involved in the regulation of protein translation and degradation through binding with three complexes: the eukaryotic translation initiation factor 3, the proteasome regulatory lid, and the constitutive photomorphogenesis 9 signalosome. ', 'The COP9 Signalosome (CSN) is a multiprotein complex that was originally identified in Arabidopsis thaliana as a negative regulator of photomorphogenesis and subsequently shown to be a general eukaryotic regulator of developmental signaling. ', 'In this report we demonstrate a JNK-independent activation of c-Jun in vivo directed by the constitutive photomorphogenesis (COP9) signalosome. ', 'The COP9 signalosome (CSN) is a multiprotein complex that was initially identified in plants as a repressor of photomorphogenesis.', 'This study suggests that AtItpk-1 may function as a protein kinase that is involved in photomorphogenesis possibly via interaction with COP9 signalosome under red light.', 'The Arabidopsis inositol 1,3,4-trisphosphate 5/6 kinase, AtItpk-1, is involved in plant photomorphogenesis under red light conditions, possibly via interaction with COP9 signalosome.', 'The COP9 (constitutive photomorphogenesis 9) signalosome (CSN) is a protein complex involved in the ubiquitin proteasome system and a common host target of diverse pathogens in Arabidopsis.', 'Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN).', 'The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this has not been tested in a critical vertebrate organ.', 'The constitutive photomorphogenesis 9 signalosome directs vascular endothelial growth factor production in tumor cells.']

['The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a protein complex involved in the ubiquitin proteasome system and plays a role in regulating the degradation of polyubiquitinated proteins. The mammalian CSN is also involved in embryonic development, in cancer and the DNA damage response, whereas in plants CSN plays a role in innate immunity.']

[]

Which molecule is targeted by a monoclonal antibody Mepolizumab?

['Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma.', ' Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. ', 'Among developing therapies, biologics designed to block certain pro-inflammatory cytokines, such as IL-5 (mepolizumab) and IL-13 (lebrikizumab), have a greater chance of being used in the clinic.', 'Imatinib and mepolizumab, a humanized anti-interleukin 5 monoclonal antibody, may be useful in patients with eosinophilic myositis as part of a hypereosinophilic syndrome.', ' Recent results of the treatment of idiopathic hypereosinophilic syndrome (HES) with the anti-interleukin 5 monoclonal antibody mepolizumab showed its efficacy and manageable safety profile. ', 'Individuals also received a segmental bronchoprovocation with allergen (SBP-Ag) 1 month before and after administering a single dose of mepolizumab (anti-IL-5 monoclonal antibody) to reduce airway EOS. ', '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. ', 'Efficacy of anti-interleukin-5 therapy with mepolizumab in patients with asthma: a meta-analysis of randomized placebo-controlled trials.', 'Previous clinical trials have evaluated the efficacy and safety of mepolizumab, a monoclonal antibody against IL-5, in patients with asthma.', 'In this large (616 patients), double-blind, placebo-controlled, dose-ranging study of mepolizumab (a monoclonal antibody that blocks IL-5 binding to its receptor), patients were given placebo, 75-, 250- or 750-mg mepolizumab by intravenous infusion every 4 weeks for 1 year. ', 'BACKGROUND: We examined levels of hyaluronan, a matrix glycosaminoglycan and versican, a matrix proteoglycan, in the sputum of asthmatics treated with mepolizumab (anti-IL-5 monoclonal antibody) versus placebo to evaluate the utility of these measurements as possible biomarkers of asthma control and airway remodeling. ', 'Mepolizumab is a humanized monoclonal antibody that blocks binding of the key cytokine implicated specifically in eosinophil maturation and survival, interleukin-5, to its receptor.', 'Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. ', '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). ', '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. ', 'Mepolizumab (Bosatria(®), GlaxoSmithKline) is a biologic agent developed to treat asthma. It represents a humanized monoclonal antibody of IgG1 κ type, which targets human IL-5 and thus prevents its interaction with the α-chain of the IL-5 receptor.', 'There has been a variable effect with the leukotriene receptor antagonist montelukast and promising early results with mepolizumab, a monoclonal antibody against interleukin-5. ', 'Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody.', 'Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. ', 'Recently, encouraging results of treatment with monoclonal antibody neutralizing IL-5, mepolizumab, have been published.', 'This manuscript reviews the available treatments for HES and the range of side-effects associated with long-term corticosteroid use, and then focuses on the anti-IL-5 monoclonal antibodies, mepolizumab and reslizumab. ', "The therapeutic progress is primarily due to an explosion of biological therapies, particularly four of them very useful for internists (in an off label use) : Interleukin 1 inhibitors (anakinra, Canakinumab) to treat some auto inflammatory diseases (cryopirin associated periodic syndromes and deficency of interleukin 1 receptor antagonist), monoclonal antibody against interleukin 5 (mepolizumab) to treat some hypereosinophilic syndromes and Churg and Strauss angiitis, interleukin 6 inhibitiors to treat multifocal Castleman's disease and adult Still disease, a monoclonal antibody against vascular endothelial growth factor (Bevacizumab) to treat hereditary hemorrhagic telangiectasia.", ' Besides steroid therapy, the anti-IL-5 monoclonal antibody mepolizumab is considered as a target therapy for L-HES.', 'Mepolizumab is a humanized monoclonal antibody (mAb) with potent IL-5 neutralizing effects that represents a potential treatment for eosinophilic diseases.', 'Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.', 'The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated.', 'We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. ', 'Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. ', 'A recent study showed that a monoclonal antibody to IL-5, mepolizumab, reduced glucocorticoid therapy in HES patients who did not possess the FIP1L1-PDGFRA mutation while controlling eosinophilia and preventing recurrence or progression of tissue damage. ', 'METHODS: We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome.', 'Mepolizumab: 240563, anti-IL-5 monoclonal antibody - GlaxoSmithKline, anti-interleukin-5 monoclonal antibody - GlaxoSmithKline, SB 240563.', 'Mepolizumab is an anti-interleukin-5 monoclonal antibody that is in clinical trials with GlaxoSmithKline (GSK) for the treatment of severe asthma, nasal polyposis and hypereosinophilic syndrome and eosinophilic oesophagitis (the latter two indications are classed as eosinophilia in the phase table). ', 'A previous small dose-finding study found that mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans.', 'No effect of anti-interleukin-5 therapy (mepolizumab) on the atopy patch test in atopic dermatitis patients.', 'Mepolizumab is a monoclonal antibody to interleukin-5, which reduces peripheral blood eosinophils. Previously, we reported that mepolizumab treatment did not result in clinical improvement in AD. ', 'Mepolizumab, an anti-IL-5 monoclonal antibody, currently being evaluated, seems promising. ', 'These include imatinib mesylate, a tyrosine kinase inhibitor, and more recently, mepolizumab, an anti-IL-5 monoclonal antibody. ', 'Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis.', 'A monoclonal antibody to human interleukin-5 (mepolizumab) was developed for atopic diseases. ', 'Anti-IL-5 monoclonal antibody (mepolizumab) reduces baseline bronchial mucosal eosinophils and deposition of extracellular matrix proteins in the reticular basement membrane in mild asthma. ', 'Skin biopsies were performed in 24 atopic subjects at allergen- and diluent-injected sites before 6 and 48 h after, three infusions of a humanized, monoclonal antibody against IL-5 (mepolizumab) using a randomized double-blind, placebo-controlled design. ', 'OBJECTIVE: We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. ', 'Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.', 'Bronchial biopsies were obtained before and after three infusions of a humanized, anti-IL-5 monoclonal antibody (mepolizumab) in 24 atopic asthmatics in a randomized, double-blind, placebo-controlled study. ', 'GlaxoSmithKline (formerly SmithKline Beecham) is developing mepolizumab (SB-240563), a monoclonal antibody directed against IL-5, as a potential treatment for asthma and atopic dermatitis.', 'METHODS: Blood, bone marrow, and airway mucosal biopsy specimens were examined before and after anti-IL-5 (mepolizumab) treatment of asthmatic individuals in a double-blind, placebo-controlled trial.', 'Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics.', 'The role of eosinophils as effector cells in asthma pathogenesis has been questioned since an anti-interleukin (IL)-5 monoclonal antibody (mepolizumab), which depleted blood and sputum eosinophils, failed to inhibit allergen-induced bronchoconstriction and airway hyperresponsiveness. ', 'Mepolizumab (SB-240563), a humanized monoclonal antibody (mAb) specific for human IL-5, is currently in clinical trials for treatment of asthma.', 'CONCLUSION: These studies demonstrate that chronic antagonism of IL-5 by mepolizumab in monkeys is safe and has the potential, through long-term reductions in circulating and tissue-resident eosinophils, to be beneficial therapy for chronic inflammatory respiratory diseases.', 'Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys.', 'Mepolizumab is a fully humanized monoclonal antibody (IgG1/�) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function.', 'BACKGROUND: Mepolizumab, a monoclonal anti-IL-5 antibody, is an effective corticosteroid-sparing agent for patients with Fip1-like 1/platelet-derived growth factor receptor � fusion (F/P)-negative hypereosinophilic syndrome (HES).', 'Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function', 'Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling', 'Besides steroid therapy, the anti-IL-5 monoclonal antibody mepolizumab is considered as a target therapy for L-HES', '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)']

['Mepolizumab is a humanized monoclonal antibody that binds to and inactivates interleukin-5 that has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma.']

['interleukin-5']

Which enzyme is targeted by Evolocumab?

['Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of the proprotein convertase subtilisin/kexin type 9: the available clinical evidence.', 'AREAS COVERED: Evolocumab (AMG145) is a monoclonal antibody inhibiting the proprotein convertase subtilisin/kexin type 9 that binds to the liver LDL receptor and prevents it from normal recycling by targeting it for degradation. ', 'Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials.', 'We report a pooled analysis from four phase 2 studies of evolocumab (AMG 145), a monoclonal antibody to PCSK9. ', 'Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials.', 'METHODS: A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9, on Lp(a), the relationship between Lp(a) and lowering of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin therapy.', 'CONCLUSIONS: Inhibition of PCSK9 with evolocumab resulted in significant dose-related reductions in Lp(a). ', 'Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. ', 'Evolocumab (AMG 145) is a fully human monoclonal antibody that binds PCSK9, inhibiting its interaction with the LDL receptor to preserve LDL-receptor recycling and reduce LDL-C.', 'Antibody therapeutics in Phase 3 studies are described, with an emphasis on those with study completion dates in 2014, including antibodies targeting interleukin-17a or the interleukin-17a receptor (secukinumab, ixekizumab, brodalumab), proprotein convertase subtilisin/kexin type 9 (alirocumab, evolocumab, bococizumab), and programmed death 1 receptor (lambrolizumab, nivolumab).', "BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. ", 'These compounds act either by reducing low-density lipoprotein (LDL) production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen) or by inhibiting microsomal triglyceride transfer protein (lomitapide), or by enhancing LDL catabolism via monoclonal antibody-mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9) (evolocumab). ', 'Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial.', 'Evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced LDL cholesterol by 16% in a pilot study. ', 'PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.', 'We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. ', 'Some of the anti-dyslipidemic drugs which work by PCSK9 inhibition include evolocumab, alirocumab and ALN-PCS.', 'We highlight the different steps of this adventure and review the published clinical trials especially those with the anti-PCSK9 antibodies evolocumab (AMG 145) and alirocumab (SAR236553/REGN727), which are in phase III trials.', 'Monoclonal antibodies against PCSK9 represent so far the most advanced approach in clinical development, with alirocumab, evolocumab and bococizumab under advanced clinical development. ', 'AREAS COVERED: Evolocumab and alirocumab are fully human monoclonal antibodies inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) that binds to hepatic LDL receptor and prevents it from normal recycling by targeting it for degradation.', 'Phase II (for evolocumab and alirocumab) and III (for evolocumab) trials show that PCSK9 inhibitors are equally well tolerated, with adverse events mainly limited to mild-to-moderate nasopharyngitis, injection-site pain, arthralgia and back pain. ', 'Four classes of newer lipid-lowering drugs offer promising advances in treating FH, namely the apolipoprotein-B synthesis inhibitors (mipomersen), the microsomal transfer protein inhibitors (lomitapide), the cholesterol ester transfer protein inhibitors (anacetrapib, evacetrapib) and the proprotein convertase subtilisin/kexin type 9 inhibitors (evolocumab, alirocumab).', 'Monoclonal antibodies that inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9), which degrades the LDL receptor, like alirocumab and evolocumab, are in phase 3 trials.', 'In support of the drug development program for Evolocumab, a fully human IgG₂ antibody that targets PCSK9, a quantitative ELISA to measure free PCSK9 in human serum was developed. ', 'IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. ', 'Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.', 'Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients.', 'Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab.', 'BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials. ', 'BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. ', 'Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study.']

['Evolocumab (AMG145) is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that demonstrated marked reductions in plasma low-density lipoprotein cholesterol concentrations in statin-intolerant patients.']

['proprotein convertase subtilisin/kexin type 9']

Has field-programmable gate array (FPGA) technology been used to solve sequence alignment problems?

['A linear error model for the raw intensity data and Burrows-Wheeler transform (BWT) based alignment are combined utilizing a Bayesian score function, which is then globally optimized over all possible genomic locations using an efficient branch-and-bound approach. The algorithm has been implemented in soft- and hardware [field-programmable gate array (FPGA)] to achieve real-time performance.', 'we have designed and built a high-performance FPGA-accelerated version of BLASTP, Mercury BLASTP. In this paper, we describe the architecture of the portions of the application that are accelerated in the FPGA, and we also describe the integration of these FPGA-accelerated portions with the existing BLASTP software. We have implemented Mercury BLASTP on a commodity workstation with two Xilinx Virtex-II 6000 FPGAs.', 'This paper shows how reconfigurable architectures can be used to derive an efficient fine-grained parallelization of the dynamic programming calculation. We describe how this technique leads to significant runtime savings for HMM database scanning on a standard off-the-shelf field-programmable gate array (FPGA).', 'We have constructed a linear systolic array to perform pairwise sequence distance computations using dynamic programming. This results in an implementation with significant runtime savings on a standard FPGA.', 'in this paper, we focused on accelerating the Smith-Waterman algorithm by modifying the computationally repeated portion of the algorithm by FPGA hardware custom instructions.', 'We present a reconfigurable systolic architecture that can be applied for the efficient treatment of several dynamic programming methods for resolving well-known problems, such as global and local sequence alignment, approximate string matching and longest common subsequence. The dynamicity of the reconfigurability was found to be useful for practical applications in the construction of sequence alignments. A VHDL (VHSIC hardware description language) version of this new architecture was implemented on an APEX FPGA (Field programmable gate array).', 'This results in an implementation of ClustalW with significant runtime savings on a standard off-the-shelf FPGA.', 'The accelerator implements a version of the Needleman-Wunsch algorithm for nucleotide sequence alignment. Sequence lengths are constrained only by available memory; the product of sequence lengths in the current implementation can be up to 2(22). The machine is implemented as two NuBus boards connected to a Mac IIf/x, using a mixture of TTL and FPGA technology clocked at 10 MHz.']

['Yes. Field-Programmable Gate Arrays (FPGAs) are reconfigurable computing platforms that have found several applications in diverse domains, including digital signal processing, medical imaging and bioinformatics. Specific applications of FPGAs for biological sequence alignment have been reported for dynamic programming-based pairwise (local or global) sequence alignment, progressive multiple sequence alignment, profile alignment, Burrows-Wheeler transform (BWT) based alignment, heuristic pairwise alignment.']

['yes']

What are the biological roles proposed for proteins containing the SPRY domain?

['monkey TRIM5α SPRY domain recognizes multiple epitopes that span several capsid monomers on the surface of the HIV-1 mature viral core', 'These properties, which may enhance resistance of TRIM5α to capsid mutations, result in relatively low affinity of the individual SPRY domains for the capsid', 'RIM5α is a retroviral restriction factor, in which the B30.2 (SPRY) and coiled-coil domains cooperate to determine the specificity of TRIM5α-mediated capture of retroviral capsids', 'function of the SPRY/B30.2 domain proteins involved in innate immunity', 'SPRY domain is a protein interaction module found in 77 murine and ~100 human proteins, and is implicated in important biological pathways, including those that regulate innate and adaptive immunity', 'TRIM5α) is a potent antiviral protein that restricts infection by HIV-1 and other retroviruses', ' TRIM5α recognizes the lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a species-specific manner', 'binding of the PRY-SPRY domain from the TRIM50 C-terminal region to phosphatidylinositol species, suggesting that TRIM50 is involved in vesicular dynamics by sensing the phosphorylated state of phosphoinositol lipids', 'TRIM50 seems to play an essential role in tubulovesicular dynamics', 'TRIM67 regulates Ras signaling via degradation of 80K-H, leading to neural differentiation including neuritogenesis', 'TRIM67, which has a TRIM motif, an FN3 domain and a SPRY domain, is highly expressed in the cerebellum', 'Vasa coding region is sufficient for its selective enrichment and find that gustavus, the B30.2/SPRY and SOCS box domain gene', 'We propose that Gustavus has a conserved, positive regulatory role in Vasa protein accumulation during embryonic development', 'two zebrafish genes, SSB-1 and SSB-4 (SPRY domain SOCS box proteins', 'We hypothesize that SSB-4 plays a role in the early development of germ cells', 'SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing', 'TRIM proteins may be conducive to the convergent evolution of virus-restricting factors.', 'SPRY and B30.2 protein domains. Evolution of a component of immune defence', '. The combination of SPRY and PRY to produce B30.2 domains may have been selected and maintained as a component of immune defence', ' evolution of primate TRIM5alpha, a gene restricting HIV-1 infection', 'The SPRY domain of TRIM5alpha, which may be responsible for recognition of incoming viral capsids showed higher nonsynonymous/synonymous substitution ratios than the non-SPRY domain, indicating that the adaptive evolution of TRIM5alpha in primates might be an innate strategy developed in defending retrovirus infection during primate evolutio', 'The results are consistent with a role for TRIM5alpha in innate immunity against retroviruses', 'B30.2(SPRY) domain of the retroviral restriction factor TRIM5alpha', 'primate TRIM5alpha identifies a critical species-specific retroviral restriction domain', 'By using functional studies of chimeric TRIM5alpha genes, we show that this patch is generally essential for retroviral restriction and is responsible for most of the species-specific antiretroviral restriction activity', 'SPRY protein domain', 'Heterozygotes for gus or a deletion including gus produce embryos with fewer pole cells and posterior patterning defects', 'SPRY-domain and SOCS-box containing protein, GUSTAVUS.']

['defence against retroviral infection\ninnate and adaptative immunity\nvesicular trafficking\nneural differentiation\nembryonic development']

['defence against retroviral infection', 'immunity', 'vesicular trafficking', 'neural differentiation', 'embryonic development']

What is Eteplirsen (Exondys 51)?

['Eteplirsen (Exondys\xa051) is an antisense oligonucleotide designed to induce exon 51 skipping that is developed by Sarepta Therapeutics. Intravenous eteplirsen has received accelerated approval from the US FDA for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping.', 'Exon skipping is a therapeutic approach for Duchenne muscular dystrophy (DMD) that has been in development for close to two decades. This approach uses antisense oligonucleotides (AONs) to modulate pre-mRNA splicing of dystrophin transcripts to restore the disrupted DMD reading frame. ', 'By the method of exon skipping in dystrophin pre-mRNA the reading frame is restored and the internally deleted but functional dystrophin is produced. ', 's, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. ', 'Restoration of the open reading frame of the DMD gene and dystrophin protein production in Duchenne muscular dystrophy (DMD) can be achieved by exon skipping using antisense oligomers (AOs) targeted to splicing elements. ', 'We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection.', 'AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD).']

['Eteplirsen (Exondys 51) is an antisense oligonucleotide designed to induce exon 51 skipping that is developed by Sarepta Therapeutics. Intravenous eteplirsen has received accelerated approval from the US FDA for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping.\nBy the method of exon skipping in dystrophin pre-mRNA the reading frame is restored and the internally deleted but functional dystrophin is produced.']

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How does the phosphorylation of MAPK8/JNK1 and EIF2S1 contribute to the regulation of autophagy in cells?

[' A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1.", "A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1. These results reveal an unsuspected crosstalk between cellular metabolism (fatty acids), pro-inflammatory signaling (STAT3), innate immunity (EIF2AK2), and translational control (EIF2S1) that regulates autophagy.", "Thus, STAT3 may act as a competitive inhibitor of EIF2AK2. Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy.", "Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. Conversely, the overexpression of wild-type STAT3 as well as of STAT3 mutants that cannot be phosphorylated by JAK2 or are excluded from the nucleus inhibits autophagy.", ", Stattic, JSI-124 and WP1066) and EIF2AK2 activators (such as the double-strand RNA mimetic polyinosinic:polycytidylic acid) are capable of disrupting the inhibitory interaction between STAT3 and EIF2AK2 in cellula, yet only the latter does so in cell-free systems in vitro. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1."]']

The phosphorylation of MAPK8/JNK1 and EIF2S1 contributes to the regulation of autophagy in cells by triggering autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex. Additionally, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy, while overexpression of wild-type STAT3 or STAT3 mutants that cannot be phosphorylated by JAK2 inhibits autophagy.

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What is the mechanism of action of DNA topoisomerase II inhibitors?

['DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks.', 'We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair.', 'Induction of apoptotic cell death by DNA topoisomerase II inhibitors', 'The results we have obtained clearly indicate that topoisomerase II poisons induce cell death by apoptosis.', 'Histone eviction deregulates the transcriptome in cancer cells', 'We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription']

['DNA topoisomerase II inhibitors eliminate cancer cells by causing DNA double-strand breaks, finally leading to apoptotic cell death. Moreover, drug-induced histone eviction was also shown to be associated with attenuated DNA repair, epigenetic changes and transcpription deregulation.']

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is pharmacological treatment of subclinical hypothyroidism effective in reducing cardiovascular events?

['The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment.', 'The lack of specific randomized trials enrolling either old or very old subjects, aimed at evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction along with the negative effects of possible over-treatment, makes the decision to treat older people a still unresolved clinical challenge', 'In patients with type 2 DM, the presence of SH serves as an additional risk factor for endothelial dysfunction.', 'Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people.', 'Subclinical hyperthyroidism seems to be a risk factor of developing major cardiovascular events, especially stroke in older adults from the general population with normal left ventricular function.', 'SCH appears to influence the postoperative outcome for patients by increasing the development of postoperative atrial fibrillation. However, it is still unproven whether preoperative thyroxine replacement therapy for patients with SCH might prevent postoperative atrial fibrillation after CABG.', 'In CHF patients TSH levels even slightly above normal range are independently associated with a greater likelihood of heart failure progression.', 'In current RCTs, levothyroxine replacement therapy for subclinical hypothyroidism did not result in improved survival or decreased cardiovascular morbidity. Data on health-related quality of life and symptoms did not demonstrate significant differences between intervention groups.', 'However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events remains to be elucidated. In conclusion, the multiplicity and the possible reversibility of subclinical hypothyroidism-associated cardiovascular abnormalities suggest that the decision to treat a patient should depend on the presence of risk factors, rather than on a TSH threshold. ', 'However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy.']

['whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy.']

['no']

Describe clinical applications of the PIM2 scoring system.

['In this study, we examine if transfusion is an independent predictor of mortality, or if outcomes are merely a result of the initial severity as predicted by Pediatric Risk of Mortality (PRISM) III, Pediatric Index of Mortality (PIM2), and day 1 Pediatric Logistic Organ Dysfunction (PELOD) scores.', 'INTRODUCTION: The Pediatric Index of Mortality 2 (PIM2) is one of the most commonly used scoring systems to predict mortality in patients admitted to pediatric intensive care units (PICU) in Argentina.', 'CONCLUSIONS: The PIM2 score adequately discriminates survivors from non-survivors.', 'PIM2 scoring did not explain the outcome adequately, suggesting need for recalibration.', 'CONCLUSION: PIM2 scoring system show adequate discriminatory function and well calibrated for the case mix of patients in PICU of Fayoum, Egypt. It can be used as beneficial tool for evaluation of risk adjusted mortality. ', 'The aim of the study was to explore the association between Glasgow Coma Scale (GCS), Paediatric Index of Mortality (PIM2) and Injury Severity Score (ISS), and the long-term outcome of children with injuries.', 'Pediatric index of mortality 2 score as an outcome predictor in pediatric Intensive Care Unit in India.', 'BACKGROUND AND AIMS: Pediatric index of mortality (PIM) 2 score is one of the severity scoring systems being used for predicting outcome of patients admitted to intensive care units (ICUs).', 'CONCLUSION: PIM2 score discriminated well between survivors and death at PICU.', 'OBJECTIVE: A study to validate and calibrate Pediatric Index of Mortality-2 (PIM2) in children admitted to our pediatric intensive care unit (PICU).', 'CONCLUSION: PIM2 is a good index for prediction of mortality in our pediatric intensive care unit. ', 'The Pediatric Index of Mortality 2 (PIM2) is one of the most commonly used scoring systems to predict mortality in patients admitted to pediatric intensive care units (PICU) in Argentina.', "Pediatric Index of Mortality 2 (PIM2) and Pediatric Risk of Mortality (PRISM) are scoring systems to predict mortality likehood; thus, it is necessary to validate such predictors in Pediatric Intensive Care Units' population.", 'Although PRISM, PIM and PIM2 have displayed good discrimination and calibration in the present setting, PIM is considered as the most accurate and appropriate tool for predicting mortality in the studied NICU.', 'The PIM2 score adequately discriminates survivors from non-survivors.']

['The Pediatric Index of Mortality 2 (PIM2) is one of the most commonly used scoring systems to predict mortality in patients admitted to pediatric intensive care units. The PIM2 score adequately discriminates survivors from non-survivor']

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Which phenomenon is described as oncogene addiction?

['Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed.', 'The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called "oncogene addiction.', 'A given tumor is usually dependent on the oncogene that is activated in the respective tumor entity. This phenomenon called oncogene addiction provides the rationale for attempts to target oncogene products in a therapeutic manner, be it by small molecules, by small interfering RNAs (siRNA) or by antigen-specific T cells.', 'It has long been established that cancers can become addicted to particular oncogenes. Despite the genetic complexity that governs tumorigenesis, certain cancers can exhibit a critical dependency on the expression of a single oncogene, which when removed leads to death of the cancer cell. ', 'We now know that oncogenes are dysfunctional proto-oncogenes and that dysfunctional tumor suppressor genes contribute to the cancer process. Furthermore, Weinstein and others have hypothesized the phenomenon of oncogene addiction as a distinct characteristic of the malignant cell. It can be assumed that cancer cells, indeed, become dependent on such vital oncogenes. The products of these vital oncogenes, such as c-myc, may well be the Achilles heel by which targeted molecular therapy may lead to truly personalized cancer therapy.', 'Despite complex genomic and epigenetic abnormalities, many cancers are irrevocably dependent on an initiating oncogenic lesion whose restoration to a normal physiological activation can elicit a dramatic and sudden reversal of their neoplastic properties. This phenomenon of the reversal of tumorigenesis has been described as oncogene addiction. Oncogene addiction had been thought to occur largely through tumour cell-autonomous mechanisms such as proliferative arrest, apoptosis, differentiation and cellular senescence. ', 'Cancers can exhibit marked tumor regression after oncogene inhibition through a phenomenon called "oncogene addiction." The ability to predict when a tumor will exhibit oncogene addiction would be useful in the development of targeted therapeutics. Oncogene addiction is likely the consequence of many cellular programs. However, we reasoned that many of these inputs may converge on aggregate survival and death signals.', 'The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, and/or apoptosis, a phenomenon known as oncogene addiction.', 'Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets.', "Oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the 'Achilles heel' of the successful molecular targeted therapies in cancer.", 'Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anticancer agents.', 'Cancer is a multistep process whereby genetic events that result in the activation of proto-oncogenes or the inactivation of tumor suppressor genes usurp physiologic programs mandating relentless proliferation and growth. Experimental evidence surprisingly illustrates that the inactivation of even a single oncogene can be sufficient to induce sustained tumor regression. These observations suggest the hypothesis that tumors become irrevocably addicted to the oncogenes that initiated tumorigenesis. The proposed explanation for this phenomenon is that activated oncogenes result in a signaling state in which the sudden abatement of oncogene activity balances towards proliferative arrest and apoptosis. Indeed, substantial evidence supports this hypothesis.', 'Cancer cells contain multiple genetic and epigenetic abnormalities. Despite this complexity, their growth and survival can often be impaired by the inactivation of a single oncogene. This phenomenon, called "oncogene addiction," provides a rationale for molecular targeted therapy.', 'Does an activated oncogene that initiates tumor growth need to remain activated to maintain the cancer phenotype? This question has been answered affirmatively by experiments in which doxycycline-regulated oncogene activation induces growth of large tumors that regress completely upon oncogene inactivation--a phenomenon called oncogene addiction. We assemble here the evidence that oncogene addiction is angiogenesis-dependent.', '"Oncogene addiction" describes the curious acquired dependence of tumor cells on an activated oncogene for their survival and/or proliferation, a phenomenon that has important implications for the success of targeted cancer therapies. However, the mechanisms explaining oncogene addiction remain elusive. We propose that "addiction" may be an illusion generated as a consequence of differential attenuation rates of prosurvival and proapoptotic signals emanating from an oncoprotein acutely following its inactivation. According to this model, which we call "oncogenic shock," prosurvival signals dissipate quickly on oncoprotein inactivation whereas proapoptotic signals linger sufficiently long to commit the cell to an apoptotic death.', 'Does an activated oncogene that initiates tumor growth need to remain activated to maintain the cancer phenotype? This question has been answered affirmatively by experiments in which doxycycline-regulated oncogene activation induces growth of large tumors that regress completely upon oncogene inactivation--a phenomenon called oncogene addiction.', '"Oncogene addiction" describes the curious acquired dependence of tumor cells on an activated oncogene for their survival and/or proliferation, a phenomenon that has important implications for the success of targeted cancer therapies.', 'Oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the Achilles heel of the successful molecular targeted therapies in cancer.', '"Oncogene addiction" describes the curious acquired dependence of tumor cells on an activated oncogene for their survival and/or proliferation, a phenomenon that has important implications for the success of targeted cancer therapies', 'Does an activated oncogene that initiates tumor growth need to remain activated to maintain the cancer phenotype? This question has been answered affirmatively by experiments in which doxycycline-regulated oncogene activation induces growth of large tumors that regress completely upon oncogene inactivation--a phenomenon called oncogene addiction']

[' Oncogene addiction describes the curious acquired dependence of tumor cells on an activated oncogene for their survival and/or proliferation, a phenomenon that has important implications for the success of targeted cancer therapies. However, the mechanisms explaining oncogene addiction remain elusive. We propose that addiction may be an illusion generated as a consequence of differential attenuation rates of prosurvival and proapoptotic signals emanating from an oncoprotein acutely following its inactivation. According to this model, which we call oncogenic shock, prosurvival signals dissipate quickly on oncoprotein inactivation whereas proapoptotic signals linger sufficiently long to commit the cell to an apoptotic death. ', '"Oncogene addiction" describes the curious acquired dependence of tumor cells on an activated oncogene for their survival and/or proliferation, a phenomenon that has important implications for the success of targeted cancer therapies. However, the mechanisms explaining oncogene addiction remain elusive. "Addiction" may be an illusion generated as a consequence of differential attenuation rates of prosurvival and proapoptotic signals emanating from an oncoprotein acutely following its inactivation. According to this model, which we call "oncogenic shock," prosurvival signals dissipate quickly on oncoprotein inactivation whereas proapoptotic signals linger sufficiently long to commit the cell to an apoptotic death.']

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Which substances are dangerous to g6PD deficient individuals?

['The principal clinical manifestation encountered was favism.', 'G6PD deficiency is the most common enzymopathy of red blood cells. The clinical symptoms of favism are jaundice, hematuria and haemolytic anaemia that seem to affect liver and kidney in long term. Thus we evaluate kidney and liver function of favism patients in an endemic area of the disease with a high rate of fava beans cultivation. ']

['Antimalarial drugs (primaquine, pamaquine, chloriquine), fava beans, sulfonamides, some antibiotics( nalidixic acid, nitrofurantoin, isoniazid, dapsone, and furazolidone) and henna']

['primaquine', 'pamaquine', 'chloroquine', 'fava beans', 'sulfonamides', 'antibiotics', 'henna']

Which are the Proprotein Convertase Subtilisin Kexin 9 (PCSK9) inhibitors that are FDA approved?

['Inhibition of the PCSK9 protein by monoclonal antibodies results in a dramatic 40%-60% lowering of serum low-density lipoprotein cholesterol (LDL-C). ', 'Alirocumab and evolocumab have been approved by the FDA for the treatment of patients with heterozygous familial hypercholesterolemia and patients with clinical atherosclerotic cardiovascular disease) who do not achieve their LDL-C target on maximal tolerated statin treatment and dietary modification. In addition, evolocumab has been approved by the FDA for homozygous familial hypercholesterolemia.', 'LDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient.', 'A new class of lipid-lowering drugs, inhibitors of PCSK9 has been generating impressive clinical trial data over the last several years, and alirocumab (Praluent) has become the first to be approved by the US FDA.', 'The second FDA-approved PCSK9 inhibitor evolocumab (Repatha) appears to be similar in efficacy and safety to alirocumab (Praluent), but no comparative studies are available. ', 'Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, have recently been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia.', 'Newer agents for LDL cholesterol reduction include the cholesterol ester transfer protein inhibitors, the microsomal triglyceride transfer protein inhibitor lomitapide, the apolipoprotein B antisense oligonucleotide mipomersen and several molecules that inhibit or interfere with proprotein convertase subtilisin/kexin 9 (PCSK9).Among the various PCSK9 inhibitors, human data are available for monoclonal antibodies against PCSK9 of which the two most advanced are alirocumab (SAR236553/REGN727) and AMG 145', 'The 2 or 4‑week subcutaneous therapy with the recently approved antibodies alirocumab and evolocumab for inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces low-density lipoprotein cholesterol (LDL-C) in addition to statins and ezetimibe by 50-60\u2009%.', 'In 2015 the U.S. Food and Drug Administration approved the first two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab (Praluent®; Sanofi/ Regeneron) and evolocumab (Repatha®; Amgen), for use in patients with heterozygous and homozygous familial hypercholesterolemia and for patients intolerant of statins or those with a major risk of cardiovascular disease (CVD) but unable to lower their LDL cholesterol (LDL-C) to optimal levels with statins and ezetimibe.', 'Very recent clinical trials have proven overwhelmingly the effectiveness and safety of PCSK9 inhibitors for lowering LDL-C. Both alirocumab and evolocumab have now been approved by the US FDA and there are some initial favorable outcomes data.', 'Food and Drug Administration approved the first two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab (Praluent®; Sanofi/ Regeneron) and evolocumab (Repatha®; Amgen), for use in patients with heterozygous and homozygous familial hypercholesterolemia and for patients intolerant of statins or those with a major risk of cardiovascular disease (CVD) but unable to lower their LDL cholesterol (LDL-C) to optimal levels with statins and ezetimibe.']

['The PCSK9 inhibitors that are FDA approved are:\n1) Alirocumab and \n2) Evolocumab.']

['Alirocumab', 'Praluent', 'Evolocumab', 'Repatha']

Which pathological condition of the heart is known as hypertrophic cardiomyopathy (HCM)?

['Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance.', 'Familial hypertrophic cardiomyopathy (HCM), due to point mutations in genes for sarcomere proteins such as myosin, occurs in 1/500 people and is the most common cause of sudden death in young individuals.', 'n HCM, the modified protein function leads, over years to decades, to secondary remodeling with substantial morphological changes, such as hypertrophy, myofibrillar disarray, and extensive fibrosis associated with severe functional deterioration.', 'Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in the young, particularly among athletes.', 'Familial hypertrophic cardiomyopathy (HCM) is one the most common heart disorders, with gene mutations in the cardiac sarcomere.', 'Hypertrophic cardiomyopathy (HCM) has been recently recognized as the most common inherited cardiovascular disorder, affecting 1 in 500 adults worldwide. HCM is characterized by myocyte hypertrophy resulting in thickening of the ventricular wall, myocyte disarray, interstitial and/or replacement fibrosis, decreased ventricular cavity volume and diastolic dysfunction. HCM is also the most common cause of sudden death in the young. A large proportion of patients diagnosed with HCM have mutations in sarcomeric proteins.', 'Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy. The prevalence of phenotypic expression, in the absence of another systemic or cardiac disease causing increased left ventricular (LV) wall thickness, is estimated to be 1:500. ', 'HCM is the most prevalent genetic disorder affecting the heart, it often goes undiagnosed until midlife after patients show symptoms of myocardial remodeling. Adults with cardiomyopathy suffer SCD or adverse events such as stroke and heart failure from HCM.', 'Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous autosomal dominant heart disease characterised by left ventricular hypertrophy in the absence of another cardiac or systemic disease that is capable of producing significant wall thickening.', 'Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction.', 'Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening.']

['Hypertrophic cardiomyopathy (HCM) has been recently recognized as the most common inherited cardiovascular disorder, affecting 1 in 500 adults worldwide. HCM is characterized by myocyte hypertrophy resulting in thickening of the ventricular wall, myocyte disarray, interstitial and/or replacement fibrosis, decreased ventricular cavity volume and diastolic dysfunction. HCM is also the most common cause of sudden death in the young particularly among athletes. A large proportion of patients diagnosed with HCM have mutations in sarcomeric proteins. HCM is the most prevalent genetic disorder affecting the heart and is typically inherited in an autosomal dominant pattern. Adults with cardiomyopathy suffer SCD or adverse events such as stroke and heart failure from HCM.']

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Which is the protein implicated in Spinocerebellar ataxia type 3?

['Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem', 'Spinocerebellar ataxia type 3 (SCA3) is an inherited spinocerebellar ataxia caused by the expansion of trinucleotide CAG repeats in the gene encoding ataxin-3', 'Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3)', 'Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein.', 'Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein.', 'Here, we provide insight into the mechanism by which ubiquitination directly enhances the activity of ataxin-3, a DUb implicated in protein quality control and the disease protein in the polyglutamine neurodegenerative disorder, Spinocerebellar Ataxia Type 3', 'Ataxin-3, the disease protein in the neurodegenerative disorder Spinocerebellar Ataxia Type 3 or Machado Joseph disease, is a cysteine protease implicated in the ubiquitin proteasome pathway', 'Ataxin-3 (AT3) is the protein that triggers the inherited neurodegenerative disorder spinocerebellar ataxia type 3 when its polyglutamine (polyQ) stretch close to the C-terminus exceeds a critical length', 'Here, in studies of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions.', 'This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3.', 'Machado-Joseph disease (MJD), also called spinocerebellar ataxia type 3, is caused by mutant ataxin-3 with a polyglutamine expansion.', ' Mutant ataxin-3 is aberrantly folded and proteolytically cleaved in spinocerebellar ataxia type 3. The C-terminal region of the protein includes a polyglutamine stretch that is expanded in spinocerebellar ataxia type 3.', 'Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein.']

['Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3).', 'Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem']

['Ataxin-3']

Is curcumin a phytochemical?

['we analyzed turmeric from different agroclimatic regions for influence of various factors on its growth and yield of important phytochemicals', 'The phytochemical, curcumin, has been reported to play many beneficial roles.', 'Curcumin (CUR), the major component in Curcuma longa, has been shown as a potent chemopreventive phytochemical that modulates various signaling pathways. ', 'Curcumin (CUR) is a phytochemical that inhibits the xenobiotic ABC efflux transporters implicated in cancer multidrug resistance (MDR), such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5). ', 'In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved.', ' In the present study, we investigate whether curcumin (cur), a phytochemical compound with potent anti-inflammatory effect', 'the Phytochemicals Curcumin ', 'in combination with the phytochemicals curcumin and quercetin', 'Curcumin is a phytochemical derived from rhizome of turmeric Curcuma longa, present in the curry spice. ', 'Curcumin, a naturally occurring polyphenolic phytochemical isolated from the medicinal plant Curcuma longa, has anti-inflammatory activities', 'In the present study curcumin (CUR), a known anticancer phytochemical, ', ' Curcumin, a natural phytochemical, exhibits potent anticancer activities.', 'hat curcumin, a phytochemical compound with potent anti-inflammatory properties ', 'curcumin, a phytochemical']

['Yes, curcumin is a phytochemical derived from rhizome of turmeric Curcuma longa.']

['yes']

Is there an association between bruxism and reflux

['Rhythmic masticatory muscle activity, including sleep bruxism (SB), can be induced in healthy individuals by experimental esophageal acidification, which plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD). However, no robust evidence supports the association between SB and GERD.', 'Sleep bruxism is prevalent in GERD patients, and GERD is highly associated with SB.', 'Our large-scale cross-sectional study found that problem behaviors in adolescents were associated with sleep problems, including sleep bruxism, as well as lifestyle and food habits and GERD symptoms.', 'The frequencies of EMG bursts, rhythmic masticatory muscle activity (RMMA) episodes, grinding noise, and the RMMA/microarousal ratio were significantly higher in the 20-minute period after acidic infusion than after saline infusion. RMMA episodes including SB were induced by esophageal acidification. ', 'Direct restorative treatment of dental erosion caused by gastroesophageal reflux disease associated with bruxism:', 'This article presents a case report of a 27-year-old male smoker with tooth wear and dentin sensitivity caused by GERD associated with bruxism', 'Dental wear caused by association between bruxism and gastroesophageal reflux disease:', 'This paper presents a case report in which bruxism associated with acid feeding, smoking habit and episodes of gastric reflow caused severe tooth wear and great muscular discomfort with daily headache episodes.', 'most jaw muscle activities, ie, RMMA, single short-burst, and clenching episodes, occur in relation to gastroesophageal reflux mainly in the supine position.', 'Association between nocturnal bruxism and gastroesophageal reflux.', 'Nocturnal bruxism may be secondary to nocturnal gastroesophageal reflux, occurring via sleep arousal and often together with swallowing.']

['There is an association between bruxism and reflux.']

['yes']

What is the mode of inheritance of nemaline myopathy?

['The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance.', 'Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases', 'Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations.', 'Finding the causative mutation(s) determines the mode of inheritance', 'We conclude that in the Finnish CNM patients, the mode of inheritance appears to be recessive. Apart from a few instances of dominant inheritance, most cases published also seem compatible with recessive inheritance.']

['Nemaline myopathy has a autosomal dominant or recessive mode of inheritance.']

['autosomal dominant', 'autosomal recessive']

Describe crowned dens syndrome.

['BACKGROUND: Patients with crowned dens syndrome (CDS), which is pseudogout of the atlantoaxial junction induced by "crown-like" calcifications around the dens, present with symptoms of severe neck pain, rigidity, and high fever. ', 'BACKGROUND CONTEXT: Crowned dens syndrome (CDS) is a rare form of calcium phosphate crystal depositions and often presents with recurrent neck pain, stiffness of neck, increased erythrocyte sedimentation rate, and episodes of fever.', 'A CT scan revealed calcification of the transverse ligament and crown-like calcification around the odontoid process. According to the clinical and radiological findings, she was diagnosed with crowned dens syndrome (CDS).', 'Crystal deposition in the cervical spine around the odontoid process may lead to acute neck pain. This rare condition is called crowned dens syndrome and should be considered in the differential diagnosis of a possible etiology for fever, headache and cervical pain of unknown origin. ', 'Crowned dens syndrome (CDS), related to microcrystalline deposition in the periodontoid process, is the main cause of acute or chronic cervical pain.', 'Axial calcium pyrophosphate dihydrate deposition disease (CPDD) is well known for cervical spine involvement with the crowned dens syndrome but other localisations are probably underdiagnosed in sterile spondylodiscitis. ', 'We describe a patient with crowned dens syndrome which manifested with clinical (acute occipital headache) and radiographic (calcium deposits in the alar ligament) features.', 'FDG uptake in the immediate vicinity of the odontoid process, with a crownlike calcification, was identified on the CT scan on the posterior side of the dens, thus confirming the diagnosis of crowned dens syndrome.', 'We describe a patient with crowned dens syndrome which manifested with clinical (acute occipital headache) and radiographic (calcium deposits in the alar ligament) features', 'Crowned dens syndrome (CDS), related to microcrystalline deposition in the periodontoid process, is the main cause of acute or chronic cervical pain.This report describes the case of an 87-year-old woman who had severe bradykinesia, muscle rigidity, gait disturbance and neck pain', 'The crowned dens syndrome, related to microcrystalline deposition in the peri-odontoid articular and abarticular structures, is mainly responsible for acute or chronic cervical pain.We report eight cases of crowned dens syndrome with atypical presentations mimicking giant cell arteritis, polymyalgia rheumatica, meningitis or discitis', 'The crowned dens syndrome as a cause of neck pain: clinical and computed tomography study in patients with calcium pyrophosphate dihydrate deposition disease', 'Computed tomography of the cervical spine demonstrated linear calcific deposits in the transverse ligament of atlas (crowned dens syndrome) in all patients.', 'Crystals located in the transverse ligament of the atlas give rise to the crowned dens syndrome, usually in patients affected by severe degenerative lesions of the atlantoaxial joint and peripheral chondrocalcinosis.', 'BACKGROUND: Patients with crowned dens syndrome typically present with severe neck pain and have calcium deposits around the odontoid process of the axis on radiographs.', 'We describe a patient with crowned dens syndrome which manifested with clinical (acute occipital headache) and radiographic (calcium deposits in the alar ligament) features.']

['Crowned dens syndrome is a rare form of "crown-like" calcifications around the dens and often presents with recurrent neck pain, stiffness of neck, increased erythrocyte sedimentation rate, and episodes of fever.']

[]

What disease is the drug aducanumab targeting?

[' Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. ', 'ecent results from trials of agents such as aducanumab are encouraging but must also be interpreted with caution. Such medicines could potentially delay the onset of dementia and would therefore markedly reduce its prevalence.', 'Aducanumab is an anti-Aβ antibody being developed for the treatment of AD, and interim analyses of a phase 1b clinical trial have suggested potential beneficial effects on the amyloid pathology and the cognitive status in patients treated with aducanumab', "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease."]

["Aducanumab is an anti-Aβ antibody being developed for the treatment of Alzheimer's disease (AD)."]

["Alzheimer's disease"]

Which drugs acting via bradykinin system are effective for treatment of ACE-inhibitor-induced angioedema?

['Medications recently developed, primarily icatibant and ecallantide, to control hereditary angioedema, a disorder also associated with kallikrein-kinin activation, have been used to treat ACEI angioedema with some success. ', 'A patient with acute ACE inhibitor-induced angioedema was treated with icatibant, a specific bradykinin B2 receptor antagonist approved for the treatment of hereditary angioedema. ', 'A patient with acute ACE inhibitor-induced angioedema was treated with icatibant, a specific bradykinin B2 receptor antagonist approved for the treatment of hereditary angioedema.']

['Icatibant and ecallantide are medication acting via bradykinin system that are used for treatment of ACE-inhibitor-induced angioedema.']

['icatibant', 'ecallantide']

What is the function of transthyretin in cerebrospinal fluid?

['Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs). TTR synthesised in the liver is secreted into the bloodstream and distributes THs around the body, whereas TTR synthesised in the choroid plexus is involved in movement of thyroxine from the blood into the cerebrospinal fluid and the distribution of THs in the brain. This is important because an adequate amount of TH is required for normal development of the brain. ', 'The choroid plexus forms the blood-cerebrospinal fluid barrier. In reptiles, birds and mammals, the main protein synthesized and secreted by the choroid plexus is a thyroid hormone distributor protein: transthyretin. This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid. Maximal transthyretin synthesis in the choroid plexus occurs just prior to the period of rapid brain growth, suggesting that choroid plexus-derived transthyretin moves thyroid hormones from blood into cerebrospinal fluid just prior to when thyroid hormones are required for rapid brain growth. ', 'Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid. ', 'Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood-brain-barrier (BBB) and the blood-CSF-barrier will be explicated regarding fetal and adult status. ', 'Some POPs, i.e., hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs), pentachlorophenol (PCP), and perfluorooctane sulfonate (PFOS), compete with thyroxin (T4) for binding sites on transthyretin (TTR), a T4 transport protein found in plasma and cerebrospinal fluid. ', 'Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid plexus, is mainly known as the physiological carrier of thyroxine (T(4)) and retinol. ', 'The secretion of transthyretin by the choroid plexus into the cerebrospinal fluid may have an important function in the transport of thyroxine from the blood to the brain.', 'This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid.', 'Thyroid hormones enter the choroid plexus via thyroid hormone transmembrane transporters and leave the choroid plexus to enter the cerebrospinal fluid via either thyroid hormone transmembrane transporters or via choroid plexus-derived transthyretin secreted into the cerebrospinal fluid.', 'This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid', 'Maximal transthyretin synthesis in the choroid plexus occurs just prior to the period of rapid brain growth, suggesting that choroid plexus-derived transthyretin moves thyroid hormones from blood into cerebrospinal fluid just prior to when thyroid hormones are required for rapid brain growth', 'Thyroid hormones enter the choroid plexus via thyroid hormone transmembrane transporters and leave the choroid plexus to enter the cerebrospinal fluid via either thyroid hormone transmembrane transporters or via choroid plexus-derived transthyretin secreted into the cerebrospinal fluid', 'Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid', 'Transthyretin (TTR) is a plasma and cerebrospinal fluid (CSF)-circulating homotetrameric protein', 'Some POPs, i.e., hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs), pentachlorophenol (PCP), and perfluorooctane sulfonate (PFOS), compete with thyroxin (T4) for binding sites on transthyretin (TTR), a T4 transport protein found in plasma and cerebrospinal fluid', 'Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP)', 'Dose-dependent transthyretin inhibition of T4 uptake from cerebrospinal fluid in sheep.', 'The secretion of transthyretin by the choroid plexus into the cerebrospinal fluid may have an important function in the transport of thyroxine from the blood to the brain.', 'High-affinity cellular binding sites for TTR have been described; however, their function and that of choroid plexus synthesis of TTR and transport of T4 into the cerebrospinal fluid remain unclear.', 'Transthyretin is the major thyroxine-binding protein in the plasma of rodents, and the main thyroxine-binding protein in the cerebrospinal fluid of both rodents and humans.', 'This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid.', 'Thyroid hormones enter the choroid plexus via thyroid hormone transmembrane transporters and leave the choroid plexus to enter the cerebrospinal fluid via either thyroid hormone transmembrane transporters or via choroid plexus-derived transthyretin secreted into the cerebrospinal fluid.']

['Transthyretin (TTR) is a protein synthesized in the choroid plexus, which forms the blood-cerebrospinal fluid barrier. TTR is the physiological carrier of thyroxine (T4) and retinol from the blood into the cerebrospinal fluid and their distribution in the brain. The transport of T4 is important for normal development of the brain.']

[]

Does Serca2a bind PLN in the heart?

['The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase.', 'Moreover, PLN-R14Del did not co-immunoprecipitate with SERCA2a (as did WT-PLN),', 'n this review, we attempted to highlight the functional significance of PLN in vertebrate cardiac physiology. We will refer to the huge literature on mammals in order to describe the molecular characteristics of this protein, its interaction with SERCA2a', 'There is clear evidence for direct regulatory protein-protein interactions between phospholamban (PLN) and the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) in cytoplasmic domains', 'These results suggest that PLN modulates the apparent Ca2+ affinity of SERCA2a through intramembrane interactions, which are disrupted at long range and in concert with disruption of the well characterized cytoplasmic interactions.', 'Phospholamban (PLN), a homopentameric, integral membrane protein, reversibly inhibits cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity through intramembrane interactions.', 'The concentration of this inhibited complex is determined by the dissociation constant for the PLN pentamer (which is mutation-sensitive) and by the dissociation constant for the PLN/SERCA2a heterodimer (which is likely to be mutation-sensitive).', 'These results support the proposal that PLN inhibition of SERCA2a involves, first, depolymerization of PLN and, second, the formation of inhibitory interactions between monomeric PLN and SERCA2a.', 'SLN and PLN appear to bind to the same regulatory site in SERCA. However, in a ternary complex, PLN occupies the regulatory site and SLN binds to the exposed side of PLN and to SERCA.', 'Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a.', '. Conversely, using anti-SERCA2a antibody, both PLN and acylphosphatase were co-immunoprecipitated with SERCA2a, and the PLN amount in the precipitate decreased with increasing acylphosphatase concentrations.', 'Reconstitution of the cytoplasmic interaction between phospholamban and Ca(2+)-ATPase of cardiac sarcoplasmic reticulum.', 'Phospholamban (PLN) reversibly inhibits the Ca(2+)-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) through a direct protein-protein interaction, playing a pivotal role in the regulation of intracellular Ca(2+) in heart muscle cells.', 'Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity', 'In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes.']

['Yes, Serca2a bind PLN in the heart.']

['yes']

Is the Dictyostelium discoideum proteome known?

