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Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC The expression and clinical course of RA are influenced by gender. In developed countries the prevalence of RA is 0,5 to 1.0%, with a male:female ratio of 1:3. women were found to have higher disease activity scores, more pain and greater loss of function, both in early and established disease Intense anti-CCP2 reaction was 19.8-fold higher in females vs. males, men (n = 67) and women (n = 225) Responses to treatment over time were better among men in this prebiologic era; women had worse progression despite similar treatment. BMI appears to be associated with RA disease activity in women, but not in men. A total of 5,161 RA patients (4,082 women and 1,079 men) In women the DAS28 was significantly higher than in men due to higher scores for general health and tender joints. Likewise, HAQ and VAS pain were rated significantly higher in women. 432 females, 125 males ESR significantly increased with age, independent of other variables of disease activity. This increase was more pronounced in male than in female patients Disease patterns in RA vary between the sexes; the condition is more commonly seen in women, who exhibit a more aggressive disease and a poorer long-term outcome. The mean age of the patients was 62 years (range 19–96 years) and 71% were female; The female to male ratio was 2.5:1 and the mean age at diagnosis was 49.4 +/- 14.9 years for women and 55.3 +/-15.6 years for men (P < 0.0003) in 244 female and 91 male patients with rheumatoid arthritis.
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<question>
Is Rheumatoid Arthritis more common in men or women?
</question>
<answer>
Women
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Gene fusion is an important evolutionary process. It can yield valuable information to infer the interactions and functions of proteins. Aside from their novelty, proteins with BLAST hits to two or more proteins in other organisms have been posited as Rosetta Stones since the fusion of two or more catalytic domains as part of a metabolic or regulatory pathway has been used to infer the association of orthologous proteins containing single domains that exist as separate entities in other genomes Gene fusion also enforces the co-regulation of two domains and co-regulated genes in multienzyme complexes. We have developed a Bayesian framework to infer phosphorylation networks from time series measurements of phosphosite concentrations upon ligand stimulation. To increase the prediction accuracy we integrated different types of data, e.g., amino acid sequence data, genomic context data (gene fusion, gene neighborhood, and phylogentic profiles) It is assumed that two proteins, which are found to be transcribed by a single transcript in one (or several) genomes are likely to be functionally linked, for example by acting in a same metabolic pathway or by forming a multiprotein complex. This method is of particular interest for studying genes that exhibit no, or only remote, homologies with already well-characterized proteins. PLEX search results are accompanied by quantitative estimates of linkage confidence, enabling users to take advantage of coinheritance, operon and gene fusion-based methods for inferring gene function and reconstructing cellular systems and pathways. While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships. The gene-fusion approach relies on the observation that pairs of genes encoding proteins of known function (usually interacting or forming a complex) tend to be found in other species as a fused composite gene encoding a single multifunctional protein. the detection of a gene fusion in one (query) genome allows the prediction of functional association between corresponding homologous genes that remain separate in another (reference) genome detection of gene fusion events can contribute towards the elucidation of functional associations of proteins within entire genomes This fusion analysis (also known as "Rosetta stone" method) takes advantage of the study of genomic structures and sequence similarity to detect putative interacting protein pairs, which, importantly might not have been suspected based on current biochemical knowledge. Briefly, if a pair of non-homologous proteins which are found in different genomic regions in organism A, are found fused into a single ORF in organism B, this suggests that the two independent proteins in organism A may interact. These protein-protein interactions may be transient or more long-lived, either within a metabolic pathway, or as part of a multi-subunit protein complex. Two polypeptides A and B in one organism, are likely to interact if their homologues are expressed as a single polypeptide AB in another. The in silico method used to detect such protein fusions is called domain fusion analysis and the composite polypeptide AB, is referred to as a Rosetta Stone protein, as it gives information about a functional link between domains A and B. a number of methods were proposed for the inference of protein interactions, using whole-genome information from gene clusters, gene fusions and phylogenetic profiles. This structural and evolutionary view of entire genomes has provided a valuable approach for the functional characterization of proteins, especially those without sequence similarity to proteins of known function. Inference of gene function based on gene fusion events: the rosetta-stone method. inferred functional association networks obtained by gene fusion analysis Here we have applied gene fusion analysis to a number of recently sequenced protists, and in particular tried to infer interacting protein pairs in the pathogenic parasite Trypanosoma brucei. protein domain fusions in human protein interaction networks prediction Some proteins, involved in a common biological process and encoded by separate genes in one organism, can be found fused within a single protein chain in other organisms. By detecting these triplets, a functional relationship can be established between the unfused proteins. These results suggest that domain fusion is an appropriate method for predicting protein complexes. The detection of gene fusion events across genomes can be used for the prediction of functional associations of proteins, including physical interactions or complex formation. Interacting proteins encoded by separate genes in some species, may sometimes occur as a single, multi-domain fusion protein in other species. Detecting fusion of non-homologous proteins in another organism has been shown to be a significant predictor of functional association between genes These genomic constraints form the basis for a variety of techniques that employ systematic genome comparisons to predict functional associations among genes. The most powerful techniques to date are based on conserved gene neighborhood, gene fusion events, and common phylogenetic distributions of gene families Functional links between proteins can often be inferred from genomic associations between the genes that encode them: groups of genes that are required for the same function tend to show similar species coverage, are often located in close proximity on the genome (in prokaryotes), and tend to be involved in gene-fusion events. Recent progress in genome analysis has shown that it is possible to predict protein interactions or, more generally, functional associations of proteins using genome sequences alone [1,2,3]. These powerful methods rely on the observation that pairs of genes encoding proteins of known function (usually interacting or forming a complex) tend to be found in other species as a fused gene encoding a single multifunctional protein the detection of gene fusions in one genome (defined as 'composite' proteins) allows the prediction of functional associations between homologous genes that remain separate in another genome (defined as 'component' proteins). the accurate detection of a gene fusion event in one genome allows interactions to be predicted between many proteins in other genomes. It is this kind of one-to-many relationship that makes this method unique for discovering possible interactions or functional associations between proteins, even for those of unknown function. The exhaustive detection of gene fusion events in entire genome sequences allows the prediction of functionally associated components based merely on genome structure. Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions Genes linked by fusion events are generally of the same functional category a functional association between two genes can be derived from the existence of a fusion of the two as one continuous sequence in another genome Protein interaction maps for complete genomes based on gene fusion events Because there must be selective pressure for certain genes to be fused over the course of evolution, we are able to predict functional associations of proteins. We observed that gene fusion events are more related to physical interaction between proteins than to other weaker functional relationships such as participation in a common biological pathway. CONCLUSIONS: We illustrate the phylogenetic and functional diversity of gene fusion events across genomes, and their usefulness for accurate prediction of protein interaction and function. FusionDB provides a characterization of a large number of gene fusion events at hand of multiple sequence alignments. RESULTS: We present a novel method for identifying genes encoding for a specific metabolic function based on a local structure of metabolic network and multiple types of functional association evidence, including clustering of genes on the chromosome, similarity of phylogenetic profiles, gene expression, protein fusion events and others. Domain fusion analysis has been proposed recently to infer the functional association of the component proteins. BACKGROUND: It has recently been shown that the detection of gene fusion events across genomes can be used for predicting functional associations of proteins, including physical interaction or complex formation. Here we present a method that identifies gene-fusion events in complete genomes, solely based on sequence comparison. Finally, the domain fusion method [20,21,22,23] is based on the observation that distinct non-homologous genes are functionally related if their orthologs are fused in another organism Gene or domain fusion is one of several genome context methods which can be used to predict functional associations between pairs of proteins [1], [2]. Genome context methods allow inheritance of functional information between non-homologous proteins and are thus an orthogonal approach to homology-based methods of function prediction. Pairs of distinct genes that are fused in at least one genome have been termed fusion-linked [3]. A gene fusion is presumably fixed during evolution only when the partners cooperate functionally and, by inference, a functional link can be predicted to exist between fusion-linked genes. Identification of gene fusion events (F)Associations of genes can also be deduced with the Rosetta stone technique [13,14] by detecting gene fusion events. Two distinct genes of a given organism that are found fused as a continuous sequence (referred to as the Rosetta Stone sequence) in another genome tend to physically interact. Analysis of gene fusion/division events to infer functional relatedness, commonly known as the Rosetta Stone method, is illustrated in Figure 1, and has been described in detail elsewhere [17,18]. Proteins that carry out consecutive metabolic steps or are components of molecular complexes are often expressed as a single polypeptide chain to maximize kinetic or expression efficiency. The basis for domain fusion analysis is the observation that certain proteins found separately in a given organism, form one full-length protein in another organism through fusion events. The composite proteins are also known as Rosetta stones. The component proteins are expected to be linked functionally, if not also physically. Viewing multi-domain proteins as sequences of domains also enables the identification of gene fusion events, interacting proteins (7,8) and preferred domain associations (9–14), and the comparison of sequences of domains helps in obtaining clues about domain function. Because fused genes often have similar functions, identification of fusion events can aid in inferring gene functions. The Rosetta-Stone approach [6] is a
method to predict function based on protein fusion events. Two polypeptides A and B in one organism are likely to
interact if their homologs are expressed as a single polypeptide AB in another organism. For example, among the most reliable methods, the Rosetta stone technique [5,6] detects functional associations based on protein-domain fusion events. Two polypeptides A and B in one organism are likely to interact if their homologs are expressed as a single polypeptide AB in another. The latter polypeptide (AB) is called a Rosetta Stone protein, as it contains information about both A and B.
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<question>
How could we infer functional associations from gene fusion events?
</question>
<answer>
</answer>
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De novo DNA methylation in Arabidopsis thaliana is catalyzed by the methyltransferase DRM2, a homolog of the mammalian de novo methyltransferase DNMT3. Three functional classes of DNA methyltransferase exist in A.thaliana; METHYLTRANSFERASE1 (MET1) (orthologous to mammalian Dnmt1) which maintains CG methylation, CHROMOMETHYLASE3 (CMT3) (plant specific) which maintains methylation in non-CG sequence contexts and DOMAINS REARRANGED METHYLTRANSFERASE2 (DRM2) (orthologous to Dnmt3a/Dnmt3b) which both de novo methylates DNA and maintains non-CG methylation redundantly with CMT3 [2]. The drm2 mutation blocks all de novo DNA methylation driven by repeat containing transgenes [15]–[17]. The mammalian DRM2 orthologs, Dnmt3a and Dnmt3b, are required to de novo methylate integrated retroviral sequences and imprinted genes [38], [39]. Here we describe DNA methyltransferase genes from both Arabidopsis and maize that show a high level of sequence similarity to Dnmt3, suggesting that they encode plant de novo methyltransferases. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. The N termini of these methyltransferases contain a series of ubiquitin-associated (UBA) domains. BLASTX searches and phylogenetic analysis suggested that five cDNAs belonged to four classes (Dnmt1, Dnmt2, CMT and Dnmt3) of DNA methyltransferase genes.
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<question>
Are there any DNMT3 proteins present in plants?
</question>
<answer>
yes
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ver the last few years, advances in methodology have made it possible to recover peptides from FFPE tissues that yield a reasonable representation of the proteins recovered from identical fresh or frozen specimens. Thus, laser capture microdissection of FFPE tissue coupled with downstream proteomic analysis is a valid approach Qualitative proteome profiling of formalin-fixed, paraffin-embedded (FFPE) tissue is advancing the field of clinical proteomics. Pressure-assisted protein extraction: a novel method for recovering proteins from archival tissue for proteomic analysis. provements in techniques such as mTRAQ have
made relative quantitation of disease biomarkers in FFPE tissue possible. A variety of methods for profiling FFPE tissue
have been employed
recently. Some are practical for slide-mounted FFPE tissue, such as
quantitative fluorescence imaging analysis (QFIA), which is reproducible
and sensitive for specific standardized proteins,12−14 or MALDI-imaging
mass spectrometry (MS).15−17 Other encouraging mass spectrometry
(MS)-based proteomic studies of FFPE tissues have appeared in the
recent literature;2−7,9,18−20 however, these investigations have typically been
restricted to minute tissue specimens, such as those obtained by laser
capture microdissection. Although the FFPE proteomic literature is still quite limited, it
is not unreasonable to propose that the same situation applies to
the proteomic analysis of FFPE tissues. The ability of elevated pressure to significantly
improve the recovery of intact proteins from FFPE tissues over the
use of heat alone has great potential for broad application to top-down
proteomic studies for the identification of disease biomarkers. Toward deciphering proteomes of formalin-fixed paraffin-embedded (FFPE) tissues. Recent improvements in proteomics technologies, from the 2D gel analysis of intact proteins to the "shotgun" quantification of peptides and the use of isobaric tags for absolute and relative quantification (iTRAQ) method, have made the analysis of FFPE tissues possible. The ability to investigate the proteome of formalin-fixed, paraffin-embedded (FFPE) tissues can be considered a major recent achievement in the field of clinical proteomics. The label-free approach enables the quantitative measurement of radiation-induced alterations in FFPE tissue and facilitates retrospective biomarker identification using clinical archives. Proteomic analysis of formalin-fixed paraffin-embedded pancreatic tissue using liquid chromatography tandem mass spectrometry. We report that differentially expressed proteins can be identified among FFPE tissue specimens originating from individuals with different pancreatic histologic findings. Initial development and validation of a novel extraction method for quantitative mining of the formalin-fixed, paraffin-embedded tissue proteome for biomarker investigations. Formalin-fixed paraffin-embedded (FFPE) proteome analysis using gel-free and gel-based proteomics. This study will facilitate the development of future proteomic analysis of FFPE tissue and provide a tool for the validation in archival samples of biomarkers of exposure, prognosis and disease. The CAAR method presented here complements previously described antigen-retrieval protocols and is an important step in being able to fully analyze the proteome of archived FFPE tissue. Proteome, phosphoproteome, and N-glycoproteome are quantitatively preserved in formalin-fixed paraffin-embedded tissue and analyzable by high-resolution mass spectrometry. It has only recently been shown that proteins in FFPE tissues can be identified by mass spectrometry-based proteomics but analysis of post-translational modifications is thought to be difficult or impossible Results from the FFPE-FASP procedure do not indicate any discernible changes due to storage time, hematoxylin staining or laser capture microdissection. Thus, FFPE biobank material can be analyzed by quantitative proteomics at the level of proteins and post-translational modifications. A novel tissue microdissection technique has been developed and combined with a method to extract soluble peptides directly from FFPE tissue for mass spectral analysis of prostate cancer (PCa) and benign prostate hyperplasia (BPH). Hundreds of proteins from PCa and BPH tissue were identified, espite using tissue blocks stored for as many as 28 years, high confidence and comparative proteome analysis between the leiomyomas and the sarcoma is achieved. we expect that our conclusions regarding the equivalence of FFPE and frozen tissues apply to laser capture microdissected specimens. These results provide evidence that use of archival FFPE specimens for retrospective studies is possible. In 2005, Hood et al. (7) first described the successful application of shotgun proteome analysis to FFPE tissue. Using laser capture microdissected cells and an optimized extraction method, hundreds of proteins were identified from a cancerous prostate lesion and benign prostate hyperplasia, thus opening the door to comparative proteomic analyses of FFPE tissue. These findings demonstrate that formalin fixation, paraffin processing, and LCM do not negatively impact protein quality and quantity as determined by MS and that FFPE samples are amenable to global proteomic analysis. Protein extraction of formalin-fixed, paraffin-embedded tissue enables robust proteomic profiles by mass spectrometry.
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<question>
Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue?
</question>
<answer>
yes
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Different cutaneous side effects have been described for anti-TNF-α therapy such as psoriasis Anti-TNF drug-induced alopecia is a less well-known side effect of this class of drugs. 3 patients who developed scalp alopecia Psoriasis and psoriatic arthritis induced in a patient treated with infliximab for Crohn's disease side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity Persistent corneal endothelial deposits associated with rifabutin therapy for Crohn's disease complained of alopecia 3 days after starting 6-mercaptopurine (6-MP) and then developed severe myelosuppression Leucopoenia was the more frequent side effect observed, occurring in 36 (34%) Nausea, vomit, although slight, occurred in 29 (27.4%) Nodular regenerative hyperplasia as a side effect of azathioprine in a patient with Crohn's disease The whole blood count revealed a pancytopenia, hyperbilirubinemia and slightly elevated transaminases Analysis of the liver histology was highly suggestive of an azathioprine-related, nodular regenerative hyperplasia 3 serious adverse events (SAEs) known to be associated with CD treatment (progressive multifocal leukoencephalopathy (PML), serious infections, and lymphoma) Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease A severe side effect is acute pancreatitis, which is specific for Crohn's disease Recurrent myopericarditis in association with Crohn's disease Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine Pancreatitis in a patient with Crohn disease treated with mesalazine and azathioprine Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. resulted to watery stools, vomiting, and fever Eosionophilia was present and the lymphocyte stimulation test with mesalazine was positive Pericarditis as a side effect induced by sulfasalazine or 5-aminosalicylic acid The commonest side-effect was hyperaesthesia, but one patient developed nephrotoxicity and one developed hepatotoxicity The only troublesome side effect is paresthesia, which apparently is dose-related and not progressive The only major side effect observed was paresthesias. These occurred in 50% of the patients and developed in the patients at a mean of 6.5 mo after the onset of treatment. Hemolysis is not a rare side-effect of sulfasalazine therapy 17 of 40 (43%) patients with inflammatory bowel disease receiving sulfasalazine had evidence of hemolysis as detected by starch gel electrophoresis
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<question>
Which are the most widely reported side-effects in the treatment of Crohn's disease?