['The Negative Proteome Database (NPD) is populated with pair-wise protein sequence comparisons between each of the following proteomes: Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Dictyostelium discoideum, Chlamydomonus reinhardti, Escherichia coli K12, Arabidopsis thaliana and Methanoscarcina acetivorans.', 'The Dictyostelium discoideum proteome--the SWISS-2DPAGE database of the multicellular aggregate (slug).', 'Consequently, this genomic sequence information can now be exploited to realize D. discoideum proteomics projects. ', 'The Dictyostelium discoideum genome has been sequenced, assembled and annotated to a high degree of reliability. The parts-list of proteins and RNA encoded by the six chromosomes can now be accessed and analyzed. ', 'The 34 Mb genome of Dictyostelium discoideum is carried on 6 chromosomes and has been fully sequenced by an international consortium. The sequence was assembled on the classical and physical maps that had been built up over the years and refined by HAPPY mapping. Annotation of the sequence predicted about 12,000 genes for proteins of at least 50 amino acids in length.', 'In this study, a quantitative comparative proteomics approach has been used to analyze the Dictyostelium discoideum mitochondrial proteome variations during vegetative growth, starvation and the early stages of development. ', 'The secreted proteome profile of developing Dictyostelium discoideum cells.', 'The present repertoire validates our purification method and paves the way for a future proteomics approach to study the dynamics of macropinocytosis.', 'Proteomic analysis of a developmentally regulated secretory vesicle.']

['Yes, The Dictyostelium discoideum genome has been sequenced, assembled and annotated to a high degree of reliability. The parts-list of proteins and RNA encoded by the six chromosomes can now be accessed and analyzed. Consequently, this genomic sequence information can now be exploited to realize D. discoideum proteomics projects.']

['yes']

From which cell type is leptin secreted?

[' Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland.', 'Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY)', 'Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode.', 'Leptin was also detected in some microglobules in whole saliva obtained from four healthy volunteers. Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands.', 'Leptin, a circulating hormone secreted mainly from adipose tissues, possesses protective effects on many cell types.', 'Leptin, the adipocyte-secreted hormone that regulates weight, is known to link lipid metabolism with inflammation in various cell types', 'Leptin, a 16-kDa protein that is mainly secreted by adipocytes, plays a protective role in many cell types', 'Do the adipocytokines, leptin and adiponectin affect the granulosa cell expression of anti-Mullerian hormone (AMH) and its receptor (AMHR-II)?Leptin suppresses AMH mRNA levels in human luteinized granulosa cells through the JAK2/STAT3 pathway, while adiponectin has no such effect.AMH is one of the most reliable markers of ovarian reserve', 'Leptin, the adipocyte-secreted hormone, exerts its main function as regulator of food intake and energy expenditure through central effects at the hypothalamic level.', 'Adipokines are a group of fat-secreted hormones and cytokines, including leptin and adiponectin, with important functions in humans.', 'Leptin, an adipose-secreted hormone, links metabolism and immunity.', 'Since the discovery of leptin secreted from adipocytes, specialized tissues and cells have been found that secrete the several peptides (or cytokines) that are characterized to negatively and positively regulate the metabolic process.', 'Adipokines (leptin, adiponectin, and hepatocyte growth factor (HGF)) secreted from adipose tissue have come to be recognized for their contribution to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk.', 'These results show that there is a distinct female-type and male-type leptin pulsatility pattern and each is amenable to augmentation by gonadal steroids either involving mechanisms that impart leptin pulsatility patterns directly at the level of adipocytes and/or at hypothalamic target sites..', 'Leptin is a circulating hormone secreted by adipose and a few other tissues.', 'Cyclin D1 is expressed exclusively in luminal keratin 8 immunoreactive tumor cells and is dependent on the adipose secreted hormone leptin.', 'In gastric cells leptin follows a rapid regulated secretion pathway whereas adipocytes secrete leptin in a constitutive slow fashion.']

['leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode.', ' Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland.', ' Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland. Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY)', 'Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland. Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY). Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode. Leptin was also detected in some microglobules in whole saliva obtained from four healthy volunteers. Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands. ', 'Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode. Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands.', 'Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode.', 'Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands. Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode.', 'Leptin is a 16 kDa protein that exerts important effects on the regulation of food intake and energy expenditure by interacting with the leptin receptor in the brain and in many other tissues. Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland.', 'Leptin was also detected in some microglobules in whole saliva obtained from four healthy volunteers. Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands. Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland.']

['adipocytes']

What is the role of thyroid hormone receptor alpha1 in insulin secretion?

['loss of Thra protects mice from high-fat diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.', 'liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass during postnatal development. Thus, liganded TR(alpha) may be a target for therapeutic strategies that can induce the expansion and regeneration of beta-cells.', 'the TRalpha P398H mutation is associated with visceral adiposity and insulin resistance']

['Liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass. the TRalpha P398H mutation which cannot bind T3, is associated with insulin resistance. Loss of Thra protects mice from high-fat diet-induced hepatic and peripheral insulin resistance.']

[]

Do U6-associated proteins Lsm4 and Lsm6 interact with SMN?

['SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. ', 'Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6', 'Furthermore, we present evidence for two separate binding sites in SMN for Sm/Lsm proteins.', 'Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. ', "Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein.", 'Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. Furthermore, the carboxyl-terminal arginine- and glycine-rich domain of Lsm4 directly interacts with SMN.', 'This entity promotes the binding of a set of factors, termed LSm/Sm proteins, onto snRNA to form the core structure of these particles. ', 'Toward an assembly line for U7 snRNPs: interactions of U7-specific Lsm proteins with PRMT5 and SMN complexes.', 'In this report, we demonstrate that the coilin C-terminal domain binds directly to various Sm and Lsm proteins via their Sm motifs. We show that the region of coilin responsible for this binding activity is separable from that which binds to SMN.', "Thus, the ability to interact with free Sm (and Lsm) proteins as well as with intact snRNPs, indicates that coilin and CBs may facilitate the modification of newly formed snRNPs, the regeneration of 'mature' snRNPs, or the reclamation of unassembled snRNP components.", 'Moreover this structure has important consequences for snRNP assembly that is mediated by two complexes containing the PRMT5 methyltransferase and the SMN (survival of motor neurons) protein, respectively.', 'Arginine/glycine (RG)-rich domains in components of the SMN complex interact with Sm, like-Sm (LSm), fibrillarin, RNA helicase A (Gu), and coilin proteins, all of which are antigen targets in a variety of diseases. ']

['SMN interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6.', 'yes', 'SMN was found to interact with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6.']

['yes']

In which kingdom do microsporidia belong, according to their current classification scheme?

['Microsporidia are a diverse group of obligate, intracellular, eukaryotic, spore-forming parasites. Traditionally, these were considered as protozoans but recently have been reclassified as fungi. ', 'Microsporidia are ubiquitous fungi with genomes that have undergone a strong reduction', 'Microsporidia are unicellular fungi that are obligate endoparasites. ', 'Phylogenomics supports microsporidia as the earliest diverging clade of sequenced fungi.', 'A combined analysis of thousands of gene trees supports a topology in which microsporidia is a sister group to all other sequenced fungi.', 'Altogether, our data strongly support a scenario in which microsporidia is the earliest-diverging clade of sequenced fungi.', 'Microsporidia are a large diverse group of intracellular parasites now considered as fungi.', 'The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi.', 'The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa.', 'The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it.', 'In a subsequent analysis, we excluded the other Microsporidia from the analysis to look for relationships before the divergence of Microsporidia, and found that 43% of the microsporidial genes scored highest with fungal genes, and a higher mean LPI was found with Fungi than with other kingdoms, suggesting that Microsporidia is closely related to Fungi at the genomic level.', 'CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi.', 'The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi.', 'The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa.', 'Microorganisms of the microsporidia group are obligated intracellular protozoa that belong to the phylum Microspora; currently they are considered to be related or belong to the fungi reign']

['Traditionally, microsporidia were considered as protozoans, but recently they have been reclassified as the earliest-diverging clade of sequenced fungi. Microsporidia are a diverse group of obligate, intracellular, eukaryotic, spore-forming parasites; they are ubiquitous fungi, with genomes that have undergone a strong reduction.']

['Fungi']

What is the effect induced by sympathetic nervous system on pupil size?

['Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system.', 'The sympathetic nervous system acts either directly on the dilator muscle (peripherally) or centrally by inhibiting the Edinger-Westphal nucleus.', 'The mechanism of reflex pupillary dilation was investigated in eight patients who were declared brain dead after rupture of intracranial vascular malformations and in eight awake volunteers. The authors hypothesized that the reflex was primarily a spinal sympathetic reflex', 'The authors conclude that pupillary reflex dilation, as it is clinically performed in awake subjects by stimulating somatic nociceptors, is a sympathetic reflex.', 'Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system.', 'Sympathetic nervous system activation, with reflex dilation of the pupil', 'reproducibly larger pupil size--indicative of increased sympathetic arousal--', 'activation of autonomic sympathetic preganglionic neurons in the thoracic spinal cord produces pupillary dilatation', 'sympathetic responses (sweating, pupil dilatation, piloerection, etc.)', 'In the absence of anesthesia, dilation is primarily mediated by the sympathetic nervous system.', 'Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system.', 'Sympathetic nervous system activation, with reflex dilation of the pupil, was produced by noxious electrical stimulation during 4% and 8% end-tidal desflurane, and by a rapid 4%-to-8% step-up in the desflurane concentration.', 'BACKGROUND: Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system.', 'Dark-adapted pupil size after topical PNS blockade (an index of iris sympathetic nervous system [SNS] activity) was also smaller in both groups of diabetic subjects (NIDD, P less than 0.01; IDD, P less than 0.05).', 'However, dark-adapted pupil size during parasympathetic nervous system blockade, an index of iris sympathetic nervous system activity, declined with age (r = -0.81, p less than 0.001).', 'However, dark-adapted pupil size during parasympathetic nervous system blockade, an index of iris sympathetic nervous system activity, declined with age (r = -0.81, p less than 0.001)', 'Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system', 'Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system']

['Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system. The sympathetic nervous system acts either directly on the dilator muscle (peripherally) or centrally by inhibiting the Edinger-Westphal nucleus. Thus, the sympathetic nervous system mediates pupillary dilatation.']

['pupillary dilatation (increase of the pupil size)']

List Kartagener Syndrome Triad.

['The triad of situs inversus, bronchiectasis and sinusitis is known as Kartagener syndrome. ', 'BACKGROUND: KARTAGENER SYNDROME (KS) IS A RARE CONGENITAL DISEASE CHARACTERISED BY A CLINICAL TRIAD OF SYMPTOMS: situs inversus, chronic rhinosinusitis, and bronchiectasis. ', "Kartagener's syndrome is a very rare congenital malformation comprising of a classic triad of sinusitis, situs inversus and bronchiectasis.", 'We present a case of a patient with clinically definite ALS, who had earlier suffered from Kartagener syndrome, which is characterized by the triad comprising chronic sinusitis, bronchiectasis, and situs inversus.', 'Kartagener syndrome (KS), an autosomal recessively inherited disease, is characterized by the triad of situs inversus, bronchiectasis and sinusitis.', 'In 1933, Manes Kartagener, a Zurich pulmonary physician, reported four patients with the triad of sinusitis, bronchiectasis, and situs inversus.', 'A case of a nine year and eight months old child with Kartagener\'s syndrome (triad) is described: chronic maxillary sinusitis, bronchiectasis and "situs inversus totalis".', "Kartagener's syndrome is an inherited disease characterized by a triad of symptoms--bronchiectasis, situs inversus and sinusitis--and is classified as an immotile cilia syndrome.", "Kartagener's syndrome is characterized by the clinical triad of bronchitis, sinusitis, and situs inversus.", "Kartagener's syndrome is a well known classical triad of presentations consisting of bronchiectasis, sinusitis and situs inversus.", "Kartagener's syndrome is a rare disorder characterized by the triad of situs inversus, including dextrocardia, bronchiectasis and paranasal sinusitis.", "Kartagener's syndrome is an inherited disease characterized by a triad of symptoms: bronchiectasis, situs inversus and sinusitis resulting from defective cilial motility.", "Ear, nose and throat symptoms and signs were studied in 15 patients with Kartagener's syndrome: a triad consisting of chronic rhinosinusitis, chronic bronchitis with bronchiectasis, and situs inversus.", 'Kartagener syndrome (a clinical variant of primary ciliary dyskinesia) is a recessive autossomical disease characterized by the triad of chronic sinusitis, bronchiectasis and situs inversus with dextrocardia', 'Kartagener Syndrome is a rare autosomal recessive disorder consisting of triad of sinusitis, bronchiectasis and situs inversus with dextrocardia', 'Kartagener syndrome (KS), an autosomal recessively inherited disease, is characterized by the triad of situs inversus, bronchiectasis and sinusitis', 'Kartagener's syndrome is an inherited disease characterized by a triad of symptoms--bronchiectasis, situs inversus and sinusitis--and is classified as an immotile cilia syndrome', 'Kartagener's syndrome is a very rare congenital malformation comprising of a classic triad of sinusitis, situs inversus and bronchiectasis', 'A comprehensive clinicomorphological examination of 24 children with Zivert-Kartagener syndrome ascertained the complete triad (bronchiectasis, maldevelopment of the sinuses and transposition of the viscera) in all of them', 'The triad situs viscerum inversus, bronchiectasis and sinusitis is known as Kartagener syndrome', 'We present a case of a patient with clinically definite ALS, who had earlier suffered from Kartagener syndrome, which is characterized by the triad comprising chronic sinusitis, bronchiectasis, and situs inversus. Recent linkage and mutational analyses identified several genes that are responsible for Kartagener syndrome.']

['The triad of situs inversus, bronchiectasis and sinusitis is known as Kartagener syndrome.']

['situs inversus', 'bronchiectasis', 'sinusitis']

Which diseases are associated with Primary intestinal lymphangiectasia (PIL)?

["Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is an exudative enteropathy resulting from morphologic abnormalities in the intestinal lymphatics. ", "Secondary hypogammaglobulinemia in Waldmann's disease treated with subcutaneous immunoglobulins.", 'Octreotide in Hennekam syndrome-associated intestinal lymphangiectasia.', 'Primary intestinal lymphangiectasia (PIL) is one mechanism leading to PLE. Few syndromes are associated with PIL; Hennekam syndrome (HS) is one of them. ', 'There are no publications on the treatment of PIL with octreotide in patients with HS. ', 'To the best of our knowledge, this is the first case report on the use of octreotide in HS-associated PIL.', "Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia.", "Primary intestinal lymphangiectasia (Waldmann's disease).", "Limb lymphedema as a first manifestation of primary intestinal lymphangiectasia (Waldmann's disease)", "Primary intestinal lymphangiectasia (Waldmann's disease) is characterized by protein-losing enteropathy occurring more frequently in childhood. ", "Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is an exudative enteropathy resulting from morphologic abnormalities in the intestinal lymphatics.", "Primary intestinal lymphangiectasia (PIL), so-called Waldmann's disease, is an uncommon condition, characterized by dilated intestinal submucosal and subserosal lymphatics of the gastrointestinal tract.", "Primary intestinal lymphangiectasia (PIL) or Waldmann's disease is a rare protein-losing gastroenteropathy of unknown etiology.", 'Primary intestinal lymphangiectasia (PIL), also known as Waldmanns disease, is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia', 'Primary intestinal lymphangiectasia (PIL) or Waldmanns disease is a rare protein-losing gastroenteropathy of unknown etiology', 'Primary intestinal lymphangiectasia (PIL), so-called Waldmanns disease, is an uncommon condition, characterized by dilated intestinal submucosal and subserosal lymphatics of the gastrointestinal tract', 'Primary intestinal lymphangiectasia (Waldmanns disease) is a rare disease characterized by dilated lymphatics in the small bowel leading to an exudative enteropathy with lymphopenia, hypoalbuminemia and hypogammaglobulinemia.We report the case of a 23 year-old male who presented with chronic anemia and in whom primary intestinal lymphangiectasia was diagnosed', 'Primary intestinal lymphangiectasis (PIL), also known as Waldmanns disease, is a rare protein-losing enteropathy characterized by abnormal enlargement of the lymphatic ducts in the bowel wall', 'Few syndromes are associated with PIL; Hennekam syndrome (HS) is one of them. ', "Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. ", "Primary intestinal lymphangiectasia (Waldmann's disease) is characterized by protein-losing enteropathy occurring more frequently in childhood.", "Primary intestinal lymphangiectasia (Waldmann's disease).", 'Octreotide in Hennekam syndrome-associated intestinal lymphangiectasia.']

["Primary intestinal lymphangiectasia (PIL) is associated with:\n1) Waldmann's disease and\n2) Hennekam syndrome (HS)."]

["Waldmann's disease", 'Hennekam syndrome', 'HS']

Has overexpression of sirtuins been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae)?

['In addition, Sir2 overexpression prevents Rif1 deletion from disrupting Sir2 at IGS1 and shortening lifespan. ', 'Roles for sirtuin proteins at telomeres are thought to promote lifespan in yeast and mammals.', 'Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae)', 'When overexpressed, the NAD-dependent protein deacetylase Sir2 extends the lifespan of both budding yeast ', 'When overexpressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence. ']

['Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae).']

['yes']

What is the mechanism of action of peginesatide?

['The erythropoietin-mimetic peptide (EMP) peginesatide belongs to the group of erythropoiesis-stimulating agents (ESAs) that are prohibited when misused in sports. Peginesatide is a synthetic pegylated homodimer of two cyclic 21-amino acid chains. ', 'Epo mimetic peptides have also raised expectations. Yet the prototype peginesatide was recalled after just 1 year of its widespread use in the USA because of serious side-effects including cases of death.', 'The erythropoietin analog peginesatide was withdrawn from marketing due to unexpected severe anaphylactic reactions associated with administration of the multi-use formulation. ', 'Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL).', 'PURPOSE: Peginesatide, a long-acting erythropoiesis-stimulating agent, was recalled in February 2013 following reports of serious and sometimes fatal hypersensitivity reactions in dialysis patients who received a first dose. ', 'BACKGROUND AND OBJECTIVES: Peginesatide (Omontys) is a novel, synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent (ESA) that is designed to specifically stimulate the erythropoietin receptor. ', 'Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. ', 'Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis.', 'Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis.', 'BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis.', 'Peginesatide is a synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis.', 'BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease.', 'The pharmacokinetics (PK) (absorption, distribution, metabolism, excretion) of peginesatide, a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent (ESA), was evaluated in rats.', 'Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats.', 'Peginesatide is an investigational pegylated, peptide-based, once-monthly ESA for increasing and maintaining hemoglobin (Hb).', 'Peginesatide: a potential erythropoiesis stimulating agent for the treatment of anemia of chronic renal failure.', 'Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. It is undetectable using current anti-doping tests due to its lack of sequence homology to EPO.', 'Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v.', 'Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose.', 'Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. It is undetectable using current anti-doping tests due to its lack of sequence homology to EPO. To detect and deter potential abuse of peginesatide, we initiated an industry/antidoping laboratory collaboration to develop and validate screening and confirmation assays so that they would be available before peginesatide reaches the market.', 'Peginesatide is a synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. Peginesatide has a unique structure that consists of a synthetic peptide dimer (with no sequence similarity to erythropoietin) conjugated to a 40-kDa PEG moiety. Peginesatide is being developed for the treatment of anemia associated with chronic kidney disease in dialysis patients.', 'Peginesatide is a synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. Peginesatide has a unique structure that consists of a synthetic peptide dimer (with no sequence similarity to erythropoietin) conjugated to a 40-kDa PEG moiety.', 'Peginesatide: a potential erythropoiesis stimulating agent for the treatment of anemia of chronic renal failure.']

['Peginesatide (Omontys) is synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent that is designed to specifically stimulate the erythropoietin receptor. It was recalled because of serious side-effects including cases of death.']

[]

Which histone marks are deposited by Set7?

['the loss of H4 lysine 20 methylation', 'Transcriptionally competent regions lack H4 lysine 20 methylation', 'a human histone H4 lysine 20 methyltransferase and cloned the encoding gene, PR/SET07', 'Localization of PR-Set7 to mitotic chromosomes and subsequent increase in H4 Lys 20 methylation', 'the H4-K20 methyltransferase PR-Set7. Indeed, upregulation of PR-Set7 expression upon loss of HCF-1 leads to improper mitotic H4-K20 methylation']

['Set7 is H4K20 monomethyltransferase. Upregulation of PR-Set7 expression upon loss of HCF-1 leads to improper mitotic H4-K20 methylation. Set7 (or some variant) has also been reported to perform mono-methylation on lysine-4 of H3.']

['H4K20 monomethylation', 'H3K4 monomethylation']

Between which types of DNA bases are mutational biases introduced due to directional mutation pressure?

['directional mutation pressure for variation of the DNA G + C content due to mutational biases between alpha-bases (A or T) and gamma-bases (G or C)', 'A/T-biased directional mutation pressure', 'Rates of substitution mutations in two directions, v [from an A-T or T-A nucleotide pair (AT-pair) to a G-C or C-G nucleotide pair (GC-pair)] and u [from a GC-pair to an AT-pair], are usually not the same. The net effect, v/(u + v), has previously been defined as directional mutation pressure (mu D), which explains the wide interspecific variation and narrow intragenomic heterogeneity of DNA G + C content in bacteria.', 'The prokaryotic genetic code has been influenced by directional mutation pressure (GC/AT pressure) that has been exerted on the entire genome.', 'directional mutation pressure affecting the base composition of DNA, sometimes in the direction of increased GC content and at other times, in the direction of AT.', 'GC content of DNA varies, as a result of directional mutation pressure (AT/GC pressure), especially in bacteria.', 'the effect of mutation on a genome is not random but has a directionality toward higher or lower guanine-plus-cytosine content of DNA, and this pressure generates directional changes more in neutral parts of the genome than in functionally significant parts.', 'GC-biased mutation pressure', 'Directional mutation theory predicts that when the mutational bias between A/T and G/C nucleotide pairs is equilibrated with the base composition of a neutral set of DNA nucleotides, the mutation frequency per gene will be much lower than the frequency immediately after the mutator mutation takes place.', 'The parity rules lay the foundation for evaluating the biases in synonymous codon usage in terms of (1) directional mutation pressure for variation of the DNA G + C content due to mutational biases between alpha-bases (A or T) and gamma-bases (G or C), (2) strand-bias mutation, for example, by DNA repair during transcription, and (3) functional selection in evolution, for example, due to tRNA abundance.', 'Directional mutation theory predicts that when the mutational bias between A/T and G/C nucleotide pairs is equilibrated with the base composition of a neutral set of DNA nucleotides, the mutation frequency per gene will be much lower than the frequency immediately after the mutator mutation takes place.', 'Directional mutation pressure, the heterogenicity in the likelihood of different nucleotide substitutions, is used to explain the increasing or decreasing guanine-cytosine content (GC%) in DNA and is represented by microD, in agreement with Sueoka (1962, Proc Natl Acad Sci USA 48:582-592).', 'The net effect, v/(u + v), has previously been defined as directional mutation pressure (mu D), which explains the wide interspecific variation and narrow intragenomic heterogeneity of DNA G + C content in bacteria.', 'The parity rules lay the foundation for evaluating the biases in synonymous codon usage in terms of (1) directional mutation pressure for variation of the DNA G + C content due to mutational biases between alpha-bases (A or T) and gamma-bases (G or C), (2) strand-bias mutation, for example, by DNA repair during transcription, and (3) functional selection in evolution, for example, due to tRNA abundance.', 'The parity rules lay the foundation for evaluating the biases in synonymous codon usage in terms of (1) directional mutation pressure for variation of the DNA G + C content due to mutational biases between alpha-bases (A or T) and gamma-bases (G or C), (2) strand-bias mutation, for example, by DNA repair during transcription, and (3) functional selection in evolution, for example, due to tRNA abundance', 'Directional mutation theory predicts that when the mutational bias between A/T and G/C nucleotide pairs is equilibrated with the base composition of a neutral set of DNA nucleotides, the mutation frequency per gene will be much lower than the frequency immediately after the mutator mutation takes place']

['The rates of substitution mutations in two directions, v (from an AT-pair to a GC-pair) and u (from a GC-pair to an AT-pair), are usually not the same. Thereafter, the effect of mutation on a genome is not random but has a directionality toward higher or lower GC content of DNA. The net effect, v/(u + v), has previously been defined as directional mutation pressure. Thus, directional mutation pressure (GC/AT pressure) refers to mutational biases between alpha-bases (A or T) and gamma-bases (G or C).']

[]

Are microRNA (miR) regulated through DNA methylation of their promoters?

['We found that Tcf3 down-regulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs', 'ene silencing of MIR22 in acute lymphoblastic leukaemia involves histone modifications independent of promoter DNA methylation', 'Whereas a CpG island was identified within the promoter element of MIR22, no promoter DNA methylation was detected in these cells', 'xtensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia', 'Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation', 'Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL', 'NA methylation of microRNA genes in multiple myeloma', 'Recently, epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM)', 'ethylation of tumor suppressor microRNAs', 'Dysregulation of miRNA expression involved in cancer can be triggered by multiple mechanisms including aberrant DNA methylation of the miRNA gene promoter', 'Of note, DNA methylation of tumor suppressor miRNAs has been implicated in various human cancers', 'Moreover, miRNA silencing mediated by aberrant promoter DNA methylation can potentially be reversed by hypomethylating agents, and hence may pose a new therapeutic target in cancer', ' In this review, the authors will focus on the aberrant methylation of miRNAs in the pathogenesis of lymphoid malignancies including chronic lymphocytic leukemia, multiple myeloma and acute lymphoblastic leukemia', 'Here, we review those miRNAs implicated in AD that are regulated by promoter DNA methylation and/or chromatin modifications and, which frequently direct the expression of constituents of the epigenetic machinery, concluding with the delineation of a complex epigenetic-miRNA regulatory network and its alterations in AD', 'Furthermore, we also discuss epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation and the interaction of DNA methylation with miRNAs involved in the regulation of HSC activation and liver fibrosi', 'Instead, the cell type-specific silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma promoter DNA methylation and reduced processing of the miR-34a primary transcript', 'Some tumor-suppressive miRNAs are known to be epigenetically silenced by promoter DNA methylation in cancer', 'In the present study, we aimed to identify miRNA genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC)', "It was found that miR-335, which is harbored within an intron of its protein-coding host gene, MEST, was downregulated by aberrant promoter hypermethylation via further methylation assays, including methylation-specific PCR, combined bisulfite and restriction analysis, bisulfite sequencing analysis and 5-aza-2'-deoxycytidine treatment", 'he levels of miR-335/MEST methylation were significantly higher in 18 (90%) out of 20 primary HCC tumors, compared to their non-tumor tissue counterparts (P<0.001)', 'In conclusion, our results indicate that expression of miR-335 is reduced by aberrant DNA methylation in HCC.']

["Dysregulation of miRNA expression involved in cancer and Alzheimer's disease can be triggered by multiple mechanisms including aberrant DNA methylation of the miRNA gene promoter. Epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM).", 'Dysregulation of miRNA expression involved in cancer can be triggered by multiple mechanisms including aberrant DNA methylation of the miRNA gene promoterRecently, epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM)']

['yes']

Which enzyme does MLN4924 inhibit?

['Finally, MLN4924, an investigational small molecule inhibitor of NEDD8-activating enzyme (NAE) that inhibits CRL, suppresses in vitro migration, proliferation and tube formation, as well as in vivo angiogenesis and tumorigenesis. ', 'MLN4924, a small molecule inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit an anti-tumor effect on various malignancies. ', 'The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models.', 'A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924.', 'Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924.', 'Quantifiable analysis of cellular pathway inhibition of a Nedd8-activating enzyme inhibitor, MLN4924, using AlphaScreen.', 'Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored.', 'Quantitative proteomic analysis of cellular protein modulation upon inhibition of the NEDD8-activating enzyme by MLN4924.', 'Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells.', 'The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells.', 'Inhibition of Nedd8-activating enzyme by MLN4924 prevents the conjugation of cullin proteins with NEDD8, resulting in inactivation of the entire family of CRLs.', 'Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ.', 'To inhibit cellular neddylation, we used a cell line with tetracycline-inducible expression of a dominant-negative form of the Nedd8 E2 enzyme or treatment of cells with the Nedd8 E1 inhibitor MLN4924', 'MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates', 'MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE)', 'MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates', 'We used MLN4924, a phase 2 oncology therapeutic, which targets and inhibits the NEDD8-activating enzyme pathway involved in the ubiquitin-proteasome system', 'Neddylation occurs through a multistep enzymatic process involving Nedd8 activating enzymes, and recent studies have shown that the pharmacological agent, MLN4924, can potently inhibit Nedd8 activating enzymes, thereby preventing neddylation of Cullin proteins and preventing the degradation of CRL target proteins', 'The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. ', 'MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. ', 'The NEDD8-activating enzyme inhibitor, MLN4924, cooperates with TRAIL to augment apoptosis through facilitating c-FLIP degradation in head and neck cancer cells.', 'Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program.', 'MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma.', ' MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells.', 'Neddylation can be prevented by MLN4924, a drug that inhibits the nedd8-activating enzyme. We report that MLN4924 inhibits the neddylation of CRL4, blocking Vpx-induced degradation of SAMHD1 and maintaining the restriction.', ' MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage.', 'MLN4924 inhibits NAE (NEDD8 Activating Enzyme),', ' MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct.', 'Ubiquitin-activating enzyme (UAE or E1) activates ubiquitin via an adenylate intermediate and catalyzes its transfer to a ubiquitin-conjugating enzyme (E2). MLN4924 is an adenosine sulfamate analogue that was identified as a selective, mechanism-based inhibitor of NEDD8-activating enzyme (NAE), another E1 enzyme, by forming a NEDD8-MLN4924 adduct that tightly binds at the active site of NAE, a novel mechanism termed substrate-assisted inhibition (Brownell, J.', '(2010) elucidate the mechanism of action of MLN4924, a NEDD8-activating enzyme inhibitor. MLN4924 requires the activity of the enzyme to generate a NEDD8-adenylate analog that potently and selectively shuts down this posttranslational modification system.', ' Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct.', 'MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells.', 'MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage.', 'MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct.', 'Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct.']

['MLN4924 is an investigational small molecule inhibitor of NEDD8-activating enzyme (NAE).']

['NEDD8-activating enzyme']

Which is the process that Conserved noncoding elements mostly regulate?

['Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development.', 'This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development.', 'Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes', 'Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development.', 'HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish.', 'HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes.', 'These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.', 'Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation.', 'The majority of tetrapod-specific UCEs are noncoding and associated with genes involved in regulation of transcription and development.', 'Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development', 'In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family', 'The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development']

['Conserved noncoding elements play a fundamental role in regulating animal development']

['Development']

What is the biological role of K-48 linked protein ubiquitination?

['On the LCV, AnkB triggers docking of K(48)-linked polyubiquitinated proteins that are degraded by the host proteasomes to elevate cellular levels of amino acids needed for intracellular proliferation. ', 'Transcription and injection of ankB is triggered by attached extracellular bacteria followed by rapid farnesylation and anchoring of AnkB to the cytosolic side of the plasma membrane beneath bacterial attachment, where K(48)-linked polyubiquitinated proteins are assembled and degraded by the proteasomes, leading to a rapid rise in the cellular levels of amino acids.', 'Although it has been known for a long time that ubiquitylation has a major role in the activation and regulation of the nuclear factor kappa B (NF-κB) pathway, recent studies have revealed that the picture is a lot more complex than originally thought. NF-κB and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-κB precursors and the degradation of inhibitor of kappa B (IκB) proteins. ', 'The proteasome, which identifies and destroys unwanted proteins rapidly, plays a vital role in maintaining cellular protein homeostasis. Proteins that are destined for proteasome-mediated degradation are usually tagged with a chain of ubiquitin linked via lysine (K) 48 that targets them to the proteolytic machinery. ', 'Covalent and reversible post-translational modifications of proteins are a common theme in signaling. Ubiquitin conjugation was originally described to target proteins to proteasomal degradation by ubiquitin polymerization involving lysine (K) 48 residues.', 'Proteins tagged with lysine (Lys, K) 48 polyubiquitins chains are destined for degradation by the 26S proteasomal system.', '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.', '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.', 'NF-κB and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-κB precursors and the degradation of inhibitor of kappa B (IκB) proteins', 'NF-κB and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-κB precursors and the degradation of inhibitor of kappa B (IκB) proteins', 'Proteins that are destined for proteasome-mediated degradation are usually tagged with a chain of ubiquitin linked via lysine (K) 48 that targets them to the proteolytic machinery']

['The proteasome, which identifies and destroys unwanted proteins rapidly, plays a vital role in maintaining cellular protein homeostasis. Proteins that are destined for proteasome-mediated degradation are usually tagged with a chain of ubiquitin linked via lysine (K) 48 that targets them to the proteolytic machinery. K(48)-linked polyubiquitinated proteins are degraded by the proteasomes to elevate cellular levels of amino acids needed for intracellular proliferation. NF-κB and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-κB precursors and the degradation of inhibitor of kappa B (IκB) proteins.']

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How does neuroticism affect Alzheimer's risk, given its link to dementia and cognition?

['["RESULTS: Individuals with scores in the top quartile of neuroticism (hazard ratio = 3.1; 95% confidence interval = 1.6-6.0) or the lowest quartile of conscientiousness (hazard ratio = 3.3; 95% confidence interval = 1.4-7.4) had a threefold increased risk of incident AD.", "Five of nine studies found that higher neuroticism was associated with greater dementia risk (pooled hazard ratio [HR] per unit increase on neuroticism score, HR\\u00a0= 1.13, 95% confidence interval [CI]\\u00a0= 1.08-1.18, z\\u00a0= 5.11, p\\u00a0<0.001, N\\u00a0= 3,285), and two studies showed it increased risk of MCI. ", "CONCLUSIONS: Neuroticism increased risk for dementia, and conscientiousness reduced risk. ", "RESULTS: Fully adjusted multivariate analyses showed that the association between the presence of APOE [Latin Small Letter Open E]-4 allele(s) and both outcomes was evident among individuals with high levels of neuroticism and extraversion but not among persons with low levels of these traits. CONCLUSIONS: Phenotypic personality dimensions, primarily neuroticism and extraversion, moderate the relationship between APOE [Latin Small Letter Open E]-4 genotype and cognitive outcomes among older adults.", " Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2-3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = -0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and A\\u03b2 neuritic plaques.", "Using mixed models adjusted for age, sex, education, race, social network size, depression, chronic conditions, disability, neuroticism, extraversion, cognitive activity, and physical activity, more social activity was associated with less cognitive decline during average follow-up of 5.2 years (SD = 2.7).", "RESULTS: After controlling for age, the Alzheimer disease group presented significantly higher scores than normal control subjects on current neuroticism, and significantly lower scores on current extraversion, openness, and conscientiousness, while no significant difference was observed on agreeableness. ", " In analyses of specific cognitive systems, neuroticism subscales were related to decline in episodic memory, working memory, and perceptual speed, but not in semantic memory or visuospatial ability. No component of neuroticism was related to the neuropathologic lesions most commonly associated with late-life dementia. CONCLUSIONS: Neuroticism\'s association with late-life dementia mainly reflects vulnerability to stress and anxiety and their correlation with decline in the ability to process and retain new information.", "The finding that AD risk is associated with elevated Neuroticism and lower Conscientiousness can be added to the accumulating literature documenting the pathogenic effects of these two traits. ", "tau was also correlated with the psychometric measures of episodic/semantic memory, working memory, and processing speed, and with the personality traits of neuroticism and conscientiousness.", "The pre-morbid personality domain of Neuroticism constituted an interesting and theoretically plausible, yet uninvestigated, candidate for such an association. ", "RESULTS: Midlife Neuroticism predicted younger age of dementia onset in females but not in males.", "Preliminary research suggests that cognitively impaired MS patients exhibit elevation in Neuroticism, and diminution in Extraversion, Agreeableness, and Conscientiousness, as do patients with Alzheimer\'s disease. ", "On the basis of both self-report and informant report, there was an increase in neuroticism and a decrease in conscientiousness in persons with very mild DAT relative to healthy individuals without it, and in persons with mild DAT relative to those with very mild DAT. ", "CONCLUSIONS: As subjective cognitive complaints in the AACD group were related to neuroticism and gender rather than to cognitive performance, their inclusion in diagnostic concepts such as AACD should be revaluated. ", "Multiple studies of individuals with Alzheimer disease have substantiated significant levels of informant-rated change in several domains and facets of the Neuroticism-Extraversion-Openness Personality Inventory, including increases in Neuroticism and decreases in Extraversion and Conscientiousness relative to premorbid personality traits. ", "RESULTS: The AD patients showed higher neuroticism']

Neuroticism increases the risk for dementia and Alzheimer's disease, while conscientiousness reduces the risk. Higher neuroticism scores are associated with greater dementia risk and cognitive decline, as well as vulnerability to stress and anxiety. Neuroticism is also linked to advanced stages of neurofibrillary tangles, which are associated with dementia.

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What is the function of mTOR?

['Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function,', 'mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators', 'Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism', ' (mTOR) is a serine-threonine kinase that controls several important aspects of mammalian cell function. mTOR activity is modulated by various intra- and extracellular factors; in turn, mTOR changes rates of translation, transcription, protein degradation, cell signaling, metabolism, and cytoskeleton dynamics. mTOR has been repeatedly shown to participate in neuronal development and the proper functioning of mature neurons.', 'mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase related kinase (PIKK) family, plays a central role in the regulation of cell growth', '(mTOR) is a serine/threonine kinase and that forms two multiprotein complexes known as the mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR regulates cell growth, proliferation and survival', '(mTOR), a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation,']

['The mTOR protein regulates assembly of the translation initiation machinery and are master regulators of cellular survival, growth and metabolism.']

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Viliuisk encephalomyelitis is diagnosed in which geographical area?

['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 the Eastern Highlands of Papua New Guinea, 4 patients with Viliuisk encephalomyelitis from the Iakut region of eastern Siberia, 45 Italian patients with multiple sclerosis, and 56 patients with polymyositis (49 from the United States and 7 from Jamaica).', 'Viliuisk encephalomyelitis (VE), a progressive neurological disorder with a fatal outcome usually in several months to 6 yrs after disease onset, is seen only among the Iakut people of Siberia.', 'Transmission to unrelated persons was documented in a densely populated region around the city of Yakutsk in which Viliuisk encephalomyelitis had not been previously known.', '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..', 'Epidemiology of Viliuisk encephalomyelitis in Eastern Siberia.', 'Viliuisk encephalomyelitis in the Iakut people of Siberia.', 'Viliuisk encephalomyelitis in Eastern Siberia - analysis of 390 cases.']

['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.']

['Northeast Siberia']

Does the histone chaperone ASF1 interact with histones H1/H2?

['The C terminus of the histone chaperone Asf1 cross-links to histone H3 in yeast and promotes interaction with histones H3 and H4.', 'The central histone H3/H4 chaperone Asf1 comprises a highly conserved globular core and a divergent C-terminal tail. ', 'The histone H3-H4 chaperone Asf1 is involved in chromatin assembly (or disassembly), histone exchange, regulation of transcription, and chromatin silencing in several organisms. ', 'An ASF1-EGFP fusion protein localizes to the nucleus. By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners. ', ' This inhibition requires Asf1 binding to H3-H4 and Rtt109 KAT activity, but not tail acetylation of H3-H4 or K56 acetylation of H3. ', 'Asf1 is a conserved histone H3/H4 chaperone that can assemble and disassemble nucleosomes and promote histone acetylation. ', 'Here we characterize further interactions between budding yeast (Saccharomyces cerevisiae) Asf1 and Set2 using assays of intragenic transcription, H3/H4 posttranslational modification, coding region cross-linking of Asf1 and Set2, and cooccurrence of Asf1 and Set2 in protein complexes. ', 'Consistent with this possibility, we show that Asf1 stimulates Set2 occupancy of the coding region of a highly transcribed gene by a mechanism that depends on Asf1 binding to H3/H4. ', 'Drosophila histones H3 and H4 can also be produced as a soluble (H3H4)(2) heterotetrameric complex if they are co-expressed with the histone chaperone Asf1.', 'Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4.', 'Newly synthesized histones H3-H4 first bind histone chaperone Asf1 and are then transferred to other chaperones for nucleosome assembly', 'The C terminus of the histone chaperone Asf1 cross-links to histone H3 in yeast and promotes interaction with histones H3 and H4', 'Histone chaperone Asf1 is required for histone H3 lysine 56 acetylation, a modification associated with S phase in mitosis and meiosis', 'Antisilencing function 1 (ASF1) is a major histone H3-H4 chaperone that deposits histones H3 and H4 onto DNA', 'Rtt109, a recently discovered histone acetyltransferase (HAT) from Saccharomyces cerevisiae, functions with the histone chaperone Asf1 to acetylate lysine K56 on histone H3 (H3K56), a modification associated with newly synthesized histones', 'In this issue of Cell, English et al. present the first crystal structure of a histone chaperone (Asf1) bound to histones (the H3/H4 heterodimer)', 'By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners.', 'Anti-silencing function 1 (Asf1) is a highly conserved chaperone of histones H3/H4 that assembles or disassembles chromatin during transcription, replication, and repair.', 'Analysis of a panel of Asf1 mutations that modulate the ability of Asf1 to bind to histones H3/H4 demonstrates that the histone binding activity of Asf1 is required for the acetylation of Lys-9 and Lys-56 on newly synthesized H3.', 'Thus Rad53 competes with histones H3-H4 and cochaperones HirA/CAF-I for binding to Asf1.', 'Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4.', 'Currently, the best-characterized chaperone-histone interaction is that between the ubiquitous chaperone Asf1 and a dimer of H3 and H4.']

['No, the histone chaperone ASF1 interacts with histones H3/H4.']

['no']

Does MicroRNA-21 (miR-21) contribute to cardiovascular disease?

['The synergistic effect of miR-21 and miR-1 were functionally validated for their significant influences on myocardial apoptosis, cardiac hypertrophy and fibrosis.', 'Taken together, we found a novel reciprocal loop between miR-21 and TGFβRIII in cardiac fibrosis caused by myocardial infarction in mice, and targeting this pathway could be a new strategy for the prevention and treatment of myocardial remodeling.', 'It is still controversial whether microRNA-21 (miR-21) participates in the process of cardiac fibrosis.', 'In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. ', 'The myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with the controls and correlated directly with the echocardiographic mean transvalvular gradients.', 'Our results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis.', 'Ad-miR-21 improves LV remodeling and decreases the apoptosis of myocardial cells, suggesting the possible mechanism by which Ad-miR-21 functions in protecting against I/R injury.', 'In the Ad-miR-21 group, LV dimensions, myocardial infarct size, LV/BW, collagen type Ⅰ, type Ⅲ and PCNA positive cells all significantly decreased compared with the Ad-GFP group.', 'While miR-21, -133, -150, -195, and -214 regulate cardiomyocyte hypertrophy, miR-1/-133 and miR-208 have been elucidated to influence myocardial contractile function. In addition, miR-21, -24, -133, -210, -494, and -499 appear to protect myocytes against I/R-induced apoptosis, whereas miR-1, -29, -199a, and -320 promote apoptosis. Myocardial fibrosis can be regulated by the miR-29 family and miR-21.', 'The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation.', 'During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described.', "On the other hand, miR-21, miR-199a, miR-210, and miR-494 have been proven critical for the myocytes' adaptation and survival during hypoxia/ischemia. ", 'Studies have shown that several miRs, including miR-1, miR-133, miR-21, miR-126, miR-320, miR-92a, and miR-199a, are regulated after preconditioning and play an active role in protecting the heart against ischemia/reperfusion injury.', 'Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction.', 'MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system. Recent studies have revealed that its expression is deregulated in heart and vasculature under cardiovascular disease conditions such as proliferative vascular disease, cardiac hypertrophy and heart failure, and ischemic heart disease. miR-21 is found to play important roles in vascular smooth muscle cell proliferation and apoptosis, cardiac cell growth and death, and cardiac fibroblast functions. Accordingly, miR-21 is proven to be involved in the pathogenesis of the above-mentioned cardiovascular diseases as demonstrated by both loss-of-function and gain-of-function approaches.', 'miR-21 might be a novel therapeutic target in cardiovascular diseases.', 'This review article summarizes the research progress regarding the roles of miR-21 in cardiovascular disease.', 'Remarkably, miR-21 was one of most upregulated miRNAs in hearts after IP. In vivo, IP-mediated cardiac protection against ischaemia/reperfusion injury was inhibited by knockdown of cardiac miR-21. In cultured cardiac myocytes, we identified that miR-21 also had a protective effect on hypoxia/reoxygenation-induced cell apoptosis that was associated with its target gene, programmed cell death 4. The protective effect of miR-21 on cardiac cell apoptosis was further confirmed in rat hearts after ischaemia/reperfusion injury in vivo.', 'Lately, some highlight articles revealed that the altered expression of miRNAs such as miR-1, miR-133, miR-21, miR-208 etc in hearts also contributed to cardiovascular diseases, such as heart ischemia, cardiac hypertrophy, and arrhythmias.', 'Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-of-function approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI.', 'The results suggest that miR-21 is sensitive to H(2)O(2) stimulation. miR-21 participates in H(2)O(2)-mediated gene regulation and functional modulation in cardiac myocytes. miR-21 might play an essential role in heart diseases related to ROS such as cardiac hypertrophy, heart failure, myocardial infarction, and myocardial ischemia/reperfusion injury.', 'MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts', 'Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients', 'MicroRNA 21 inhibits left ventricular remodeling in the early phase of rat model with ischemia-reperfusion injury by suppressing cell apoptosis', 'MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4', 'MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system.', 'MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts.', 'MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system', 'miR-21 might be a novel therapeutic target in cardiovascular diseases', 'MicroRNA-21 as therapeutic target in cancer and cardiovascular disease.', 'These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts.', 'Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.']

['MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system. Recent studies have revealed that its expression is deregulated in heart and vasculature under cardiovascular disease conditions such as proliferative vascular disease, cardiac hypertrophy and heart failure, and ischemic heart disease. miR-21 is found to play important roles in vascular smooth muscle cell proliferation and apoptosis, cardiac cell growth and death, and cardiac fibroblast functions. Accordingly, miR-21 is proven to be involved in the pathogenesis of the above-mentioned cardiovascular diseases as demonstrated by both loss-of-function and gain-of-function approaches']

['yes']

What is LedPred?

['LedPred: an R/bioconductor package to predict regulatory sequences using support vector machines', 'Here, we present LedPred, a flexible SVM workflow that predicts new regulatory sequences based on the annotation of known CRMs, which are associated to a large variety of feature types. LedPred is provided as an R/Bioconductor package connected to an online server to avoid installation of non-R software. Due to the heterogeneous CRM feature integration, LedPred excels at the prediction of regulatory sequences in Drosophila and mouse datasets compared with similar SVM-based software.', 'LedPred: an R/bioconductor package to predict regulatory sequences using support vector machines.', 'Due to the heterogeneous CRM feature integration, LedPred excels at the prediction of regulatory sequences in Drosophila and mouse datasets compared with similar SVM-based software.', 'Here, we present LedPred, a flexible SVM workflow that predicts new regulatory sequences based on the annotation of known CRMs, which are associated to a large variety of feature types.', 'Due to the heterogeneous CRM feature integration, LedPred excels at the prediction of regulatory sequences in Drosophila and mouse datasets compared with similar SVM-based software.LedPred is available on GitHub: https://github.com/aitgon/LedPred and Bioconductor: http://bioconductor.org/packages/release/bioc/html/LedPred.html under the MIT license.aitor.gonzalez@univ-amu.frSupplementary data are available at Bioinformatics online.<CopyrightInformation>© The Author 2015.', 'LedPred: an R/bioconductor package to predict regulatory sequences using support vector machines.', 'Due to the heterogeneous CRM feature integration, LedPred excels at the prediction of regulatory sequences in Drosophila and mouse datasets compared with similar SVM-based software.', 'Here, we present LedPred, a flexible SVM workflow that predicts new regulatory sequences based on the annotation of known CRMs, which are associated to a large variety of feature types.']

['LedPred is an R/bioconductor package to predict regulatory sequences using support vector machines. LedPred is provided as an R/Bioconductor package connected to an online server to avoid installation of non-R software. Due to the heterogeneous CRM feature integration, LedPred excels at the prediction of regulatory sequences in Drosophila and mouse datasets compared with similar SVM-based software.']

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What is FFI, fatal familial insomnia

['Fatal familial insomnia is a rare disease caused by a D178N mutation in combination with methionine (Met) at codon 129 in the mutated allele of PRNP (D178N-129M haplotype).', 'FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms', 'Familial fatal insomnia (FFI) is fatal disorder characterized by damage to select thalamic nuclei, together with progressive insomnia and dysautonomia.', 'Point mutations or the insertions of one or more copies of a 24 bp repeat are associated with familial human prion diseases including familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. ', 'Fatal familial insomnia (FFI) is a unique hereditary prion disease with characteristic disturbances of sleep.', 'Fatal familial insomnia (FFI) is a rare hereditary human prion disease with unique clinical features including progressive sleep impairment and autonomic dysfunction.', 'Fatal familial insomnia (FFI), a condition characterized by inability to sleep, dysautonomia, motor disturbances, and selective thalamic atrophy is a prion disease linked to a GAC----AAC mutation at codon 178 of the prion gene.', 'Fatal familial insomnia (FFI), or familial selective thalamic degeneration with a mutation at codon 178 of the prion protein (PrP) gene, is a rapidly progressive autosomal dominant disease characterized by progressive insomnia, dysautonomia, and myoclonus.', 'BACKGROUND: Fatal familial insomnia (FFI) is an autosomal dominant disease linked to a mutation in the prion protein gene. Fatal familial insomnia is characterized by sleep disturbance and loss of neurons, with gliosis in the thalamic nuclei.OBJECTIVE: To describe the clinical, neurophysiological, radiological, and neuropathological data in a Chinese family with FFI.SETTING: Tertiary referral university hospital setting.PATIENTS: Patient 1 was a 36-year-old man who presented with insomnia and myoclonus.', 'Fatal familial insomnia (FFI) is a rare genetic disease characterized by intractable insomnia, dysautonomia, and dementia.', 'FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. ', 'FFI is associated with an aspartic acid to asparagine mutation at codon 178 of the PrP gene (D178N) in conjunction with methionine at the codon 129 polymorphic site on the mutant allele (cis-129M).', 'The propositus had behavioral, sleep, cognitive, and motor impairment associated with thalamic and olivary atrophy', ' Sporadic fatal insomnia (sFI) and fatal familial insomnia (FFI) are rare human prion diseases.', 'Fatal familial insomnia (FFI) is an autosomal dominant prion disease characterized clinically by inattention, sleep loss, dysautonomia, and motor signs. ']

['Familial fatal insomnia (FFI) is a prion disease caused by a mutation (D178N-129M haplotype) in the Prion Protein gene (PRNP). FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. FFI is considered to be a rare disease.']

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Which enzyme is inhibited by ribociclib?

['Three CDK 4/6 inhibitors have been investigated for the treatment of HR(+) breast cancer, including palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219). ', 'The CDK 4/6 inhibitors are a novel class of therapeutics that target the CDK 4/6 kinases that promote transition through the cell cycle. Currently, palbociclib (PD0332991, Pfizer), abemaciclib (LY2835219, Lilly) and ribociclib (LEE011, Novartis) are being investigated in clinical trials. ', 'SUMMARY: Palbociclib, abemaciclib and ribociclib have demonstrated very promising clinical activity in breast cancer, liposarcoma, mantel cell lymphoma and melanoma. Moreover, CDK4/6 inhibitors have shown promising preclinical activity in glioblastoma, renal and ovarian cancer models that may provide directions for their future clinical development.', 'Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219).', 'The combination of antiestrogen therapy and ribociclib, an investigational CDK4/6 inhibitor, led to improved outcomes in women with metastatic HR-positive, HER2-negative breast cancer, according to findings presented at a meeting of the European Society for Medical Oncology. ', 'OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting', 'Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. ', 'After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell cycle analysis, Ki67 immunostaining, timelapse microscopy and xenograft studies.', 'Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. ', 'Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. ', 'Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer.', 'Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. ', 'Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer.']

['Ribociclib is inhibitor of cyclin D-cyclin-dependent kinase 4/6 (CDK 4/6). It is used for breast cancer treatment.']

['cyclin D-cyclin-dependent kinase 4/6', 'CDK4/6']

What is MRSA?