</question>
<answer>
Leukopenia; paresthesia; psoriasis; alopecia; hemolysis; pancreatitis; liver toxicity; pericarditis
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Tissue kallikreins are a group of closely related serine proteinases that are represented by multigene families in mice and rats. Our map specifies the distance between genes to one base pair accuracy, the relative location, and the direction of transcription of all 15 genes. The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. The prognostic value of at least 11 out of 15 members of the human kallikrein family in ovarian cancer has been also published (Clements et al, 2004; Yousef et al, 2005; Prezas et al, 2006; Dorn et al, 2007). The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The 15 human and 24 mouse kallikreins have been implicated in pathophysiology of brain, kidney, and respiratory and reproductive systems and often are used as cancer biomarkers. Kallikrein gene families have been identified previously in genomes of the human, the mouse, and the rat, and individual kallikrein-like genes have been found in many more species. The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. The tissue kallikrein gene family consists of 15 genes tandemly arranged on human chromosome 19q13.4. Human kallikreins are a cluster of 15 serine protease genes located in the chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors, including pancreatic cancer. Tissue kallikrein genes (KLKs) are found on chromosome 19q13.3-4 as a gene cluster encoding 15 different serine proteases. Kallikreins are a family of 15 genes clustered together on chromosome 19 (Yousef and Diamandis, 2001,2003) and encode for serine protease enzymes (Clements et al, 2001; Yousef and Diamandis, 2002b). The mRNA sequences of the 15 human kallikrein genes were used to identify unique sequence tags of UniGene clusters for each kallikrein (the GenBank reference sequences were used). Project to perform in silico analyses of the expression pattern of the 15 human KLK genes in normal and cancerous ovarian tissues and cell lines. Novel kallikrein genes were cloned recently, and it was shown that the human kallikrein family contains 15 genes tandemly aligned on chromosomal locus 19q13.3-q13.4. The human kallikrein gene family includes 15 serine protease genes, clustered on chromosome 19q13.4. The kallikrein genes, denoted KLK1–KLK15, are located on chromosome 19q13.4 and encode for corresponding kallikrein enzymes, hK1–hK15 (Diamandis et al, 2000a; Yousef et al, 2000b). The human kallikrein gene family consists of 15 serine proteases. We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes. The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. that forms the largest cluster of contiguous protease genes in the human genome. Amongst the genes in this region is a cluster of the kallikrein genes. Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases encoded by the largest uninterrupted cluster of protease-encoding genes within the human genome. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. The human tissue kallikrein gene family is the largest contiguous family of proteases in the human genome, containing 15 genes. Human tissue kallikrein genes represent the largest contiguous group of proteases within the human genome. Human tissue kallikreins (hKs), which are encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Human tissue kallikrein-related serine peptidases (KLKs) constitute a single family of 15 highly conserved trypsin- or chymotrypsin-like serine proteases encoded by the largest contiguous cluster of protease-encoding genes (KLK1-15) in the human genome mapped to chromosomal locus 19q13.4 [1]. These phylogenies suggest that, apart from the fifteen “conventional” KLK family members, three ‘orphan’ KLKs are present in anole lizard. The lizard KLK orphans appear to arise from the basal node (Figure 4) leading to the suggestion that they are the members of the KLK family that diverged earliest (“proto-KLKs”).
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<question>
How many tissue kallikrein genes are present in the human genome?
</question>
<answer>
15
</answer>
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The topologies of the trees were overall congruent: four monophyletic groups corresponding to the four plant C5-MTase families were clearly distinguished. In addition, sequence analyses of the plant C5-MTase target recognition domain sequences were performed and phylogenetic trees were reconstructed showing that there is good conservation among but not within the plant C5-MTase families. To determine the inheritance of DNA methyltransferase genes and their expression patterns we examined three major DNA methyltransferase families (MET1, CMT3 and DRM) from tobacco and the progenitor species. However, phylogenetic analysis indicates that the Dnmt3 and DRM protein families diverged independently in plants and mammals (Figure 1A). Although an intriguing parallel exists between the functional relationships of DRM2/DRM3 and Dnmt3a/Dnmt3L, phylogenetic analysis strongly suggests that these protein families diverged independently in plants and animals (Figure 1A). The comparative investigation of transcription levels of different genes of cytosine DNA methyltransferase family MET (MET1, MET2a, MET2b, MET3) and their methylation patterns shows that there may exist some mechanisms defending the most actively transcribed gene MET1 of this family from methylation mediated silencing. In contrast to DRM2 gene we could not find any adenine methylated GATC sites in the MET1 gene. Using the 1kb 3' terminal DNA fragment of the mouse methyltransferase cDNA as a probe and low stringent hybridisation conditions, a new potential methyltransferase (MTase) gene family was isolated from an Arabidopsis thaliana genomic DNA library. The Dnmt3 family of de novo DNA methyltransferases has recently been characterized in animals. Here we describe DNA methyltransferase genes from both Arabidopsis and maize that show a high level of sequence similarity to Dnmt3, suggesting that they encode plant de novo methyltransferases. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. These results provide the first direct demonstration that DNA-METases of a higher eukaryote are encoded by a gene family. Here we show that Arabidopsis DNA methyltransferase2 (AtDNMT2) is localized in nucleus and associates with histone deacetylation. To explore possible relationships between DNA methylation level and accumulation of DNA-(cytosine-5) methyltransferase (DNMT) transcripts, the full-length coding sequences corresponding to three different DNMT families in oil palm, namely the MET, CMT, and DRM classes, have been isolated and characterized. In Arabidopsis a SWI2/SNF2 chromatin remodeling factor-related protein DDM1 and a cytosine methyltransferase MET1 are required for maintenance of genomic cytosine methylation. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. In the present study, the isolation and characterization of two distinct cDNAs that code for carrot DNA (cytosine-5)-methyltransferase (DNA-METase) are reported. The Arabidopsis methylase has eight of the ten conserved sequence motifs found in prokaryote cytosine-5 methyltransferases and shows 50% homology to the murine enzyme in the methyltransferase domain. As deduced form the DNA sequence this protein contains all conserved sequence motifs specific for the 5m cytosine MTases.
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<question>
Which are the plant DNA (cytosine-5) methyltransferase families?
</question>
<answer>
MET; CMT; DRM
</answer>
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miR-21* and miR-203 were significantly dysregulated (P < 0.05) in PTC tissues with BRAFV600E. Expressions of miRNAs in papillary thyroid carcinoma and their associations with the BRAFV600E mutation. Levels of miRNA-21 (miR-21) and miR-106a in gastric cancer tissues were significantly higher compared with the levels in adjacent tissues (P = .006 and P = .001, respectively). Patients who had gastric cancer had significantly different levels of gastric juice miR-21 and miR-106a compared with patients who had benign gastric diseases (both P < .001). miR-21 levels in intestinal type gastric cancer specimens were higher than that in diffuse (P = .003) or mixed (P < .001) gastric cancer types. MiR-155 and miR-21 appeared significantly over-expressed in the colonic mucosa of IBD subjects without CRC, but also in neoplastic tissues of IBD patients compared to non-IBD controls (p<0.001). Importantly, in patients with IBD-CRCs, miR-155 and miR-21 over-expression extended to the distant non-neoplastic mucosa (p<0.001). Here we hypothesize that over-expression of miR-155 and miR-21, two inflammation-related miRNAs that target core MMR proteins, may constitute a pre-neoplastic event for the development of MSI IBD-CRCs. After administration, we determined the expressions of miR-21, miR-27a, miR-34a, miR-93, miR-143, miR-146a, miR-148a, miR-155, miR-196a, miR-203, miR-205, miR-221 and nuclear factor kappa-light-chain enhancer of activated B-cells-1 (Nfκb1), mitogen-activated protein kinase-8 (Mapk8) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) genes in the liver of mice. Programmed cell death 4 (PDCD4) is a tumor suppressor gene whose expression is controlled by miR-21. Consistently with PDCD4 downregulation, miR-21 was upregulated in neoplastic by comparison with nonneoplastic tissue samples. Expression of miR-21 (p=0.027), miR-181b (p=0.002), and miR-146b (p=0.021) in tumor tissue and miR-21 (p=0.003) in noncancerous tissue were associated with patients' overall survival. We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9*, miR-183, and miR-375) by quantitative real-time-polymerase chain reaction in 34 cases of sMTC, 6 cases of hMTC, and 2 cases of C-cell hyperplasia (CCH). MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323, 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183, and 10.1 for miR-375, p<0.0001). As demonstrated in Figure 3A, the five miRNAs (mir-21, mir-223, mir-224, mir-29A and mir-29B) were significantly up-regulated in CRC tissues, except for mir-27a due to non-efficient amplification (CT value in most of the samples was either higher than 35 or even cannot be defined). The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Results: MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323 and 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183 and 10.1 for miR-375, p<0.0001). We found that the onco-miRNAs miR-21 and miR-221 displayed upregulated expression while the liver-specific miR-122 was downregulated. The aim of the present review was to describe the mechanisms of several known miR, summarize recent studies on oncogenic miR (e.g. miR-21, miR-106a and miR-17), tumor suppressor miR (e.g. miR-101, miR-181, miR-449, miR-486, let-7a) and controversial roles of miR (e.g. miR-107, miR-126) for gastric cancer. MiR-15b and miR-21 were differentially expressed in CSF samples from patients with gliomas, compared to control subjects with various neurologic disorders, including patients with primary CNS lymphoma and carcinomatous brain metastases. Moreover, inclusion of miR-15b and miR-21 in combined expression analyses resulted in an increased diagnostic accuracy with 90% sensitivity and 100% specificity to distinguish patients with glioma from control subjects and patients with primary CNS lymphoma. Many aberrantly expressed miRNAs were related to various cancers (e.g., miR-125b, hepatocellular carcinoma; miR-21, leukemia; miR-16, chronic lymphocytic leukemia; miR-192, pituitary adenomas; miR-199a-3p, ovarian cancer; miR-34a, pancreatic cancer). Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. In addition, diet and carcinogen exposure modulated a number of microRNAs (miR-16, miR-19b, miR-21, miR26b, miR27b, miR-93, and miR-203) linked to canonical oncogenic signaling pathways. RESULTS: Elevated miR-21 (HR 2.06, 1.13-3.75), miR-17 (HR 2.00, 1.10-3.61), and miR-155 (HR 2.37, 1.27-4.42) was associated with worse cancer-specific mortality in the Maryland cohort. NF-κB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors. Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. hese two miRNAs have previously been identified as being overexpressed in MCF-7 breast cancer cells, with miR-21 specifically implicated in down-regulating the tumor suppressor gene, tropomyosin-1. MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis. We showed here that among several hundred miRNAs, miR-21 was the only one that increased 6 folds in high-LET IR-promoted mouse liver tumors when compared with that in the non-irradiated liver tissues. We also showed that miR-21 was up-regulated in human or mouse hepatocytes after exposure to IR, as well as in liver tissues derived from whole body irradiated mice. After the non-irradiated, low-LET or high-LET irradiated human hepatocytes were over-expressed with miR-21, these cells became tumorigenesis in nude mice. Among others, the oncogenic microRNA miR-21 (hsa-miR-21) has been shown to specifically target the PDCD4 3′-UTR, which negatively regulates PDCD4 expression. 19–24 PDCD4 protein levels have been found to be inversely correlated with miR-21 expression in oesophageal squamous cell carcinoma cell lines,18 and we have shown that PDCD4 expression is significantly downregulated in oesophageal cancers (adenocarcinoma and squamous cell carcinoma histotypes) and it predicts patient outcome. Figure 4miR-21 is overexpressed in high-grade intraepithelial neoplasia (HG-IEN) and Barrett's adenocarcinoma (BAc). The nuclear-to-cytoplasm shift documented in preneoplastic/neoplastic lesions could theoretically result from epigenetic (and/or genetic) gene dysregulation.In oesophageal squamous carcinoma cell lines, Hiyoshi et al recently demonstrated that PDCD4 gene expression is regulated by miR-21. miR-21 is overexpressed in different human cancers, being causally linked to cell proliferation, apoptosis and migration. 14–19 miR-21 was also found to be upregulated in both oesophageal adenocarcinoma and squamous cell carcinoma,18 40 41 suggesting a major oncogenic function for miR-21 (acquired early in both of these oncogenic pathways). METHODS: We used this combined ISH/IHC assay to study a subset of cancer-associated miRNAs, including miRNAs frequently detected at low (miR-34a and miR-126) and high (miR-21 and miR-155) levels, in a panel of breast, colorectal, lung, pancreas, and prostate carcinomas. The miR-15a, miR-16, miR-143, miR-155, and miR-21 were upregulated in M059K, and the modulation of these miRNAs fluctuated in M059J cells in a time-dependent manner. Aberrantly increased expression of miR-21 plays a significant role in lung carcinogenesis and is a potential therapeutic target in both epidermal growth factor receptor-mutant and wild-type cases. Additionally, high miR-21 expression was associated with significantly decreased 5 year survival in patients (hazard ratio, 1.68; 95% CI: 1.04-2.77) in a model controlled for patient age, gender and tumor stage. ESULTS: In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. In mice treated with VC and given I3C in the diet, levels of miR-21, mir-31, miR-130a, miR-146b and miR-377 were reduced relative to the level in mice treated with the carcinogen only. Further studies with miR-21 indicated that phosphatase and tensin homolog, programmed cell death 4 and rich protein with Kazal motifs are potential targets for the oncogenic effect of miR-21 and the chemopreventive activity of I3C. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression. CONCLUSIONS: IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients. Figure 4qRT-PCR analysis of miR-21 and miR-16 in three cancer and three normal tissues. Correlation with cancersquamous cell carcinoma vs normal cheek pouch tissuehsa-miR-212. Using miRNA microarray analysis, Chang et al. identified seven miRNAs that were up-regulated (mir-21, let-7, 18, 29c, 142-3p, 155, and 146b) and one miRNA that was down-regulated (mir-494) in HNSCC primary tissue and cell lines. Moreover, they demonstrated that cytochrome c release was decreased by mir-21 knockdown, which suggested mir-21 inhibited several mRNAs that then led to a cascade of events that prevented apoptosis and increased cellular proliferation [35] The most highly expressed miRNAs in gastric cancer tissues were miR-20b, miR-20a, miR-17, miR-106a, miR-18a, miR-21, miR-106b, miR-18b, miR-421, miR-340*, miR-19a and miR-658. Recent findings report their involvement in hair follicle morphogenesis (ablation of miRNAs from keratinocytes causes several defects, such as evagination instead of invagination), in psoriasis (skin-specific expression of miR-203 and psoriasisspecific expression of miR-146a, miR-21 and miR-125b in the skin), in autoimmune diseases affecting the skin, such as SLE and ITP, in wound healing (changes in the expression of specific miRNA at specific phases of the regeneration process), and in skin carcinogenesis (a novel miRNA signature that includes induction of miR-21, a candidate oncogenic miRNA). An expression abundance analysis, based on a signal density ≥20,000, showed that both normal and cancerous cervical tissues had abundant expression of miR-23a, miR-23b, let-7a, let-7c, and let-7d, whereas high expression of miR-26a, miR-29a, miR-99a, miR-100, miR-125b, miR-143, miR-145, miR195, and miR-199a was only observed in normal cervical tissues, and high expression of miR-16, miR-21, miR-205, and let-7f was only observed in cervical cancer tissues, despite that relatively low levels of miR-16 and miR-21 were noticed from a homogeneous cell population in some cell lines (Fig. 2B). Although upregulation of miR-15a and miR-223 and downregulation of miR-218 and miR-424 were observed both in the rafts (pre-neoplastic lesions) and in cervical cancer tissues, the majority of the miRNA expression signatures showed no correlation between the two tissues (compare Fig. 4A to Fig. 3A). In contrast, a slight increased expression of miR-21 and miR-26b was observed in both the pre-neoplastic lesions (HPV-infected rafts) and cervical cancer tissues and thus their expression appears not cancer-specific (Fig. 5). Although both cervical cancer tissues and HPV-infected raft tissues with pre-neoplastic lesions showed an upregulation of miR-15a and miR-223 and downregulation of miR-143, miR-145, miR-218, and miR-424, the majority of the miRNA expression showed no correlation between the two tissues and might delineate the disease progression. RESULTS: Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16, and miR-99a, which were each differentially expressed in >16 patients. Selected for validation were miR-20a, miR-21, miR-106a, miR-181b, and miR-203, and all 5 were enriched in tumors from the validation cohort (P < .001). Higher miR-21 expression was present in adenomas (P = .006) and in tumors with more advanced TNM staging (P < .001). In situ hybridization demonstrated miR-21 to be expressed at high levels in colonic carcinoma cells. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growth-inhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that approximately 30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Conversely, expression of other miRNAs was detected at varying levels predominantly within luminal epithelial cells in normal tissue; expression of miR-21 was frequently increased, whereas that of let-7a was decreased in malignant cells. We describe a novel EMT-specific microRNA signature that includes induction of miR-21, a candidate oncogenic microRNA associated with carcinogenesis. Notable was the high expression of miR-21 and miR-205. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. These results indicated that miR-21 plays a role in the carcinogenesis and metastasis of O. viverrini-associated CCA by suppressing the function of PDCD4. Importantly, in patients with IBD CRCs, miR-155 and miR-21 overexpression extended to the distant non-neoplastic mucosa (P < 0.001). Ectopic overexpression of miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and EZH2 phosphorylation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. The expression levels of miR-21 (p = 0.027), miR-181b (p = 0.002) and miR-146b (p = 0.021) in tumor tissue and miR-21 (p = 0.003) in noncancerous tissue were associated with overall survival of patients. For instance, Schetter and colleagues showed that miR-21 corresponded to colorectal cancer related mortality [15]. MiR-21 is an oncogenic microRNA with known roles in inflammation, cell proliferation and tumorigenesis. OBJECTIVE: As an important oncogenic miRNA, miR-21 has been reported to play crucial roles in glioblastoma (GBM) carcinogenesis. We further analyzed the expression of microRNA-21 (miR-21), an oncogenic noncoding RNA involved in oncogenic Ras signaling, by quantitative reverse-transcription polymerase chain reaction and in situ hybridization. MicroRNA-21 (miR-21) plays crucial roles in carcinogenesis and is considered as one of the most studied oncomiRNAs. Although microRNA-21 (miR-21) has been implicated in various aspects of carcinogenesis, its functions and molecular mechanisms in carcinogen-induced tumorigenesis are unclear. Substantial evidence indicates that microRNA-21 (miR-21) is a key oncomiR in carcinogenesis and is significantly elevated in multiple myeloma (MM). MicroRNA 21 (miR-21) has been implicated in various aspects of carcinogenesis. Conversely, pAkt and miR-21 expression was significantly up-regulated in the whole spectrum of preneoplastic/neoplastic lesions considered. Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. RESULTS: Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. However, the potential novel target gene of miR-21 in radiation induced carcinogenesis is still unclear. As expected, miR-21 expression was significantly upregulated in preneoplastic/neoplastic samples, consistent with PDCD4 downregulation. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). We found that miR-16 and miR-21 were upregulated upon nicotine stimulation, transfection with anti-miR-16 or anti-miR-21 significantly abrogated cell proliferation. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Although altered expressions of miR-21 and miR-34a were manifested within cancer cells, those of miR-126 and miR-155 were predominantly confined to endothelial cells and immune cells, respectively. However, the function of miR-21 in osteosarcoma is still unclear. Specifically, miR-21 is overexpressed in very diverse types of malignancy. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. Precancerous adenomas also frequently showed miR-21 up-regulation. Higher miR-21 expression was present in adenomas (P = .006) We aimed to identify whether four miRNAs (miR-223, miR-21, miR-218 and miR-25) closely associated with the tumorigenesis or metastasis of GC can serve as novel potential biomarkers for GC detection. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some upregulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. OBJECTIVE: MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC. Inhibition of microRNA-21 (mir‑21) induced upregulation of Spry2 and PTEN which underscores the importance of mir-21 in Spry2-associated tumorigenesis of the colon. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. The microRNA miR-21, a known oncogenic miRNA, was found to be upregulated in papillary and clear cell carcinomas. Since microRNA-21 (miR-21) may contribute to tumorigenesis and chemoresistance in many cancer types, we aimed to investigate its efficacy in TCCs. In both HIV associated dementia in humans and its monkey model SIV encephalitis we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. The aim of this study was to determine whether microRNA-21 (miR-21), a specific microRNA implicated in multiple aspects of carcinogenesis, impacts breast cancer invasion by regulating the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. The microRNA-21 (miR-21) has been identified as the only miRNA overexpressed in a variety of cancers, including leukemia. Aberrant expression of microRNAs (miRNAs), including miR-21, and alteration of their target genes stability have been associated with cellular transformation and tumorigenesis. OBJECTIVE: The contribution of overexpressed microRNA-21 and -221 (miR-21 and miR-221) to the malignant phenotype was determined by inhibiting these miRNAs using antisense oligonucleotides. The microRNA-21(miR-21) has been identified as the only miRNA over-expressed in a wide variety of cancers, including cervical cancer. To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines overexpressing one or both of these miRNAs. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The oncogenic miRNA, microRNA-21 (miR-21), was found to be upregulated in laryngeal carcinoma tissues. OBJECTIVE: To better understand microRNA miR-21 function in carcinogenesis, we analyzed miR-21 expression patterns in different stages of colorectal cancer development using in situ hybridization (ISH). Of these miRNAs, miR-21 appears to be important in tumorigenesis given its up-regulation in almost all types of human cancer examined. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly overexpressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. RESULTS: Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21). Volinia et al. (2006) conducted a large-scale microarray analysis on six solid tumors (including lung, breast, stomach, prostate, colon, and pancreatic tumors) and identified a common miRNA signature for solid tumors largely composed of overexpressed miRNAs, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155 (45).
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<question>
Is miR-21 related to carcinogenesis?
</question>
<answer>
yes
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antifungal protein KP4 Killer protein 4 (KP4) is a well studied viral toxin secreted by the maize smut fungus Ustilago maydis that kills sensitive Ustilago strains as well as inhibits Fusarium and plant root growth by inhibiting calcium uptake. Our previous work on a virally encoded fungal toxin, KP4, from Ustilago maydis and subsequently with the plant defensin, MsDef1, from Medicago sativa demonstrated that some of these proteins specifically blocked calcium channels in both fungi and animals. The results presented here demonstrate that KP4 and three plant defensins, MsDef1, MtDef2, and RsAFP2, all inhibit root growth in germinating Arabidopsis seeds at low micromolar concentrations . There are three well-characterized killer toxins in U. maydis-KP1, KP4, and KP6-which are secreted by the P1, P4, and P6 subtypes, respectively. These killer toxins are small polypeptides encoded by segments of an endogenous, persistent double-stranded RNA (dsRNA) virus in each U. maydis subtype. The viral gene for the killer protein 4 (KP4) has been explored for its antifungal effect antifungal protein KP4 from Ustilago maydis-infecting virus The antifungal activity correlated with the presence of the KP4 transgene. These results suggest that KP4 may inhibit cell growth and division by blocking calcium-regulated signal transduction pathways. KP4 is a virally encoded fungal toxin secreted by the P4 killer strain of Ustilago maydis. KP4 is a virally encoded fungal toxin secreted by the P4 killer strain of Ustilago maydis. Our results defining the type of mammalian channel affected by this fungal toxin further support our contention that KP4 inhibits fungal growth by blocking transmembrane calcium flux through fungal calcium channels, Killer toxins are polypeptides secreted by some fungal species that kill sensitive cells of the same or related species. In the best-characterized cases, they function by creating new pores in the cell membrane and disrupting ion fluxes KP4 is a virally encoded and highly specific toxin that kills fungi closely related to the fungus Ustilago maydis. The P4 strain of the corn smut fungus, Ustilago maydis, secretes a fungal toxin, KP4, encoded by a fungal virus (UMV4) that persistently infects its cells. These results led to experiments demonstrating that the toxin specifically inhibits voltage-gated Ca2+ channels in mammalian cells. Ustilago maydis killer toxins are small polypeptides (7-14 kDa) which kill susceptible cells of closely related fungal species. The KP4 toxin is a single polypeptide subunit with a molecular weight of 11.1 kDa
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<question>
What is the function of the viral KP4 protein?
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<answer>
The virally encoded fungal toxin KP4 specifically blocks L-type voltage-gated calcium channels.
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higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Two of them received etanercept and the remainder adalimumab. with a possible differential risk between the three anti-TNF drugs: infliximab (INF) and adalimumab (ADA) (both monoclonal antibodies) having a higher risk than etanercept (ETA) 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) During the period of recruitment, etanercept was administered as a subcutaneous injection either once (50 mg) or twice (25 mg) weekly and adalimumab was administered as a subcutaneous injection 40 mg fortnightly The suggested starting dose of infliximab was 3 mg/kg administered in conjunction with MTX Of these, 4458 (41%) started etanercept, 3956 (36%) infliximab and 2579 (23%) adalimumab as their first anti-TNF drug Second anti-TNF (n = 331)Etanercept (%)4445Infliximab (%)3717Adalimumab (%)1938
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<question>
Which is the most widely used anti-TNF drug?
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<answer>
Etanercept
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The histone marks appeared mainly in generic regions and were enriched around the transcription start sites (TSSs) of genes Tri-methylated H3 lysine 4 (H3K4me3) is associated with transcriptionally active genes, but its function in the transcription process is still unclear However, the catalytic function is critically required for transcription as H3K4me3 levels determine the efficiency of transcription elongation In particular, tri-methyl H3K4 (H3K4me3) occurs at the transcription-start site (TSS) of active genes and is important for transcription activation Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised promoters. Histone H3 lysine 4 trimethylation (H3K4me3) is well known to occur in the promoter region of genes for transcription activation 3'-H3K4me3 is associated with ~15% of protein-coding genes in both tissues Furthermore, 3'-H3K4me3 modification levels correlate positively with the antisense expression levels of the associated sense genes, implying that 3'-H3K4me3 is involved in the activation of antisense transcription. indicated that H3K4me1, but not H3K4me3, was enriched around distal cis-elements for the E1A binding protein p300 (EP300), while both modifications were enriched at promoters Among these are forms of histone 3 that are mono- or tri-methylated at lysine 4 (H3K4me1 or H3K4me3, respectively), which bind preferentially to promoter and enhancer elements in the mammalian genome we find that H3K4me1 and H3K4me3 are enriched at transcriptional start sites in the genome H3K4me1 and H3K4me3 generally mark cis regulatory elements
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<question>
Is the H3K4me3 histone mark related to transcriptional initiation or elongation?
</question>
<answer>
transcriptional initiation
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Using H3K4me2 as a mark for active enhancers Hyperacetylation of histones H3 and H4, a mark of active chromatin, is established broadly across target loci by enhancers that function over long distances The enhancer region itself was marked by mono-methylation at K4 and K9, distinguishing it from the methyl marks in the gene coding region H3K4 methylation to monovalent and bivalent domains
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<question>
Which are the main histone modifications associated with enhancers?
</question>
<answer>
Histone 3 lysine 4 mono-methylation (H3K4me1); Histone 3 lysine 4 di-methylation (H3K4me2)
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In group 2 and 3, two anomalies, anorectal malformation and cystic fibrosis, were detected postnatally Six had chromosomal/genetic abnormalities, two had congenital cytomegalovirus, none had cystic fibrosis Primary bowel pathology is rare following the finding of FEB Maternal serology for cytomegalovirus (CMV) was performed in 49 (78%) cases Thirty-three pregnancies (53%) were tested for cystic fibrosis (CF) and 1 baby was confirmed to have CF postnatally This study reiterates the increased prevalence of aneuploidy, CMV, CF and fetal growth restriction in pregnancies complicated by the midtrimester sonographic finding of FEB Primary outcomes were IUGR, defined as birth weight less than the 10th percentile for gestational age and intrauterine fetal demise at 20 weeks or more of gestatio Analyses were repeated after excluding cases of aneuploidy, cytomegalovirus (CMV) infection, The presence of echogenic bowel on ultrasonography is independently associated with an increased risk for both IUGR and intrauterine fetal demise This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%). A potential association with placental abnormalities and a low prevalence of viral infections was observed Our data suggests an inverse relationship between the maternal BMI and the detection of fetal EIF and/or EB Fetal echogenic bowel at 17 weeks' gestational age as the early and only sign of a very long segment of Hirschsprung disease. fetal ultrasound findings associated with intrauterine cytomegalovirus (CMV) infection the combination of hydrops fetalis, cerebral hemorrhage, and hyperechoic bowel should raise the possibility of a CMV infection strongly associated with adverse pregnancy outcome due to utero-placental insufficiency, particularly in women with elevated maternal serum alpha-fetoprotein concentration due to severe feto-maternal bleeding Congenital cytomegalovirus infection presenting with echogenic bowel and oligohydramnios. Five cases of trisomy 21 and one case of trisomy 18 were detected Brightly echogenic bowel in the second trimester was found to be associated with a significant risk of fetal aneuploidy. echogenic bowel does not uniformly herald an abnormal outcome. Echogenic bowel coexistent with other abnormalities (such as growth deficiency or structural malformations) may be a comarker for aneuploidy. Congenital cytomegalovirus infection with oligohydramnios and echogenic bowel at 14 weeks' gestation Parental CF carrier testing and amniocentesis to identify aneuploidy or fetal CF status has a high positive ascertainment rate in fetuses with echogenic bowel grades 2 and 3. Swallowing of amniotic fluid after intraamniotic bleeding seems implicated in the etiology of second-trimester echogenic bowel in both euploid and aneuploid fetuses Fetal echogenic bowel and a dilated loop of bowel associated with cystic fibrosis (CF) mutations delta F508 and 2183AA-->G Fifteen cases (19%) were associated with maternal vaginal bleeding Five fetuses (6.3%) had evidence of bowel obstruction or perforation not associated with cystic fibrosis (CF) Chromosomal aberrations were found in 5 fetuses (6.3%). Intrauterine infection with cytomegalovirus, herpes simplex virus, varicella-zoster virus, or parvovirus B-19 was documented in 5 patients (6.3%). Fetal echogenic bowel has been reported as a normal variant in the second trimester, and has also been associated with an adverse fetal outcome, including cystic fibrosis (CF) Intra-amniotic bleeding can lead to echogenic bowel 112 cases (57%) had a known etiology, which included chromosomal abnormality (7%), infection (4%), cystic fibrosis (1.5%), bowel abnormality (3%), bleeding or stained amniotic fluid (11%), Doppler abnormality (14%), malformation (16%) and miscellaneous (0.5%)
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<question>
Which are the main causes of fetal echogenic bowel?
</question>
<answer>
Itramniotic bleeding; CMV infection; Cystic Fibrosis (CF); Fetal aneuploidy
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our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes. These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. CpG islands are stretches of DNA sequence that are enriched in the (CpG)n repeat and are present in close association with all housekeeping genes as well as some tissue-specific genes in the mammalian genome. CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. Unmethylated CpG rich islands are a feature of vertebrate DNA: they are associated with housekeeping and many tissue specific genes. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes.
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<question>
Are CpG islands located close to housekeeping genes?
</question>
<answer>
yes
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the cannonical polyadenylation signal sequence AATAAA Two AATAAA motifs are coded in the last exon of this gene The results demonstrate that the intact AAUAAA is not required for RNA polyadenylation but is required for the cleavage step preceding polyadenylation to occur efficiently the early poly(A) consensus signal was mutated from AAUAAA to UGUAAA Functional polyadenylation [poly(A)] sites consist of two sequence elements, the AAUAAA and G/U box signals, that closely flank the site of mRNA 3'-end formation the appropriate spacing of the AAUAAA and G/U box signals is critical for poly(A) site function Two AATAAA hexanucleotide sequences are present in the 2092 nucleotide interval. The first one functions as the major polyA signal
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<question>
What is the most prominent sequence consensus for the polyadenylation site?
</question>
<answer>
AATAAA; AAUAAA
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yeast origins are characterized by an asymmetric pattern of positioned nucleosomes flanking the ACS. The origin sequences are sufficient to maintain a nucleosome-free origin; however, ORC is required for the precise positioning of nucleosomes flanking the origin. ORC binds to Nucleosome free regions (NFRs) in both budding yeast and Drosophila (1,37,38), suggesting that nucleosome organization may be a defining feature of origins in all eukaryotes the presence of a well-positioned nucleosome adjacent to the origin NFR was shown to be essential for ORC to nucleate pre-RC assembly and for origin activity Together, our results demonstrate significant enrichment of pre-RC proteins at regions of generally low nucleosome occupancy that are found within a de-localized region of initiation Here, we identify nucleosome occupancy as a likely candidate to set up ORI distribution we demonstrate that open chromatin domains, characterized by nucleosome depletion, are preferentially permissive for replication Nucleosome assembly of the template prevented DNA replication. Replication of chromosomes was severely inhibited at more than two-thirds of physiological nucleosome density
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<question>
Are nucleosomes positioned at DNA replication origins?