['(MRSA, methicillin-resistant S. aureus)', 'Community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) has become a severe health concern because of its treatment difficulties.', 'We investigated the distribution of MRSA (methicillin-resistant Staphylococcus aureus) on and around six patients with MRSA infection in our neurosurgical ward.', 'The aim of this study was to assess to what extent patients with meticillin-resistant Staphylococcus aureus (MRSA) at respiratory sites shed viable MRSA into the air of hospital rooms.', 'Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasing in prevalence among asymptomatic carriers and in cases of paediatric soft-tissue infections alike.', 'Most of MRSA strains and a part of methicillin-susceptible S. aureus (MSSA) strains harbored unique combinations of non-ß-lactamase genes aac(6)/aph(2″), aph(3)-III, ant (4,4″), ermA, ermC, mrsA, tetM, and tetK', 'Healthcare- and Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) and Fatal Pneumonia with Pediatric Deaths in Krasnoyarsk, Siberian Russia: Unique MRSAs Multiple Virulence Factors, Genome, and Stepwise Evolution', 'It was found in the present study that combined use of fusidic acid (FA) and berberine chloride (BBR) offered an in vitro synergistic action against 7 of the 30 clinical methicillin-resistant Staphylococcus aureus (MRSA) strains, with a fractional inhibitory concentration (FIC) index ranging from 0.5 to 0.19', 'Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China', 'To assess whether vancomycin minimum inhibitory concentration (MIC) creeps among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in a regional hospital in China', 'Detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens from various body sites: performance characteristics of the BD GeneOhm MRSA assay, the Xpert MRSA assay, and broth-enriched culture in an area with a low prevalence of MRSA infections.', 'Rapid detection of Methicillin-Resistant Staphylococcus aureus MRSA in nose, groin, and axilla swabs by the BD GeneOhm MRSA achromopeptidase assay and comparison with culture.', 'Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs.', 'Comparison of the Xpert methicillin-resistant Staphylococcus aureus (MRSA) assay, BD GeneOhm MRSA assay, and culture for detection of nasal and cutaneous groin colonization by MRSA.', 'Comparison of the BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay and the BD GeneOhm MRSA achromopeptidase assay with direct- and enriched-culture techniques using clinical specimens for detection of MRSA.', 'Comparison of MRSASelect Agar, CHROMagar Methicillin-Resistant Staphylococcus aureus (MRSA) Medium, and Xpert MRSA PCR for detection of MRSA in Nares: diagnostic accuracy for surveillance samples with various bacterial densities.', 'Rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) in diverse clinical specimens by the BD GeneOhm MRSA assay and comparison with culture.', 'Multicenter evaluation of the Cepheid Xpert methicillin-resistant Staphylococcus aureus (MRSA) test as a rapid screening method for detection of MRSA in nares.', 'Prospective comparison of the clinical impacts of heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-susceptible MRSA.', 'Long-term control of endemic hospital-wide methicillin-resistant Staphylococcus aureus (MRSA): the impact of targeted active surveillance for MRSA in patients and healthcare workers.', 'Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a major challenge in health care, yet the limited heterogeneity within this group hinders molecular investigations of related outbreaks.', "In a previous study, we reported that two kaempferol glycosides isolated from Laurus nobilis L., kaempferol-3-O-alpha-L-(2'',4''-di-E-p-coumaroyl)-rhamnoside (C2) and kaempferol-3-O-alpha-L-(2''-E-p-coumaroyl-4''-Z-p-coumaroyl)-rhamnoside (C3), showed strong antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci.", 'This article explains what methicillin-resistant Staphylococcus aureus (MRSA) is, how it is spread and what the real challenges are in healthcare settings in the UK.', 'Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging threat to public health, especially in correctional settings.', 'There are few more compelling questions in clinical microbiology today than the issue of whether or not to screen for the presence of methicillin-resistant Staphylococcus aureus (MRSA), with the results being used to institute infection control interventions aimed at preventing transmission of MRSA in health care environments.', 'Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs.', 'Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family?', 'methicillin-resistant Staphylococcus aureus (MRSA)', ' methicillin-resistant Staphylococcus aureus (CA-MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA) ', 'methicillin-resistant Staphylococcus aureus (MRSA) infections', 'methicillin resistant Staphylococcus aureus (MRSA CC398) ', ' (methicillin-resistant Staphylococcus aureus) MRSA ', 'Methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA) ', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'Methicillin-resistant Staphylococcus aureus', ' methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus-(CA-MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'Methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA)', 'methicillin-resistant Staphylococcus aureus (HA-MRSA)', 'methicillin-resistant Staphylococcus aureus (MRSA) ', 'methicillin-resistant Staphylococcus aureus (MRSA).', 'methicillin-resistant Staphylococcus aureus (MRSA)']

['community-associated methicillin resistant staphylococcus aureus (ca-mrsa) has become a severe health concern because of its treatment difficulties.', 'Methicillin resistant Staphylococcus aureus (MRSA) has become a severe health concern because of its treatment difficulties.', '(MRSA, methicillin-resistant S. aureus)']

['methicillin-resistant S. aureus', 'MRSA']

What is the role of AMPK kinase in myocardial remodeling after myocardial infarction

['These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.', 'The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P < 0.05).', 'Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin.', 'AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The activation of AMPK by metformin prevents cardiac remodeling after myocardial infarction (MI).', 'These results suggest that AMPK activation by metformin and the subsequent suppression of TLRs activity could be considered as a target in protecting the infarcted heart, which may indicate a link between AMPK and TLRs.']

['AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The activation of AMPK by metformin prevents cardiac remodeling after myocardial infarction (MI). \nAdiponectin protects the heart from ischemia-reperfusion injury through an AMPK-dependent mechanism.\nAMPK activation by metformin and the subsequent suppression of TLRs activity could be considered as a target in protecting the infarcted heart.']

[]

In which phase of cell cycle does stress-induced transcription-associated mutagenesis (TAM) occur?

['factors involved in RNA polymerase (RNAP) processivity or transcriptional derepression contribute to the generation of stress-induced mutations. In Bacillus subtilis, transcription-associated mutagenesis has been shown to be independent of recombination-dependent repair and, in some cases, of the Y DNA polymerases. Central to stationary-phase mutagenesis in B. subtilis is the requirement for Mfd, transcription coupling repair factor', 'Adaptive (stationary phase) mutagenesis is a phenomenon by which nondividing cells acquire beneficial mutations as a response to stress.', 'the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels. This mutagenic response was not observed under conditions of exponential growth. Since transcription is a ubiquitous biological process, transcription-associated mutagenesis may influence evolutionary processes in all organisms.', 'Transcription-associated mutation in Bacillus subtilis cells under stress.', 'Transcription-associated mutagenesis is increased under stress and depends on the DNA sequence.', 'Nonrandom transcription-associated mutagenesis under stress should improve the survival of E.', 'Transcription-associated mutagenesis is increased under stress and depends on the DNA sequence.', 'Stress-induced mutagenesis describes the accumulation of mutations that occur in nongrowing cells, in contrast to mutagenesis that occurs in actively dividing populations, and has been referred to as stationary-phase or adaptive mutagenesis.', 'Central to stationary-phase mutagenesis in B']

['Factors involved in RNA polymerase (RNAP) processivity or transcriptional derepression, such as Mfd (transcription coupling repair factor), contribute to the generation of stress-induced mutations. Under stress, transcription-associated mutagenesis is increased. Stress-induced transcription-associated mutations are acquired by nondividing cells, during stationary phase, and are not observed under conditions of exponential growth.']

['stationary phase']

Is bapineuzumab effective for treatment of patients with Alzheimer's disease?

[' Thus far, results from two large phase 3 trial programs with bapineuzumab and solaneuzumab, respectively, have brought rather disappointing results.', 'More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. ', 'Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function.', "The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric Aβ, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in amyloid plaques.", 'Phase III trials showed that bapineuzumab failed to improve cognitive and functional performances in AD patients, and was associated with a high incidence of amyloid-related imaging abnormalities (ARIA).', 'Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits. ', 'Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.', 'Despite negative topline phase 3 clinical trial results for bapineuzumab and solanezumab in mild to moderate AD, findings from these trials and recent advances suggest renewed optimism for anti-amyloid therapies. ', "The lack of progress in the development of disease-modifying therapy in Alzheimer's disease (AD) was highlighted recently by the cessation of a phase 3 clinical trial studying the effects of bapineuzumab on mild to moderate disease. No treatment benefit was apparent, whereas several serious side effects occurred more commonly in the treatment group compared to placebo. ", 'Clinical studies using the N-terminal-directed anti-Aβ antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aβ plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aβ plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models.', 'The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. ', ' The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg).', 'However, the preliminary cognitive efficacy of bapineuzumab, a humanized anti-Aβ monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ϵ4 carriers, have led to abandoning of the highest dose of the drug. ', 'However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD. ', 'The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Aβ due to immunotherapy.', 'These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment.', 'Bapineuzumab has been shown to reduce Aβ burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ε4 carriers, and vasogenic edema may limit its clinical use. ', "Bapineuzumab appears capable of reducing the cerebral beta-amyloid peptide burden in patients with Alzheimer's disease. However, particularly in APOE 4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema - a dose-limiting and potentially severe adverse reaction - may limit its clinical applicability.", 'The first is a phase 2 study of passive immunotherapy with bapineuzumab, a humanized anti-Abeta monoclonal antibody directed against the N-terminus of Abeta. This trial showed no differences within dose cohorts on the primary efficacy analysis. Exploratory analyses showed potential treatment differences on cognitive and functional endpoints in study completers and apolipoprotein E epsilon4 noncarriers. A safety concern was the occurrence of reversible vasogenic edema. ', 'The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers.']

["Clinical trials have demonstrated that bapineuzumab, a humanized monoclonal antibody against the end terminus of amyloid plaques, is not effective for treatment of patients with Alzheimer's disease. The burden of beta amyloid plaques was reduced in response to bapineuzumab therapy. However, bapineuzumab therapy did not improve cognitive functioning and was associated with significant adverse effects in Alzheimer's disease patients."]

['no']

Which human syndromes have been detected with Fluorescence in situ hybridization (FISH)?

['We demonstrate that, using a sensitive FISH technique, 12p deletion occurs significantly more frequently in MDS than previously described (7.6% by CD34+ PB-FISH vs. 1.6% by CBA, P<0.001) and is often associated with other aberrations (93% by CD34+ PB-FISH vs. 60% by CBA)', 'Somatic chromosomal mosaicism arising from post-zygotic errors is known to cause several well-defined genetic syndromes as well as contribute to phenotypic variation in diseases.', 'The mosaicism was characterized and confirmed by fluorescence in situ hybridization (FISH) and/or chromosome analysis. Different categories of abnormal cell lines were detected: (1) aneuploidy, including sex chromosome abnormalities and isochromosomes (22 cases), (2) ring or marker chromosomes (12 cases), (3) single deletion/duplication copy number variations (CNVs) (11 cases), (4) multiple deletion/duplication CNVs (5 cases), (5) exonic CNVs (4 cases), and (6) unbalanced translocations (3 cases). ', 'Positive cases with MLPA technique were confirmed using either fluorescence in situ hybridization (FISH) or follow up confirmatory MLPA probe sets.', 'The deletions/duplications detected in non telomeric regions include regions for Prader Willi/Angelman regions, Williams syndrome, Smith Magenis syndrome and Velocardiofacial syndrome.', 'The bone marrow specimen from a patient with MDS was comprehensively analyzed by a combination of genomic approaches, including chromosomal karyotyping, fluorescence in situ hybridization (FISH), genome scanning using Affymetrix high density SNP microarray platform, and next-generation sequencing (NGS) analysis using IonTorrent Cancer Gene Panel.', 'Detection of TET2 abnormalities by fluorescence in situ hybridization in 41 patients with myelodysplastic syndrome.', 'Fluorescence in situ hybridization of TP53 for the detection of chromosome 17 abnormalities in myelodysplastic syndromes.', 'Fluorescence in situ hybridization (FISH) can effectively demonstrate TET2 deletions and is often used to validate molecular results. ', 'These findings demonstrate that 1) FISH is an effective and economical method to reveal cryptic abnormalities of band 4q22-q24 resulting in TET2 deletions;', 'FISH and SNP-A karyotyping in myelodysplastic syndromes: improving cytogenetic detection of del(5q), monosomy 7, del(7q), trisomy 8 and del(20q).', ' Using a standardized approach, we focused our investigation on detection of -5/del(5q), -7/del(7q), trisomy 8 and del(20q) in patients with MDS (N=52), MDS/myeloproliferative overlap syndromes (N=7) and acute myeloid leukemia (N=15) using MC, FISH and SNP-A karyotyping. ', 'We conclude that MC, FISH and SNP-A are complementary techniques that, when applied and interpreted together, can improve the diagnostic yield for identifying genetic lesions in MDS and contribute to the better description of abnormal karyotypes.', 'Here, we report the detection of a reciprocal translocation t(7;21)(p22;q22) in the marrow of two adults with MDS and AML, using conventional cytogenetic analysis and fluorescence-in situ-hybridization (FISH).', 'Detection of cytogenetic abnormalities involving chromosomes 5,7 and 8 in myelodysplastic syndromes with fluorescence in situ hybridization and its clinical significance', 'To identify the abnormal karyotypes by fluorescence in situ hybridization (FISH) and explore prognostic implications in patients with myelodysplastic syndromes (MDS).', 'FISH was used to detect the frequently occurring chromosome abnormalities (-5/5q, +8, -7/7q-) in 37 MDS cases. ', 'FISH detected monosomy 7 in 6 samples at the time MDS was diagnosed and in 2 samples at the time AA was diagnosed.', 'As chromosomal instability may contribute to leukemogenesis in patients with congenital bone marrow failure (CBMF) disorders, it was the aim of this study to characterize chromosomally aberrant clones that arise during the clinical course of disease by means of R-banding and fluorescence in situ hybridization (FISH) analyses.', 'In one child with congenital thrombocytopenia, Jacobsen syndrome [del(11)(q24)c] was diagnosed, and thus a CBMF could be excluded. In a girl with Shwachman-Diamond syndrome, two independent clones, one with an isochromosome i(7)(q10), another with a complex aberrant karyotype, were identified. Simultaneously, transition into a myelodysplastic syndrome (MDS) occurred. The brother, who was also afflicted with Shwachman-Diamond syndrome, showed an isochromosome i(7q) as a single aberration. ', 'In summary, we suggest that follow-up of patients with CBMF using chromosome and FISH analyses will be helpful for the early detection of transition into MDS or AML and thus should be an integral part of the clinical management of these patients.', 'Here we assess this capability by applying array CGH to the analysis of copy number alterations in 44 patients with a phenotype of the 22q11.2 deletion syndrome. Twenty-five patients had the deletion on chromosome 22 characteristic of this syndrome as determined by fluorescence in situ hybridization (FISH). ', 'Subtelomeric aberrations previously detected by fluorescence in situ hybridization (FISH) analysis were confirmed in two patients, and accurate diagnosis was provided in two previously undiagnosed complex cases. Microdeletions at 15q11.2-q13 in a newborn with hypotonia, cryptorchidism, and hypopigmentation were detected with few discrepancies between the array results and FISH analysis. Contiguous microdeletion of GSCL, HIRA and TBX1 genes at 22q11.2 was identified in a previously undiagnosed boy with an unusual presentation of the VCF/DiGeorge spectrum. ', 'Detection of 20q(-) chromosome abnormality in myelodysplastic syndrome by interphase fluorescence in situ hybridization', 'The results showed that among 52 cases of MDS, 7 (13.5%) cases were positive by FISH, however, of which, 4 cases were positive and the other 3 cases were negative by CC assay. It is concluded that YAC912C3 and interphase FISH providing a powerful technique in the detection of 20q(-) in MDS is an important complement to CC assay.', 'A FISH assay was performed to analyze 70 AML/MDS patients who had received conventional cytogenetic analysis (CCA). ', 'FISH is a powerful tool to identify or refine chromosomal structural aberrations involving 7q, and it provides accurate evaluation of -7/7q- in all the patients. -7 and 7q- clone frequently coexist in the same specimen, and the significantly increasing percentage of 7q- cells implies that -7 clone secondary to 7q- clone is a result from loss of 7q-.', 'Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by craniofacial and limb anomalies.', 'We propose that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybridization (FISH) for deletion detection of TWIST, is sufficient to detect mutations in>80% of patients with the Saethre-Chotzen phenotype.', 'We clearly present that the use of SKY combined with conventional G-banding analysis and FISH has assisted in the identification of important chromosomal events that may play a key role in the development of t-MDS.', 'n this study, we used spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) as complementary techniques for the analysis of two therapy-related secondary myelodysplastic syndrome (t-MDS) cases with complex karyotypes, previously analyzed by G-banding. ', 'Comparison of detection of trisomy 8 with fluorescence in situ hybridization and conventional karyotype analysis in myelodysplastic syndrome', 'The trisomy 8 clones were simultaneously detected in 48 MDS cases with FISH and conventional cytogenetic analysis (CCA).', 'Trisomy 8 was detected in 1 of 15 specimens with normal or abnormal karyotype without trisomy 8 by FISH.', 'In conclusion, our results showed that FISH is a sensitive and accurate technique to detect trisomy 8 in MDS patients. It can provide contribute to diagnosis, assessment of curative effect and predicting progress of disease in MDS. ', 'Detection of common chromosome abnormalities in myelodysplastic syndrome with a panel fluorescence in situ hybridization', 'Panel FISH is a useful tool of molecular cytogenetics in the detection of common chromosome abnormalities in MDS.', 'Among 20 cases, 13 cases were found to carry common chromosome abnormalities by panel FISH (trisomy 8, five cases; -5/5q-, one case; 20q-, five cases; 5q- accompanying 20q-, one case; complex abnormalities, one case)', 'Detection of -5/5q- chromosome abnormality in myelodysplastic syndromes by interphase fluorescence in situ hybridization', 'In 48 MDS patients, 13 were positive for interphase FISH, of whom, 7 were positive and 6 were negative for conventional cytogenetics (CC).', 'Interphase FISH is more sensitive than CC for the detection of -5/5q- in MDS.', 'Three cases displayed -7/7q- by conventional cytogenetics(CC) and were confirmed by interphase FISH. Six cases in 43 cases who did not show -7/7q- by CC displayed -7/7q- by interphase FISH.CONCLUSION: Interphase FISH is very useful for the detection of -7 or 7q- in MDS and it is more sensitive than CC.', 'Diagnosis of microdeletion syndromes by fluorescence in situ hybridization (FISH).', 'Detection of trisomy 8 with interphase fluorescence in situ hybridization in myelodysplastic syndromes', 'Interphase FISH was a useful method for the detection of trisomy 8 in MDS, especially in patients with normal karyotype or marker chromosome. ', 'Congenital cardiovascular (c-v) malformations are the leading signs of two syndromes of highly variable phenotypes, the DiGeorge syndrome (DGS) and the velo-cardio-facial syndrome (VCFS), both of which in the majority of cases are caused by microdeletion in the chromosome region 22q11.2. ', 'In patients with congenital c-v and associated malformations of dysmorphism microdeletion diagnosis of 22q11.2 by FISH is indicated in addition to conventional cytogenetic testing. ', 'Discordant detection of monosomy 7 by GTG-banding and FISH in a patient with Shwachman-Diamond syndrome without evidence of myelodysplastic syndrome or acute myelogenous leukemia.', 'Fluorescence in situ hybridization of progenitor cells obtained by fluorescence-activated cell sorting for the detection of cells affected by chromosome abnormality trisomy 8 in patients with myelodysplastic syndromes.', 'We conclude that the combination of FACS/FISH/BUdR, which determines the number, phenotype and proliferation rate of very rare leukaemic cells in patients with AML or MDS in clinical remission, provides information that is useful in the identification of patients with high and low likelihood of relapse.', 'FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes.', 'We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered.', 'We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. ', 'Study of clonality in myelodysplastic syndromes: detection of trisomy 8 in bone marrow cell smears by fluorescence in situ hybridization.', 'Investigations with fluorescence in situ hybridization (FISH) demonstrate loss of the telomeres on the reciprocal chromosome in three unbalanced translocations involving chromosome 15 in the Prader-Willi and Angelman syndromes.', 'Fluorescence in situ hybridization (FISH) was used for the detection of chromosome 15(q11-13) deletions (with probes from the PWS/AS region) and to define the involvement of the telomere in the derivative chromosomes (with library probes and telomere-specific probes).', 'Fluorescence in situ hybridization improves the detection of monosomy 7 in myelodysplastic syndromes.', 'Detection of monosomy 7 by fluorescence in situ hybridization in acute nonlymphocytic leukemia and myelodysplastic syndrome.', 'Fluorescence in situ hybridization (FISH) with a chromosome 7 specific alpha satellite DNA probe was used to detect monosomy 7 in interphase and metaphase cells obtained from patients with myelodysplastic syndrome (MDS) and acute nonlymphocytic leukemia (ANLL).', 'A 15-year-old male with myelodysplastic syndrome (MDS) characterized by monosomy 7 was cytogenetically evaluated by metaphase karyotyping and fluorescence in situ hybridization (FISH) of interphase cells at six different points during the course of his disease.', 'Fluorescence in situ hybridization (FISH) using two cosmid probes (41A and P13) from the Miller-Dieker syndrome (MDS) critical region in 17p13.3 was performed in a blinded comparison of three MDS patients with submicroscopic deletions and in four normal relatives used as controls.', 'These studies demonstrate that in situ hybridization is an efficient method for deletion detection in Miller-Dieker syndrome. ', 'This study identified cytogenetic abnormalities in a population screened for deletion 22q11.2 syndrome (D22S) by fluorescence in situ hybridization (FISH) and G-banding and correlated these abnormalities to referring specialty and submitted indications. ', 'Positive test results for D22S FISH and other abnormalities found by other FISH assays and G-banding were correlated to submitting specialist and indication', 'Use of fluorescence in situ hybridization (FISH) in the diagnosis of DiGeorge sequence and related diseases.', 'Deletions of 22q11.2 have been detected in the majority of patients with DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes by either cytogenetic analysis, fluorescence in situ hybridization (FISH), or Southern blot hybridization.', 'Fluorescence in situ hybridization improves the detection of 5q31 deletion in myelodysplastic syndromes without cytogenetic evidence of 5q-.', 'To explore the value of multiplex fluorescence in situ hybridization (M-FISH) technique in the detection of the complex chromosomal aberrations (CCAs) in myelodysplastic syndromes (MDS).M-FISH was used in ten MDS patients with R-banding CCAs to refine the complex chromosomal rearrangements, the constitute of marker chromosomes, and to identify the cryptic translocations.Thirty-seven kinds of structural rearrangements were detected by M-FISH including insertion, deletion, translocation and derivative chromosomes, among which 34 kinds were unbalanced rearrangements, and 3 were balanced rearrangements including t(6;22) (q21; q12), t(9; 19) (q13; p13) and t(3;5) (?; ?).', 'To explore the clonal evolution of monosomy 7 in patients with aplastic anemia (AA).Monosomy 7 (-7) in 81 AA patients with normal karyotype at diagnosis and 46 AA treated with immunosuppressive therapy (IST) and more than 6 months of recombinant human granulocyte colony-stimulating factor (rhuG-CSF) were detected by interphase- fluorescence in situ hybridization (FISH) retrospectively.There were 5.4% - 7.6% of -7 cells in 11 (13.6%) of 81 patients at diagnosis, the survival and response rate to IST in -7 positive patients did not differ significantly from that in -7 negative patients (P = 0.', 'To compare the results of fluorescence in situ hybridization (FISH) versus conventional cytogenetics (CC) in the detection of common chromosomal abnormalities and evaluate the significance of FISH in myelodysplastic syndrome (MDS) .A total of 344 patients with de novo MDS from June 2008 to October 2012 were detected by 6 pairs of probes, including CSF1R/D5S23-D5S721 (5q33) , EGR1/ D5S23-D5S721 (5q31) , D7S486 (7q31) /CSP7, D7S522 (7q31) /CSP7, D20S108/CSP8 (20q12/CSP8) and CSPX/CSPY', 'Unbalanced translocation, t(18;21), detected by fluorescence in situ hybridization (FISH) in a child with 18q- syndrome and a ring chromosome 21', 'To evaluate the conventional cytogenetic methods in genetic diagnosis and prenatal diagnosis in the family with a proband of Angelman syndrome (AS).High-resolution G-banding karyotyping and fluorescence in situ hybridization (FISH) on metaphase chromosomes were performed.Two AS patients and 1 normal fetus in the family were successfully detected by FISH.Our result demonstrated that patient with type I AS could be detected by combining the techniques of high-resolution G-banding and FISH with clinical observation, which would offer accurate genetic counseling information to the geneticists and provide the prenatal diagnosis for the AS family', 'To investigate the prenatal diagnosis of trisomy 21 syndrome using chromosome 13/21 alpha satellite probe fluorescence in situ hybridization (FISH) on uncultured interphase cells from amniotic fluid.The interphase amniocytes of 10 fetuses who were detected normal and 3 fetus who were detected trisomy by prenatal cytogenetic diagnosis were selected', 'To optimize the prenatal diagnosis platform by using domestically made fluorescence in situ hybridization(FISH) kit and to explore the clinical application of FISH to rapid prenatal diagnosis of a wide range of chromosomal abnormalities.Amniotic fluid samples from 110 pregnant women were studied with the rapid prenatal diagnosis method of FISH and the conventional cell culture method of karyotyping, the results from both methods were compared.Four cases of trisomy 21, 1 case of trisomy 18, 58 cases of 46, XX, and 47 cases of 46, XY were detected by FISH in the 110 amniotic fluid samples.', 'Implementation of Fluorescent in situ hybridization (FISH) as a method for detecting microdeletion syndromes - our first experiences.', 'Prenatal detection of cri du chat syndrome on uncultured amniocytes using fluorescence in situ hybridization (FISH).', 'Fluorescence in situ hybridization (FISH) using non-commercial probes in the diagnosis of clinically suspected microdeletion syndromes.', 'Unbalanced translocation, t(18;21), detected by fluorescence in situ hybridization (FISH) in a child with 18q- syndrome and a ring chromosome 21.', 'Using this technique, followed by cell-by-cell multicolor fluorescence in situ hybridization (FISH) analysis of purified FNRBCs, we were able to detect some of the most common human aneuploidies (including Down syndrome, Klinefelter syndrome, and trisomy 13) in 33 pregnant women referred for amniocentesis.', 'FISH with 5p subtelomeric probes and 18p subtelomeric probe further confirmed that the derivative chromosome 5 has derived from a translocation between 5p and 18p, which has given rise to a 46,XY,der(5)t(5;18)(p15.1;p11.31)dn karyotype.A de novo 5p partial deletion in conjunction with a cryptic 18p duplication has been detected in a boy featuring Cri-du-Chat syndrome.', 'We conclude that FISH is a useful, easily applied technique for the diagnosis of 22q11.2 microdeletion syndromes, particularly DGS.', "In group B (n=79), the 5q deletion had been observed by cytogenetics and was confirmed to be present in all cases by fluorescence in situ hybridization of 5q31.CONCLUSIONS: Fluorescence in situ hybridization of 5q31 detected the 5q deletion in 6% of cases without clear evidence of del(5q) by conventional banding cytogenetics. We suggest that fluorescence in situ hybridization of 5q31 should be performed in cases of a suspected '5q- syndrome' and/or if the cytogenetic study shows no metaphases or an aberrant karyotype with chromosome 5 involved (no 5q- chromosome).", 'Although conventional cytogenetics is considered the gold standard to detect chromosomal abnormalities in myelodysplastic syndromes (MDS), fluorescence in situ hybridization (FISH) is being increasingly used additionally.', 'Cytogenetic aberrations in myelodysplastic syndrome detected by comparative genomic hybridization and fluorescence in situ hybridization.', 'To detect chromosomal abnormalities in myelodysplastic syndrome (MDS) patients by fluorescence in situ hybridization (FISH) and conventional cytogenetic analysis (CCA).', 'Comparison of high resolution chromosome banding and fluorescence in situ hybridization (FISH) for the laboratory evaluation of Prader-Willi syndrome and Angelman syndrome.', 'Deletion of small nuclear ribonucleoprotein polypeptide N (SNRPN) in Prader-Willi syndrome detected by fluorescence in situ hybridization: two sibs with the typical phenotype without a cytogenetic deletion in chromosome 15q.', 'We describe two sibs with typical PWS presenting deletion of SNRPN detected by fluorescence in situ hybridization (FISH).', 'Use of fluorescence in situ hybridization (FISH) in the diagnosis of DiGeorge sequence and related diseases.']

['To explore the clonal evolution of monosomy 7 in patients with aplastic anemia (AA).Monosomy 7 (-7) in 81 AA patients with normal karyotype at diagnosis and 46 AA treated with immunosuppressive therapy (IST) and more than 6 months of recombinant human granulocyte colony-stimulating factor (rhuG-CSF) were detected by interphase- fluorescence in situ hybridization (FISH) retrospectively.There were 5.4% - 7.6% of -7 cells in 11 (13.6%) of 81 patients at diagnosis, the survival and response rate to IST in -7 positive patients did not differ s Former molecular cytogenetic studies showed that such aberrations as an equivalent of intrinsic radiosensitivity can be detected by fluorescence in-situ hybridization (FISH) techniques using whole chromosome painting (wcp) probes. Five-color FISH was performed using human DNA segments specific for peri-CEN or subTEL, which were labeled with five different fluorescent dyes [7-diethylaminocoumarin (DEAC): blue, fluorescein isothiocyanate (FITC): green, rhodamine 6G (R6G): yellow, TexRed: red, and cyanine5 (Cy5): purple]. Using this technique, followed by cell-by-cell multicolor fluorescence in situ hybridization (FISH) analysis of purified FNRBCs, we were able to detect some of the most common human aneuploidies (including Down syndrome, Klinefelter syndrome, and trisomy 13) in 33 pregnant women referred for amniocentesis.', 'The human syndromes which can be detected with FISH are:\n1) Myelodysplastic Syndrome (MDS)\n2) Genetic syndromes caused by somatic chromosomal mosaicism\n3) Prader Willi syndrome (PWS)\n4) Angelman syndrome (AS)\n5) Williams syndrome\n6) Smith Magenis syndrome \n7) Velocardiofacial syndrome\n8) Jacobsen syndrome\n9) Shwachman-Diamond syndrome\n10) Saethre-Chotzen syndrome \n11) DiGeorge syndrome (DGS) \n12) Velo-cardio-facial syndrome (VCFS)\n13) Miller-Dieker syndrome\n14) Deletion 22q11.2 syndrome (D22S)']

['Myelodysplastic Syndrome', 'MDS', 'Genetic syndromes caused by somatic chromosomal mosaicism', 'Prader Willi syndrome', 'PWS', 'Angelman syndrome', 'AS', 'Williams syndrome', 'Smith Magenis syndrome', 'Velocardiofacial syndrome', 'Jacobsen syndrome', 'Shwachman-Diamond syndrome', 'Saethre-Chotzen syndrome', 'DiGeorge syndrome', 'DGS', 'Velo-cardio-facial syndrome', 'VCFS', 'Miller-Dieker syndrome', 'Deletion 22q11.2 syndrome', 'D22S', 'Down syndrome', 'Trisomy 21', 'DS', 'DNS', 'Klinefelter Syndrome', '47', 'XXY', 'KS', 'Trisomy 13', 'Patau Syndrome']

List GATA-1 interacting partners as discovered with the help of the biotinylation tagging approach.

['Our work describes, for the first time, distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex, and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes', 'We also provide evidence that distinct GATA-1 complexes are associated with specific GATA-1 functions in erythroid differentiation, for example, GATA-1/Gfi-1b with the suppression of cell proliferation and GATA-1/FOG-1/MeCP1 with the repression of other hematopoietic transcription programs', 'We next applied the biotinylation tag to Ldb-1, a known partner of GATA-1, and characterized a number of novel interaction partners that are essential in erythroid development, in particular, Eto-2, Lmo4, and CdK9', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes', ' Importantly, we show that FOG-1 mediates GATA-1 interactions with the MeCP1 complex, thus providing an explanation for the overlapping functions of these two factors in erythropoiesis. We also show that subsets of GATA-1 gene targets are bound in vivo by distinct complexes, thus linking specific GATA-1 partners to distinct aspects of its functions', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes.', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes.', 'We also provide evidence that distinct GATA-1 complexes are associated with specific GATA-1 functions in erythroid differentiation, for example, GATA-1/Gfi-1b with the suppression of cell proliferation and GATA-1/FOG-1/MeCP1 with the repression of other hematopoietic transcription programs.', 'Our work describes, for the first time, distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex, and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes.']

['Our work describes, for the first time, distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex, and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes', 'Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes ', 'The biotinylation tagging approach revealed, for the first time, distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex, and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes.']

['Gfi-1b', 'MeCP1 complex', 'ACF/WCRF complex', 'fog-1', 'tal-1']

What are the computational methods for the prediction of beta-barrel transmembrane proteins?

['BETAWARE: a machine-learning tool to detect and predict transmembrane beta-barrel proteins in prokaryotes', 'Recently, we developed two top-performing methods based on machine-learning approaches to tackle both the detection of TMBBs in sets of proteins and the prediction of their topology. Here, we present our BETAWARE program that includes both approaches and can run as a standalone program on a linux-based computer to easily address in-home massive protein annotation or filtering.', 'We introduce a graph-theoretic model for predicting the supersecondary structure of transmembrane β-barrel proteins--a particular class of proteins that performs diverse important functions but it is difficult to determine their structure with experimental methods. This ab initio model resolves the protein folding problem based on pseudo-energy minimization with the aid of a simple probabilistic filter. It also allows for determining structures whose barrel follows a given permutation on the arrangement of β-strands, and allows for rapidly discriminating the transmembrane β-barrels from other kinds of proteins.', 'BOCTOPUS: improved topology prediction of transmembrane β barrel proteins', 'Improving the detection of transmembrane β-barrel chains with N-to-1 extreme learning machines', 'we introduce a new machine learning approach for TMBB detection based on N-to-1 Extreme Learning Machines', 'TMBHMM: a frequency profile based HMM for predicting the topology of transmembrane beta barrel proteins and the exposure status of transmembrane residues', 'We present here TMBHMM, a computational method based on a hidden Markov model for predicting the structural topology of putative TMBs from sequence. In addition to predicting transmembrane strands, TMBHMM also predicts the exposure status (i.e., exposed to the membrane or hidden in the protein structure) of the residues in the transmembrane region, which is a novel feature of the TMBHMM method. Furthermore, TMBHMM can also predict the membrane residues that are not part of beta barrel forming strands.', 'Prediction of the exposure status of transmembrane beta barrel residues from protein sequence', 'We present BTMX (Beta barrel TransMembrane eXposure), a computational method to predict the exposure status (i.e. exposed to the bilayer or hidden in the protein structure) of transmembrane residues in transmembrane beta barrel proteins (TMBs).', 'Combined prediction of transmembrane topology and signal peptide of beta-barrel proteins: using a hidden Markov model and genetic algorithms', 'We present here, an HMM that combine a transmembrane barrel submodel and an SP submodel for both topology and SP predictions. A new genetic algorithm (GA) is presented here to training the model, at the same time the Posterior-Viterbi algorithm is adopted for decoding.', 'In this work, we propose a method based on radial basis networks for predicting the number of beta-strands in OMPs and identifying their membrane spanning segments.', 'We have developed a web server, TMBETAPRED-RBF for predicting the transmembrane beta-strands from amino acid sequence and it is available at http://rbf.bioinfo.tw/~sachen/tmrbf.html', 'We have developed a novel approach for dissecting transmembrane beta-barrel proteins (TMBs) in genomic sequences. The features include (i) the identification of TMBs using the preference of residue pairs in globular, transmembrane helical (TMH) and TMBs, (ii) elimination of globular/TMH proteins that show sequence identity of more than 70% for the coverage of 80% residues with known structures, (iii) elimination of globular/TMH proteins that have sequence identity of more than 60% with known sequences in SWISS-PROT, and (iv) exclusion of TMH proteins using SOSUI, a prediction system for TMH proteins.', 'TMBpro: secondary structure, beta-contact and tertiary structure prediction of transmembrane beta-barrel proteins', 'We develop a suite (TMBpro) of specialized predictors for predicting secondary structure (TMBpro-SS), beta-contacts (TMBpro-CON) and tertiary structure (TMBpro-3D) of transmembrane beta-barrel proteins.', 'This paper presents a k-nearest neighbor (K-NN) method for discriminating TMB and non-TMB proteins.', 'In this paper, based on the concept of pseudo amino acid composition (PseAA) that can incorporate sequence-order information of a protein sequence so as to remarkably enhance the power of discrete models (Chou, K. C., Proteins: Structure, Function, and Genetics, 2001, 43: 246-255), cellular automata and Lempel-Ziv complexity are introduced to predict the TM regions of integral membrane proteins including both alpha-helical and beta-barrel membrane proteins, validated by jackknife test', 'we present BOCTOPUS; an improved method for the topology prediction of TMBs by employing a combination of support vector machines (SVMs) and Hidden Markov Models (HMMs). The SVMs and HMMs account for local and global residue preferences, respectively.', 'PRED-TMBB: a web server for predicting the topology of beta-barrel outer membrane proteins', 'We present here a web server (PRED-TMBB, http://bioinformatics.biol.uoa.gr/PRED-TMBB) which is capable of predicting the transmembrane strands and the topology of beta-barrel outer membrane proteins of Gram-negative bacteria. The method is based on a Hidden Markov Model, trained according to the Conditional Maximum Likelihood criterion.', 'Prediction of transmembrane regions of beta-barrel proteins using ANN- and SVM-based methods', 'his article describes a method developed for predicting transmembrane beta-barrel regions in membrane proteins using machine learning techniques: artificial neural network (ANN) and support vector machine (SVM). The ANN used in this study is a feed-forward neural network with a standard back-propagation training algorithm.', 'We have also developed an SVM-based method using a primary sequence as input and achieved an accuracy of 77.4%. The SVM model was modified by adding 36 physicochemical parameters to the amino acid sequence information. Finally, ANN- and SVM-based methods were combined to utilize the full potential of both techniques.', 'we have developed a Web server, TBBPred, for predicting transmembrane beta-barrel regions in proteins', 'Predicting transmembrane beta-barrels in proteomes', 'Here we introduced the design, statistics and results of a novel profile-based hidden Markov model for the prediction and discrimination of TMBs.', 'All proteome predictions and the PROFtmb prediction method are available', 'The beta-barrel finder (BBF) program, allowing identification of outer membrane beta-barrel proteins encoded within prokaryotic genomes', 'We here report computational analyses of six outer membrane proteins of known 3D structures with respect to (1) secondary structure, (2) hydropathy, and (3) amphipathicity. Using these characteristics, as well as the presence of an N-terminal targeting sequence, a program was developed allowing prediction of integral membrane beta-barrel proteins encoded within any completely sequenced prokaryotic genome. This program, termed the beta-barrel finder (BBF) program, was used to analyze the proteins encoded within the Escherichia coli genome.', 'A sequence-profile-based HMM for predicting and discriminating beta barrel membrane proteins', 'We develop a HMM model, which can predict the topology of beta barrel membrane proteins using, as input, evolutionary information. The model is cyclic with 6 types of states: two for the beta strand transmembrane core, one for the beta strand cap on either side of the membrane, one for the inner loop, one for the outer loop and one for the globular domain state in the middle of each loop. The development of a specific input for HMM based on multiple sequence alignment is novel.', 'Prediction of the transmembrane regions of beta-barrel membrane proteins with a neural network-based predictor', 'A method based on neural networks is trained and tested on a nonredundant set of beta-barrel membrane proteins known at atomic resolution with a jackknife procedure. The method predicts the topography of transmembrane beta strands with residue accuracy as high as 78% when evolutionary information is used as input to the network.', 'A web server based on the proposed method is available at http://yanbioinformatics.cs.usu.edu:8080/TMBKNNsubmit.', 'Predicting three-dimensional structures of transmembrane domains of β-barrel membrane proteins', 'We have developed a computational method for predicting structures of the transmembrane (TM) domains of β-barrel membrane proteins. Based on physical principles, our method can predict structures of the TM domain of β-barrel membrane proteins of novel topology, including those from eukaryotic mitochondria. Our method is based on a model of physical interactions, a discrete conformational state space, an empirical potential function, as well as a model to account for interstrand loop entropy.', 'exposure status classification of transmembrane beta barrel residues', 'Several computational methods exist for the identification of transmembrane beta barrel proteins (TMBs) from sequence. Some of these methods also provide the transmembrane (TM) boundaries of the putative TMBs. The aim of this study is to (1) derive the propensities of the TM residues to be exposed to the lipid bilayer and (2) to predict the exposure status (i.e. exposed to the bilayer or hidden in protein structure) of TMB residues.', "The modified Mahalanobis Discriminant for predicting outer membrane proteins by using Chou's pseudo amino acid composition.", "In this study, a method that combines increment of diversity with modified Mahalanobis Discriminant, called IDQD, is presented to predict 208 OMPs, 206 transmembrane helical proteins (TMHPs) and 673 globular proteins (GPs) by using Chou's pseudo amino acid compositions as parameters.", 'Predicting transmembrane beta-barrels and interstrand residue interactions from sequence', 'A novel method using pairwise interstrand residue statistical potentials derived from globular (nonouter membrane) proteins is introduced to predict the supersecondary structure of transmembrane beta-barrel proteins. The algorithm transFold employs a generalized hidden Markov model (i.e., multitape S-attribute grammar) to describe potential beta-barrel supersecondary structures and then computes by dynamic programming the minimum free energy beta-barrel structure.', 'Predicting the solvent accessibility of transmembrane residues from protein sequence', 'In this study, we propose a novel method to predict the solvent accessible surface areas of transmembrane residues. For both transmembrane alpha-helix and beta-barrel residues, the correlation coefficients between the predicted and observed accessible surface areas are around 0.65.', 'BOMP: a program to predict integral beta-barrel outer membrane proteins encoded within genomes of Gram-negative bacteria', 'This work describes the development of a program that predicts whether or not a polypeptide sequence from a Gram-negative bacterium is an integral beta-barrel outer membrane protein. The program, called the beta-barrel Outer Membrane protein Predictor (BOMP), is based on two separate components to recognize integral beta-barrel proteins. The first component is a C-terminal pattern typical of many integral beta-barrel proteins. The second component calculates an integral beta-barrel score of the sequence based on the extent to which the sequence contains stretches of amino acids typical of transmembrane beta-strands.', 'A HMM-based method to predict the transmembrane regions of beta-barrel membrane proteins', "A novel method is developed to model and predict the transmembrane regions of beta-barrel membrane proteins. It is based on a Hidden Markov model (HMM) with architecture obeying those proteins' construction principles.", 'First, an algorithm that calculates the mean hydrophobicity of one side of putative beta-strands predicted the positions of 16 transmembrane segments, a structure common to known porins. Second, outer loops typical of porins were assigned using an artificial neural network trained to predict the topology of bacterial outer-membrane proteins with a predominance of beta-strands', 'Prediction of the membrane-spanning beta-strands of the major outer membrane protein of Chlamydia', 'Topology prediction of Brucella abortus Omp2b and Omp2a porins after critical assessment of transmembrane beta strands prediction by several secondary structure prediction methods', 'Four porins of known structure were selected as test-cases and their secondary structure delineated. The specificity and sensitivity of 11 methods were separately evaluated. Our critical assessment shows that some secondary structure prediction methods (PHD, Dsc, Sopma) originally designed to predict globular protein structure are useful on porin topology prediction. The overall best prediction is obtained by combining these three "generalist" methods with a transmembrane beta strand prediction technique', 'A knowledge-based potential highlights unique features of membrane α-helical and β-barrel protein insertion and folding', 'In previous work, a depth-dependent insertion potential, E(z) , was derived for α-helical inner membrane proteins. We have generated an equivalent potential for TM β-barrel proteins. The similarities and differences between these two potentials provide insight into unique aspects of the folding and insertion of β-barrel membrane proteins. This potential can predict orientation within the membrane and identify functional residues involved in intermolecular interactions.', 'Improved identification of outer membrane beta barrel proteins using primary sequence, predicted secondary structure, and evolutionary information', 'We present an accurate sequence-based predictor of OMBBs, called OMBBpred, which utilizes a Support Vector Machine classifier and a custom-designed set of 34 novel numerical descriptors derived from predicted secondary structures, hydrophobicity, and evolutionary information.', 'Predicting weakly stable regions, oligomerization state, and protein-protein interfaces in transmembrane domains of outer membrane proteins.', 'We have also discovered that out-clamps, in-plugs, and oligomerization are 3 general mechanisms for stabilizing weakly stable TM regions. In addition, we have found that extended and contiguous weakly stable regions often signal the existence of an oligomer and that strands located in the interfaces of protein-protein interactions are considerably less stable. Based on these observations, we can predict oligomerization states and can identify the interfaces of protein-protein interactions for beta-barrel membrane proteins by using either structure or sequence information', 'Recently, we developed two top-performing methods based on machine-learning approaches to tackle both the detection of TMBBs in sets of proteins and the prediction of their topology.', 'We introduce a graph-theoretic model for predicting the supersecondary structure of transmembrane β-barrel proteins--a particular class of proteins that performs diverse important functions but it is difficult to determine their structure with experimental methods.', 'Several computational methods have been developed to discriminate TMBBs from other types of proteins.', 'To conquer this limitation, we developed a new computational model that can be used for predicting the ASA of both TM α-helix and β-barrel residues.', 'Transmembrane beta barrel (TMB) proteins are found in the outer membranes of bacteria, mitochondria and chloroplasts.', 'RESULTS: We present here, an HMM that combine a transmembrane barrel submodel and an SP submodel for both topology and SP predictions.', 'Prediction of membrane spanning segments in beta-barrel outer membrane proteins (OMP) and their topology is an important problem in structural and functional genomics.', 'In the simplest of these, the target "model" is another protein sequence, while the more elaborate methods group together the entire set of t ansmembrane helical or transmembrane beta-barrel proteins.', 'Based on this study, we have developed a Web server, TBBPred, for predicting transmembrane beta-barrel regions in proteins (available at http://www.imtech.res.in/raghava/tbbpred).']

['Computational tools have been developed for beta-barrel transmembrane protein discrimination, topology prediction and prediction of their structural features.\nInitial methods developed for the prediction of the transmembrane beta strands were based on hydrophobicity analysis, using sliding windows along the sequence, in order to capture the alternating patterns of hydrophobic-hydrophilic residues of the transmembrane strands, or using generalized secondary structure prediction methods. Other approaches included the construction of special empirical rules using amino-acid propensities and prior knowledge of the structural nature of the proteins, and the development of Neural Network-based predictors to predict the location of alpha-carbon atoms with respect to the membrane. During the last few years, other more refined methods, appeared, including: Neural Networks, Hidden Markov Models, Support Vector Machines, k-Nearest Neighbors, Radial Basis Functions, Bayesian Networks, Genetic Algorithms, Mahalanobis Discriminant Functions, Cellular Automata, N-to-1 Extreme Learning Machines. Hidden Markov Model-based methods are among the most successful in topology prediction, being able to capture the unique architecture of beta-barrel transmembrane proteins. Consensus methods, as well as pipelines of several related tools (e.g. subcellular localization prediciton, alpha-helical transmembrane protein prediction, signal-peptide/lipoprotein prediction) have also used for discriminating beta-barrel transmembrane proteins. Recently, a number of methods for predicting more detailed structural features (e.g. surface accessibility, residue contacts, even detailed atomic 3D models) tailored to beta-barrel transmembrane proteins have been developed, based on knowledge-based potential functions, graph theoretic models, physical models and multi-tape S-attribute grammars. Methods/tools falling in the aforementioned classes are (listed in alphabetical order): BBF (beta-barrel finder), BETAWARE, BOCTOPUS, BOMP, BTMX (Beta barrel TransMembrane eXposure), HHomp, HMM-B2TMR, OMBBpred, PROFtmb, PRED-TMBB, TMB-Hunt, TBBPred, TMBETAPRED-RBF, TMBHMM, TransFold, TMBpro, TMBKNN, Wimley']

['BBF', 'beta-barrel finder', 'BETAWARE', 'BOCTOPUS', 'BOMP', 'BTMX', 'Beta barrel TransMembrane eXposure', 'HHomp', 'HMM-B2TMR', 'OMBBpred', 'PROFtmb', 'PRED-TMBB', 'TMB-Hunt', 'TBBPred', 'TMBETAPRED-RBF', 'TMBHMM', 'TransFold', 'TMBpro', 'TMBKNN', 'Wimley', 'TMBETA-NET']

Which are the most common symptoms in Lambert-Eaton Myasthenic Syndrome?

['Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms. There are 2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer (P-Lambert-Eaton myasthenic syndrome) and the other that is a pure autoimmune form (NP-Lambert-Eaton myasthenic syndrome)', 'LEMS weakness typically involves lower and upper limbs and the proximal muscles are predominantly affected. A significant proportion of patients also have dysfunction of the autonomic nervous system that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. LEMS recognition is based on clinical, electrophysiological and immunological criteria. Nearly 50-60% of patients with LEMS have an underlying tumour that, in almost all cases, is a small-cell lung cancer;', 'In Lambert-Eaton myasthenic syndrome (LEMS), antibodies against presynaptic voltage-gated calcium channels reduce the quantal release of acetylcholine, causing muscle weakness and autonomic dysfunction. More than half of the affected patients have associated small cell lung cancer', 'The Lambert-Eaton myasthenic syndrome (LEMS) is a disease of neuromuscular transmission in which autoantibodies against the P/Q-type voltage-gated calcium channel (VGCC) at the presynaptic nerve terminal play a major role in decreasing quantal release of acetylcholine (ACh), resulting in skeletal muscle weakness and autonomic symptoms.', 'Primary respiratory failure as the presenting symptom in Lambert-Eaton myasthenic syndrome.', 'Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms.', ' Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms. There are 2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer (P-Lambert-Eaton myasthenic syndrome) and the other that is a pure autoimmune form (NP-Lambert-Eaton myasthenic syndrome).', 'The Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder, often associated with small cell lung carcinoma (SCLC), which is characterized by reduced quantal release of acetylcholine from the motor nerve terminals. LAMBERT-EATON MYASTHENIC SYNDROME: The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterized by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile failure) and augmentation of strength during initial voluntary activation.', 'LAMBERT-EATON MYASTHENIC SYNDROME: The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterized by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile failure) and augmentation of strength during initial voluntary activation.', 'Primary respiratory failure as the presenting symptom in Lambert-Eaton myasthenic syndrome.']

['Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms. There are 2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer (P-Lambert-Eaton myasthenic syndrome) and the other that is a pure autoimmune form (NP-Lambert-Eaton myasthenic syndrome)', 'Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms, that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. There are 2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer, and the other that is a pure autoimmune form.']

['proximal limb muscle weakness', 'fatigability', 'decreased deep-tendon reflexes', 'autonomic symptoms', 'small-cell lung cancer']

What are the birth defects associated with Zika-virus infection?

['the first time after the discovery of ZIKV, the Brazilian scientists are studying the possibility for the virus to cause severe congenital infection related to microcephaly and serious birth defects due to the time-spatial coincidence of the alarming increase of newborns with microcephaly and the Brazilian ZIKV epidemic.', ' Although a causal relationship between Zika infection during pregnancy and microcephaly is strongly suspected, such a connection has not yet been scientifically proven. ', 'a convincing association between Zika virus infection during pregnancy and birth defects, like microcephaly, among some of the newborns.', 'counseling pregnant women on the risks of fetal microcephaly and other birth defects', 'evidence suggests that congenital Zika virus infection is associated with microcephaly and other adverse pregnancy and infant outcomes.', 'the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. ', ' severe birth defects, such as microcephaly, have been linked to infection during early pregnancy.', 'n can be prenatally passed from a pregnant woman to her fetus. There is sufficient evidence to conclude that intrauterine Zika virus infection is a cause of microcephaly and serious brain anomalies, but the full spectrum of anomalies has not been delineated. ', 'Although the full spectrum of adverse reproductive outcomes caused by Zika virus infection is not yet determined, a distinctive phenotype-the congenital Zika syndrome-has emerged.', 'The current Zika virus (ZIKV) outbreak is associated with high numbers of human congenital birth defects', 'However, ZIKV infection in early pregnancy has been associated with severe birth defects, including microcephaly and other developmental issues. ', 'Zika virus (ZIKV) infection is a new emerging threat around the globe which might be responsible for microcephaly and Guillain-Barre syndrome in the infants. ', 'Zika virus infection during pregnancy is a cause of microcephaly and other severe birth defects ']

['Although the full spectrum of adverse reproductive outcomes caused by Zika virus infection is not yet determined, a distinctive phenotype-the congenital Zika syndrome-has emerged. Zika virus infection during pregnancy is a cause of microcephaly and other severe birth defects.']

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What are the generic versions of Viagra?

['The authors conducted a 12-week case series to study the efficacy and safety of Elonza (generic sildenafil) in PAH patients.']

['Generic versions of sildenafil are Elonza, Caverta, Zenegra-100, Vega Asia, Suhagra-100, Vega, Revatio.']

['Elonza', 'Caverta', 'Zenegra-100', 'Vega Asia', 'Suhagra-100', 'Vega']

What is the role of NETs in systemic lupus erythematosus?

['Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways.', 'Neutrophil extracellular traps (NETs) are released via a novel form of cell death called NETosis. NETs, consisting of a chromatin meshwork decorated with antimicrobial peptides, play an important role in the innate response to microbial infections. Some lupus patients do not clear NETs normally, a phenotype that correlates with disease activity. Further, lupus neutrophils - and, in particular, an aberrant subset called low-density granulocytes - have an increased propensity to undergo NETosis.', ' NETs can also directly damage tissues - including the endothelium - with implications for lupus nephritis and accelerated atherosclerosis. ', 'Antimicrobial neutrophil extracellular traps (NETs) are composed of secreted chromatin that may act as a source of autoantigens typical for SLE.', 'Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of systemic Lupus erythematosus (SLE), since netting neutrophils release potentially immunogenic autoantigens including histones, LL37, human neutrophil peptide (HNP), and self-DNA', 'Elevated Plasma cfDNA May be Associated with Active Lupus Nephritis and Partially Attributed to Abnormal Regulation of Neutrophil Extracellular Traps (NETs) in Patients with Systemic Lupus Erythematosus', 'The ability to degrade neutrophil extracellular traps (NETs) is reduced in a subset of patients with systemic lupus erythematosus (SLE)', 'A decreased ability to degrade neutrophil extracellular traps (NETs) is seen in a subgroup of patients with systemic lupus erythematosus (SLE) and correlates with the presence of autoantibodies', 'Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus', 'Both exuberant NETosis and impaired clearance of NETs have been implicated in the organ damage of autoimmune diseases, such as systemic lupus erythematosus (SLE), small vessel vasculitis (SVV), and psoriasis', 'Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.', 'Neutrophil extracellular trap (NET) formation is increased in SLE and has been proposed to contribute to endothelial damage, but the mechanism remains unclear.OBJECTIVE: To determine the mechanism by which enhanced NET formation by low-density granulocytes (LDGs) in SLE contributes to endothelial damage and disrupts the endothelium.RESULTS: The putative role of NET-externalised matrix metalloproteinases (MMPs) in altering the functional integrity of the endothelium was examined. ', 'In this study, we investigated how complement interacts with NETs and how NET degradation is affected by complement in SLE patients. ', 'NETs are a potent stimulus for IFNα release by plasmacytoid dendritic cells, and, as such, may play an important role in propagation of the lupus phenotype. NETs can also directly damage tissues - including the endothelium - with implications for lupus nephritis and accelerated atherosclerosis.', 'Active NOS, NOX, and MPO within NETs significantly modify HDL, rendering the lipoprotein proatherogenic. Since NET formation is enhanced in SLE, these findings support a novel role for NET-derived lipoprotein oxidation in SLE-associated CVD and identify additional proatherogenic roles of neutrophils and putative protective roles of antimalarials in autoimmunity.']

['Neutrophil extracellular traps (NETs) are released via a novel form of cell death called NETosis. NETs, consisting of a chromatin meshwork decorated with antimicrobial peptides, play an important role in the innate response to microbial infections. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in these patients low-density granulocytes, a phenotype that correlates with disease activity. NETs are composed of secreted chromatin that may act as a source of autoantigens typical for SLE. NETs can directly damage tissues - including the endothelium - with implications for lupus nephritis and accelerated atherosclerosis.']

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What is the mode of inheritance of Marchesani syndrome?

['Autosomal recessive and autosomal dominant WMS cannot be distinguished by clinical findings alone. ', 'Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. ', 'Finally, WMS is transmitted either by an autosomal dominant or an autosomal recessive (AR) mode of inheritance, GD by an autosomal recessive mode of inheritance and AD by an autosomal dominant mode of inheritance. ', 'Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of lens, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described for WMS.', 'Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2.', 'Both autosomal recessive and autosomal dominant modes of inheritance have been described in association with WMS. ', 'We report 6 patients with Weill-Marchesani syndrome (with or without ocular involvement) in three generations, identified by screening 26 members of two families. This is the largest family in the literature showing an autosomal dominant pattern of inheritance.', 'Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait', 'We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome.', 'Weill-Marchesani syndrome is a rare, generalized disorder of connective tissue manifested by short stature, brachymorphia, and spherophakia. Inheritance is autosomal recessive.']

['Marchesani syndrome is transmitted either by an autosomal dominant (mutations in FBN1) or an autosomal recessive (mutations in ADAMTS10) mode of inheritance']

['autosomal dominant or autosomal recessive']

Are DNA helicases involved in progeroid syndromes?

['Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases,', 'Progeroid syndromes (PSs) constitute a group of disorders characterized by clinical features mimicking physiological aging at an early age.', 'However, all the characterized PSs enter in the field of rare monogenic disorders and several causative genes have been identified. These can be separated in subcategories corresponding to (i) genes encoding DNA repair factors, in particular, DNA helicases, and (ii) genes affecting the structure or post-translational maturation of lamin A, a major nuclear component.', 'None of the known progerias represents true precocious ageing. Some of them, including Werner (WS), Bloom (BS), and Rothmund-Thomson syndromes (RTS) as well as combined xeroderma pigmentosa-Cockayne syndrome (XP-CS) are characterised by features resembling precocious ageing and the increased risk of malignant disease. Such phenotypes result from the mutations of the genes encoding proteins involved in the maintenance of genomic integrity, in most cases DNA helicases.', 'Single-gene mutations can produce human progeroid syndromes--phenotypes that mimic usual or "normative" aging.', 'The prototypic example of the former is the Werner syndrome, a condition caused by mutations of the RecQ family of DNA helicases.', 'Progeria and progeroid syndromes are characterized by the earlier onset of complex senescent phenotypes. WRN was originally identified as a gene responsible for Werner syndrome (WS; "Progeria of Adults"). The WRN gene product has RecQ-type helicase domains in the central region of the protein.']

['Yes, mutations in genes coding for DNA helicases were found to induce progeroid syndromes, such as Werner syndrome (WS) or Bloom syndrome (BS).']

['yes']

How do Ecm22 and Upc2 proteins affect filamentation in Saccharomyces cerevisiae via sterol biosynthesis?

['["Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation.", "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways.", "Upc2, a zinc-cluster transcription factor, is a regulator of ergosterol biosynthesis in yeast.", "The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae.", "Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes.", "Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes.", "RNA-seq analysis shows that hypoxic regulation of sterol synthesis genes in Y. lipolytica is predominantly mediated by Upc2.", "However, in yeasts such as Saccharomyces cerevisiae and Candida albicans sterol synthesis is instead regulated by Upc2, an unrelated transcription factor with a Gal4-type zinc finger.", "Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression.", "One such factor could be the mammalian equivalent of the gene product of UPC2.", "Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways.", "Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4.", "Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place.", "A yeast mutant (upc2-1) with a defect in the aerobic exclusion of sterols was found to have increased sensitivity to LiCl and NaCl.", "The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function.", "Secretion of apoE was achieved only by the use of a mutant (upc2) strain of yeast with the phenotype of enhanced uptake and intracellular esterification of exogenous cholesterol.", "Gas chromatographic analysis of the nonsaponifiable fractions of the various strains showed that the major sterol for all YLR228c and UPC2 combinations was ergosterol, the consensus yeast sterol..", "In the pathogenic yeast Candida albicans, the zinc cluster transcription factor Upc2p has been shown to regulate the expression of ERG11 and other genes involved in ergosterol biosynthesis upon exposure to azole antifungals.", "By comparing the gene expression profiles of the fluconazole-resistant isolate and of strains carrying wild-type and mutated UPC2 alleles, we identified target genes that are controlled by Upc2p."]', '["Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation.", "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways.", "Upc2, a zinc-cluster transcription factor, is a regulator of ergosterol biosynthesis in yeast.", "The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae.", "Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes.", "Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes.", "RNA-seq analysis shows that hypoxic regulation of sterol synthesis genes in Y. lipolytica is predominantly mediated by Upc2.", "However, in yeasts such as Saccharomyces cerevisiae and Candida albicans sterol synthesis is instead regulated by Upc2, an unrelated transcription factor with a Gal4-type zinc finger.", "Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression.", "One such factor could be the mammalian equivalent of the gene product of UPC2.", "Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways.", "Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4.", "Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place.", "A yeast mutant (upc2-1) with a defect in the aerobic exclusion of sterols was found to have increased sensitivity to LiCl and NaCl.", "The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function.", "Secretion of apoE was achieved only by the use of a mutant (upc2) strain of yeast with the phenotype of enhanced uptake and intracellular esterification of exogenous cholesterol.", "Gas chromatographic analysis of the nonsaponifiable fractions of the various strains showed that the major sterol for all YLR228c and UPC2 combinations was ergosterol, the consensus yeast sterol..", "In the pathogenic yeast Candida albicans, the zinc cluster transcription factor Upc2p has been shown to regulate the expression of ERG11 and other genes involved in ergosterol biosynthesis upon exposure to azole antifungals.", "By comparing the gene expression profiles of the fluconazole-resistant isolate and of strains carrying wild-type and mutated UPC2 alleles, we identified target genes that are controlled by Upc2p."]']

Ecm22 and Upc2 proteins promote filamentation in Saccharomyces cerevisiae through sterol biosynthesis-dependent and -independent pathways. They positively control the expression of FHN1, NPR1, PRR2, and sterol biosynthesis genes. Upc2 is a regulator of ergosterol biosynthesis in yeast. Ecm22 and Upc2 must occupy UPC2 AR1b elements for ERG gene expression induction to occur. The AR1b elements are required for auto-induction of UPC2 gene expression and protein, and they require Upc2 and Ecm22 for function.

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Is physical performance influenced by thyroid hormone metabolism?

['Longitudinal analysis showed that in Eut men higher baseline FT4 was significantly (p = 0.02) predictive of a lower SPPB score at the 3-year follow-up', 'Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men.', 'Oral L-thyroxine treatment was started and at a 1-month follow-up examination, mental status and physical performance were improved', 'In a population of independently living elderly men, higher FT4 and rT3 concentrations are associated with a lower physical function', 'She had generalised weakness of muscles, cold intolerance and a reduced physical performance.', "Replacement therapy by oral administration of L-thyroxin resulted in a gradual improvement of the patient's state", 'multivariate analysis revealed that total T3 was an independent predictor of VO2max', 'changes in thyroid hormone were closely correlated to myocardial functional status in patients with heart failure.', 'THR among patients with SCH is beneficial not only by improvement in lipid profile, as well as by improvement in cognitive and functional status,', 'CONCLUSIONS: Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men.', 'Subclinical hyperthyroidism (SH) may be responsible for many cardiovascular changes, including an impaired exercise performance.', 'BACKGROUND: Physiological changes in thyroid hormone concentrations might be related to changes in the overall physical function in the elderly.']

['Yes.']

['yes']

What is the aim of the Human Chromosome-centric Proteome Project (C-HPP)?

['The Chromosome-Centric Human Proteome Project (C-HPP) is an international effort for creating an annotated proteomic catalog for each chromosome', 'The chromosome-centric human proteome project aims to systematically map all human proteins, chromosome by chromosome, in a gene-centric manner through dedicated efforts from national and international teams', 'A gene-centric Human Proteome Project has been proposed to characterize the human protein-coding genes in a chromosome-centered manner to understand human biology and disease.', 'dedicated to a systematic description of proteins as gene products encoded in the human genome (the C-HPP)', 'a chromosome-centric protein mapping strategy, termed C-HPP', 'The Chromosome-centric Human Proteome Project (C-HPP) aims to systematically map the entire human proteome with the intent to enhance our understanding of human biology at the cellular level.', 'The objective of the international Chromosome-Centric Human Proteome Project (C-HPP) is to map and annotate all proteins encoded by the genes on each human chromosome. The C-HPP consortium was established to organize a collaborative network among the research teams responsible for protein mapping of individual chromosomes and to identify compelling biological and genetic mechanisms influencing colocated genes and their protein products. The C-HPP aims to foster the development of proteome analysis and integration of the findings from related molecular -omics technology platforms through collaborations among universities, industries, and private research groups.', 'The goal of the Human Proteome Project (HPP) is to fully characterize the 21,000 human protein-coding genes with respect to the estimated two million proteins they encode. As such, the HPP aims to create a comprehensive, detailed resource to help elucidate protein functions and to advance medical treatment.', 'The Chromosome-centric Human Proteome Project (C-HPP) aims to define all proteins encoded in each chromosome and especially to identify proteins that currently lack evidence by mass spectrometry.', 'Our results will contribute to the accomplishment of the primary goal of the C-HPP in identifying so-called "missing proteins" and generating a whole protein catalog for each chromosome.', 'there is only little information relative to their abundance, distribution, subcellular localization, interactions, or cellular functions. The aim of the HUPO Human Proteome Project (HPP, www.thehpp.org ) is to collect this information for every human protein.', '. To support the efforts of the Chromosome-centric Human Proteome Project Consortium, we have annotated these proteins with their respective chromosome location.', 'One of the major challenges of a chromosome-centric proteome project is to explore in a systematic manner the potential proteins identified from the chromosomal genome sequence, but not yet characterized on a protein level.', 'The Chromosome 16 Consortium forms part of the Human Proteome Project that aims to develop an entire map of the proteins encoded by the human genome following a chromosome-centric strategy (C-HPP) to make progress in the understanding of human biology in health and disease (B/D-HPP).', 'A first research development progress report of the Chromosome 19 Consortium with members from Sweden, Norway, Spain, United States, China and India, a part of the Chromosome-centric Human Proteome Project (C-HPP) global initiative, is presented ( http://www.c-hpp.org ).', 'In an effort to map the human proteome, the Chromosome-centric Human Proteome Project (C-HPP) was recently initiated.']

['The chromosome-centric human proteome project aims to systematically map all human proteins, chromosome by chromosome, in a gene-centric manner through dedicated efforts from national and international teams', 'The Chromosome-Centric Human Proteome Project (C-HPP) is an international effort for creating an annotated proteomic catalog for each chromosome. (PMID: 23312004) The chromosome-centric human proteome project aims to systematically map all human proteins, chromosome by chromosome, in a gene-centric manner through dedicated efforts from national and international teams. (PMID: 23308364) The Chromosome-centric Human Proteome Project (C-HPP) aims to systematically map the entire human proteome with the intent to enhance our understanding of human biology at the cellular level. (PMID: 23253012)']

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List packages for transcription factor binding sites' (TFBS) analysis available in R/Bioconductor

['Clustered occurrence of multiple TFs at genomic sites may arise from chromatin accessibility and local cooperation between TFs, or binding sites may simply appear clustered if the profiles are generated from diverse cell populations. Overlaps in TF binding profiles may also result from measurements taken at closely related time intervals. It is thus of great interest to distinguish TFs that directly regulate gene expression from those that are indirectly associated with gene expression. Graphical models, in particular Bayesian networks, provide a powerful mathematical framework to infer different types of dependencies. However, existing methods do not perform well when the features (here: TF binding profiles) are highly correlated, when their association with the biological outcome is weak, and when the sample size is small. Here, we develop a novel computational method, the Neighbourhood Consistent PC (NCPC) algorithms, which deal with these scenarios much more effectively than existing methods do. We further present a novel graphical representation, the Direct Dependence Graph (DDGraph), to better display the complex interactions among variables. NCPC and DDGraph can also be applied to other problems involving highly correlated biological features. Both methods are implemented in the R package ddgraph, available as part of Bioconductor', 'Here, we present MMDiff, a robust, broadly applicable method for detecting differences between sequence count data sets. Based on quantifying shape changes in signal profiles, it overcomes challenges imposed by the highly structured nature of the data and the paucity of replicates', 'Supervised detection of conserved motifs in DNA sequences with cosmo', 'We here introduce an algorithm, called cosmo, that allows this search to be supervised by specifying a set of constraints that the position weight matrix of the unknown motif must satisfy. Such constraints may be formulated, for example, on the basis of prior knowledge about the structure of the transcription factor in question. The algorithm is based on the same two-component multinomial mixture model used by MEME, with stronger reliance, however, on the likelihood principle instead of more ad-hoc criteria like the E-value', 'dPattern: transcription factor binding site (TFBS) discovery in human genome using a discriminative pattern analysis.', 'TFBS: Computational framework for transcription factor binding site analysis.']

['Neighbourhood Consistent PC (NCPC) algorithms, MMDiff and cosmo.']

['Neighbourhood Consistent PC (NCPC) algorithms', 'MMDiff', 'cosmo', 'dPattern', 'TFBS']

List angiocrine factors

['Ccl4 and neurotensin (Nts) (angiocrine factors)', 'vascular endothelial growth factor (VEGF)-A was identified as the most abundantly expressed factor, ', 'angiocrine factors tissue inhibitor of metalloproteinases-1 (Timp-1) and thrombospondin 3 (THBS3) ', 'We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. ', 'angiocrine factors, including hepatocyte growth factor (HGF) and Wnt2.']

['Angiocrine factors are: Ccl4, neurotensin, vascular endothelial growth factor, metalloproteinases-1, thrombospondin 3, Slit2, hepatocyte growth factor, Wnt2. ']

['Ccl4', 'neurotensin', 'vascular endothelial growth factor', 'metalloproteinases-1', 'thrombospondin 3', 'Slit2', 'hepatocyte growth factor', 'Wnt2']

List all reported treatment options for anxiety in autism spectrum disorder.

['A parent report of comorbid diagnosis of attention-deficit/hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, depression, or anxiety was associated with a high rate of use, with 80% receiving ≥ 1 psychotropic medication', 'Mindfulness-based therapy (MBT) has been found effective in reducing anxiety and depression symptoms, however research in autism is limited.', 'Therefore, we examined the effects of a modified MBT protocol (MBT-AS) in high-functioning adults with ASD.', 'the present study is the first controlled trial to demonstrate that adults with ASD can benefit from MBT-AS.', 'This pilot, randomized controlled trial evaluated the feasibility and preliminary outcomes of the Multimodal Anxiety and Social Skills Intervention (MASSI) program in a sample of 30 adolescents with ASD and anxiety symptoms of moderate or greater severity.', 'These findings suggest MASSI is a feasible treatment program and further evaluation is warranted.', 'The purpose of this pilot study was to evaluate whether a modified version of the Coping Cat program could be effective in reducing anxiety in children with autism spectrum disorder (ASD).', 'the Coping Cat program (cognitive-behavioral therapy; CBT)', 'Results provide preliminary evidence that a modified version of the Coping Cat program may be a feasible and effective program for reducing clinically significant levels of anxiety in children with high-functioning ASD.', 'The intent of this article is to explore the efficacy of both the literal and concrete externalization aspects within narrative therapy, and the implementation of interactive metaphors as a combined psychotherapeutic approach for decreasing anxiety with people who present with high-functioning autism.', 'This paper reports a case series of children and adolescents with ASD and an anxiety disorder who were treated with a standard cognitive behaviour therapy (CBT) rationale adapted to take account of the neuropsychological features of ASD.', 'children with moderate autistic symptomology (per SRS-P) were significantly more likely to improve from family CBT (FCBT) than individual CBT (ICBT; OR\xa0=\xa08.67)', 'Though both treatments reduced anxiety, FCBT outperformed ICBT for children with moderate ASD symptoms, a benefit potentially linked to more at-home exposures and greater child involvement in FCBT.', 'A structural model-building approach was used to test the extent to which family and peer variables directly or indirectly affected ASD via child anxiety/depression.', 'The key findings were that anxiety/depression and ASD symptomatology were significantly related, and family conflict was more predictive of ASD symptomatology than positive family/peer influences. The results point to the utility of expanding interventions to include conflict management for couples, even when conflict and family distress is low.', 'A family-based, cognitive behavioural treatment for anxiety in 47 children with comorbid anxiety disorders and High Functioning Autism Spectrum Disorder (HFA) was evaluated.', 'Following treatment, 71.4% of the treated participants no longer fulfilled diagnostic criteria for an anxiety disorder. Comparisons between the two conditions indicated significant reductions in anxiety symptoms as measured by self-report, parent report and teacher report']

['The predominant approach is to use versions of cognitive behavioural therapies, such as:\nMindfulness Based Therapy (MBT)\nMultimodal Anxiety and Social Skills Intervention (MASSI) program\nmodified version of the Coping Cat program, (cognitive-behavioral therapy; CBT)\nFamily cognitive-behavioral therapy has been found to be more effective than Individual cognitive-behavioral therapy \nConflict management for couples, even when conflict and family distress is low\n\nDrugtherapy: \nSertraline']

['Mindfulness Based Therapy (MBT)', 'Multimodal Anxiety and Social Skills Intervention (MASSI) program', 'modified version of the Coping Cat program', '(cognitive-behavioral therapy; CBT', 'Family cognitive-behavioral therapy', 'Individual cognitive-behavioral therapy', 'Conflict management for couples', 'even when conflict and family distress is low', 'Sertraline']

In which nuclear compartments is heterochromatin located?

['This compartment localizes into three main regions: the peripheral heterochromatin, perinucleolar heterochromatin, and pericentromeric heterochromatin', 'By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3), DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications', 'The cell nucleus is divided into chromosome territories and the extrachromosomal domain. The latter includes several structural and functional compartments involved in RNA processing and transport.', 'We also describe a new apocentric nuclear compartment with a unique set of histone modifications that occurs as a zone of chromatin surrounding centromeric heterochromatin in differentiated lymphocytes. ', 'Little is known about the mechanisms of gene targeting within the nucleus and its effect on gene expression, but most studies have concluded that genes located near the nuclear periphery are silenced by heterochromatin', 'After TSA and NaBt treatment, the HP1 proteins were repositioned more internally in the nucleus, being closely associated with interchromatin compartments, while centromeric heterochromatin was relocated closer to the nuclear periphery', 'Taking into account the different heterochromatic and euchromatic compartments of the genome, our data suggest that the relative abundance of Ty3/gypsy LTRrs along each chromosome arm is determined mainly by the different proportions of heterochromatin, particularly pericentric heterochromatin, relative to total arm length']

['This compartment localizes into three main regions: the peripheral heterochromatin, perinucleolar heterochromatin, and pericentromeric heterochromatin. Silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3), DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modification']

['peripheral heterochromatin', 'perinucleolar heterochromatin', 'pericentromeric heterochromatin']

What is the molecular function of the Chd1 protein?

['The DNA-binding domain of the Chd1 chromatin-remodelling enzyme contains SANT and SLIDE domains', 'The ATP-dependent chromatin-remodelling enzyme Chd1 is a 168-kDa protein consisting of a double chromodomain, Snf2-related ATPase domain, and a C-terminal DNA-binding domain.', 'The presence of these domains in ISWI and Chd1 chromatin-remodelling enzymes may provide a means of efficiently harnessing the action of the Snf2-related ATPase domain for the purpose of nucleosome spacing and provide an explanation for partial redundancy between these proteins.', 'Here we identify the chromatin remodelling protein Chd1 (chromo-ATPase/helicase-DNA binding domain 1) as a component of SAGA and SLIK', 'one of the two chromodomains of Chd1 specifically interacts with the methylated lysine 4 mark on histone H3 that is associated with transcriptional activity', 'Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains', 'In the current study, we identify human CHD1, an ATP-dependent chromatin remodeling protein, as a factor that directly and selectively recognizes histone H3 methylated on lysine 4', 'human CHD1 binds to methylated H3K4 in a manner that requires both of its tandem chromodomains.', 'Our findings indicate that yeast and human CHD1 have diverged in their ability to discriminate covalently modified histones and link histone modification-recognition and non-covalent chromatin remodeling activities within a single human protein.', 'We find that the yeast Isw1a, Isw2, and Chd1 enzymes preferentially move nucleosomes toward more central locations on short DNA fragments whereas Isw1b does not. ', 'Analysis of nucleosome repositioning by yeast ISWI and Chd1 chromatin remodeling complexes.', 'However, a key difference is that the Isw1a, Isw2, and Chd1 enzymes are unable to move nucleosomes to positions closer than 15 bp from a DNA end, whereas Isw1b can.', 'The ISWI and CHD1 chromatin remodelling activities influence ADH2 expression and chromatin organization', 'Here we show that the absence of the Isw1 and Chd1 ATP-dependent chromatin remodelling activities delays the maximal expression of ADH2 without impairing the chromatin remodelling that occurs upon activation.', 'Thus, the ISWI and Chd1 remodelling factors are not only involved in transcription-related chromatin remodelling, but also are required to maintain a specific chromatin configuration across the yeast genome.', 'the lack of Chd1 combined with the absence of Isw1 and Isw2 impairs nucleosome spacing along the ADH2 gene, and genome-wide in S. cerevisiae', 'Through inclusion of Chd1 sequences in homology searches SLIDE domains were identified in CHD6-9 proteins. ', 'The molecular motor protein CHD1 has been implicated in the regulation of transcription and in the transcription-independent genome-wide incorporation of H3.3 into paternal chromatin in Drosophila melanogaster.', 'Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II.', 'CHD1 is known to bind H3K4me3 in mammalian cells, and Neurospora CHD1 is required for proper regulation of the frequency (frq) gene.', 'The molecular motor protein CHD1 has been implicated in the regulation of transcription and in the transcription-independent genome-wide incorporation of H3.3 into paternal chromatin in Drosophila melanogaster. ', 'Thus, while CHD1 is localized to transcriptionally active regions of the genome, it can function to alter the levels of HP1a, perhaps through changes in methylation of H3K9.', 'Histone H3K4 and K36 methylation, Chd1 and Rpd3S oppose the functions of Saccharomyces cerevisiae Spt4-Spt5 in transcription.', 'Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II.', 'The molecular motor protein CHD1 has been implicated in the regulation of transcription and in the transcription-independent genome-wide incorporation of H3.3 into paternal chromatin in Drosophila melanogaster.', 'Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II. Thus, while CHD1 is localized to transcriptionally active regions of the genome, it can function to alter the levels of HP1a, perhaps through changes in methylation of H3K9.', ' Chromodomain from heterochromatin protein 1 and polycomb protein is known to be a lysine-methylated histone H3 tail-binding module. Chromo-helicase/ATPase DNA-binding protein 1 (CHD1) is an ATP-dependent chromatin remodeling factor, containing two tandem chromodomains.', 'Over-expression of an ATPase inactive form of CHD1 did not result in severe chromosomal defects, suggesting that the ATPase activity is required for this in vivo phenotype. Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II.', 'Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II.']

['The ATP-dependent chromatin-remodelling enzyme Chd1 is a 168-kDa protein consisting of a double chromodomain, Snf2-related ATPase domain, and a C-terminal DNA-binding domain. One of the two chromodomains of Chd1 specifically interacts with the methylated lysine 4 mark on histone H3 that is associated with transcriptional activity. Human CHD1 is an ATP-dependent chromatin remodeling protein, as a factor that directly and selectively recognizes histone H3 methylated on lysine 4.']

['Chd1 is an ATP-dependent DNA helicase']

What causes erucism?