</question>
<answer>
no
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he etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. Subacute thyroiditis is an inflammatory disorder of the thyroid caused probably by viruses. I We believe that the etiologic agent was the Epstein-Barr virus because heterophile and Epstein-Barr virus-specific antibodies were positive. ltogether, these results indicate that the mechanism of inhibition of Spumavirinae infection by interferon differs from that described for the other Retroviridae, and particularly for types B, C and D viruses. Our data is of therapeutic interest since Spumavirinae have been linked to pathological processes such as de Quervain thyroiditis.
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<question>
Are viruses involved in the etiology of human subacute thyroiditis?
</question>
<answer>
yes
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we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses IRG1 is highly upregulated in murine ANA-1 macrophages by several proinflammatory cytokines and Toll-like receptor (TLR) agonists, as well as in spleen and lung of Listeria monocytogenes or Toxoplasma gondii infected mice, respectively The proinflammatory cytokine-induced IRG1 protein associates with mitochondria multiple genes induced by Borrelia burgdorferi in macrophages to regulate Lyme disease inflammation One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Murine immune-responsive gene 1 (IRG1) plays significant roles in embryonic implantation and neurodegeneration the IRG1 gene is differentially expressed in human fetal PBMCs and LPS-stimulated adult PBMCs. we identified the immune-responsive gene 1 (IRG1), which was expressed substantially higher in lipopolysaccharide (LPS)-stimulated than in MAP-infected murine macrophage cell lines. The inhibitor also blocked induction by LIF of several LIF-regulated genes in the LE including Irg1, which has been shown previously to be essential for implantation. Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. our studies identified Irg1 as a novel target of PR in the pregnant uterus and also revealed that it is a critical regulator of the early events leading to implantation This resulted in the identification of one novel P4-regulated gene that had been previously found in lipopolysaccharide-stimulated macrophages and called immune response gene-1 (Irg1) and which is the mammalian ortholog of the bacterial gene encoding methylcitrate dehydratase the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). T Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). This gene exhibits significant homology to interferon (IFN)-alpha/beta-inducible human genes p27 and 6-16, indicating that these genes may belong to the same family The level of IRG1 mRNA again rose transiently on day 4 immediately preceding implantation. Although the functional roles of IRG1 and p27 remain unclear, we describe for the first time, identification of a gene family regulated by IFNalpha in both rodent and human uteri Hence, the induction of IRG1 by LPS is mediated by tyrosine kinase and protein kinase C pathway.
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<question>
What is the function of the mammalian gene Irg1?
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<answer>
Human IRG1 and mouse Irg1 mediates antiviral and antimicrobial immune responses, without its exact role having been elucidated. Irg1 has been suggested to have a role in apoptosis and to play a significant role in embryonic implantation. Irg1 is reported as the mammalian ortholog of methylcitrate dehydratase.
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Putative HCNE peak targets are characterized by a tight association with particular promoter motifs, higher incidence of severe mutant phenotypes, and evidence of a more precise regulation of gene expression during important developmental transitions 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. Several lines of evidence indicate that these highly conserved noncoding elements (HCNEs) play a fundamental role in regulating animal development and constraining genome evolution 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 HCNEs typically cluster around one particular gene in the region, most often encoding a transcription factor involved in the regulation of embryonic development and differentiation, referred to as the GRB target gene A GRB target gene, which is often a developmental transcription factor, is spanned by a synteny-maintaining array of HCNEs 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 The identification of a large number of putative novel regulatory elements in a subset of synaptic genes provides an important list of novel functional 'targets' for gene regulation during nervous system development and for dysregulation in disease CRCNE000111095 may show a more accurate representation of the function of the CNE with this CNE being responsible for enhancing limb development in human but having little enhancer activity in Fugu Functional assay of such elements in transgenic mouse and zebrafish have indeed indicated that a large number of them function as transcriptional enhancers directing tissue-specific expression of reporter genes during embryonic development This inference is in agreement with our previous findings that genes that are involved in development, in particular development of the central nervous system, are enriched with CNEs This suggests that CNE4 may be active in the central nervous system at some other stage of development highly conserved noncoding elements and their association with developmental regulatory genes Several lines of evidence indicate that these highly conserved noncoding elements (HCNEs) play a fundamental role in regulating animal development and constraining genome evolution HCNEs tend to cluster in the vicinity of developmental regulatory genes many HCNE sequences have shown the ability to induce part of the embryonic expression pattern of a developmental regulatory gene located in the genomic neighborhood of the endogenous HCNE These experiments have associated HCNEs and developmental genes Hundreds of HCNEs have now been characterized as developmental enhancers in transgenic mice, frogs or zebrafish, and the list is growing rapidly Plots of HCNE density along chromosomes highlight regions that harbor large HCNE arrays and, thus, are likely to contain key developmental regulatory genes and correspond to regulatory domains Since there is a strong association between HCNE arrays and developmental regulatory genes it is likely that most regions of high HCNE-density contain at least one developmental regulatory gene They found 41 of these regions to contain a gene known to be involved in embryonic development. Inspection of other HCNE-dense regions has revealed that several coincide with microRNA gene loci [18], a class of regulators implicated in multiple aspects of development the GRB of PAX7, a transcription factor gene implicated in muscle development [37] and situated within an array of HCNEs . A valuable section of CONDOR provides developmental expression patterns for about 100 HCNEs that have been investigated by reporter assays in zebrafish Ancora is a new web resource that provides data and tools for exploring HCNEs and their association with developmental regulatory genes The GRBs typically coincide with loci of developmental regulatory genes, for which HCNEs appear to act as enhancers
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<question>
Which is the process that Conserved noncoding elements mostly regulate?
</question>
<answer>
Development
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experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis Therefore, a well characterized homogeneous animal model, experimental autoimmune encephalomyelitis (EAE), was selected for this study to obtain a sample of the inflammatory lesions using experimental allergic encephalomyelitis (EAE) in rats as a disease model for M Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE) the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS The aim of our study was to characterize the sensory abnormalities and in particular the clinical signs linked to persistent pain in two models of Experimental Autoimmune Encephalomyelitis (EAE) in the rat Experimental autoimmune encephalomyelitis (EAE) is an animal model for studying multiple sclerosis (MS) Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS) experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) In this study we investigated whether in an animal model for MS, namely in experimental autoimmune encephalomyelitis (EAE), similar changes occur experimental autoimmune encephalomyelitis (EAE), the animal model of MS Experimental autoimmune encephalomyelitis (EAE), a widely recognized animal model of multiple sclerosis (MS) we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD) experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis Theiler's murine encephalomyelitis virus (TMEV) Inflammatory diseases of the CNS, such as MS and its animal model EAE the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE) an animal model of multiple sclerosis (MS): disease modifying activity on acute and chronic relapsing experimental allergic encephalomyelitis (EAE). The immunology of multiple sclerosis and its animal model, experimental allergic encephalomyelitis EAE is the best available model for the inflammatory processes that occur in MS, and for the disease process The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE) The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE) To assess neurological impairments quantitatively in an animal model of multiple sclerosis (MS), we have used a targeted model of experimental autoimmune encephalomyelitis (EAE) Experimental autoimmune encephalomyelitis (EAE) is a well-studied disease in rodents that mimics many clinical and pathological features of MS, including central nervous system inflammation and demyelination The neuropathology of MS and its animal model, experimental autoimmune encephalomyelitis (EAE) Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE) In the MS animal model experimental autoimmune encephalomyelitis (EAE) multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis inflammatory demyelination in multiple sclerosis (MS) lesions and experimental autoimmune encephalomyelitis (EAE)
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<question>
Which is the most widely used model for the study of multiple sclerosis (MS)?
</question>
<answer>
Experimental autoimmune encephalomyelitis (EAE)
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transcriptional enhancers in developing mouse embryos, found that the enhancers directed reporter expression most frequently in the brain and neural tube. More recently, a similar association between ultraconserved noncoding elements (noncoding sequences exceedingly conserved in human, chimp and mouse) and genes that preferentially express in the central nervous system has been described [51]. Using the GNF Human GeneAtlas, this study found that nine out of the ten tissues that express genes most significantly associated with ultraconserved noncoding elements constitute various members of the central nervous system.10.1371/journal.pone.0020088.g007Figure 7TF-encoding genes predominantly expressed in the central nervous system are enriched with CNEs. In this study we have used evolutionary constraint as an indicator of putative enhancers in the vertebrate Lhx2 locus. Due to selective pressure, noncoding functional elements such as enhancers tend to evolve slowly compared to their neighboring sequences and hence can be identified as conserved noncoding elements in comparisons of related genomes. This strategy has been effectively used to identify a large number of putative enhancers conserved in distantly related vertebrates such as mammals and teleost fishes [26], [27], [28], [29]. Functional assay of such elements in transgenic mouse and zebrafish have indeed indicated that a large number of them function as transcriptional enhancers directing tissue-specific expression of reporter genes during embryonic development [26], [28], [29]. We have aligned sequences of the Lhx2 locus from human, mouse and pufferfish (fugu) genomes and predicted conserved noncoding elements (CNEs) in the locus. Functional assay of these CNEs in a transgenic mouse assay system showed that half of them function as tissue-specific enhancers at embryonic day 11.5. A CNE was classified as a transcriptional enhancer if it directed reproducible reporter gene expression in the same anatomical structure in at least three independent transgenic mouse embryos.CNE1CNE1 is a 76-bp sequence located approximately 619 kb upstream of human LHX2 within the 20th intron of DENND1A. We therefore concluded that CNE1 does not act as a transcriptional enhancer at stage E11.5.CNE2/3CNE2/3 is a combination of two CNEs, CNE2 and CNE3, which were tested together due to their close proximity to each other (41 bp apart). Hence, CNE4 is not an enhancer at E11.5.CNE5/6CNE5/6 is a combination of two CNEs, CNE5 and CNE6, that are 38 bp apart and are located approximately 269 kb upstream of human LHX2 within the fifth intron of DENND1A. This CNE does not act as an enhancer at E11.5, because no lacZ expression was detected in four out of the six (67%) transgenic embryos obtained for this developmental stage. Hence, CNE9 does not act as an enhancer at E11.5.CNE10CNE10 is a 145-bp element that has the highest percentage identity (∼90%) in human and fugu among all the CNEs assayed. Hence, CNE7 acts as a transcriptional enhancer at stage E11.5. Indeed, CNE10 was found to act as a transcriptional enhancer. Summary of the expression patterns of CNEsIn summary, four out of the eight elements (50%) that we assayed for enhancer activity in transgenic mouse embryos, directed reproducible reporter gene expression in specific tissues at E11.5 Finally, a third study searched 13 forebrain enhancers conserved in human and zebrafish and identified five hexamer motifs that were enriched [54]. Hence, through the mutation of the predicted motif, the enhancer activity of CNE2/3 was either significantly reduced or completely abolished. The four CNEs that were showed to be functional enhancers in our transgenic mouse assay directed expression, among other domains, to the midbrain and hindbrain. Out of the four CNEs that showed expression in the central nervous system and the dorsal root ganglia, three showed overlapping expression in the hindbrain and all showed similar expression in the neural tube. These overlapping expression patterns of the different enhancers suggest that they are either associated with different genes in this locus or alternatively, redundant enhancers of the same gene. Similar enhancers showing overlapping patterns of expression have been previously identified in the screening of mammal-chicken CNEs in the Sox10 locus [59] and in a 1-Mb region surrounding the Shh locus [61]. The aCNEs are rich in tissue-specific enhancers Transgenic zebrafish assay of some human CNE enhancers that have been lost in teleosts strong DNA sequence conservation of enhancers of developmental regulator genes [3-8] implies purifying selection to keep such regions preserved across species and functionally constrained in their cis-regulatory functions. The orthologous Otx2 enhancers FM and AM [24] and the HoxC8 early enhancer [25] revealed strong conservation in DNA sequence and in enhancer expression in mouse transgenic experiments. In our report, we demonstrate that the Latimeria menadoensis shh locus contains all conserved proximal enhancers shared nonuniformly by fishes and land vertebrates. We provide experimental verification for enhancer activity of the putative Latimeria enhancers in transgenic zebrafish and electroporated chick embryos. From DNA sequence comparison of the shh locus of different vertebrate lineages, we infer that Latimeria conserved noncoding elements represent the ancestral gnathostome set of enhancers that diverged variably during vertebrate evolution. Several noncoding conserved sequences were detected in intronic and upstream regions of shh, and the distribution and frequency of these conserved blocks followed recognizable patterns. They overlap with the previously characterized enhancer regions of zebrafish and mouse (Figure 2a). Furthermore, the ar-D enhancer is not conserved in pufferfishes (e.g., Takifugu rubripes) and medaka (Oryzias latipes). This result suggests that the ar-B enhancer has been lost independently in the different tetrapod lineages. In summary, Latimeria has retained conservation of all four putative enhancers that were previously described in the actinopterygian zebrafish. Conserved Latimeria enhancer sequences we examined the rates of divergence within conserved shh enhancer sequences among sarcopterygian species with the relative rate test [51]. Congruent to the overall conservation, the mammalian enhancer sequences showed elevated rates of divergence compared to chick or Latimeria, with opossum putative enhancer sequences at intermediate rates and the placental mammalian species at highest rates (Table 1). In conclusion, all CNEs that were previously identified either in mouse or in zebrafish are present in Latimeria and thus are candidate enhancers of shh expression in the Latimeria embryonic midline is too large to suggest that the CNE within contains the functional enhancer. The region that is responsible for the ar-D enhancer effect overlaps fully with a CNE that is present in all the other compared sarcopterygian sequences Conserved noncoding elements of Latimeria shh intron 1 located between exon 1 and the intronic enhancer ar-A did not drive specific reporter gene expression (data not shown). These results indicate that the CNE in the Latimeria upstream region is a functional midline enhancer which has similar but not identical activity in zebrafish to the zebrafish ar-D enhancer Conservation of Latimeria shh noncoding DNAThe shh genomic region of Latimeria menadoensis reveals conservation of all four actinopterygian shh midline enhancers, which indicates an ancestral-like and rather unchanged cis-regulatory architecture of Latimeria shh. The Latimeria orthologous Otx2 enhancers FM and AM [24] as well as the HoxC8 early enhancer [25] revealed strong DNA sequence conservation across vertebrates. Conservation of the four enhancers ar-A, ar-B, ar-C and ar-D in Latimeria and zebrafish reveals preservation of an ancestral set of enhancers that originated before the split between ray-finned and lobe-finned vertebrates The Latimeria menadoensis shh genomic region represents a locus with the ancestral set of enhancers that emerged before the split of lobe-finned and ray-finned fishes. Conserved noncoding elements (CNEs) in vertebrate genomes often act as developmental enhancers, In all four cases where the zebra fish and human CNE display a similar expression pattern in zebra fish, the human CNE also displays a similar expression pattern in mouse. This suggests that the endogenous enhancer activity of ∼30% of human CNEs can be determined from experiments in zebra fish If these ancient CNEs are indeed enhancers directing tissue-specific expression of Hox genes, divergence of their sequences in vertebrate lineages might have led to altered expression patterns and presumably the functions of their associated Hox genes. Comparisons of noncoding sequences of the elephant shark and human Hox clusters have identified a large number of conserved noncoding elements (CNEs), which represent putative cis-regulatory elements that may be involved in the regulation of Hox genes. Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development. We test 42 of our PCNEs in transgenic zebrafish assays--including examples from vertebrates and amphioxus--and find that the majority are functional enhancers. The genomes of vertebrates, flies, and nematodes contain highly conserved noncoding elements (CNEs). CNEs cluster around genes that regulate development, and where tested, they can act as transcriptional enhancers. , we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. several transcriptional enhancers are conserved between amphioxus and vertebrates--a very wide phylogenetic distance. The same was shown by Woolfe and coworkers [6] by using 1,373 regions extracted from a direct comparison of the genomes of human and fish. The same report also provided the first systematic experimental evidence of enhancer activity for a subset of these elements in zebrafish (see below). Recognition and testing of individual highly conserved noncoding elementsThere is mounting evidence for the regulatory role of HCNEs. Soon after their genome wide discovery, it was realized that a significant number of previously characterized developmental enhancers overlap with HCNEs. Göttgens and coworkers [31] reported the discovery of enhancers that are highly conserved between human and mouse, and some in chicken. several such elements conserved between human and fugu near the SOX9 gene, of which they considered at least three candidate enhancers. isolated two HCNEs upstream of the mouse Pax3 gene as enhancers the question of whether the conservation is essential for the transcription factor binding properties of those enhancers a large number of HCNEs from the vertebrate iroquois clusters were tested in zebrafish and Xenopus, and the majority of them were shown to act as specific enhancers tested 167 HCNEs in a mouse transgenic enhancer assay. Seventy-five (43%) of the tested elements exhibited enhancer activity wo equivalent regions of a genomic sequence in human and zebrafish are both able to act as an enhancer in zebrafish, Mechanism of enhancer activity of highly conserved noncoding elementsWe still have no adequate explanation for the mechanism by which HCNEs act as enhancers, Five conserved noncoding sequences (>80% human-mouse identity) were identified within the 17 kb intergenic sequence. That some of these enhancers are shared We recently described GRBs in vertebrates, where most HCNEs function as enhancers Besides developmental regulators that are likely targets of HCNE enhancers We identify and characterize highly conserved noncoding elements flanking the TNF gene, which undergo activation-dependent intrachromosomal interactions. These elements, hypersensitive site (HSS)-9 and HSS+3 (9 kb upstream and 3 kb downstream of the TNF gene, respectively), contain DNase I hypersensitive sites in naive, T helper 1, and T helper 2 primary T cells. Both HSS-9 and HSS+3 inducibly associate with acetylated histones, indicative of chromatin remodeling, bind the transcription factor nuclear factor of activated T cells (NFAT)p in vitro and in vivo, and function as enhancers We used the sequence signatures identified by this approach to successfully assign tissue-specific predictions to approximately 328,000 human-mouse conserved noncoding elements in the human genome. By overlapping these genome-wide predictions with a data set of enhancers validated in vivo, in transgenic mice, we were able to confirm our results with a 28% sensitivity and 50% precision. 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. uncovered two anciently conserved noncoding sequences (CNS) upstream of COUP-TFII (CNS-62kb and CNS-66kb). Testing these two elements using reporter constructs in liver cells (HepG2) revealed that CNS-66kb, but not CNS-62kb, yielded robust in vitro enhancer activity.