['Erucism is a skin reaction to envenomation from certain poisonous caterpillar bristles.', 'Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, for example erucism (envenomation by caterpillars) or lepidopterism (dermatitis from moths).', 'We present a case of erucism (caterpillar dermatitis) in a British serviceman deployed in Croatia on Operation Resolute. ', 'The hair on the dorsum of the last instar larvae of the moth may cause urticarial reactions (erucism) as well as eye problems and temporary blindness.', 'In the South of Brazil during the last years caterpillars of this butterfly caused a great number of cases of erucism including some deaths. ', 'Urticating moths (genus Hylesia and Anaphae) protect their eggs and young caterpillars with urticating hairs, thus it is very ambiguous to label erucism as the contact dermatitis produced by caterpillar production or Lepidopterism as the contact dermatitis caused by moth urticating hairs.', 'Erucism is defined as urtication by Lepidoptera larvae. ', 'Specific syndromes caused by Lepidoptera include erucism (cutaneous reactions from contact with caterpillars, moths, or cocoons), lepidopterism (systemic involvement), ophthalmia nodosa (ocular involvement), dendrolimiasis and pararamose (each with joint symptoms relating to a specific species of caterpillar), lonomism (a severe hemorrhagic disease related to Lonomia species), and seasonal ataxia (related to ingestion of Anaphe venata). ', 'Specific syndromes caused by Lepidoptera include erucism (cutaneous reactions from contact with caterpillars, moths, or cocoons), lepidopterism (systemic involvement), ophthalmia nodosa (ocular involvement), dendrolimiasis and pararamose (each with joint symptoms relating to a specific species of caterpillar), lonomism (a severe hemorrhagic disease related to Lonomia species), and seasonal ataxia (related to ingestion of Anaphe venata).', 'Urticating moths (genus Hylesia and Anaphae) protect their eggs and young caterpillars with urticating hairs, thus it is very ambiguous to label erucism as the contact dermatitis produced by caterpillar production or Lepidopterism as the contact dermatitis caused by moth urticating hairs.', 'Erucism is defined as urtication by Lepidoptera larvae.', 'Erucism is defined as urtication by Lepidoptera larvae.', 'Specific syndromes caused by Lepidoptera include erucism (cutaneous reactions from contact with caterpillars,', 'thus it is very ambiguous to label erucism as the contact dermatitis produced by caterpillar production or Lepidopterism as the contact dermatitis caused by moth urticating hairs.', 'Specific syndromes caused by Lepidoptera include erucism (cutaneous reactions from contact with caterpillars, moths, or cocoons), lepidopterism (systemic involvement), ophthalmia nodosa (ocular involvement), dendrolimiasis and pararamose (each with joint symptoms relating to a specific species of caterpillar), lonomism (a severe hemorrhagic disease related to Lonomia species), and seasonal ataxia (related to ingestion of Anaphe venata).', 'Urticating moths (genus Hylesia and Anaphae) protect their eggs and young caterpillars with urticating hairs, thus it is very ambiguous to label erucism as the contact dermatitis produced by caterpillar production or Lepidopterism as the contact dermatitis caused by moth urticating hairs.']

['Erucism is defined as urtication by Lepidoptera larvae. It is a skin reaction to envenomation from certain poisonous caterpillar bristles. The hair on the dorsum of the last instar larvae of the moth may cause urticarial reactions (erucism) as well as eye problems and temporary blindness.']

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How does the Small Ubiquitin-like Modifier (SUMO) E2-conjugating enzyme Ubc9 play a central role in sumoylation?

['oylation and plays a central role by interacting with almost all of the partners 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", "Here, we investigated inhibition of sumoylation as a novel antifibrotic approach.Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation", "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", "A new pathway that contributes to mutant CFTR degradation is mediated by the small heat shock protein, Hsp27, which cooperates with Ubc9, the E2 enzyme for SUMOylation, to selectively conjugate mutant CFTR with SUMO-2/3", "Using transfection of Ets-1 wildtype (WT) or its sumoylation deficient version (Ets-1 K15R/K227R), as well as WT or mutant proteins of the SUMO pathway, we further demonstrated that the E2 SUMO-conjugating enzyme Ubc9 and a E3 SUMO ligase, PIASy, can enhance Ets-1 sumoylation, while a SUMO protease, SENP1, can desumoylate Ets-1", "The results show that basal SUMO modification is required for stimuli-induced p100 phosphorylation and that blocking SUMOylation of p100, either by site-directed mutation or by short interfering RNA-targeted diminution of E2 SUMO-conjugating enzyme Ubc9, inhibits various physiological stimuli-induced p100 processing and ultimate activation of the alternative NF-kappaB pathway", "Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme", "SUMO-conjugating enzyme E2 UBC9 mediates viral immediate-early protein SUMOylation in crayfish to facilitate reproduction of white spot syndrome virus.", "OBJECTIVE: To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein quality control. ", "Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays a key role in tumorigenesis. ", "UBC9 is the only E2 conjugating enzyme involved in this process, and loss of UBC9 completely abolishes the SUMOylation pathway.", "Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity.", "Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme.", "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.", "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.", "In this study, we revisited the role of Tax SUMOylation using a strategy based on the targeting of Ubc9, the unique E2 SUMO-conjugating enzyme.", "Taken together, these findings provide evidence for regulated sumoylation as a mechanism to modulate the activity of Tec1 and validate Ubc9 fusion-directed sumoylation as a useful approach for studying']

The Small Ubiquitin-like Modifier (SUMO) E2-conjugating enzyme Ubc9 plays a central role in sumoylation by interacting with almost all partners required for sumoylation, regulating synaptic diffusion, mediating viral protein SUMOylation, enhancing sumoylation of specific proteins, and facilitating the SUMOylation pathway.

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Does splicing occur co-transcriptionally?

['Researchers working in multiple model organisms - notably yeast, insects and mammalian cells - have shown that pre-mRNA can be spliced during the process of transcription (i.e. co-transcriptionally), as well as after transcription termination (i.e. post-transcriptionally)', 'The consensus view, based on four organisms, is that the majority of splicing events take place co-transcriptionally in most cells and tissues.', 'Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional', 'We show that in the human genome, splicing occurs predominantly during transcription.', 'Consistent with co-transcriptional spliceosome assembly and splicing, we have found significant enrichment of spliceosomal snRNAs in chromatin-associated RNA compared with other cellular RNA fractions and other nonspliceosomal snRNAs. ', 'The majority of introns in higher eukaryotes are excised prior to transcript release in a manner that is dependent on transcription through pol II', 's a result of co-transcriptional splicing, variations in pol II elongation influence alternative splicing patterns, wherein a slower elongation rate is associated with increased inclusion of alternative exons within mature mRNA. ', 'We show that the pattern of intronic sequence read coverage is explained by nascent transcription in combination with co-transcriptional splicing', 'Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing', "RNA processing events that take place on the transcribed pre-mRNA include capping, splicing, editing, 3' processing, and polyadenylation. Most of these processes occur co-transcriptionally while the RNA polymerase II (Pol II) enzyme is engaged in transcriptional elongation", 'Abundant evidence indicates that splicing to excise introns occurs co-transcriptionally, prior to release of the nascent transcript from RNAP II', "Together, our work establishes a system for co-transcriptional splicing in vitro, in which the spliceosome containing the 5' and 3' exons are tethered to RNAP II for splicing.", 'Co-transcriptional splicing of constitutive and alternative exons', 'Current evidence supports co-transcriptional spliceosomal assembly, but there is little quantitative information on how much splicing is completed during RNA synthesis', 'Thus, we demonstrate that the decision to include or skip an alternative exon is made during transcription and not post-transcriptionally', 'Here, we demonstrated that the co-transcriptional splicing of the intron in vitro was blocked by antisense oligonucleotides (AONs) targeting the P3-P7 core of the intron', 'RNA editing and alternative splicing: the importance of co-transcriptional coordination', 'Co-transcriptional splicing of pre-messenger RNAs: considerations for the mechanism of alternative splicing', 'The realization that splicing occurs co-transcriptionally requires two important considerations']

["The consensus view, based on four organisms, is that the majority of splicing events take place co-transcriptionally in most cells and tissues. RNA processing events that take place on the transcribed pre-mRNA include capping, splicing, editing, 3' processing, and polyadenylation. Most of these processes occur co-transcriptionally while the RNA polymerase II (Pol II) enzyme is engaged in transcriptional elongation."]

['yes']

Which biological process in known as Endoplasmic Reticulum-Associated Protein Degradation (ERAD)?

['Endoplasmic reticulum-associated protein degradation (ERAD) removes improperly-folded proteins from the ER membrane into the cytosol where they undergo proteasomal degradation. ', 'In the secretory pathway, quality control for the correct folding of proteins is largely occurring in the endoplasmic reticulum (ER), at the earliest possible stage and in an environment where early folding intermediates mix with terminally misfolded species. An elaborate cellular mechanism aims at dividing the former from the latter and promotes the selective transport of misfolded species back into the cytosol, a step called retrotranslocation. During retrotranslocation proteins will become ubiquitinated on the cytosolic side of the ER membrane by dedicated machineries and will be targeted to the proteasome for degradation. The entire process, from protein recognition to final degradation, has been named ER-associated protein degradation, or simply ERAD.', 'From the many cellular processes, Cdc48 is involved in, its function in endoplasmic reticulum associated protein degradation (ERAD) is understood best. This quality control process for proteins of the secretory pathway scans protein folding and discovers misfolded proteins in the endoplasmic reticulum (ER), the organelle, destined for folding of these proteins and their further delivery to their site of action. Misfolded lumenal and membrane proteins of the ER are detected by chaperones and lectins and retro-translocated out of the ER for degradation. ', 'After polyubiquitylation of the protein substrate, Cdc48 together with its dimeric co-factor complex Ufd1-Npl4 pulls the misfolded protein out and away from the ER membrane and delivers it to down-stream components for degradation by a cytosolic proteinase machine, the proteasome.', 'Recognition and elimination of misfolded proteins are essential cellular processes. More than thirty percent of the cellular proteins are proteins of the secretory pathway. They fold in the lumen or membrane of the endoplasmic reticulum from where they are sorted to their site of action. The folding process, as well as any refolding after cell stress, depends on chaperone activity. In case proteins are unable to acquire their native conformation, chaperones with different substrate specificity and activity guide them to elimination. For most misfolded proteins of the endoplasmic reticulum this requires retro-translocation to the cytosol and polyubiquitylation of the misfolded protein by an endoplasmic reticulum associated machinery. Thereafter ubiquitylated proteins are guided to the proteasome for degradation.', 'The endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway eliminates aberrant proteins from the ER.', 'Terminally misfolded or unassembled proteins are degraded by the cytoplasmic ubiquitin-proteasome pathway in a process known as ERAD (endoplasmic reticulum-associated protein degradation).', 'Endoplasmic reticulum-associated protein degradation (ERAD) is a protein quality control mechanism that minimizes the detrimental effects of protein misfolding in the secretory pathway. Molecular chaperones and ER lumenal lectins are essential components of this process because they maintain the solubility of unfolded proteins and can target ERAD substrates to the cytoplasmic proteasome. Other factors are likely required to aid in the selection of ERAD substrates, and distinct proteinaceous machineries are required for substrate retrotranslocation/dislocation from the ER and proteasome targeting.', 'The endoplasmic reticulum (ER) quality control processes recognize and remove aberrant proteins from the secretory pathway. Several variants of the plasma protein fibrinogen are recognized as aberrant and degraded by ER-associated protein degradation (ERAD), thus leading to hypofibrinogenemia.', 'The endoplasmic reticulum (ER) is the eukaryotic organelle where most secretory proteins are folded for subsequent delivery to their site of action. Proper folding of newly synthesized proteins is monitored by a stringent ER quality control system. This system recognizes misfolded or unassembled proteins and prevents them from reaching their final destination. Instead, they are extracted from the ER, polyubiquitinated and degraded by the cytosolic proteasome.', 'Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, elicits an adaptive response, the unfolded protein response (UPR). One component of the UPR, the endoplasmic reticulum-associated protein degradation (ERAD) system, has an important function in the survival of ER stressed cells.', 'Proteins that fail to fold properly as well as constitutive or regulated short-lived proteins of the endoplasmatic reticulum (ER) are subjected to proteolysis by cytosolic 26 S proteasomes. This process, termed ER-associated protein degradation (ERAD), has also been implicated in the generation of some important human disorders, for example, cystic fibrosis. To become accessible to the proteasome, ERAD substrates must first be retrogradely transported from the ER into the cytosol, in a process termed dislocation. Surprisingly, protein dislocation from the ER seems to require at least some components that also mediate import into this compartment. Moreover, polyubiquitination of ERAD substrates at the ER membrane as well as the cytoplasmic Cdc48p/Npl4p/Ufd1p complex were shown to contribute to this export reaction.', 'Proteins that fail to fold properly as well as constitutive or regulated short-lived proteins of the endoplasmic reticulum are subjected to proteolysis by cytosolic 26S proteasomes. This process is known as endoplasmic reticulum-associated protein degradation. In order to become accessible to the proteasome of this system substrates must first be retrogradely transported from the endoplasmic reticulum into the cytosol, in a process termed dislocation. This export step seems to be accompanied by polyubiquitination of such molecules.', 'Endoplasmic reticulum-associated degradation (ERAD) disposes of aberrant proteins in the secretory pathway. Protein substrates of ERAD are dislocated via the Sec61p translocon from the endoplasmic reticulum to the cytosol, where they are ubiquitinated and degraded by the proteasome.', 'Membrane and secretory proteins fold in the endoplasmic reticulum (ER), and misfolded proteins may be retained and targeted for ER-associated protein degradation (ERAD).', 'The endoplasmic reticulum contains a protein quality control system that discovers malfolded or unassembled secretory proteins and subjects them to degradation in the cytosol. This requires retrograde transport of the respective proteins from the endoplasmic reticulum back to the cytosol via the Sec61 translocon. In addition, a fully competent ubiquitination machinery and the 26 S proteasome are necessary for retrotranslocation and degradation. Ubiquitination of mutated and malfolded proteins of the endoplasmic reticulum is dependent mainly on the ubiquitin-conjugating enzyme Ubc7p. In addition, several new membrane components of the endoplasmic reticulum are required for degradation.', 'The quality control system in the endoplasmic reticulum of eukaryotic cells ensures that newly synthesized proteins that fail to fold into the correct conformation or unassembled orphan subunits of oligomeric proteins are rapidly eliminated by proteolytic degradation. This entails the export of proteins from the endoplasmic reticulum to the cytosol followed by their destruction by the cytosolic ubiquitin/proteasome pathway. While this mechanism effectively prevents the cellular accumulation of non-functional or unwanted endogenous proteins, it renders the cell vulnerable to certain viruses and toxins that are able to subvert this degradative mechanism for their own advantage.', 'Endoplasmic reticulum-associated protein degradation.', 'Until recently, the degradation of aberrant and unassembled proteins retained in the endoplasmic reticulum (ER) was thought to involve unidentified ER-localized proteases. We now show that the ER-associated degradation (ERAD) of two mutant proteins that accumulate in the ER lumen is inhibited in a proteasome-defective yeast strain and when cytosol from this mutant is used in an in vitro assay. In addition, ERAD is limited in vitro in the presence of the proteasome inhibitors, 3,4-dichloroisocoumarin and lactacystin.', 'We conclude that lumenal ERAD substrates are exported from the yeast ER to the cytoplasm for degradation by the proteasome complex.', 'Misfolded proteins in the endoplasmic reticulum (ER) are eliminated by a process known as ER-associated degradation (ERAD), which starts with misfolded protein recognition, followed by ubiquitination, retrotranslocation to the cytosol, deglycosylation, and targeting to the proteasome for degradation.', 'Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated degradation (ERAD).', 'Proteins that fail to correctly fold or assemble into oligomeric complexes in the endoplasmic reticulum (ER) are degraded by a ubiquitin- and proteasome-dependent process known as ER-associated degradation (ERAD).', 'Proteins that cannot fold properly will be directed to a process known as endoplasmic reticulum associated degradation (ERAD).', 'Endoplasmic reticulum-associated degradation (ERAD) is an essential quality control process whereby misfolded proteins are exported from the endoplasmic reticulum and degraded by the proteasome in the cytosol.', 'Quality control mechanisms in the endoplasmic reticulum prevent deployment of aberrant or unwanted proteins to distal destinations and target them to degradation by a process known as endoplasmic reticulum-associated degradation, or ERAD.', 'Proteins that fail to fold in the endoplasmic reticulum (ER) or cannot find a pattern for assembly are often disposed of by a process named ER-associated degradation (ERAD), which involves transport of the substrate protein across the ER membrane (dislocation) followed by rapid proteasome-mediated proteolysis.', 'Quality control mechanisms in the endoplasmic reticulum prevent deployment of aberrant or unwanted proteins to distal destinations and target them to degradation by a process known as endoplasmic reticulum-associated degradation, or ERAD', 'Misfolded proteins in the endoplasmic reticulum (ER) are eliminated by a process known as ER-associated degradation (ERAD), which starts with misfolded protein recognition, followed by ubiquitination, retrotranslocation to the cytosol, deglycosylation, and targeting to the proteasome for degradation', 'Misfolded proteins in the endoplasmic reticulum (ER) are dislocated out of the ER to the cytosol, polyubiquitinated, and degraded by the ubiquitin-proteasome system in a process collectively termed ER-associated degradation (ERAD)', 'Eukaryotic organisms have evolved a highly conserved endoplasmic reticulum-mediated protein quality control (ERQC) mechanism to monitor folding processes of secretory and membrane proteins, allowing export of only correctly folded proteins to their physiological destinations, retaining incompletely/mis-folded ones in the ER for additional folding attempts, marking and removing terminally misfolded ones via a unique multiple-step degradation process known as ER-associated degradation (ERAD)']

['Endoplasmic reticulum-associated protein degradation (ERAD) is the quality control system in the endoplasmic reticulum of eukaryotic cells which ensures that newly synthesized proteins that fail to fold into the correct conformation or unassembled orphan subunits of oligomeric proteins are rapidly eliminated by proteolytic degradation. This entails the export of proteins from the endoplasmic reticulum to the cytosol followed by their destruction by the cytosolic ubiquitin/proteasome pathway. While this mechanism effectively prevents the cellular accumulation of non-functional or unwanted endogenous proteins, it renders the cell vulnerable to certain viruses and toxins that are able to subvert this degradative mechanism for their own advantage.', 'In the secretory pathway, quality control for the correct folding of proteins is largely occurring in the endoplasmic reticulum (ER), at the earliest possible stage and in an environment where early folding intermediates mix with terminally misfolded species. An elaborate cellular mechanism aims at dividing the former from the latter and promotes the selective transport of misfolded species back into the cytosol, a step called retrotranslocation. During retrotranslocation proteins will become ubiquitinated on the cytosolic side of the ER membrane by dedicated machineries and will be targeted to the proteasome for degradation. The entire process, from protein recognition to final degradation, has been named ER-associated protein degradation, or simply ERAD. ']

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Describe Wellens' Syndrome.

['NTRODUCTION: Wellens Syndrome (WS) is a condition characterized by typical changes in ECG, which are biphasic T-wave inversions (less common) or symmetric and deeply inverted T waves (including 75%) in lead V2-V3 chest derivations. ', "BACKGROUND: Reperfusion after coronary occlusion (myocardial infarction, MI), as in Wellens' syndrome, is often represented on ECG as T-wave inversion in the leads overlying the affected myocardial wall(s). ", 'Her presentation was concerning for acute coronary syndrome, Wellens syndrome in particular, given the elevated troponin levels, lack of ST segment changes, and characteristic T-wave findings. ', "Omnious T-wave inversions: Wellens' syndrome revisited.", "Wellens' syndrome is characterized by T-wave changes in electrocardiogram (EKG) during pain-free period in a patient with intermittent angina chest pain. ", "We describe a case of a 42-year-old man, with a previous episode of angina and a normal ECG and serum cardiac markers, and a two months later finding of biphasic T wave in leads V2-V3 and deeply inverted T wave in V4-V5 at a asymptomatic occupational evaluation. This is a typical ECG pattern of Wellens' syndrome.", "Whereas the Wellens' syndrome is characterized by symmetrically inverted T-waves with preserved R waves in the precordial leads suggestive of impending myocardial infarction due to a critical proximal left anterior descending stenosis, the pseudo-Wellens' syndrome caused by coronary artery spasm has also rarely been reported in literature.", 'The Wellens electrocardiogram (ECG) pattern of dynamic T-wave inversion in the anterior leads is observed in clinical conditions characterized by reversible left ventricular (LV) dysfunction (stunned myocardium), either ischemic or nonischemic', 'Wellens Syndrome (WS) is a condition characterized by typical changes in ECG, which are biphasic T-wave inversions (less common) or symmetric and deeply inverted T waves (including 75%) in lead V2-V3 chest derivations.', "The initial electrocardiogram (ECG) showed biphasic T-waves in V2-V4, which was recognized as Wellens' syndrome, or acute coronary T-wave syndrome."]

['Wellens Syndrome (WS) is a condition characterized by typical changes in ECG, which are biphasic T-wave inversions (less common) or symmetric and deeply inverted T waves (including 75%) in lead V2-V3 chest derivations.']

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Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?

['IFNAR1 ubiquitination is facilitated by the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron phosphorylation, which is induced by the ligand.', 'Both ligand-dependent and -independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation.', 'The SCF(betaTrcp) (Skp1-Cullin1-F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro.', ' Levels of IFNAR1 (regulated via degradation mediated by the betaTrcp E3 ubiquitin ligase) and IFNalpha signaling were reduced in 1205Lu melanoma cell line that harbors activated BRAF and exhibits high levels of betaTrcp ubiquitin ligase.', 'IFNalpha promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, beta-TrCP2 (beta-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis. ', 'Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner.', 'Here we show that IFNAR1 interacts with the Homolog of Slimb (HOS) F-box protein in a phosphorylation-dependent manner, and that this interaction is promoted by interferon alpha (IFNalpha). IFNAR1 is ubiquitinated by the Skp1-Cullin1-HOS-Roc1 (SCF(HOS)) ubiquitin ligase in vitro. ', 'The SCF(betaTrcp) (Skp1-Cullin1-F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro.', 'IFNAR1 ubiquitination is facilitated by the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron phosphorylation, which is induced by the ligand.', 'IFNalpha promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, beta-TrCP2 (beta-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis.', 'Both ligand-dependent and -independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation.', 'Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner', 'The SCF(betaTrcp) (Skp1-Cullin1-F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro']

['Ubiquitination and degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner.', 'Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. ']

['βTrcp', 'beta-Trcp', 'SCFbeta-Trcp', 'SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein)', 'Skp1-Cullin1-HOS-Roc1 (SCF(HOS))']

Why does cranberry juice help combat urinary tract infections?

[' Cranberry products affect the surface properties, such as fimbriae and lipopolysaccharides, and adhesion of fimbriated and nonfimbriated E. coli. ', ' Cranberry juice has been shown to be effective in preventing adhesion of bacteria such as Escherichia coli to the bladder epithelium.', 'Inhibition of adherence to an extent of about 70% with multi-drug resistant E. coli strains was observed on uroepithelial cell. The anti-adherence bioactivity of the proanthocyanidin was detected at concentrations of 10-50 µg/ml with significant bacteriuria. ', 'Still with regard to antibiotic treatment in women, a recently published study investigated also the potential cranberry juice interaction with beta-lactam antibiotics supporting the hypothesis that cranberry juice in usual quantities as prophylaxis for UTI is not likely to alter the pharmacokinetics of these oral antibiotics.', 'In vitro studies have shown that binding of the P fimbriae of Escherichia coli to the uroepithelial tissue can be inhibited in the presence of proanthocyanidins, the active ingredient of cranberries.', 'NDM at concentrations between 0.2/mL and 1mg/mL significantly (P<.05) decreased secretion of extracellular FTF, as well as down-regulated ftf expression in a dose-dependent manner. NDM also markedly reduced the luciferase activity under the ftf promoter.', 'Cranberry juice has long been recognized in folk medicine as a therapeutic agent, mainly in urinary tract infections. Its proposed mechanism of action is antiadhesion of bacteria. ', 'The AFM adhesion force measurements were consistent with the results of a hemagglutination assay, confirming that oral consumption of CJC could act against adhesion of uropathogenic E. coli.', 'These data suggest that daily consumption of concentrated cranberry juice can significantly prevent the recurrence of symptomatic UTIs in children.']

['Cranberry products affect the surface properties, such as fimbriae and lipopolysaccharides, and adhesion of fimbriated and nonfimbriated E. coli.']

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What is known about the effect of acupuncture in smoking cessation ?

['Ear acupressure (EAP) and ear acupuncture have been used for smoking cessation, and some positive results have been reported', 'Auricular (ear) acupressure has been purported to be beneficial in achieving smoking cessation in some studies, while in others has been deemed insignificant', 'Acupuncture combined with auricular point sticking and pressing has reliable therapeutic effect for smoking cessation', 'Acupuncture has been promoted as a treatment modality for smoking cessation. However, its efficacy still remains controversial', 'Our results showed that auricular acupuncture did not have a better efficacy in smoking cessation compared to sham acupuncture. Combined acupuncture with behavior counseling or with nicotine replacement therapy should be used in further smoking cessation trials to enhance the success rate of smoking cessation.', "Combining ten studies showed auricular acupuncture at 'correct' points to be more effective than control interventions, odds ratio 2.24 (95% CI 1.61, 3.10),", 'Auricular acupuncture appears to be effective for smoking cessation, but the effect may not depend on point location.', 'The combination of auricular acupressure and Internet-assisted smoking cessation program was more efficacious than auricular acupressure alone in terms of quit rate.', 'auricular acupuncture in smoking cessation has some effect.', 'With a one-year success rate of 41.1% ear acupuncture is a competitive alternative to orthodox medicine withdrawal methods. Acupuncture treatment can be applied and adapted individually, furthermore it is economical and without side effects.', 'Auriculotherapy is an useful aid for giving up smoking. It is easy and painless, has no secondary effects and it is economic.', 'the combined acupuncture-education group showing the greatest effect from treatment.', 'Acupuncture and education, alone and in combination, significantly reduce smoking; however, combined they show a significantly greater effect, as seen in subjects with a greater pack-year history.', 'A double blind, randomized, placebo-controlled clinical study was conducted to evaluate the efficacy of laser acupuncture treatment in adolescent smokers. ', 'Thus, there was no significant difference in the rates of smoking cessation in the treatment and control groups.', 'This simple ear electroacupuncture treatment was significantly more effective in helping volunteers to quit smoking than placebo treatment.']

['Ear acupressure (EAP) and ear acupuncture have been used for smoking cessation, and some positive results have been reported.\nAuricular (ear) acupressure has been purported to be beneficial in achieving smoking cessation in some studies, while in others has been deemed insignificant.\nThe combined acupuncture-education group showing the greatest effect from treatment.']

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What is the role of trifluridine in the novel nucleoside antitumor agent TAS-102?

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

Trifluridine (TFT) is an antitumor component of TAS-102, which is a novel nucleoside antitumor agent. It is combined with tipiracil hydrochloride (thymidine phosphorylase inhibitor) in TAS-102.

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What role does Synapsin III play in presynaptic terminals?

['["Synapsin is an evolutionarily conserved presynaptic phosphoprotein.", "Synapsins as a family of presynaptic terminal phosphoprotein participates in neuronal development", "Synapsin III (SynIII) is a phosphoprotein", "The neuronal phosphoprotein synapsin III", "Synapsin II is a member of the neuronal phosphoprotein family.", "phosphoprotein synapsin"]', '["Synapsin is an evolutionarily conserved presynaptic phosphoprotein.", "Synapsins as a family of presynaptic terminal phosphoprotein participates in neuronal development", "Synapsin III (SynIII) is a phosphoprotein", "The neuronal phosphoprotein synapsin III", "Synapsin II is a member of the neuronal phosphoprotein family.", "phosphoprotein synapsin"]']

Synapsin III (SynIII) is a phosphoprotein that plays a role in presynaptic terminals.

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