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<question>
Do Conserved noncoding elements act as enhancers?
</question>
<answer>
yes
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Thrombophilia does hardly increase the risk of IUGR/PMPC or if so, it can be prevented by LMWH for illustrative purposes, a patient presenting with combined thrombophilia--both genetic and acquired--will be discussed. This patient had suffered severe gestational complications that led to devastating obstetrical outcome Thrombophilias have been implicated in complications related to ischemic placental disease including recurrent pregnancy loss, intrauterine fetal demise, preeclampsia, fetal growth restriction, placental abruption, and preterm delivery Further information about the combined risk of aPC resistance and pregnancy is needed before guidance on the management of affected women can be formulated. Thrombotic risk during pregnancy and the puerperium is higher in asymptomatic women with than without thrombophilia Further studies are required to assess the thrombotic risk in women with preeclampsia as well as early or late recurrent pregnancy loss. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period Careful diagnosis, observation and monitoring can add significant benefit to LMWH therapy during pregnancy Pregnancy in healthy women is accompanied by hypercoagulable changes that may interact with thrombophilia risk factors and threaten pregnancy. Fifty-three (13 %) women had antiphospholipid antibodies (lupus anticoagulant and/or anti-beta2-glycoprotein 1 antibodies) mainly associated with the risk of spontaneous abortion during the first trimester thrombophilia was found to be considerably more common in women with pregnancy-associated complications in comparison with the general population, and most frequently in conjunction with venous thromboembolism during pregnancy and the postpartum period When counseling white women with a history of preeclampsia, screening for thrombophilia can be useful for preconceptional counseling and pregnancy management. knowledge combined with the appropriate use of thromboprophylaxis and treatment in women who have objectively confirmed VTE continue to improve maternal and perinatal outcomes The risk of having thrombophilia is doubled in men who have fathered pregnancies which ended in perinatal death as well as in the mothers of such pregnancies. The prevalence of thrombophilic variants is of possible public health significance for other morbidity; but perhaps not in relation to preeclampsia This study suggests that thrombophilia "mediates" in lowering of cardiovascular risk factors in women with a history of preeclampsia
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<question>
Is thrombophilia related to increased risk of miscarriage?
</question>
<answer>
yes
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The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses GNAS, the gene for guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (gene for PHP1A), identified a de novo heterozygous 3 bp in frame deletion predicting a deletion of the asparagine residue at position 377 (deltaN377 craniosynostosis genes (FGFR2, FGFR3) Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication early fusion of cranial sutures commonly observed in the dup(5q) syndrome is caused by triplication of the MSX2 gene further evidence that extra copy of MSX2 gene leads to craniosynostosis Our results support the previous finding that distal 5q-trisomy together with an extra copy of the MSX2 gene leads to abnormal closure of sutures and craniosynostosis Craniosynostosis-associated gene nell-1 is regulated by runx2 We studied the transcriptional regulation of NELL-1, a craniosynostosis-related gene Runx2 directly binds to the OSE2 elements and transactivates the human NELL-1 promoter. These results suggest that Nell-1 is likely a downstream target of Runx2 The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes SOX6 mutation screening of another 104 craniosynostosis patients revealed one missense mutation leading to the exchange of a highly conserved amino acid (p.D68N) in a single patient and his reportedly healthy mother Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene Overexpression of Nell-1, a craniosynostosis-associated gene Mutations in five genes (FGFR1-, -2, -3, TWIST, and MSX2) causing craniosynostosis as the main clinical feature were described. One of the genes involved in craniosynostosis syndromes is the fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene Most mutations in Crouzon, Pfeiffer, and Apert syndromes are in the extracellular, third immunoglobulin-like domain and adjacent linker regions (exons IIIa and IIIc) of the fibroblast growth factor receptor 2 (FGFR2) gene Familial craniosynostosis due to Pro250Arg mutation in the fibroblast growth factor receptor 3 gene. Apert (Ap) syndrome is characterized by premature cranial suture ossification caused by fibroblast growth factor receptor 2 (FGFR-2) mutations Recently, the substitution of proline 250 by arginine in the fibroblast growth factor receptor 3 (FGFR3) gene, has been identified in patients with craniosynostosis and defines a new syndrome on a molecular basis Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. A unique Pro250Arg mutation in fibroblast growth factor receptor 3 (FGFR3) was recently found in patients with non-syndromic craniosynostosis a possible mechanism for MSX2-mediated craniosynostosis in humans We found previously that a single amino acid substitution in the homeodomain of the human MSX2 gene is associated with the autosomal dominant disorder craniosynostosis, Boston type. Recently, a unique Pro250Arg point mutation in fibroblast growth factor receptor 3 (FGFR3) was reported in 61 individuals with coronal craniosynostosis from 20 unrelated families We identified a novel TWIST gene mutation in this patient, a Glu181Stop mutation predicting a premature termination of the protein carboxy-terminal to the helix 2 domain A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis
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<question>
Which human genes are more commonly related to craniosynostosis?
</question>
<answer>
FGFR3; FGFR2; FGFR1; MSX2; NELL1; RUNX2; RECQL4; TWIST; SOX6; GNAS
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role of primary cilia in autosomal dominant polycystic kidney disease Recent research has focused on defects in signaling mediated by the primary cilia as the causative factor in ADPKD Interestingly, primary cilia concentrate p75NTR receptors in their membranes and are abnormally structured/damaged in transgenic (Tg) AD‑model mice, which could impact on the adult neurogenesis occurring in the dentate gyrus's subgranular zone (SGZ) that is necessary for new memory encoding, thereby favouring typical AD cognitive decline malformation of primary cilia, and in the collecting ducts of kidney tubules this is accompanied by development of autosomal recessive polycystic kidney disease (PKD) While PKD was one of the first diseases to be linked to dysfunctional primary cilia, defects in this organelle have subsequently been associated with many other phenotypes, including cancer, obesity, diabetes as well as a number of developmental defects mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease Although Glis3(zf/zf) mice form normal primary cilia, renal cysts contain relatively fewer cells with a primary cilium When ciliary function is perturbed, photoreceptors may die, kidney tubules develop cysts, limb digits multiply and brains form improperly. Here, we report that CP110 interacts with CEP290--a protein whose deficiency is implicated in human ciliary disease The cholangiociliopathies include but are not limited to cystic and fibrotic liver diseases associated with mutations Cysts in the kidney are among the most common inherited human pathologies, and recent research has uncovered that a defect in cilia-mediated signaling activity is a key factor that leads to cyst formation Multiple proteins whose functions are disrupted in cystic diseases have now been localized to the cilium or at the basal body at the base of the cilium Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts hus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas In cultured renal cells, the PKHD1 gene product colocalized with polycystin-2, the gene product of autosomal dominant polycystic disease type 2, at the basal bodies of primary cilia. Mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene The autosomal recessive polycystic kidney disease protein is localized to primary cilia It is proposed that the pathogenesis of autosomal recessive polycystic kidney disease is linked to the dysfunction of primary cilia
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<question>
Which is the most common disease attributed to malfunction or absence of primary cilia?
</question>
<answer>
Polycystic kidney disease (PKD)
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The allelic frequency of this variant was calculated to be 0.7% for this population The results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98 The age related prevalence of CF among the South Asian and general populations was: 0-14 years, 1:9200 versus 1:6600; 15-24 years, 1:13,200 versus 1:7600; older than 25 years, 1:56,600 versus 1:12,400. A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants) CF mutations were identified in 374 (4.0%) individuals. The aim of this study was to evaluate the screening policies of cystic fibrosis (CF) in the Jewish population.
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<question>
Which is the prevalence of cystic fibrosis in the human population?
</question>
<answer>
0.7–7/100000 inhabitants
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interactions with alpha-expansin in cell wall extension and polysaccharide degradation cell wall swelling may not be a significant event during the action of expansin and hydrolases To evaluate a putative implication of three newly identified expansin/family 45 endoglucanase-like (EEL) proteins in lignocellulose degradation Our results show that EglD is a conidial cell wall localized expansin-like protein, which could be involved in cell wall remodeling during germination Swollenin, a protein first characterized in the saprophytic fungus Trichoderma reesei, contains an N-terminal carbohydrate-binding module family 1 domain (CBD) with cellulose-binding function and a C-terminal expansin-like domain alpha-Expansins are extracellular proteins that increase plant cell-wall extensibility these wall-loosening proteins are directly involved in the accommodation of the fungus by infected cortical cells
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<question>
What is the biological role of expansins in fungi?
</question>
<answer>
Expansins are extracellular proteins that increase plant cell-wall extensibility. These wall-loosening proteins are involved in cell wall extension and polysaccharide degradation. In fungi expansins and expansin-like proteins have been found to localize in the conidial cell wall and are probably involved in cell wall remodeling during germination.
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Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus. Influenza immunization or infection may cause subacute thyroiditis. Coxsackie virus has been reported to be one of the viruses associated with the disease. The etiology of subacute granulomatous thyroiditis (SAT) is obscure, although it is postulated to be associated with viral infections and genetic factors. The results suggest that SAT is not usually associated with acute infections No evidence was obtained to support the proposed role of enteroviruses as an important etiologic agent of SAT. The viral antibodies evaluated were those of Influenza A and B, Coxsackie A9, B1, B2, B3, B4, B5 and B6, Echo 3, 7, 11 and 12, Parainfluenza 1, 2, 3 and 4, and Adeno 8 virus. The following results were obtained: In class I HLA typing, the frequency of HLA-Bw35 in SAT was 67.4%, which was significantly (p less than 0.0001) higher than that in the control (14.1%). On the other hand, the frequency of Cw1 in SAT (14.6%) was significantly (p less than 0.01) lower than that of the control (32.1%), and that of Cw3 (65.2%) was significantly (p less than 0.01) higher than that of the control (46.5%).
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<question>
Is paramyxovirus involved in human subacute thyroiditis?
</question>
<answer>
no
</answer>
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Proton-pump inhibitors, antacids and a long list of drugs may decrease thyroxine absorption Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine. Pantoprazole did not influence endocrine function in healthy male volunteers during short-term treatment. PPIs should be added to the list of medications affecting the level of thyroid hormone in patients with hypothyroidism treated with LT4 replacement. Patients with hypothyroidism and normal TSH values during LT4 replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT4 dose.
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<question>
Do proton pump inhibitors affect thyroxine absorption?
</question>
<answer>
yes
</answer>
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ommonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine Hypothyroid patients taking sevelamer hydrochloride or chromium picolinate should be advised to separate the time of ingestion of these drugs from their thyroid hormone preparation by several hours.
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<question>
Which drugs may interfere thyroxine absorption?
</question>
<answer>
bile acide sequestrant; ferrous sulphate; sucralfate; Calcium carbonate; aluminium-containing antacids; raloxifene; proton pump inhibithors; sevelamer; chromium picolinate
</answer>
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Myocardial ischaemia/reperfusion (I/R)-induced remodelling generally includes cell death (necrosis and apoptosis), myocyte hypertrophy, angiogenesis, cardiac fibrosis, and myocardial dysfunction. I 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 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. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.
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<question>
Is microRNA(miRNA) 29 involved in post-ischemic cardiac remodeling?
</question>
<answer>
yes
</answer>
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The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosi Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target CTGF is importantly regulated by 2 major cardiac microRNAs (miRNAs), miR-133 and miR-30. the expression of both miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart disease and in human pathological left ventricular hypertrophy. Second, in cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, which was accompanied by decreased production of collagens. miR-30 importantly limit the production of CTGF miR-30 directly downregulate CTGF, a key profibrotic protein, and thereby establish an important role for these miRNAs in the control of structural changes in the extracellular matrix of the myocardium.
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<question>
Is microRNA(miRNA) 30 involved in post-ischemic cardiac remodeling?
</question>
<answer>
yes
</answer>
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GD orbital fibroblasts, which comprise a mixture of CD34(+) and CD34(-) cells, express much lower levels of Tg and TSHR Previously, we found that CD34(+) progenitor cells, known as fibrocytes, express functional TSHR, infiltrate the orbit, and comprise a large subset of orbital fibroblasts in TAO. TSH induced lipolysis in adipose tissues. TSH worked as a lipolytic factor in white adipose tissues, These fibrocytes infiltrate orbital connective tissues in thyroid-associated ophthalmopathy and express functional TSH receptor (TSHR). TSHR levels are higher than those in orbital fibroblasts.
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<question>
Which extra thyroid tissues have thyrotropin (TSH) receptors?
</question>
<answer>
adipose tissue; fibrotic tissue
</answer>
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T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt. L-T3 significantly increased angiogenesis and cell survival and enhanced the expression of nuclear-encoded transcription factors involved in these processes. T(3) administration restored TRbeta mRNA expression level in AAC hearts to the control level. Rbeta knockout and TRalpha/TRbeta double-knockout mice both exhibited significantly less capillary density in LV compared with wild-type mice. TRbeta in the coronary ECs regulates capillary density during cardiac development, and down-regulation of TRbeta results in coronary microvascular rarefaction during pathological hypertrophy.
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<question>
Does triiodothyronine (T3) has cardiac angiogenic effects?
</question>
<answer>
yes
</answer>
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The product of the dcm gene is the only DNA cytosine-C5 methyltransferase of Escherichia coli K-12; it catalyses transfer of a methyl group from S-adenosyl methionine (SAM) to the C-5 position of the inner cytosine residue of the cognate sequence CCA/TGG. Deoxycytosine methylase (Dcm) enzyme activity causes mutagenesis in vitro either directly by enzyme-induced deamination of cytosine to uracil in the absence of the methyl donor, S-adenosylmethionine (SAM), or indirectly through spontaneous deamination of [5-methyl]cytosine to thymine In the absence of DNA substrate, the DNA methyltransferase (MTase) M.BspRI can methylate itself using the methyl donor S-adenosyl-L-methionine (AdoMet). The methyl group is transferred to two Cys residues of the MTase. The reaction is fairly insensitive to the methyl donor in the reaction, S-adenosylmethionine. Formation of the complex was dependent upon the presence of the methyl donor S-adenosylmethionine, suggesting that it comprises an enzyme-linked 5-substituted dihydrocytosine moiety in DNA. The DNA (cytosine-5)-methyltransferase (m5C-MTase) M.BspRI is able to accept the methyl group from the methyl donor S-adenosyl-L-methionine (AdoMet) in the absence of DNA. Transfer of the methyl group to the enzyme is a slow reaction relative to DNA methylation. S Here, we report the structure of HhaI methyltransferase in complex with DNA containing a south-constrained abasic carbocyclic sugar at the target site in the presence of the methyl donor byproduct AdoHcy.
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<question>
What is the methyl donor of DNA (cytosine-5)-methyltransferases?
</question>
<answer>
S-adenosyl-L-methionine
</answer>
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<context>
Most luminal lysosomal proteins are synthesized as precursors containing mannose 6-phosphate (Man6-P) and a number of recent studies have conducted affinity purification of Man6-P containing proteins as a step toward defining the composition of the lysosome This chapter describes the process of production, purification, separation, and mass spectrometry identification of soluble lysosomal proteins. The rationale for purification of these proteins resides in their characteristic sugar, the mannose-6-phosphate (M6P), which allows an easy purification by affinity chromatography on immobilized M6P receptor (MPR ecretions of these cells were affinity purified using an affinity matrix derivatized with MPR46 and MPR300. In the protein fraction bound to the affinity matrix and eluted with mannose 6-phosphate, Proteins containing mannose 6-phosphate (Man6-P), a carbohydrate modification used for targeting resident soluble lysosomal proteins to the lysosome, were affinity-purified using immobilized Man6-P receptor. . We purified mannose 6-phosphorylated proteins by affinity chromatography Since lysosomal soluble proteins are characterized by the presence of mannose-6-phosphate, they were purified on an affinity support bearing mannose-6-phosphate receptor The most abundant lysosomal substrates of Acp2 and Acp5 were identified by Man6P affinity chromatography and mass spectrometry. urinary proteins were affinity purified on immobilized Man-6-P receptors, A number of proteomic studies have focused on lysosomal proteins, exploiting the fact that Man-6-P-containing forms can be purified by affinity chromatography on immobilized MPRs. In this study, we purified the Man-6-P glycoforms of proteins from human plasma by affinity chromatography on immobilized MPRs
</context>
<question>
What kind of affinity purification would you use in order to isolate soluble lysosomal proteins?
</question>
<answer>
The rationale for purification of the soluble lysosomal proteins resides in their characteristic sugar, the mannose-6-phosphate (M6P), which allows an easy purification by affinity chromatography on immobilized M6P receptors.
</answer>
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The lysosomal storage disorder Fabry disease is characterized by excessive globotriaosylceramide (Gb3) accumulation in major organs such as the heart and kidney. Defective lysosomal alpha-galactosidase A (Gla) is responsible for excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3 accumulation is vascular endothelium. Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Human alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal alpha-galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). Transgenic mice expressing a human mutant alpha-galactosidase with an R301Q substitution, which was found in a patient with a variant form of Fabry disease, were established.
</context>
<question>
Which is the defective protein causing the lysosomal storage disease Fabry?
</question>
<answer>
alpha-galactosidase A
</answer>
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<context>
Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus
</context>
<question>
What is known as the cause of subacute thyroiditis?
</question>
<answer>
Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus
</answer>
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<context>
Oral glucocorticoids are administered in moderate and severe cases of subacute thyroiditis (SAT) he treatment protocol that we employed had 15 mg/day of PSL as the initial dosage for the treatment of SAT, with tapering by 5 mg every 2 weeks
</context>
<question>
What is the treatment of subacute thyroiditis?
</question>
<answer>
Common treatment of subacute thyroiditis is with anti-inflammatory drug agents, namely corticosteroids
</answer>
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myc regulates hepatic glycolysis increase in c-Myc protein was able to induce liver glucose utilization and accumulation, and suggested that c-Myc transcription factor is involved in the control in vivo of liver carbohydrate metabolism p53 regulates mitochondrial oxidative phosphorylation, glycolysis, glutamine metabolism, lipid metabolism, and antioxidant defense STAT3 is a negative regulator of aerobic glycolysis. HIF1 alpha-mediated switches in the energy production of tumor cells from OXPHOS to glycolysis NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation Hypoxia-inducible factor-1α (HIF-1α), which is a transcription factor that enhances glycolysis in cells in response to hypoxia CRP plays a major role in switch control between glycolysis and gluconeogenesis the inhibition of PDK4 expression by NF-κB is related to the shift towards increased glycolysis that is observed during cardiac pathological processes induced by pro-inflammatory stimuli, such as cardiac hypertrophy and heart failure The oxygen sensor HIF-1α is a highly unstable protein that becomes stabilized under hypoxia, leading to the activation of glycolysis and the down-regulation of mitochondrial respiration several reports have linked HIF-1α induction with STAT3 activation Functionally, we have shown that glycolysis, oxidative phosphorylation, and cellular respiratory systems are altered in response to changes in Ets-1 expression SIRT6 appears to function as a corepressor of the transcription factor Hif1alpha, a critical regulator of nutrient stress responses SIRT6-deficient cells exhibit increased Hif1alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA) loss of the widely expressed transcription factor Oct1 induces a coordinated metabolic shift: mitochondrial activity and amino acid oxidation are increased, while glucose metabolism is reduced. PVHL is a regulator of glucose metabolism Carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in the glucose-mediated induction of gene products involved in hepatic glycolysis and lipogenesis Activation of NF-kappaB, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3 p53 restricts activation of the IKK-NF-kappaB pathway through suppression of glycolysis cells express hypoxia-inducible factor (HIF)-1alpha, a transcription factor that responds to oxygen tension and regulates glycolysis The HIF-1 dependent genic products are involved in tumoral angiogenesis, in the metabolic switch to anaerobic glycolysis and in prosurvival, proliferative and apoptotic mechanisms he hypoxia-inducible transcription factor (HIF) regulates the expression of genes involved in angiogenesis, erythropoiesis and glycolysis hypoxia-inducible factor-1, which activates a gene program associated with angiogenesis, glycolysis, and adaptation to pH ChREBP (carbohydrate response element-binding protein) was recently identified as a candidate transcription factor in the glucose-signaling pathway Hypoxia-inducible factor (HIF)-1 is a master transcription factor, which up-regulates glycolysis (Src) express HIF-1alpha protein under normoxia, which results in the expression of multiple HIF-1alpha target genes. HIF-1 alpha can then translocate to the nucleus and facilitate transcription of numerous target genes, the majority of which are involved in glycolysis and angiogenesis via heterodimerisation with the beta subunit (HIF-1 beta/ARNT) We previously observed that the c-Myc oncogenic transcription factor regulates lactate dehydrogenase A and induces lactate overproduction. We, therefore, sought to determine whether c-Myc controls other genes regulating glucose metabolism overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway HNF4alpha is critical for regulating glucose transport and glycolysis and in doing so is crucial for maintaining glucose homeostasis
</context>
<question>
Which are the major transcription factors regulating glycolysis in mammals?
</question>
<answer>
HIF1-alpha; c-Myc; Src; STAT3; SIRT6; NF-κB; Oct1; HNF4-alpha; PVHL
</answer>
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<context>
Recent evidence indicates that CXCR2 signaling is crucial for cancer progression, and its antagonist SB225002 induces apoptosis in Wilms' tumor cells. CXCR2 small-molecule antagonist (SB225002) G31P, an antagonist against CXC chemokine receptors 1 and 2, inhibits growth of human prostate cancer cells in nude mice. The CXCR2 antagonist, SCH-527123, shows antitumor activity CXCR2 Antagonist SB225002 The use of a small selective antagonist for CXCR2 (SB225002) represents an attractive targeted therapeutic approach [26]. retreatment with the CXCR2 antagonist AZ10397767 The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. we report that targeting CXCR2 and CXCR1 activity using orally active small molecule antagonist (SCH-527123, SCH-479833) inhibits human colon cancer liver metastasis mediated by decreased neovascularization and enhanced malignant cell apoptosis. CXCR2-specific small molecule inhibitor (AZ10397767) to investigate the recruitment and function of human neutrophils in tumors
</context>
<question>
The CXCR2 receptor is targeted in cancer. Name five antagonists.
</question>
<answer>
SB225002; G31P; SCH-527123; AZ10397767; SCH-479833
</answer>
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<context>
In contrast, GeneView recognizes a broader set of entity types but not gene ontology terms, provides search facilities using unique database identifiers and also finds relationships between proteins in texts. It uses a multitude of state-of-the-art text-mining tools optimized for recognizing mentions from 10 different entity classes and for automatically identifying protein–protein interactions (PPI). GeneView offers all annotations as downloads to support the development of new applications by freeing developers of data analysis algorithms from the necessity to deal with a multitude of text-mining packages. PPI finder: a mining tool for human protein-protein interactions. One of the most important applications is mining correlations or associations such as protein-protein interactions (PPIs) from the literature [4], [5]. Plenty of PPI text mining approaches have been categorized into two groups, one is statistical calculation of the co-occurrence of genes or proteins, and the other is the computational linguistic method [2], [4]. In this study, we developed a novel algorithm by a frame-based approach for a web-based tool, PPI Finder, which can not only find the related genes of the gene of interest based on their co-occurrence frequencies but also extract the semantic descriptions of interactions from the co-occurring literature by computational linguistic methods. The PPI Finder system consists of two modules: Information Retrieval (IR module) and Information Extraction (IE module). Extracting interactions between proteins from the literature. In the meantime, there has been a great interest with scientific communities in text mining tools to find knowledge such as protein-protein interactions, which is most relevant and useful for specific analysis tasks. This paper provides a outline of the various information extraction methods in biomedical domain, especially for discovery of protein-protein interactions. PreBIND and Textomy--mining the biomedical literature for protein-protein interactions using a support vector machine. PreBIND and Textomy are two components of a literature-mining system designed to find protein-protein interaction information and present this to curators or public users for review and submission to the BIND database. For the purposes of this paper and the initial population of the BIND database, we have chosen to focus on extracting information from the literature that is sufficient for defining a simple protein-protein interaction record in BIND. Subsequent text-mining modules can be added to PreBIND in future that will help fill out other aspects of the BIND data model. PreBIND and Textomy differ from these methods by a combination of five factors.1) Support Vector Machine (SVM) technology is used to identify articles about biomolecular interactions and confirm sentences that mention specific protein-protein interactions. Discovering implicit protein-protein interactions in the cell cycle using bioinformatics approaches. In this paper we examine if P-P interactions in regenerating tissues and cells of the anuran Xenopus laevis can be discovered from biomedical literature using computational and literature mining techniques. P-P interactions that are implicitly appearing in literature can be effectively discovered using literature mining techniques. The developed BioMap system allows discovering implicit P-P interactions from large quantity of biomedical literature data. Also, bioinformatics techniques based on sequence, structural, or evolutionary information have been devised to predict binary protein interactions. How to link ontologies and protein-protein interactions to literature: text-mining approaches and the BioCreative experience. In particular, we will focus on the attempts that have been made to automatically extract protein–protein interaction (PPI) data taking advantage of ontologies, and to associate ontology terms to the interactions. One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. Extracting protein-protein interaction (PPI) from biomedical literature is an important task in biomedical text mining (BioTM). Automated extraction of protein-protein interactions (PPIs) from biomedical literatures is an important topic of biomedical text mining. Extraction of protein-protein interactions (PPIs) reported in scientific publications is one of the core topics of text mining in the life sciences. BACKGROUND: The automated extraction of gene and/or protein interactions from the literature is one of the most important targets of biomedical text mining research. The techniques used in text mining range from the very simple (e.g., the inference of relationships between genes from frequent proximity in documents) to the complex and computationally intensive (e.g., the analysis of sentence structures with parsers in order to extract facts about protein-protein interactions from statements in the text). A major challenge in text mining for biomedicine is automatically extracting protein-protein interactions from the vast amount of biomedical literature. One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. We have developed the Extracting Functional Impact of Phosphorylation (eFIP) text mining system, which combines several natural language processing techniques to find relevant abstracts mentioning phosphorylation of a given protein together with indications of protein-protein interactions (PPIs) and potential evidences for impact of phosphorylation on the PPIs. One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. In this paper, we present a tool called Protopia for searching for and integrating protein-protein interactions and the information about them contained in five different Protein Interaction Web Databases. It can be useful as a friendly search interface among different databases, as a validator of redundant information, as a network visualization tool and also as an export tool to SBML [15].
</context>
<question>
Which are the available biomedical text mining tools for the detection of protein-protein interactions?
</question>
<answer>
GeneView; PPI finder; PreBIND', 'Textomy; BioMap; eFIP', 'Extracting Functional Impact of Phosphorylation; Protopia; STRING
</answer>
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<context>
The paraspeckle component 1 (PSPC1) and non-POU-domain-containing octamer-binding protein (NONO) heterodimer is an essential structural component of paraspeckles, PSPC1-NONO heterodimer. Crystallization of a paraspeckle protein PSPC1-NONO heterodimer difficult heterodimeric complex of two human proteins, paraspeckle component 1 (PSPC1) and non-POU domain-containing octamer-binding protein (NONO), that are involved in gene regulation and the structural integrity of nuclear bodies termed paraspeckles is described. SFPQ (PSF) and NONO (p54) are nuclear proteins that interact with each other and have diverse roles in nucleic acids metabolism. The SFPQ/NONO heterodimer was previously found to enhance DNA strand break rejoining in vitro. We identified a heterodimer, p54nrb and PSF, P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner. e demonstrated that the PSF heterodimer partner, p54nrb (non-POU-domain-containing, octamer binding protein), can also function as a transcription corepressor, independent of PSF. The PSPC1/NONO heterodimer has a right-handed antiparallel coiled-coil Structure of the heterodimer of human NONO and paraspeckle protein component 1
</context>
<question>
The protein NONO forms heterodimers. With which proteins?
</question>
<answer>
PSPC1; SFPQ
</answer>
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<context>
, a mixture of five SILAC-labeled cell lines that accurately represents the tissue We describe a method to accurately quantify human tumor proteomes by combining a mixture of five stable-isotope labeling by amino acids in cell culture (SILAC)-labeled cell lines with human carcinoma tissue. the use of a mix of multiple SILAC-labeled cell lines as an internal standard, a technique called super-SILAC Equal amounts of the heavy lysates were mixed to generate the super-SILAC mix For accurate quantification we developed a super-SILAC mix from several labeled breast cancer cell lines and used it as an internal standard for all samples. For the preparation of super-SILAC mix (18) equal amounts of heavy lysates were mixed and then combined with nonlabeled cells as described in the RESULTS section to select five cell lines, chosen to be as dissimilar to each other as possible (Jurkat, HEK293, LnCap, HeLa, and K562).As expected from the high correlations, even the SILAC quantification experiments between binary combinations of heavy and light labeled cell lines resulted in narrow ratio distributions (Fig. 6A, 6B). This was further improved in the quantification of the heavy super-SILAC mix against a single cell line (Fig. 6C). These experiments also suggest a general strategy to construct super-SILAC mixes and to evaluate their suitability for quantifying any cell line (or tissue) of interes Knowledge of the overall similarities of the proteomes was used to construct a five cell line, heavy labeled “super-SILAC” reference standard. We developed and used a super-SILAC mix of labeled B-cell lymphoma cell lines as an internal standard to segregate subtypes of DLBCL.
</context>
<question>
Super-SILAC is a method used in quantitative proteomics. What is the super-SILAC mix?
(SILAC: Stable Isotopic labelling by aminoacids in cell culture)
</question>
<answer>
The Super-SILAC mix consists of the combination of multiple SILAC-labeled cell lines.
</answer>
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<context>
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 prediction server, TMBETADISC-RBF, which is available at http://rbf.bioinfo.tw/~sachen/OMP.html. TMB finding pipeline: novel approach for detecting beta-barrel membrane proteins in genomic sequences. Interestingly, the present approach identified TMBs from all 15 families in TCDB. Nevertheless, we show that when several concurring paths are present, as in the case of our beta-barrel HMM, PV performs better than the others. A new decoding algorithm for hidden Markov models improves the prediction of the topology of all-beta membrane proteins. A new method is presented for identification of beta-barrel membrane proteins. It is based on a hidden Markov model (HMM) with an architecture obeying these proteins' construction principles. Once the HMM is trained, log-odds score relative to a null model is used to discriminate beta-barrel membrane proteins from other proteins. Prediction of beta-barrel membrane proteins by searching for restricted domains. Now, four alternative directions are used in order to newly identify β-barrel proteins out of a genomic/proteomic data set. In the first approach, sequence profile based HMMs for predicting β-barrel membrane proteins were developed [10-12]. The second methodology is based on the alternating hydrophobicity as a measure for β-barrel transmembrane segments [13]. Thirdly, the structural data of the β-barrel membrane proteins were statistically analyzed and certain criteria developed for a linear prediction [14,15]. The fourth methodology is based on a modified k-nearest neighbor algorithm of the whole sequence amino acid composition [16,17]. Recently, the combination of several independent procedures for β-barrel membrane protein prediction [18,19] or their combination with other procedures, e.g. signal sequence prediction [15,19], was employed to improve the prediction quality. PRED-TMBB: a web server for predicting the topology of beta-barrel outer membrane proteins. 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. 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. A Hidden Markov Model method, capable of predicting and discriminating beta-barrel outer membrane proteins. A sequence-profile-based HMM for predicting and discriminating beta barrel membrane proteins. RESULTS: We develop a HMM model, which can predict the topology of beta barrel membrane proteins using, as input, evolutionary information. . For the reasons mentioned above, there is clearly a need to develop computational tools for predicting the membrane spanning strands of those proteins, and also discriminating them from water-soluble proteins when searching entire genomes. OMPdb: a database of {beta}-barrel outer membrane proteins from Gram-negative bacteria. Given these facts, and because many β-barrel OMPs nowadays attract an increased medical interest, several approaches have been made towards the development of predictive algorithms for this type of proteins. These methods are based grossly on hydrophobicity (10) and statistical analysis (11,12), remote homology detection (13), Hidden Markov Models (HMMs) (14–18), feed-forward Neural Networks (19–21), radial basis function Neural Networks (22,23) and Support Vector Machines (24), whereas others like BOMP (25), TMB-Hunt (26,27) and the TMB-finding pipeline (28) are oriented towards genome scale discrimination of β-barrel membrane proteins. transFold: a web server for predicting the structure and residue contacts of transmembrane beta-barrels. In the last few years, various methods have addressed TM β-barrel structure prediction (1–6). The transFold program extends a method introduced previously by Waldispühl and Steyaert (8) for TM α-bundle proteins, and employs statistical potentials developed for the program BETAWRAP (9,10). Our software, named transFold, applies grammars to describe all potential β-barrel supersecondary structures and then computes the global minimum energy structure by dynamic programming. Evaluation of methods for predicting the topology of beta-barrel outer membrane proteins and a consensus prediction method. We have evaluated the currently available methods, for predicting the topology of β-barrel outer membrane proteins, using a non-redundant dataset of 20 proteins with structures known at atomic resolution. By using multivariate and univariate analysis of variance, we conclude that the HMM-based methods HMM-B2TMR, ProfTMB and PRED-TMBB perform significantly better than the other (mostly NN-based) methods, in both terms of per-residue and per-segment measures of accuracy. A consensus prediction method is for the first time been applied for the prediction of the transmembrane strands, of β-barrel outer membrane proteins. 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. 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. On the basis of existing knowledge of beta-barrel outer-membrane proteins, several state of the art prediction methods, as well as a new in-house program (PROB) were employed for the systematic exploration of Mycobacterium tuberculosis predicted proteomes for potential beta-barrel structures. Computational identification of beta-barrel outer-membrane proteins in Mycobacterium tuberculosis predicted proteomes as putative vaccine candidates. 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. Supersecondary structure prediction of transmembrane beta-barrel proteins. 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. BOCTOPUS: improved topology prediction of transmembrane β barrel proteins. Here, 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). 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. 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). BTMX predicts the exposure status of known TM residues with an accuracy of 84.2% over 2,225 residues and provides a confidence score for all predictions. A method for discovering transmembrane beta-barrel proteins in Gram-negative bacterial proteomes. A web server based on the proposed method is available at http://yanbioinformatics.cs.usu.edu:8080/TMBKNNsubmit. This paper presents a k-nearest neighbor (K-NN) method for discriminating TMB and non-TMB 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. We compare our results to the recent state-of-the-art predictors transFold and PRED-TMBB using their respective benchmark datasets, and leave-one-out cross-validation. PROFtmb: a web server for predicting bacterial transmembrane beta barrel proteins. PROFtmb predicts TMBs from Gram-negative bacteria only. For each sequence, PROFtmb builds a PSI-BLAST profile and runs the prediction, attempting to find the best fit of the protein to its TMB-based architecture, indicated as a Z-value. A consensus algorithm to screen genomes for novel families of transmembrane beta barrel proteins. Here we describe a new algorithm combining composition and hidden Markov model topology based classifiers (called TMB-Hunt2), which achieves a crossvalidation accuracy of >95%, with 96.7% precision and 94.2% recall. Tools and datasets are made available through a website called TMB-Web (http://www.bioinformatics.leeds.ac.uk/TMB-Web/TMB-Hunt2). TMB-Hunt: a web server to screen sequence sets for transmembrane beta-barrel proteins. TMB-Hunt is a program that uses whole sequence amino acid composition to discriminate between TMB and non-TMB proteins. TMB-Hunt is extremely quick, and so the web server allows screening of up to 10 000 sequences in a single query. TMB-Hunt uses whole sequence amino acid composition to discriminate between TMB and non-TMB proteins. However, although studies of TMB protein composition have been made, whole sequence amino acid composition has not yet been applied to the discrimination problem.Because TMB-Hunt puts no emphasis on identification of TM β-strands, we were not dependent on sequences with resolved structures, thus allowing the use of training sets that were larger and more representative than those used for other predictors. sing the ‘leave homologues out’ cross-validation, without inclusion of evolutionary information and without differential amino acid weightings, the program was able to discriminate between TMB and NTM proteins with 85% accuracy, 83% sensitivity and 86.5% positive predictive value (PPV).
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<question>
What are the computational tools for the prediction of beta-barrel transmembrane proteins?
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<answer>
BETAWARE; BOCTOPUS; BOMP; BTMX; HMM-B2TMR; OMPdb; PRED-TMBB; PROB; ProfTMB; PV; TMB finding pipeline; TMBETADISC-RBF; TMBETAPRED-RBF; TMBHMM; TMB-Hunt', 'TMB-Hunt2; TMBKNN; TMBpro; transFold; TMBETA-NET
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Toward Single Cell Analysis by Plume Collimation in Laser Ablation Electrospray Ionization Mass Spectrometry. he advent of proteomics and genomics at a single-cell level has set the basis for an outstanding improvement in analytical technology and data acquisition. The new-generation technology of single-cell analysis is able to better characterize a cell's population, identifying and differentiating outlier cells, in order to provide both a single-cell experiment and a corresponding bulk measurement, through the identification, quantification and characterization of all system biology aspects (genomics, transcriptomics, proteomics, metabolomics, degradomics and fluxomics). The movement of omics into single-cell analysis represents a significant and outstanding shift. Laser ablation electrospray ionization (LAESI) is a novel method for the direct imaging of biological tissues by mass spectrometry. By performing ionization in the ambient environment, this technique enables in vivo studies with potential for single-cell analysis. Other approaches for MS-based chemical imaging and profiling include those based on near-field laser ablation and inductively-coupled plasma MS analysis, which offer complementary capabilities for subcellular chemical imaging and profiling. Mass spectrometry imaging and profiling of single cells. his is rapidly changing with the recent examples of single cell genomics, transcriptomics, proteomics and metabolomics. The rate of change is expected to accelerate owing to emerging technologies that range from micro/nanofluidics to microfabricated interfaces for mass spectrometry to third- and fourth-generation automated DNA sequencers Single-cell analysis (SCA) has been increasingly recognized as the key technology for the elucidation of cellular functions, which are not accessible from bulk measurements on the population level. Thus far, SCA has been achieved by miniaturization of established engineering concepts to match the dimensions of a single cell Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells. The amount of single proteins in single cells can be as low as one copy per cell and is for most proteins in the attomole range or below; usually considered as insufficient for proteomic analysis. n Arabidopsis thaliana, we have successfully identified nine unique proteins in a single-cell sample and 56 proteins from a pool of 15 single-cell samples from glucosinolate-rich S-cells by nanoLC-MS/MS proteomic analysis, thus establishing the proof-of-concept for true single-cell proteomic analysis A first step towards practical single cell proteomics: a microfluidic antibody capture chip with TIRF detection.
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<question>
Is single-cell analysis (SCA) possible in proteomics?
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<answer>
no
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In conjunction with the XFEL temporal profile and high-flux, it is a powerful tool for studying the dynamics of time-dependent systems. Photo-induced processes and fast catalytic reaction kinetics, ranging from femtoseconds to milliseconds, will be resolvable in a wide array of systems circumventing radiation damage. We discuss the pertinent physics of the intense X-ray-matter interactions, and illustrate the importance of electron-ion collisions. Detailed simulations of the interaction process conducted with a radiative-collisional code show good qualitative agreement with the experimental results. We obtain insights into the evolution of the charge state distribution of the system, the electron density and temperature, and the timescales of collisional processes. Our results should inform future high-intensity X-ray experiments involving dense samples, such as X-ray diffractive imaging of biological systems, material science investigations, and the study of matter in extreme conditions. employment of "exotic" systems, such as the Free Electron LASER (FEL), that are expected to focus on the fundamental processes of life, following chemical reactions and biological processes as they happen, on unprecedented time and size scales. New data analysis approaches are outlined for the correlated fluctuations in fast WAXS, for protein nanocrystals just a few molecules on a side, and for the continuous x-ray scattering from a single virus Research opportunities and techniques are reviewed for the application of hard x-ray pulsed free-electron lasers (XFEL) to structural biology. These include the imaging of protein nanocrystals, single particles such as viruses, pump--probe experiments for time-resolved nanocrystallography, and snapshot wide-angle x-ray scattering (WAXS) from molecules in solution. The use of femtosecond exposure times, rather than freezing of samples, as a means of minimizing radiation damage is shown to open up new opportunities for the molecular imaging of biochemical reactions at room temperature in solution New opportunities for solving the phase problem for XFEL data are outlined. A summary of the latest results is given, which now extend to atomic resolution for nanocrystals. Possibilities for time-resolved chemistry using fast WAXS (solution scattering) from mixtures is reviewed, toward the general goal of making molecular movies of biochemical processes. Molecular imaging using X-ray free-electron lasers. The recent development of X-ray free-electron laser sources has created new opportunities for the structural analysis of protein nanocrystals. X-ray free electron lasers hold the promise of enabling atomic-resolution diffractive imaging of single biological molecules. The emergence of femtosecond diffractive imaging with X-ray lasers has enabled pioneering structural studies of isolated particles, such as viruses, at nanometer length scales. In this paper we report room temperature X-ray diffraction data of PS II microcrystals obtained using ultrashort (< 50 fs) 9 keV X-ray pulses from a hard X-ray free electron laser, namely the Linac Coherent Light Source. High-resolution protein structure determination by serial femtosecond crystallography We applied serial femtosecond crystallography (SFX) using an x-ray free-electron laser (XFEL) to obtain high-resolution structural information from microcrystals (less than 1 micrometer by 1 micrometer by 3 micrometers) of the well-characterized model protein lysozyme. Time-resolved protein nanocrystallography using an X-ray free-electron laser We demonstrate the use of an X-ray free electron laser synchronized with an optical pump laser to obtain X-ray diffraction snapshots from the photoactivated states of large membrane protein complexes in the form of nanocrystals flowing in a liquid jet. We describe the experimental setup and obtain the first time-resolved femtosecond serial X-ray crystallography results from an irreversible photo-chemical reaction at the Linac Coherent Light Source. This technique opens the door to time-resolved structural studies of reaction dynamics in biological systems. X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. Here we recorded interpretable diffraction data from micrometer-sized lipidic sponge phase crystals of the Blastochloris viridis photosynthetic reaction center delivered into an X-FEL beam Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source. Single mimivirus particles intercepted and imaged with an X-ray laser Femtosecond X-ray protein nanocrystallography Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. Hard X-ray free-electron lasers (XFELs) are currently under construction in Europe (http://xfel.desy.de/) and Japan (http://www-xfel.spring8.or.jp/) and the first American XFEL facility has recently reported lasing at 8 keV (http://lcls.slac.stanford.edu/). These fourth-generation X-ray sources promise extremely intense hard X-ray bursts of approximately 100 fs in duration, and will thereby create new opportunities for imaging of biological molecules from extremely small samples (Neutze et al., 2000 ▶, 2004 ▶).Within the realm of time-resolved pump–probe structural studies, the most obvious benefit of these emerging sources will be their remarkable capability to probe the structural dynamics of light-driven reactions with a temporal resolution of 100 fs These methods can be used to image biological and materials science samples at high resolution with x-ray undulator radiation and establishes the techniques to be used in atomic-resolution ultrafast imaging at x-ray free-electron laser sources. With the prospects of the x-ray free electron lasers, this approach could provide a major new opportunity for the high-resolution three-dimensional structure determination of single biomolecules. X-ray free-electron lasers (XFELs) generate sequences of ultra-short spatially coherent pulses of X-ray radiation. Diffractive imaging using the intense and coherent beam of X-ray free-electron lasers opens new perspectives for structural studies of single nanoparticles and biomolecules. The opening of hard X-ray free-electron laser facilities, such as the Linac Coherent Light Source (LCLS) at SLAC National Accelerator Laboratory in the United States, has ushered in a new era in structural determination. Where possible we also highlight areas that we think could push this field forward with emerging technologies, such as X-ray free electron lasers (X-feL), which could have a big impact on the membrane protein structural biology community. X-ray free electron lasers (XFELs) deliver short (<100 fs) and intense (∼10(12) photons) pulses of hard X-rays, making them excellent sources for time-resolved studies. Modern imaging techniques at the molecular scale rely on utilizing novel coherent light sources like X-ray free electron lasers for the ultimate goal of visualizing such objects as individual biomolecules rather than crystals. In single-particle coherent x-ray diffraction imaging experiments, performed at x-ray free-electron lasers (XFELs), samples are exposed to intense x-ray pulses to obtain single-shot diffraction patterns. The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the "diffraction-before-destruction" approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals. Coherent diffraction imaging (CDI) of single molecules at atomic resolution is a major goal for the x-ray free-electron lasers (XFELs). Ultrashort X-ray pulses from free-electron laser X-ray sources make it feasible to conduct small- and wide-angle scattering experiments on biomolecular samples in solution at sub-picosecond timescales. The short and intense pulses of the new X-ray free electron lasers, now operational or under construction, may make possible diffraction experiments on single molecule-sized objects with high resolution, before radiation damage destroys the sample. The recent development of x-ray free electron lasers providing coherent, femtosecond-long pulses of high brilliance and variable energy opens new areas of scientific research in a variety of disciplines such as physics, chemistry, and biology. The advent of light sources based on the X-ray free-electron laser (XFEL) principle, has opened the door to a multitude of experiments in various fields of science. X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. X-ray free-electron lasers (FELs) show promise for revealing the structure of single molecules or nanocrystals, but the phase problem remains largely unsolved. Coherent diffractive imaging using x-ray free-electron lasers (XFELs) may provide a unique opportunity for high-resolution structural analysis of single particles sprayed from an aqueous solution into the laser beam. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. This work is directly relevant to the time-resolved imaging of magnetic dynamics using coherent and ultrafast radiation from x-ray free-electron lasers and also to broader classes of diffractive imaging experiments which suffer noisy data, missing data, or both. By combining serial nanocrystallography with x-ray free-electron laser sources in the future, it may be possible to produce molecular-resolution electron-density maps using membrane protein crystals that contain only a few hundred or thousand unit cells. Very strong soft X-ray free electron laser (FEL) pulses must be short to allow for investigations of ultra-fast wet chemistry, according to the principle of collect and destroy.
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<question>
Where is X-ray free electron laser used?
</question>
<answer>
high resolution protein structure determination; molecular imaging', 'single-particle imaging; study of enzyme kinetics', 'time resolved protein crystallography
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Multiple endocrine neoplasia type 1 (MEN1; formerly known as Wermer syndrome) is a rare disorder characterized by the combined occurrence of two or more tumors involving parathyroid, pancreatic islets and anterior pituitary glands; some other tumors have also been described. Hyperparathyroidism is the most common feature of MEN1 (95% of patients), pancreatic islet tumors or pancreatic NET (neuroendocrine tumor) occur in 40-70% and pituitary tumors in 30-40% of MEN 1 patients In addition, other tumors, such as adrenal cortical tumors, carcinoid tumors, lipomas, angiofibromas, colagenomas and meningiomas may be present. the most important causes malignant pancreatic neuroendocrine tumors (NET) and thymic carcinoids. Multiple endocrine neoplasia type 1 (MEN1) is inherited in an autosomal dominant fashion and predisposes to the development of hyperplastic or neoplastic changes in the parathyroid and pituitary glands and the endocrine pancreas, along with numerous other characteristic tumors and features. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid and adrenocortical tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. The pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary NETs are mostly prolactinomas and somatotrophinomas. We address the potential role of miRNAs in the endocrine pancreas, the pituitary gland, and the parathyroid glands-areas where MEN 1 shows high penetrance. Moreover, studies have provided evidence that dysregulation of miRNAs was responsible for endocrine carcinogenesis, including pancreatic, pituitary, and parathyroid tumors. MEN1 and MEN2 are rare inherited cancer syndromes which express a variety of endocrine and nonendocrine tumors. Multiple endocrine neoplasia Type 1 (MEN1) is a rare hereditary tumor syndrome predisposing to tumor development in several endocrine organs. Its major manifestations include hyperparathyroidism, tumors of endocrine pancreas and pituitary. eside these three, several other endocrine (adrenocortical, foregut carcinoid) and nonendocrine (lipoma, angiofibroma, collagenoma, ependymoma, meningioma) tumors have been described to be associated with this syndrome Both familial and sporadic forms of the disease are known. The diagnosis of MEN1 can be established if two of the three major manifestations are found in the same patient, whereas the diagnosis of familial MEN1 requires one MEN1 patient and a first degree relative with at least one MEN1 manifestation. Both benign (parathyroid, anterior pituitary) and malignant (gastrinoma, glucagonoma) lesions may develop in MEN1 patients Multiple endocrine neoplasia type 1 (MEN1) is a classic hereditary tumor syndrome characterized by a genetic predisposition to develop a variety of neuroendocrine neoplasias and hormone excess syndromes. Multiple endocrine neoplasia type 1 (MEN 1) is a familial syndrome characterized by parathyroid, enteropancreatic and pituitary tumors. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited tumor syndrome characterized by the development of multiple endocrine tumors Multiple facial angiofibromas were observed in 28 (88%) of the patients with MEN1, with 16 patients (50%) having 5 or more. Angiofibromas were clinically and histologically identical to those in individuals with tuberous sclerosis. Collagenomas were observed in 23 patients (72%). Also observed were cafe au lait macules in 12 patients (38%), lipomas in 11 patients (34%), confetti-like hypopigmented macules in 2 patients (6%), and multiple gingival papules in 2 patients (6%) Multiple angiofibromas, collagenomas, lipomas, confetti-like hypopigmented macules and multiple gingival papules are cutaneous manifestations of MEN1 and should be looked for in both family members of patients with MEN1 and individuals with hyperparathyroidism of other MEN1-associated tumors. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by nodular proliferation of the parathyroid glands and tumors of the anterior pituitary gland, the endocrine pancreas, and the neuroendocrine cell system of the gut. We report here a genetic study of a female MEN1 patient with the association of nodular hyperplasia of two parathyroid glands, an insulinoma, multiple duodenal gastrinomas, a prolactinoma, and a gastric carcinoid. Multiple endocrine neoplasia type 1 (MEN1) is defined clinically by the combined occurrence of multiple tumors, typically of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. In support of previous findings in islet tumors, we found down-regulation of the cell-cycle regulator, p18, in both the pancreatic islet and pituitary adenomas, suggesting that reduced p18 levels may be important for Men1-related tumorigenesis in multiple tissues. Surprisingly, we identified increased p16 transcript in pancreatic islet and pituitary tumors. The patient was studied and diagnosed with a multiple endocrine neoplasia type I (MEN I), familiar (mother with MEN I). A scintigraphic study with 99mTc-MIBI was performed in order to localize hyperfunctioning parathyroid glands because of biochemical diagnosis of primary hyperparathyroidism. The tumor was removed and histologically confirmed as a carcinoid within a thymus in a MEN type I syndrome. MEN I patients can benefit from the examination with this agent which can potentially localize not only parathyroid endocrine pathology but also unknown associated tumors. Pancreatic endocrine tumors occur sporadically and as part of the multiple endocrine neoplasia type 1 (MEN 1) and von Hippel-Lindau (VHL) syndromes. We have analyzed 22 nonfamilial and 16 MEN 1-associated pancreatic endocrine tumors for loss of heterozygosity (LOH) at 3p, 11q13, and 18q. LOH at 3p was revealed in 45% and 36% of tumors from 31 patients with nonfamilial and MEN 1-associated disease, respectively. The data indicate involvement of tumor suppressor genes on 3p and 18q, in addition to the MEN1 gene at 11q13, in the tumorigenesis of both nonfamilial and MEN 1-associated pancreatic endocrine tumors. Multiple endocrine neoplasia type 1 (MEN1) is characterized by the development of endocrine tumors of the parathyroid and pituitary glands, pancreas, and duodenum. Less frequently occurring tumors associated with MEN1 include non-endocrine tumors such as lipomas and angiofibromas. An increased incidence of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 population. A germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene were consistently detected in multiple neuroendocrine tumors involving the parathyroid glands and the pancreas and a hepatic neuroendocrine tumor metastasis, as predicted by Knudson's "two hit" hypothesis. Two hits of the MEN1 gene were also detected in esophageal leiomyoma tissue, suggesting that tumorigenesis was directly related to the patient's underlying MEN1. In contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal nodular hyperplasia, and adrenal cortical hyperplasia consistently showed retained heterozygosity of the MEN1 gene with flanking markers and an intragenic marker. Therefore, these tumors appear to develop along pathogenetic pathways that are different from classical MEN1-associated tumors. Twelve unrelated (German MEN1 families and their associated tumors (5 parathyroid tumors, 1 vipoma, 1 gastrinoma, 1 insulinoma) were characterized for MEN1 gene mutations by single-strand conformational variant (SSCV) analysis and DNA sequence analysis as well as for loss of heterozygosity on chromosome 11q13. Multiple endocrine neoplasia type 1 (MEN1) consists of benign, and sometimes malignant, tumors (often multiple in a tissue) of the parathyroids, enteropancreatic neuroendocrine system, anterior pituitary, and other tissues. Skin angiofibromas and skin collagenomas are common.
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<question>
Tumors of which three organs are classically associated with the multiple endocrine neoplasia type 1 syndrome?
</question>
<answer>
parathyroid gland; pancreas; pituitary gland
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The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to inhibit ICa and INa in bovine adrenal chromaffin cells, also significantly inhibited INa in SCLC cells. These results indicate that (i) action potentials in human SCLC cells result from the regenerative increase in voltage-gated Na+ channel conductance; (ii) fundamental characteristics of SCLC Na+ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na+ channels are an additional target of the pathological IgG present in the patients' sera. Clinical features were those of LES and occurred insidiously in this 68-year old man: proximal weakness predominant in the lower limbs, generalized areflexia, dryness of the mouth and partial right eye palsy. Investigations disclosed a small cell lung cancer. Voltage-gated Ca2+ channels may be important to the secretion of ectopic hormones and the etiology and pathogenesis of Lambert-Eaton syndrome, an autoimmune disorder of the motor nerve terminal in which autoantibodies directed against voltage-gated Ca2+ channels are produced. Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin which is often associated with anaplastic small-cell lung cancer. Small-cell lung cancer (SCLC) is the most common cause of LES. We report an unusual case of LES associated with large-cell neuroendocrine carcinoma (LCNEC) of the lung. The Lambert-Eaton syndrome is caused by antibodies against voltage-gated calcium channels and often occurs in patients with small cell lung cancer. A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma. LEMS is generally associated with small cell lung cancer occurring in three percent of cases. However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition. LEMS has a high degree of coincidence (approximately 60%) with small cell lung cancer; the remaining 40% of patients with LEMS have no detectable tumor. BACKGROUND: To enhance the acknowledgement of Lambert-Eaton syndrome in patients with small cell lung cancer. There were 10 cases of Lambert-Eaton syndrome in 332 pathologically diagnosed small cell lung cancer Treatment of small cell lung cancer may improve the symptoms of Lambert-Eaton syndrome Improving the recognition of Lambert-Eaton syndrome may be helpful to identify early small cell lung cancer and improve the prognosis,as the symptom of muscular weakness usually appears early before the diagnosis of small cell lung cancer. The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer. Paraneoplastic Lambert-Eaton myasthenia syndrome is presented in two cases with small cell lung cancer. Human small-cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired. Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder caused by an IgG-mediated reduction in number of presynaptic voltage-gated calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, the stimulus for antibody production may be VGCC on small cell lung cancer (SCLC) Also, there was no obvious band pattern distinguishing patients with LES from those with LES and concurrent SCLC. The cancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and epidermoid lung carcinoma in 3 cases. Etiology of this disease is uncertain but in view of its frequent association with small cell lung cancer, this specific type of neoplasm may be implicated in the initiation of autoimmune response. Recent studies indeed support the possibility that the antigenic stimulus in the neoplastic form of LES may arise from voltage-dependent Ca2+ channels found in the lung cancer cells. In the majority of LEMS patients, those having detectable tumor, the disease is thought to occur as a result of immune response directed initially against voltage-gated Ca2+ channels found on the lung tumor cells. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. Physicians need to be aware that patients may develop PCD and LEMS associated with anti-VGCC antibody caused by small cell lung cancer, and a mass survey should be conducted and careful examinations performed. Biopsy revealed small cell lung cancer (SCLC) indicating the importance of repeated chest CT in LEMS even when an existing autoimmune-like disease and negative CT may suggest an autoimmune origin. BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup. The presence of a particular symptom associated with LEMS did not predict the presence of SCLC, but in patients with rapidly progressive LEMS the possibility of underlying lung cancer should be of particular concern. We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week. Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The gene encoding the beta 2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen in humans, is found close to a region that undergoes chromosome rearrangements in small cell lung cancer, which occurs in association with LEMS. We then tested sera from 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract. In the majority of patients LEMS is associated with small cell lung cancer (SCLC). Patients with small cell lung cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in patients affected by LEMS. We present a 69-year-old woman who had preventive whole brain radiation after a diagnosis of paraneoplastic Lambert-Eaton syndrome related to small cell lung cancer Five months after radiation therapy, she developed radiation-induced leukoencephalopathy manifested by ataxia. Physicians need to be aware that patients may develop PCD and LEMS associated with anti-VGCC antibody caused by small cell lung cancer, and a mass survey should be conducted and careful examinations performed. Biopsy revealed small cell lung cancer (SCLC) indicating the importance of repeated chest CT in LEMS even when an existing autoimmune-like disease and negative CT may suggest an autoimmune origin. BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup. Among the symptoms of lung cancer LEMS can be seen, but it is very rare. The presence of a particular symptom associated with LEMS did not predict the presence of SCLC, but in patients with rapidly progressive LEMS the possibility of underlying lung cancer should be of particular concern. We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week. Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The gene encoding the beta 2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen in humans, is found close to a region that undergoes chromosome rearrangements in small cell lung cancer, which occurs in association with LEMS. We then tested sera from 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract. In the majority of patients LEMS is associated with small cell lung cancer (SCLC). Patients with small cell lung cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in patients affected by LEMS. A patient with the Lambert-Eaton syndrome (LES) and small cell lung cancer developed respiratory failure several hours after verapamil was given. Patients with LEMS have mostly small cell lung cancer (SCLC); other subtypes of lung cancer are extremely rare.
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<question>
Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?
</question>
<answer>
small-cell lung cancer
</answer>
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Krabbe disease is a lethal, demyelinating condition caused by genetic deficiency of galactocerebrosidase (GALC) and resultant accumulation of its cytotoxic substrate, psychosine (galactosylsphingosine), primarily in oligodendrocytes (OLs). In this study, we report that accumulation of endogenous psychosine under GALC deficient Krabbe conditions impedes OL differentiation process both by decreasing the expression of myelin lipids and protein and by inducing the cell death of maturating OLs. In almost all individuals with Krabbe disease, galactocerebrosidase (GALC) enzyme activity is deficient (0%-5% of normal activity) in leukocytes isolated from whole heparinized blood or in cultured skin fibroblasts. This chapter describes in detail a practical procedure for the preparation of radiolabeled galactocerebroside and its use in the assay of galactocerebrosidase (GalCase), the enzyme deficient in globoid cell leukodystrophy (Krabbe disease). Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside beta-galactosidase. Krabbe disease is an extremely rare condition with an incidence of 1 in 1,00,000 live births. It is caused by deficient activity of the Iysosomal hydrolase galactosylceramide beta-galactosidase. Globoid cell leukodystrophy (Krabbe disease) is characterized by the accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is a substrate for the deficient enzyme (galactocerebroside beta-galactosidase). Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. Beta-galactocerebrosidase (GALC) is a specific beta-galactosidase which is defective in GLD. Both galactosylceramide beta-galactosidase (GALC-GC) and GALC-PS activities were reduced by at least 85% of the normal in all but 2 of the 10 GLD patients studied. Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC) activity. The disease can be diagnosed by detecting the deficiency of GALC activity (less than 5% of normal) in any available tissue sample. Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. Globoid cell leukodystrophy (GCL or Krabbe disease) is a recessive disease caused by mutations of the lysosomal enzyme galactocerebrosidase (GALC) and twitcher is the murine model of GCL. Galactocerebrosidase (GALC) is the lysosomal enzyme deficient in human and certain animal species with globoid cell leukodystrophy (GLD) or Krabbe disease. Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Krabbe disease is an autosomal recessive inherited demyelinating disease, which is deficient in lysosomal enzyme, galactocerebrosidase. Galactocerebrosidase (GALC) activity is deficient in all patients with globoid cell leukodystrophy (GLD). Human galactocerebrosidase, the enzyme deficient in Krabbe disease, was purified, through several hydrophobic column steps and gel filtration, 22,650-fold from human lymphocytes Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. 6-Hexadecanoylamino-4-methylumbelliferyl-beta-D-galactopyranoside (HMGal) has been shown to be a specific fluorogenic substrate of galactocerebrosidase and to facilitate the simple enzymatic diagnosis of Krabbe disease in human patients and in twitcher mice. The inherited deficiency of galactosylceramide beta-galactosidase (E.C. 3.2.1.46: galactocerebrosidase) activity results in globoid cell leukodystrophy in humans (Krabbe disease) and in mice (twitcher mutant). The lack of complementation between Krabbe disease patient and twitcher mutant mouse cells provides further evidence that the twitcher mouse is an authentic murine model for Krabbe disease and supports the hypothesis that the mutations in both species are within the structural gene for the galactocerebrosidase enzyme. Galactosylceramide beta-galactosidase cross reacting material was demonstrated in brain, liver, and skin fibroblasts from patients with Krabbe disease. . In this study, LRs in the brain of the twitcher (TWI) mouse, a bona-fide model for infant variants of human globoid cell leukodystrophy or Krabbe disease, were investigated. This mouse has deficient activity of GALC (beta-galactosylceramidase) that leads to a progressive accumulation of some galactosyl-sphingolipids in the brain. A GALC genotype with one deleted and one polymorphic GALC activity-reducing allele can lead to enzymatic and clinical signs of LOGLD in the absence of marked GALC-PS deficiency. Galactocerebrosidase (GALC) is deficient in all tissues from human patients and animal models with globoid cell leukodystrophy (GLD) or Krabbe disease. The purification of GALC and the securing of amino acid sequence information will aid in the cloning of the GALC gene. This enzyme is deficient in human patients with Krabbe disease and several animal species.
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<question>
Which enzyme is deficient in Krabbe disease?
</question>
<answer>
Galactocerebrosidase is an enzyme that is deficient in Krabbe disease (also known as globoid-cell leukodystrophy). This leads to accumulation of psychosine (galactosylsphingosine) primarily in oligodendrocytes.
</answer>
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<context>
he miRNAs miR-126 and miR-508-5p are associated with the outcome of ICM and NICM patients with CHF. These two miRNAs could be useful in the diagnosis of CHF patients, and might provide novel targets for prevention and treatment of CHF. The plasma concentration of miR-126 was negatively correlated with age and NYHA class, and could be a useful biomarker for heart failure. In 10 patients with heart failure, plasma concentrations of miR-126 were up-regulated with improvement of the NYHA class from IV to III.
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<question>
Is miR-126 involved in heart failure?
</question>
<answer>
yes
</answer>
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Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Dabigatran is a potent reversible, competitive direct thrombin inhibitor which is available as the prodrug, Dabigatran etexilate. The recently introduced oral direct thrombin antagonist, dabigatran, has been shown in phase III clinical trials to be noninferior in efficacy to warfarin for the prevention of thromboembolic events in patients with atrial fibrillation, as well as in treatment of acute venous thromboembolism. Dabigatran is an oral, reversible direct thrombin inhibitor approved in Europe and in several other countries for the prevention of venous thromboembolism after elective knee and hip replacement surgery. This mechanism of action is different from that of other anticoagulants that have been or are currently used in clinical practice, such as warfarin (a vitamin K antagonist) [4], enoxaparin (an indirect thrombin/Factor Xa inhibitor) [5], [6], ximelagatran (now withdrawn) [7] and dabigatran (direct thrombin inhibitors) Dabigatran etexilate is a direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214), thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for comparison. Two agents, the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and several other countries for the prevention of VTE after total hip or knee replacement surgery. The direct thrombin inhibitor dabigatran is farthest along in development. Lastly, inhibitors of thrombin activity are composed of either indirect (UFH, LMWH), or direct thrombin (FIIa) inhibitors including: hirudin, argatroban, melagatran, ximelagatran, dabigatran, and bivalirudin. The effect of the oral direct activated factor X (factor Xa) inhibitor apixaban on tissue factor-induced thrombin generation in human plasma was investigated in vitro using the calibrated automated thrombogram (CAT) method and compared with the oral direct factor Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran. The DTI dabigatran etexilate was recently shown to provide superior risk reduction to warfarin for stroke and systemic embolism for patients with nonvalvular AF and recently gained US Food and Drug Administration approval for this indication.
</context>
<question>
What is the mechanism of action of anticoagulant medication Dabigatran?
</question>
<answer>
Dabigatran is orally administered, reverisble direct and competetive inhibitor of both free and bouded thrombin.
</answer>
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